Q4 2023 Ultragenyx Pharmaceutical Inc Earnings Conference Call

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Operator: Good afternoon, and welcome to the Ultragenyx 4th Quarter and Full Year 2023 Financial Results Conference Call. At this time, all participants are in a listen-only mode.

Speaker Change: Good afternoon, and welcome to the Altra Genex fourth quarter and full year 2023 financial results Conference call. At this time all participants are in a listen only mode. At the end of the prepared remarks, you will have an opportunity to ask questions. During the Q&A portion of the call. It is now my pleasure to turn.

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

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.

Speaker Change: Joshua <unk> turn the call to Joshua Young Vice President of Investor Relations.

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

Joshua Young: Thank you we have issued a press release detailing our financial results, which you can find on our website at ultrasonics Dot com joining.

Joshua Young: Joining me on this call our ammo package, Chief Executive Officer, and President, Eric Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and aircraft as Chief Medical Officer.

Speaker Change: Like to remind everyone that during today's call, we will be making forward looking statements. These statements are subject to certain risks and uncertainties and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings now I'll turn the call over to him.

Emil D. Kakkis: Thanks Josh, and good afternoon everyone. In 2023, we generated significant momentum across our commercial and clinical programs that have set us up for a catalyst-rich 2024. On the commercial front, we progressed international regulatory and reimbursement negotiations across our marketed products, continuing to add to new approvals and positive reimbursement decisions. This geographic expansion, along with growing demand in our existing market, put us in position to maintain our trajectory of robust year over year growth.

Speaker Change: Thanks, Josh and good afternoon, everyone.

Josh: In 2023, we generated significant momentum across our commercial and clinical programs that have set us up for a catalyst rich 2024.

Speaker Change: On the commercial front, we progressed international regulatory and reimbursement negotiations across our marketed products continuing to add new approvals and positive reimbursement decisions.

Speaker Change: This geographic expansion, along with growing manner, our existing markets.

Speaker Change: Position to maintain our trajectory of robust year over year growth.

Emil D. Kakkis: On the clinical side, we released new data on our key programs in 2023 and successfully advanced enrollment of our priority programs that can accelerate value creation for our company this year and in the coming year. At our Analyst Day in October, we shared exciting data from three programs that all will have additional data catalysts in 2024. On UX143 for osteogenesis imperfecta, interim phase 2 data showed rapid and substantial increases in bone marrow density and Z-score after just six months of treatment. This led to a 67% reduction in analyzed fracture rate, with 20 of the 24 patients showing no radiographically confirmed fractures at six months.

On the clinical side, we released new data on our key programs in 2023 and successfully advanced enrollment of our priority programs that can accelerate value creation for our company this year and in the coming year. At our Analyst Day in October, we shared exciting data from three programs that all will have additional data catalysts in 2024.

Speaker Change: On the clinical side, we released.

New data on our key programs in 2023 and successfully advanced enrolment of our priority programs that can accelerate value creation for our company this year and in the coming years.

Speaker Change: At our analyst day in October we shared exciting data from three programs at all will have additional data catalysts in 2024.

On UX143 for osteogenesis imperfecta, interim phase 2 data showed rapid and substantial increases in bone marrow density and Z-score after just six months of treatment. This led to a 67% reduction in analyzed fracture rate, with 20 of the 24 patients showing no radiographically confirmed fractures at six months.

Speaker Change: Our UX 143 for osteogenesis imperfecta interim phase two data showed rapid and substantial increases in bone mineral density and Z score apps.

Speaker Change: Just six months of treatment.

Speaker Change: This led to a 67% reduction in analytics fracture rate with 20 of the 24 patients showing no radiographically confirmed fractured at six months.

Emil D. Kakkis: On GTX-102 for Aynswern Syndrome, data from the long-term extension cohorts in the Phase 1-2 study demonstrated clinically meaningful improvements across multiple neurodevelopmental domains, including cognition, receptive communication, growth motors, behavior, and sleep. These data show we can repeatedly dose GTX-102 for much longer than one year with an acceptable safety profile. On UX701 for Wilson's disease, the data we presented showed four or five patients in the lowest dose cohort had begun tapering their standard of care, including two who were completely off key letters and or zinc therapy.

Speaker Change: On Gtx, one two for Angelman syndrome data from the long term extension cohorts in the phase one two study demonstrated clinically meaningful improvements across multiple neuro developmental domains, including cognition receptive communication gross motors behavior in sleep.

Speaker Change: These data show, we can repeatedly dose GT two for much longer than one year with acceptable safety profile.

Speaker Change: And UX seven and one for Wilson disease. The data, we presented showed four or five patients in the lowest dose cohort had begun tapering their standard of care, including two were completely off key letters <unk> therapy.

Speaker Change: While it's still early.

Emil D. Kakkis: While still early for the UX701 program, we are encouraged by the data we have observed. Our momentum is continuing into 2024 with multiple clinical development updates. Last week, GTX-102 was granted priority medicine or PRIME designation by the European Medical Authority based on the positive early clinical data from the long-term extension cohorts and the potential of GTX-102 to address the unmet need for treatment in this disease.

Speaker Change: For the <unk> 701 program, we are encouraged by the data we have observed.

Speaker Change: Our momentum is continuing into 2024 with multiple clinical development updates.

Speaker Change: Last week Gtx, one two was granted priority medicine or prime designation by the European Medical Authority based on the positive early clinical data from the long term extension cohorts and the potential of GTH wants you to address the unmet need for a treatment in these disease in this disease.

Emil D. Kakkis: The clinical data we've shared with the street, along with positive U.S. and European regulatory interactions, give us confidence that we will be able to navigate the development path for this program. For UX111 and Sanfilippo A syndrome, we released phase three data last week from extension and newly treated patients at the World Symposium Annual Research Meeting in San Diego. The results we shared demonstrated treatment with UX111 resulted in rapid and sustained decreased levels of heparin sulfate in the cerebral spinal fluid, and the sustained reductions in CSF heparin sulfate exposure over time correlated with improved long-term cognitive development. Our discussions on the Accelerated Approval Pathway with the FDA are ongoing, and we continue to believe there is a strong case to be made for this program.

Speaker Change: The clinical data, we've shared with the street, along with positive U S and European regulatory interactions give us confidence that we will be able to navigate the development path for this program.

Speaker Change: For year 211 in Sanfilippo syndrome, we released phase III data last week from extension of newly treated patients at the World Symposium in annual research meeting in San Diego.

Speaker Change: The results, we shared demonstrated treatment with <unk> hundred 11 resulted in rapid and sustained decrease levels of heparin sulfate.

Speaker Change: In the Threep of spinal fluid and the sustained reductions in CSF heparin sulfate exposure overtime was correlated with improved long term cognitive development.

Emil D. Kakkis: Our discussions on the Accelerated Approval Pathway with the FDA are ongoing, and we continue to believe there is a strong case to be made for this program. Looking ahead, we are entering 2024 in a robust financial position with $777 million on the balance sheet, including proceeds from our equity offering in Q4 that raised $326 million. We're also continuing to focus our spend and resources on the key clinical programs that will drive value for our company, many of which will be updated in the coming months.

Our discussions on the Accelerated Approval Pathway with the FDA are ongoing, and we continue to believe there is a strong case to be made for this program.

Speaker Change: Our discussions on et cetera approval pathway with the FDA are ongoing and we continue to believe there's a strong case to be made in this program.

Looking ahead, we are entering 2024 in a robust financial position with $777 million on the balance sheet, including proceeds from our equity offering in Q4 that raised $326 million. We're also continuing to focus our spend and resources on the key clinical programs that will drive value for our company, many of which will be updated in the coming months.

Speaker Change: Looking ahead, we are entering 2024 in a robust financial position with $777 million on the balance sheet, including proceeds from our equity offering in Q4 that raised $326 million.

Speaker Change: We're also continuing to focus our spend in resources on the key clinical programs that will drive value for our company many of them being data in the coming months.

Eric Schmidt: Our Chief Medical Officer, Eric Crombez will review more of these updates in his section. There's a lot to look forward to as we continue our efforts to lead the future of rare disease medicine. Now I'll turn the call over to our Chief Commercial Officer, Erik Harris, to provide an update on our commercial efforts last year that led to a 20% revenue growth in 2023. Thank you, Emil, and good afternoon everyone. I'll start with Crysvita's performance in North America.

Our Chief Medical Officer, Eric Crombez will review more of these updates in his section. There's a lot to look forward to as we continue our efforts to lead the future of rare disease medicine. Now I'll turn the call over to our Chief Commercial Officer, Erik Harris, to provide an update on our commercial efforts last year that led to a 20% revenue growth in 2023.

Speaker Change: Our Chief Medical Officer, Eric <unk> will review more of these updates in his section.

Eric Harris: There's a lot to look forward to as we continue our efforts to lead the future of rare disease medicine.

Eric Harris: Now I'll turn the call over to our Chief Commercial Officer, Eric Harris to provide an update on our commercial efforts last year that led to a 20% revenue growth in 2023.

Erik Harris: Thank you, Emil, and good afternoon everyone. I'll start with Crysvita's performance in North America.

Eric Harris: Thank you Emil and good afternoon, everyone.

Eric Harris: I'll start with Chris fetus performance in North America, I want to remind everyone that on April 27 2023.

Eric Harris: I want to remind everyone that on April 27th, 2023, we successfully transitioned the promotion of Crysvita in the U.S. to Kyowa Kirin and that Crysvita will continue to generate growing revenue for our company. During the transition period, the Ultragenyx field team continued to find patients from community physicians while introducing key accounts to Kyowa Kirin and the field team. Our patient support services team supported the transition of patients from the Ultragenyx Hub to the Kyowa Kirin Hub to ensure continuity of treatment and reimbursement. In 2023, the smooth transition and additional field resourcing will help support the growing demand for Crysvita in the US and Canada. 

Eric Harris: We successfully transitioned the promotion of Chris Vida in the U S to Kiara, Karen and that Chris Vito will continue to generate growing revenue for our company.

During the transition period, the altra, thanks, Phil team continuing to five patients from community physicians, while introducing key accounts to key our carrying fill teams.

Eric Harris: Our patient support services team supported the transition of patients from the ultrasonics hub to the key our Karen hub to ensure continuity of treatment and reimbursement.

Eric Harris: In 2023, the smooth transition and additional field Resourcing helps support the growing demand for Chris Vida in the U S and Canada. In fact, there were approximately 500 start forms generated in 2023 from a continually growing base of unique prescribers and patients on <unk>.

Eric Harris: In fact, there were approximately 500 starter forms generated in 2023 from a continually growing base of unique prescribers and patients on reimbursed therapy. The success we saw in 2023 has led us to further amend our agreement with Kyowa Kirin that will allow our experienced field team from Ultragenyx to continue to support Crysvita in the U.S. through this year. With robust demand from 2023, a fully transitioned patient support services hub, and the support of Ultragenyx's focus field team, we feel confident that 2024 will be another strong year for Crysvita in North America. Shifting to Crysvida in Latin America,

In fact, there were approximately 500 starter forms generated in 2023 from a continually growing base of unique prescribers and patients on reimbursed therapy. The success we saw in 2023 has led us to further amend our agreement with Kyowa Kirin that will allow our experienced field team from Ultragenyx to continue to support Crysvita in the U.S. through this year. With robust demand from 2023, a fully transitioned patient support services hub, and the support of Ultragenyx's focus field team, we feel confident that 2024 will be another strong year for Crysvita in North America.

Eric Harris: Members therapy.

Eric Harris: The success, we saw in 2023.

Eric Harris: That is to further amend our agreement with Kyowa Kirin that will allow our experienced field team promote eugenics to continuing to support Chris feeder in the U S through this year.

Eric Harris: With a robust demand from 2023, a fully transitioned patient support services hub and the support of Ultrahigh mixes focus field team, we feel confident that 2024 will be another strong year for Chris Vita in North America.

Shifting to Crysvida in Latin America, we finished the year with over 500 patients on reimbursed therapy, which included approximately 50 new patients who began commercial therapy in Q4 of 2023. Over the course of the year, we added approximately 200 new patients to our growing base of patients on commercial therapy. While most of the current demand in Latin America is driven by pediatric patients, we are seeing an increasing uptake in adult patients across the region, reflecting a similar pattern that we saw in North America. In Latin America, we expect quarter-to-quarter variability in revenue driven by uneven ordering patterns but remain confident in the underlying demand growth for our products. These combined efforts across our global organization generated 2023 Crysvita revenue of $328 million, which is a 17% increase compared to 2022.

Eric Harris: Shifting to Christina in Latin America.

Eric Harris: we finished the year with over 500 patients on reimbursed therapy, which included approximately 50 new patients who began commercial therapy in Q4 of 2023. Over the course of the year, we added approximately 200 new patients to our growing base of patients on commercial therapy. While most of the current demand in Latin America is driven by pediatric patients, we are seeing an increasing uptake in adult patients across the region, reflecting a similar pattern that we saw in North America. In Latin America, we expect quarter-to-quarter variability in revenue driven by uneven ordering patterns but remain confident in the underlying demand growth for our products. These combined efforts across our global organization generated 2023 Crysvita revenue of $328 million, which is a 17% increase compared to 2022. For Dojolvi in the U.S. and Canada, the demand for starter forms remains strong.

we finished the year with over 500 patients on reimbursed therapy, which included approximately 50 new patients who began commercial therapy in Q4 of 2023. Over the course of the year, we added approximately 200 new patients to our growing base of patients on commercial therapy. While most of the current demand in Latin America is driven by pediatric patients, we are seeing an increasing uptake in adult patients across the region, reflecting a similar pattern that we saw in North America. In Latin America, we expect quarter-to-quarter variability in revenue driven by uneven ordering patterns but remain confident in the underlying demand growth for our products. These combined efforts across our global organization generated 2023 Crysvita revenue of $328 million, which is a 17% increase compared to 2022.

Eric Harris: We finished the year with over 500 patients on reimbursed therapy, which included approximately 50, new patients who began commercial therapy in Q4 of 2023.

Eric Harris: Over the course of the year, we added approximately 200, new patients to our growing base of patients on commercial therapy.

Christina: While most of the current demand in Latin America is driven by pediatric patients. We are seeing an increasing uptake in adult patients across the region, reflecting a similar pattern that we saw in North America.

Christina: In Latin America, we expect quarter to quarter variability in revenue driven by uneven ordering patterns, but remain confident in the underlying demand growth for our products.

Christina: These combined efforts across our global organization generated 2023, Christopher to revenue of $328 million, which is a 17% increase compared to 2022.

For Dojolvi in the U.S. and Canada, the demand for starter forms remains strong. In 2023, we added approximately 115 starter forms and 95 patients on reimbursed therapy, resulting in over 470 reimbursed patients in the U.S. since launch. The number of prescribers continued to grow, adding approximately 40 new prescribers in 2023.

Christina: Okay.

Christina: But the <unk> in the U S and Canada. The demand for start forms remains strong in 2023, we added approximately 115 start forms and 95 patients on reimbursed therapy, resulting in over 470 reimburse patients in the U S. Since launch the.

Eric Harris: In 2023, we added approximately 115 starter forms and 95 patients on reimbursed therapy, resulting in over 470 reimbursed patients in the U.S. since launch. The number of prescribers continued to grow, adding approximately 40 new prescribers in 2023.

Christina: The number of prescribers continue to grow adding approximately 40, new prescribers in 2023.

Eric Harris: In Latin America, we are making steady progress in finding patients, despite the lack of newborn screening in the region, while expanding access for Dojolvi to more patients. Most recently, in Mexico, Dojolvi was approved by the HCA for inclusion in the National Medicine Compendium, which is an important step toward increasing reimbursed patients in 2024. Across the EMEA region, Dojolvi is driven by named patient sales requests as we continue to deepen the awareness of LC-FAOD with key stakeholders through our medical team. Though the majority of current requests are coming from France, we are seeing an increased demand throughout Europe and the Middle East. In 2023, the teams generated $71 million in Dojolvi revenue, which is 27% growth compared to 2022.

Christina: In Latin America, we are making steady progress in finding patients. Despite the lack of newborn screening and the region, while expanding access for <unk> to more patients.

Christina: Recently in Mexico did you already was approved by the HCA for inclusion in the National Medicine, Compendium, which is an important step toward increasing reimburse patients in 2024.

Christina: Across the EMEA region. The GOP is driven by named patient sales request as we continue to deepen the awareness of <unk> with key stakeholders through our medical teams.

Christina: Though the majority of current requests are coming from France, we are seeing an increased demand throughout Europe and the middle East.

Christina: In 2023, the teams generated $71 million in the jewelry revenue, which is 27%.

Christina: Growth compared to 2022.

Eric Harris: Lastly, on [inaudible], we continue progressing steadily across our launch markets in EMEA, Canada, and Japan. In EMEA, European HTAs have provided fusion with positive clinical recommendations, and we are working through the reimbursement process. On December 18th, we received approval from the European Commission for an expanded indication for [inaudible] in children aged 5 years and older with HOFH. This approval further validates the drug's clinical value and expands the addressable patient population in the EMEA region.

Christina: Lastly on F. Keizer, we continue progressing steadily across our launch markets in EMEA, Canada and Japan.

In EMEA European Hca's have provided a fluke and with positive clinical recommendations and we are working through the reimbursement processes.

Christina: On December 18th we received approval from the European Commission for an expanded indication for <unk> in children age five years and older with HOS H.

Eric Harris: This approval further validates the drug's clinical value and expands the addressable patient population in the EMEA region. In Canada, both HTA bodies, CADIS and NS, have provided positive clinical recommendations for [inaudible]. The team is preparing to accelerate the public reimbursement process with the Canadian authorities in the coming months. In the meantime, we are working to get private payers on board to expedite reimbursement. The initial uptake on the start forms has been steady since Health Canada's approval.

This approval further validates the drug's clinical value and expands the addressable patient population in the EMEA region.

Christina: This approval further validates the drug's clinical value and expands the addressable patient population in the EMEA region.

In Canada, both HTA bodies, CADIS and NS, have provided positive clinical recommendations for [inaudible]. The team is preparing to accelerate the public reimbursement process with the Canadian authorities in the coming months. In the meantime, we are working to get private payers on board to expedite reimbursement. The initial uptake on the start forms has been steady since Health Canada's approval.

Christina: And Canada, both HTH bodies, Canada, and <unk> have provided positive clinical recommendations for Rfps out there.

Christina: The team is prepared is preparing to accelerate the public reimbursement process with the Canadian authorities in the coming months.

Christina: In the meantime, we are working to get private payers on board to expedite reimbursement.

Christina: The initial uptake on the start forms has been steady since health Canada's approval.

Eric Harris: In Japan, we received regulatory approval on January 18 and pricing discussions are underway with Japanese authorities. Following reimbursement approval, we expect to launch [inaudible] in Japan next quarter. The team is busy educating physicians on the [inaudible] label and identifying appropriate patients who could benefit from the treatment. Building on this success in 2023, we expect continued strong performance across our portfolio in 2024. Crysvida will continue to drive the majority of the revenue, followed by Dojolvi and [inaudible].

Christina: In Japan, we received regulatory approval on January 18.

Christina: And pricing discussions are underway with Japanese authorities.

Christina: Following reimbursement approval, we expect to launch <unk> in Japan next quarter. The team is busy educating the physicians on the <unk> label and identifying appropriate patients who could benefit from the treatment.

Christina: Building on this success in 2023.

Christina: We expect continued strong performance across our portfolio in 2020 for Chris.

Christina: Chris Vito will continue to drive the majority of the revenue followed by the JV and <unk> with that I'll turn the call to Howard to share more details on our financial results and 2020 for guidance.

Howard Horn: With that, I'll turn the call over to Howard to share more details on our financial results and 2024 guidance. Thanks Erik and good afternoon everyone.

With that, I'll turn the call over to Howard to share more details on our financial results and 2024 guidance.

Howard Horns: Thanks Erik and good afternoon everyone. I'll focus on full year corporate financials since we just covered our individual product performance. Starting with total revenue, for 2023, we reported $434 million, representing 20% growth over 2022. Total operating expenses for the year were $1 billion, which included R&D expenses of $648 million, SG&A expenses of $310 million, and cost of sales of $45 million. Operating expenses included non-cash, stock-based compensation of $135 million. For the year, the net loss was $607 million or $8.25 per share.

Howard Horn: Thanks, Eric and good afternoon, everyone I'll focus on full year corporate financials financials. Since we just covered our individual product performance starting with total revenue for 2023, we reported $434 million, representing 20% growth over 2022.

Howard Horn: I'll focus on full year corporate financials since we just covered our individual product performance. Starting with total revenue, for 2023, we reported $434 million, representing 20% growth over 2022. Total operating expenses for the year were $1 billion, which included R&D expenses of $648 million, SG&A expenses of $310 million, and cost of sales of $45 million. Operating expenses included non-cash, stock-based compensation of $135 million. For the year, the net loss was $607 million or $8.25 per share.

Howard Horn: Total operating expenses for the year were 1 billion, which included R&D expenses of $648 million SG&A expenses of $310 million and cost of sales of $45 million.

Howard Horn: Operating expenses included noncash stock noncash stock based compensation of $135 million.

Howard Horn: For the year net loss was $607 million or $8 25 per share.

Howard Horn: As of December 31, we had $777 million in cash, cash equivalents, and marketable securities. In 2023, net cash used in operations was $475 million, which was higher than forecasted due to the timing of when certain receipts and payments landed around year end. Our 2024 net cash used in operations is expected to be less than $400 million, which is consistent with the guidance we provided last month. We are also reaffirming the 2024 revenue guidance ranges we stated last month. Total revenue is expected to be between $500 million and $530 million, which represents 15-22% growth versus 2023. Crysvita revenue is expected to be between $375 million and $400 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. Specifically, it includes Cryvita product revenue from Latin America and Turkey and the cash and non-cash royalties from North America and Europe.

As of December 31, we had $777 million in cash, cash equivalents, and marketable securities. In 2023, net cash used in operations was $475 million, which was higher than forecasted due to the timing of when certain receipts and payments landed around year end. Our 2024 net cash used in operations is expected to be less than $400 million, which is consistent with the guidance we provided last month. We are also reaffirming the 2024 revenue guidance ranges we stated last month. Total revenue is expected to be between $500 million and $530 million, which represents 15-22% growth versus 2023.

Howard Horn: As of December 31, we had $777 million in cash cash equivalents and marketable securities.

Howard Horn: In 2023 net cash used in operations was $475 million, which was higher than forecasted due to timing of when certain receipts and payments landed around year end.

Howard Horn: Our 2024 net cash used in operations is expected to be less than $400 million, which is consistent with the guidance we provided last month.

Howard Horn: We are also reaffirming the 2020 for revenue guidance ranges, we stated last month.

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

Crysvita revenue is expected to be between $375 million and $400 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. Specifically, it includes Cryvita product revenue from Latin America and Turkey and the cash and non-cash royalties from North America and Europe. Our Crysvita guidance range represents 14% to 22% growth versus 2023.

Chris feeder revenue is expected to be between 375 and $400 million.

Howard Horn: Which includes all regions and all forms of Christina revenue to ultra genetics.

Howard Horn: Specifically it includes Chris Vida product revenue from Latin America, and Turkey, and the cash and noncash royalties from North America and Europe.

Howard Horn: Our Crysvita guidance range represents 14% to 22% growth versus 2023. The Dojolvi revenue is expected to be between $75 and $80 million, which represents 6% to 13% growth versus 2023. Our Dojolvi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to named patient requests. With that, I'll turn the call over to our CMO, Eric Crombez, who will provide an update on our key clinical data readouts expected this year. Thank you Howard, and good afternoon everyone.

Our Crysvita guidance range represents 14% to 22% growth versus 2023. The Dojolvi revenue is expected to be between $75 and $80 million, which represents 6% to 13% growth versus 2023. Our Dojolvi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to named patient requests. With that, I'll turn the call over to our CMO, Eric Crombez, who will provide an update on our key clinical data readouts expected this year.

Our Crysvita guidance range represents 14% to 22% growth versus 2023.

Howard Horn: Our <unk> guidance range represents 14% to 22% growth versus 2023.

The Dojolvi revenue is expected to be between $75 and $80 million, which represents 6% to 13% growth versus 2023. Our Dojolvi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to named patient requests. With that, I'll turn the call over to our CMO, Eric Crombez, who will provide an update on our key clinical data readouts expected this year.

Howard Horn: The <unk> revenue is expected to be between 75, and $80 million, which represents 3% to 13% or excuse me, 6% to 13% growth versus 2023.

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

Howard Horn: With that I'll turn the call to our CFO, Eric <unk>, who will provide an update on our key clinical data readouts expected this year.

Eric Crombez: Thank you Howard, and good afternoon everyone. In addition to the UX111 phase 3 data that we presented at the World Symposium last week, we have a number of important clinical data readouts planned for 2024. These include GTX-102 expansion cohort data to be presented mid-first half, DTX-401 Phase III data in the second quarter, then UX-701 dose finding data, and finally UX-143, longer-term follow-up data from the Phase II part of the ongoing Phase II/III study.

Eric Harris: Thank you Howard and good afternoon, everyone and.

Eric Schmidt: In addition to the UX111 phase 3 data that we presented at the World Symposium last week, we have a number of important clinical data readouts planned for 2024. These include GTX-102 expansion cohort data to be presented mid-first half, DTX-401 Phase III data in the second quarter, then UX-701 dose finding data, and finally UX-143, longer-term follow-up data from the Phase II part of the ongoing Phase II/III study. For UX-143, there is also the potential for the phase 3 study to read out pivotal data from the first interim analysis around the end of the year. We have set a strict p-value of 0.001 for unblinding for this first [inaudible].

In addition to the UX111 phase 3 data that we presented at the World Symposium last week, we have a number of important clinical data readouts planned for 2024. These include GTX-102 expansion cohort data to be presented mid-first half, DTX-401 Phase III data in the second quarter, then UX-701 dose finding data, and finally UX-143, longer-term follow-up data from the Phase II part of the ongoing Phase II/III study.

Eric Harris: In addition to the UX 111 phase III data that we presented at the World Symposium last week, we have a number of important clinical data Readouts planned for 2024. These include Gtx 102 expansion cohort data to be presented mid first half D. TX <unk> hundred one phase III data in.

Eric Harris: The second quarter than <unk>, 701 dose finding data and finally <unk> three longer term follow up data from the phase II part of the ongoing phase III study.

For UX-143, there is also the potential for the phase 3 study to read out pivotal data from the first interim analysis around the end of the year. We have set a strict p-value of 0.001 for unblinding for this first [inaudible]. This means that the alpha spend is effectively zero while providing the opportunity to end the study early if the data are compelling and the primary end point is met. We have also built in a second interim and final analysis for the study that would occur in 2025. Regardless of the timing, the reduction in the annualized fracture rate that we saw in the Phase 2 study and shared at ASBMR last year gives us confidence that we will see a clinically meaningful and statistically significant reduction in clinical fracture rates in the Phase 3 study. Shifting now to the two near-term data readouts for GTX-102 and DTX-401.

For UX-143, there is also the potential for the phase 3 study to read out pivotal data from the first interim analysis around the end of the year. We have set a strict p-value of 0.001 for unblinding for this first [inaudible]. This means that the alpha spend is effectively zero while providing the opportunity to end the study early if the data are compelling and the primary end point is met. We have also built in a second interim and final analysis for the study that would occur in 2025. Regardless of the timing, the reduction in the annualized fracture rate that we saw in the Phase 2 study and shared at ASBMR last year gives us confidence that we will see a clinically meaningful and statistically significant reduction in clinical fracture rates in the Phase 3 study.

Eric Harris: For <unk> three there is also the potential for the phase III study to readout pivotal data from the first interim analysis around the end of the year, we have set a strict P value of point or one for on blinding for this first interim analysis. This means that the alpha spend is effectively zero, while providing the <unk>.

Eric Schmidt: This means that the alpha spend is effectively zero while providing the opportunity to end the study early if the data are compelling and the primary end point is met. We have also built in a second interim and final analysis for the study that would occur in 2025. Regardless of the timing, the reduction in the annualized fracture rate that we saw in the Phase 2 study and shared at ASBMR last year gives us confidence that we will see a clinically meaningful and statistically significant reduction in clinical fracture rates in the Phase 3 study. Shifting now to the two near-term data readouts for GTX-102 and DTX-401.

Eric Harris: Opportunity to analyst study early if the data are compelling and the primary endpoint is met we are also built in a second interim and final analysis for the study that would occur in 2025.

Eric Harris: Regardless of the timing the reduction in the annualized fracture rate that we saw on the phase III study and shared at <unk> last year gives us confidence that we will see a clinically meaningful and statistically significant reduction in clinical fracture rate in the phase III study.

Eric Harris: Shifting now to the two near term data Readouts for Gtx 102, and <unk> 401 al.

Shifting now to the two near-term data readouts for GTX-102 and DTX-401. I'll start with GTX-102 for the potential treatment of Angelman Syndrome and the Phase 2 expansion cohort data that we expect to share in the next few months. The first part of the study included a dose escalation stage to understand initial safety and efficacy. Last October, at our Analyst Day event in New York, we disclosed longer-term extension data demonstrating clinically meaningful improvements across multiple domains for the patients in these extension cohorts. We also showed the first-ever developmental milestones that many of these patients have achieved to highlight the clinical meaningfulness of these changes. Earlier last year, we began dosing a larger number of patients in expansion cohorts to further study the dose regimen that we intend to evaluate in a phase three trial. These expansion cohorts include higher loading doses and enrollment was completed at the end of last year with 53 patients enrolled globally.

Eric Schmidt: I'll start with GTX-102 for the potential treatment of Angelman Syndrome and the Phase 2 expansion cohort data that we expect to share in the next few months. The first part of the study included a dose escalation stage to understand initial safety and efficacy. Last October, at our Analyst Day event in New York, we disclosed longer-term extension data demonstrating clinically meaningful improvements across multiple domains for the patients in these extension cohorts. We also showed the first-ever developmental milestones that many of these patients have achieved to highlight the clinical meaningfulness of these changes. Earlier last year, we began dosing a larger number of patients in expansion cohorts to further study the dose regimen that we intend to evaluate in a phase three trial. These expansion cohorts include higher loading doses and enrollment was completed at the end of last year with 53 patients enrolled globally.

Eric Harris: I'll start with Gtx 102 for the potential treatment of Angelman syndrome, and the phase two expansion cohort data that we expect to share in the next few months.

Eric Harris: First part of the study included a dose escalation stage to understand initial safety and efficacy.

Eric Harris: <unk> SEC tober at our analyst day event in New York, we disclose a longer term extension data demonstrating clinically meaningful improvements across multiple domains for the patients in these extension cohorts. We also showed the first ever developmental milestones that many of these patients have achieved to highlight the clinical <unk>.

Eric Harris: The fullness of these changes.

Eric Harris: Earlier last year, we began dosing in a larger number of patients in expansion cohorts to further study the dose regimen that we intend to evaluate in our phase III trial. These expansion cohorts include a higher loading doses and enrollment was completed at the end of last year with 53 patients enrolled globally.

Eric Schmidt: The upcoming expansion cohort data in the mid-first half of this year will focus on the 20-plus patients who have been on therapy for at least 170 days. We intend to present safety and efficacy data in a similar format to what was shown at Analyst Day specifically showing domain-by-domain changes with comparisons to natural history. With higher loading doses in a greater number of patients, we expect to verify the meaningful efficacy that was presented at Analyst Day. These data will inform the dose selection and evaluation period for the Phase 3 study. Our discussions with the FDA on Phase III planning continue to go well, and we anticipate that the expansion data will support an end-of-Phase II meeting in mid-2024, which would enable the Phase III study startup later in 2024. The next near-term data readout is for DTX401, our investigational gene therapy for the treatment of glycogen storage disease type 1A.

The upcoming expansion cohort data in the mid-first half of this year will focus on the 20-plus patients who have been on therapy for at least 170 days. We intend to present safety and efficacy data in a similar format to what was shown at Analyst Day specifically showing domain-by-domain changes with comparisons to natural history. With higher loading doses in a greater number of patients, we expect to verify the meaningful efficacy that was presented at Analyst Day. These data will inform the dose selection and evaluation period for the Phase 3 study. Our discussions with the FDA on Phase III planning continue to go well, and we anticipate that the expansion data will support an end-of-Phase II meeting in mid-2024, which would enable the Phase III study startup later in 2024.

Eric Harris: The upcoming expansion cohort data in mid first half of this year, we will focus on the 20 plus patients who have been on therapy for at least a 170 days, we intend to present safety and efficacy data in a similar format to what was shown at analyst day, specifically showing domain by domain changes with compare.

Eric Harris: Prisons to natural history.

Eric Harris: With higher loading doses and a greater number of patients we expect to verify the meaningful efficacy that was presented at analyst day. These data will inform dose selection and evaluation period for the phase III study.

Eric Harris: Our discussions with the FDA on Phase III planning continue to go well and we anticipate that the expansion data will support an end of phase II meeting in mid 2024, which would enable a phase III study startup later in 2024.

The next near-term data readout is for DTX401, our investigational gene therapy for the treatment of glycogen storage disease type 1A. We have one of the largest late-stage gene therapy pipelines, and this will be our first phase three data readout. All of the patients in the Phase I-II demonstrated a clinically meaningful response to DTX-401 that has proven durable, with the earliest treated patients entering their fifth year of follow-up. In the randomized, placebo-controlled phase 3 study, we expect to see patients with clinically meaningful and statistically significant reductions in cornstarch therapy. We expect to unblind and share top-line data from the DTX-401 phase 3 study in the second quarter of this year. I'll now turn the call back to Emil to provide some closing remarks. 

Eric Harris: The next near term data readout as for <unk> 401, our investigational gene therapy for the treatment of glycogen storage disease type one error.

Eric Schmidt: We have one of the largest late-stage gene therapy pipelines, and this will be our first phase three data readout. All of the patients in the Phase I-II demonstrated a clinically meaningful response to DTX-401 that has proven durable, with the earliest treated patients entering their fifth year of follow-up. In the randomized, placebo-controlled phase 3 study, we expect to see patients with clinically meaningful and statistically significant reductions in cornstarch therapy. We expect to unblind and share top-line data from the DTX-401 phase 3 study in the second quarter of this year. I'll now turn the call back to Emil to provide some closing remarks. 

Eric Harris: We have one of the largest late stage gene therapy pipelines and this will be our first phase III data readout.

Eric Harris: All of the patients from the phase one two demonstrated a clinically meaningful response to Gtx 401 that has proven durable with the earliest treated patients entering their fifth year of follow up in the randomized placebo controlled phase III study, we expect to see patients with clinically meaningful and statistically significant.

Eric Harris: <unk> and cornstarch therapy.

Eric Harris: We expect to unwind in share top line data from the <unk> Phase III study in the second quarter of this year.

Speaker Change: Now I will turn the call back to <unk> to provide some closing remarks.

Speaker Change: Thank you Eric we've made incredible progress across our clinical pipeline, which sets us up for a number of data catalysts. This year.

Emil D. Kakkis: Thank you Eric. We've made incredible progress across the clinical pipeline, which sets us up for a number of data catalysts this year. I'll close by summarizing those catalysts so everyone can get a better sense of what to expect. As Eric mentioned, in the next few months, we'll share the expansion cohort data from the GTX-102 Phase 2 study. This is expected to be followed by the top line phase 3 DTX-401 data in the second quarter. Next, we plan on sharing the UX701 for Wilson disease stage 1 data in mid-2024. This will be data from the three-dose escalation course that recently dosed the last patient.

Speaker Change: I'll close by summarizing those catalysts, everyone can get a better sense of what to expect.

Speaker Change: As Eric mentioned in the next few months, we'll share the expansion cohort data from the Gtx, one or two phase III study.

Speaker Change: This is expect to be followed by the top line phase III Gtx 401 data in the second quarter net.

Speaker Change: Next we plan on sharing the UX 701 for Wilson disease stage, one data in mid 2024. This will be data from the three dose escalation cohorts at recently dose the last patient.

Emil D. Kakkis: This will be data from the three-dose escalation course that recently dosed the last patient. Closing with UX143 for Osteosimperfecta, we expect to share longer-term Phase II data in the second half of the year. Enrollment in the Phase III studies is going well, and we are on track to complete enrollment with approximately 150 patients in the ORBIT study around the end of the first quarter. The Cosmic Study is also enrolling well and is on track to enroll approximately 50 patients or more around the same time or just after. 2024 is an important year for Ultragenyx. We'll continue expanding global access to our commercial products, bringing these important therapies to more and more patients. It's expected to generate more than $500 million in revenue and support our path toward profitability.

This will be data from the three-dose escalation course that recently dosed the last patient.

Closing with UX143 for Osteosimperfecta, we expect to share longer-term Phase II data in the second half of the year. Enrollment in the Phase III studies is going well, and we are on track to complete enrollment with approximately 150 patients in the ORBIT study around the end of the first quarter. The Cosmic Study is also enrolling well and is on track to enroll approximately 50 patients or more around the same time or just after. 2024 is an important year for Ultragenyx. We'll continue expanding global access to our commercial products, bringing these important therapies to more and more patients. It's expected to generate more than $500 million in revenue and support our path toward profitability.

Closing with UX143 for Osteosimperfecta, we expect to share longer-term Phase II data in the second half of the year. Enrollment in the Phase III studies is going well, and we are on track to complete enrollment with approximately 150 patients in the ORBIT study around the end of the first quarter.

Speaker Change: Closing with <unk> III for us to use imperfect that we expect to share longer term phase two data in the second half of the year enrolled.

Speaker Change: Enrolment in the phase III studies is going well and we are on track to complete enrollment with approximately 150 patients in the orbit study around the end of the first quarter the.

The Cosmic Study is also enrolling well and is on track to enroll approximately 50 patients or more around the same time or just after. 2024 is an important year for Ultragenyx. We'll continue expanding global access to our commercial products, bringing these important therapies to more and more patients. It's expected to generate more than $500 million in revenue and support our path toward profitability.

Speaker Change: The Cosmic study is also enrolling well and is on track to enroll approximately 50 patients or more around the same time or just after.

Speaker Change: 'twenty 'twenty four is an important year for allogeneic will continue expanding global access to our commercial products, bringing these important therapies to more and more patients and expect to generate more than $500 million revenue and support our path towards profitability. We also expect to share meaningful data updates from four of our later stage clinical programs.

Operator: We also expect to share meaningful data updates from four of our later-stage clinical programs, making this one of the most data-rich years in our company's history. With that, let's move on to your questions. Operator, please provide the Q&A instructions. Thank you. To ask a question, please press star 1,1 on your telephone and wait for your name to be announced. To withdraw your question, press star 1,1 again.

We also expect to share meaningful data updates from four of our later-stage clinical programs, making this one of the most data-rich years in our company's history. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Speaker Change: Making this one of the most data rich.

Speaker Change: Years in our company's history.

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

Operator: Thank you. To ask a question, please press star 1,1 on your telephone and wait for your name to be announced. To withdraw your question, press star 1,1 again.

Speaker Change: Thank you to ask a question. Please press star one one on your telephone and wait for your name to be announced to withdraw your question Press Star one again.

Gena Wang: Due to time restraints, we ask that you please limit yourself to one question and one follow-up question. Please stand by while we compile the Q&A roster. Our first question will come from the line of Gena Wang with Barclays. Your line is open. Thank you for taking my questions. I have one question regarding the GTX-102 in Andromeda and one for [inaudible].

Due to time restraints, we ask that you please limit yourself to one question and one follow-up question. Please stand by while we compile the Q&A roster. Our first question will come from the line of Gena Wang with Barclays. Your line is open.

Speaker Change: Time restraints, we ask that you. Please limit yourself to one question and one follow up question. Please standby, while we compile the Q&A roster.

Speaker Change: Our first question will come from the line of Gena Wang with Barclays. Your line is open.

Gena Wang: Thank you for taking my questions. I have one question regarding the GTX-102 in Andromeda and one for [inaudible]. So for GTX-102, you received the prime designation. What is the early feedback regarding the approval path and the phase three trial design? And have you met with the FDA also regarding the phase three trial design? And for [inaudible], how will long-term phase two data in the second half of '24 inform the first interim for all phase three trials before year-end '24? 

Gena Wang: Thank you for taking my questions.

I have one question regarding the Gtx 102 in Andrew Matt and one for Joe Smith.

Emil D. Kakkis: So for GTX-102, you received the prime designation. What is the early feedback regarding the approval path and the phase three trial design? And have you met with the FDA also regarding the phase three trial design? And for [inaudible], how will long-term phase two data in the second half of '24 inform the first interim for all phase three trials before year-end '24? 

Gena Wang: <unk> for Gtx, Walter you received prime designation, what does the early feedback regarding approval path in the face.

Gena Wang: <unk> trial design.

Gena Wang: Have you met with the FDA also regarding the phase III trial design.

Gena Wang: So choose from Matt how real long term phase II data in <unk>.

Gena Wang: Second half 'twenty four we're in from the FERC in churn for phase.

Gena Wang: Phase III before year end 'twenty four.

Emil D. Kakkis: Thanks Gena, for the questions. The prime designation was just a presentation of the data that we've seen so far, and basically, I recognize the closeness of the data we saw. We have not settled on a phase three plan with the European authorities. That's something to come. With regard to the FDA, the prime designation will have no influence on the FDA.

Matt: Very good thanks gene after the questions. So.

Matt: The Prime designation was just a presentation of the data that we've seen so far and.

Matt: Basically I recognize that closed the day, we saw we have not settled on a phase III plan with the European authorities at something to become.

Matt: With regard to the FDA the prime designation will have no influence on the FDA, we have initiated our conversations with the FDA. We've had good discussions we're making good progress and we feel comfortable about putting together a plan when we have our phase two data in hand, when we meet them with end of phase two but we are encouraged by the discussions.

Emil D. Kakkis: We have initiated our conversations with the FDA, we've had good discussions, we're making good progress, and we feel comfortable about putting together a plan when we have our phase two data in hand when we meet them at the end of phase two. But we're encouraged by the discussion and think there's a way forward in terms of finalizing a plan for phase three. We have said, just for reference, that we're planning phase three to be around 100 to 120 patients in a randomized double-blind trial design, and the FDA knows that and I think that's a traditional design. I don't think there should be any problem with European authorities either with that basic design. So we'll get the phase three endpoint settled as we move through getting all the data.

Matt: I think there is a way forward in terms of finalizing the plan for phase III. We have said just for reference that we're planning the phase III to be around 100 to 120 patients in a randomized double blind trial design and FDA.

Matt: The FDA knows that and I think thats a traditional design I don't think there should be any problem with European authorities, either with that basic design.

Emil D. Kakkis: I don't think there should be any problem with European authorities either with that basic design. So we'll get the phase three endpoint settled as we move through getting all the data. For [inaudible] phase 2 data will tell us a little more about the fracture reduction rate over a longer period of time. It appeared from before that there were very few fractures after the five, six, seventh month of treatment

I don't think there should be any problem with European authorities either with that basic design. So we'll get the phase three endpoint settled as we move through getting all the data.

Matt: So we'll get the phase III endpoint, I mean phase III endpoint settle as we move through getting all the data.

For [inaudible] phase 2 data will tell us a little more about the fracture reduction rate over a longer period of time. It appeared from before that there were very few fractures after the five, six, seventh month of treatment and we'll get a lot more patients now out further to give us a good sense of the level of reduction over longer periods of time, and that will help us understand the true maximum effect that we might see on fracture reduction. Since the fracture reduction is up already at the 67% estimate rate, that puts us in a good position to potentially have a positive interim. It will depend on the variation we'll see in patients but we felt that that level of efficacy and any higher level of efficacy will put us in a position to potentially be able to end the study sooner if we have profound, highly statistical, significant results.

Matt: But the truth is mad phase III data will tell us a little more about the fracture reduction rate over a longer period of time. It appeared from before there were very few fractures. After the five sixth or seventh month of treatment and we'll get a lot more patients now further to give us a good sense of that the level of reduction over longer periods of time that will help us.

Emil D. Kakkis: and we'll get a lot more patients now out further to give us a good sense of the level of reduction over longer periods of time, and that will help us understand the true maximum effect that we might see on fracture reduction. Since the fracture reduction is up already at the 67% estimate rate, that puts us in a good position to potentially have a positive interim. It will depend on the variation we'll see in patients but we felt that that level of efficacy and any higher level of efficacy will put us in a position to potentially be able to end the study sooner if we have profound, highly statistical, significant results. We could have a very good result, though it's still not hit that standard, and we'll have another interim and final in 2025.

and we'll get a lot more patients now out further to give us a good sense of the level of reduction over longer periods of time, and that will help us understand the true maximum effect that we might see on fracture reduction. Since the fracture reduction is up already at the 67% estimate rate, that puts us in a good position to potentially have a positive interim. It will depend on the variation we'll see in patients but we felt that that level of efficacy and any higher level of efficacy will put us in a position to potentially be able to end the study sooner if we have profound, highly statistical, significant results.

Matt: I understand the true maxima factor, we might see on fracture reduction since.

Matt: Since the fractured actions up already at the 67% estimate right now.

Matt: And that puts us in good position to potentially.

Matt: Have a positive interim it will depend on the variation we see in patients, but we felt that that level of efficacy and then a higher efficacy would put us in position of potentially being able to end the steady sooner. If we have profound highly statistical significant results.

We could have a very good result, though it's still not hit that standard, and we'll have another interim and final in 2025. So we're very encouraged about [inaudible] and the path forward and the phase two data should help us see how great it is and understand a little bit more about the path forward.

Emil D. Kakkis: So we're very encouraged about [inaudible] and the path forward and the phase two data should help us see how great it is and understand a little bit more about the path forward. Thank you. One moment for our next question, and that will come from the line of Maury Raycroft with Jeffries. Your line is open.

So we're very encouraged about [inaudible] and the path forward and the phase two data should help us see how great it is and understand a little bit more about the path forward.

Matt: We could have a very good result, though still not hit that standard and we'll have another interim and final in 2025. So we're very encourage us to choose the path forward in the phase two data should help us.

Matt: See how how great it is and understand a little bit more about the path forward.

Operator: Thank you. One moment for our next question, and that will come from the line of Maury Raycroft with Jeffries. Your line is open.

Speaker Change: Thank you one moment for our next question.

Speaker Change: And that will come from the line of Maury Raycroft with Jefferies. Your line is open.

Maury Raycroft: Hi, thanks for taking my questions. Based on the totality of your Angelman data so far, including data from your natural history longitudinal study, if you think about a phase 3 design, do you have a sense of what the optimal time frame is to assess efficacy and what age group could show maximum benefits? Yeah, so, if you look at the study data we put out last year at Analyst Day, you continue to gain ground over time, right,

Maury Raycroft: Hi, thanks for taking my questions. Based on the totality of your Angelman data so far, including data from your natural history longitudinal study, if you think about a phase 3 design, do you have a sense of what the optimal time frame is to assess efficacy and what age group could show maximum benefits?

Maury Raycroft: Hi, Thanks for taking my questions.

Maury Raycroft: Based on the totality of your Angelman data so far.

Maury Raycroft: Including data from your natural history longitudinal study as you think about a phase III design do you have a sense of what the optimal timeframe is to assess efficacy and what age group could show maximum benefits.

Emil D. Kakkis: Yeah, so, if you look at the study data we put out last year at Analyst Day, you continue to gain ground over time, right, so it looks like going a little longer, like day 170 is early and if you look at day 254, the data looks much stronger. And our view is it could be anywhere from around day 254 to day 330. Somewhere in that range is the likely time frame we would do the study. Obviously, the longer it is, that means more time on placebo. It gives more time for a separation of the groups, but it's somewhere in that time frame, and the phase two data will help us try to figure out what's the right number. I'd wanna do the study not much longer than it needs to be to show meaningful, profound results. 

Speaker Change: Yes so.

Speaker Change: If you look at the steady data we put out.

Speaker Change: Last year at Analyst day.

Speaker Change: We've continued to gain ground over time right. So it looks like going little longer like day 100, Seventy's early and if you look at day $2 50 for the data look much stronger.

Emil D. Kakkis: so it looks like going a little longer, like day 170 is early and if you look at day 254, the data looks much stronger. And our view is it could be anywhere from around day 254 to day 330. Somewhere in that range is the likely time frame we would do the study. Obviously, the longer it is, that means more time on placebo. It gives more time for a separation of the groups, but it's somewhere in that time frame, and the phase two data will help us try to figure out what's the right number. I'd wanna do the study not much longer than it needs to be to show meaningful, profound results. 

And our view is it could be anywhere from around a $2 50 for two days 330 somewhere in that range as the likely timeframe, we would do the study.

Speaker Change: Obviously the longer it is that means more time on placebo.

Speaker Change: Gives more time for separation of the groups, but somewhere in that timeframe timeframe in the phase two data will help us try to figure out what the right number I'd want to do the study not lot line that needs to be to show meaningful profound results.

Speaker Change: In terms of age.

Emil D. Kakkis: In terms of age, I think right now our plan is to continue with the same age range we're using in Phase 2, the 4-17-year-olds. Early on, people thought only young patients would respond, but we've been seeing good responses in older kids too so we shouldn't need to limit phase 3 in order to get the best efficacy. I think we should include that whole group, 4 to 17, in our phase 3 design. Our expectation though is to do a separate study, an open-label study to help look at younger kids, potentially older kids, and the other genetic types to fill out the data set. But the main phase 3 study, we expect to be 4 to 17-year-olds and be somewhere between 250 days to 330 days long. 

Speaker Change: I think right now.

Speaker Change: Our plan is to continue with the same age range, we're using in the phase II of the four to 17 year old.

Speaker Change: Early on people thought only a young patients who would respond but we've been seeing good responses in older Kids too. So I don't think that should limit.

Speaker Change: Wouldn't need to limit phase III in order to get the best efficacy I think we conclude that whole group for 2017 and in our phase III design, our expectation, though is to do a separate study an open label study to help look at younger Kid substantially older Kids and the other Jack types to fill out the dataset with the main phase III study.

Speaker Change: We expect to be four to 17 year old and B <unk>.

Speaker Change: <unk> 250 days to 330 days long.

Anupam Rama: Got it. Okay, thank you. And one moment for our next question, and that will come from the line of Anupam Rama with J.P. Morgan. Your line is open. Hey guys, thanks so much for taking the questions. Maybe just a quick one from me.

Maury Raycroft: Got it. Okay, thank you.

Speaker Change: Got it okay. Thank you.

And one moment for our next question, and that will come from the line of Anupam Rama with J.P. Morgan. Your line is open. Hey guys, thanks so much for taking the questions. Maybe just a quick one from me.

Operator: And one moment for our next question, and that will come from the line of Anupam Rama with J.P. Morgan. Your line is open.

Speaker Change: And one moment for our next question.

Speaker Change: And that will come from the line of <unk> Rama with Jpmorgan. Your line is open.

Anupam Rama: Hey guys, thanks so much for taking the questions. Maybe just a quick one from me. What was the feedback on the 1-1-1 program and PS3 program update at world? And where are you with the FDA discussions in terms of what are the push-pull levers here on an accelerated approval process emerging?

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

Emil D. Kakkis: What was the feedback on the 1-1-1 program and PS3 program update at world? And where are you with the FDA discussions in terms of what are the push-pull levers here on an accelerated approval process emerging? Well, at the meeting there, we had really positive feedback from people because I think the extended data is continuing to show good developmental progression among the longer treated patients that's consistent with the heparin sulfate and being predictive of good clinical outcomes and so we're encouraged

What was the feedback on the 1-1-1 program and PS3 program update at world? And where are you with the FDA discussions in terms of what are the push-pull levers here on an accelerated approval process emerging?

Rama: Maybe just a quick one for me what was the feedback on the.

Rama: 101 program MPS III program update at World and where are you there with the FDA discussions in terms of what are the push pull levers here on Mike and emerge accelerated approval process of merging.

Emil D. Kakkis: Well, at the meeting there, we had really positive feedback from people because I think the extended data is continuing to show good developmental progression among the longer treated patients that's consistent with the heparin sulfate and being predictive of good clinical outcomes and so we're encouraged and there are a number of people using the HS marker and showing similar predictive value.

Speaker Change: Well in the in the meeting there we had really positive feedback from people because I think the extended data is continuing to show good.

Good developmental progression among the longer treated patients.

Speaker Change: That's consistent with the heparin sulfate and being predictive of a good clinical outcomes and so we're encouraged and theres been a number of people using the Hs marker and showing similar predictive value.

Emil D. Kakkis: and there are a number of people using the HS marker and showing similar predictive value. Our discussion at the FDA has been going on for a while. I think Peter Marks has been very encouraged with the idea that we should be moving with biomarkers and a workshop is planned, organized by Reagan Udall, on February 21st, which will look at heparin sulfate across multiple programs.

and there are a number of people using the HS marker and showing similar predictive value.

Our discussion at the FDA has been going on for a while. I think Peter Marks has been very encouraged with the idea that we should be moving with biomarkers and a workshop is planned, organized by Reagan Udall, on February 21st, which will look at heparin sulfate across multiple programs.

Speaker Change: Our discussion the FDA had been.

Speaker Change: I've been going on for a while I think Peter marks has been very encouraged with the idea that we should be moving with bio marker then.

Speaker Change: Our workshops planned organized by Reagan, New Dell February 'twenty one.

Speaker Change: Which will look at heparin sulfate across multiple program.

Emil D. Kakkis: We feel the data there should encourage the FDA to take the stand of accepting heparin sulfate as a reasonably likely to predict clinical benefit marker and start doing cellular approvals in the MPS brain disease area, which, if it happens, will help us move forward in other rare genetic disorders, particularly those that affect the brain. So I think we're encouraged about the progress forward of the workshop, the data we've released, and the data others have released, tell us that we have a handle on how to treat MPS disease and, particularly, MPS 3A, and that's a good thing because there hasn't been a single treatment for MPS brain disease approved to date. Thank you. One moment for our next question. And that will come from the line of Tazeen Ahmad with Bank of America. Your line is open.

We feel the data there should encourage the FDA to take the stand of accepting heparin sulfate as a reasonably likely to predict clinical benefit marker and start doing cellular approvals in the MPS brain disease area, which, if it happens, will help us move forward in other rare genetic disorders, particularly those that affect the brain. So I think we're encouraged about the progress forward of the workshop, the data we've released, and the data others have released, tell us that we have a handle on how to treat MPS disease and, particularly, MPS 3A, and that's a good thing because there hasn't been a single treatment for MPS brain disease approved to date.

Speaker Change: We feel the data there should encourage the FDA to.

Speaker Change: Take the stand of accepting heparin sulfate is reasonably likely to predict.

Speaker Change: <unk> clinical benefit marker and start doing salary approvals in the NPS brain disease area, which.

Speaker Change: As it happens I believe will help us move forward in other rare genetic disorders, particularly that affect the brain.

Speaker Change: So I think we're encouraged about the progress forward of the workshop. The data we released the data others have released.

Speaker Change: <unk> that we have a handle on how to treat NPS disease, and particularly <unk> and <unk>.

Speaker Change: Good thing because it hasn't been a single treatment for MTS brain disease approved today.

Speaker Change: Thank you one moment our next question.

Operator: Thank you. One moment for our next question. And that will come from the line of Tazeen Ahmad with Bank of America. Your line is open.

Speaker Change: And that will come from the line of <unk> Ahmad with Bank of America. Your line is open.

Tazeen Ahmad: Hi, thanks for taking my question, sorry for the background noise. I have a couple just on 701 for Wilson. You've changed the readout timeline. I think originally it was the first half, and now you're saying it's mid-2024. Is that just nomenclature or is there a reason for a slight time shift?

Ahmad: Hi, Thanks for taking my question and sorry for the background noise.

Ahmad: Have a couple of just on 701 for Wilson.

Emil D. Kakkis: You've changed the readout timeline. I think originally it was the first half, and now you're saying it's mid-2024. Is that just a gnomon creature, or is there a reason for a slight time shift?

Ahmad: You've changed the readout timeline I think originally it was first half and now Youre, saying its mid 2024 is just that is that just nomenclature.

Ahmad: Or is there a reason for our slight time shift and then I.

Emil D. Kakkis: And then I guess going back to Angelman, a question that we've been getting a lot of recently is with relation to the composite endpoint that we've talked about that includes measures including Bayley and CGI, but have you had detailed discussions with FDA about using that composite endpoint? And I think the main question around that is coming from the potential of a competitor to have their own Angelman data around the same time as yours and how that might affect the FDA's viewpoint of using a more traditional endpoint. Thanks.

Ahmad: I guess going back to to Angelman.

Ahmad: A question that we've been getting a lot of recently is with relation to the composite endpoint that we've talked about that includes measures, including Dalian CGI, but have you had detailed discussions with FDA on using that composite endpoint.

Ahmad: And I think the main question around that is coming from the potential of a competitor to have their own angelman data around the same time as yours and back might affect fda's viewpoint of using a more traditional endpoint.

Emil D. Kakkis: So the timeline and Wilson's depend on the last patient enrolled. We enrolled the last patient cohort three just earlier this year. We wanna give them enough time, at least six months to kind of have an opportunity to titrate their chelators, get through the whole treatment process and titrate chelators. So it's slightly different from where we have but not meaningfully so that's the timing. We want to make sure to give patients enough time to be able to get off their chelators if they can so that's the basic story there.

Ahmad: Okay.

Ahmad: So the timeline and Wilson is dependent on the last patient enrolled we enrolled the last patient in cohort three.

Ahmad: Just earlier this year, we want to give them enough time leased six months to kind of have an opportunity to titrate. Their key later, you'll get through the whole treatment process and titrate keillor's. So it's slightly off from different from where we have but not not meaningfully.

Emil D. Kakkis: We want to make sure to give patients enough time to be able to get off their chelators if they can so that's the basic story there. With GTX 102, we've had discussions about both MDRI and other ways of looking at the endpoints of the FDA and I think they're open to various ways of looking, and I think they showed a lot of flexibility in many ways.

We want to make sure to give patients enough time to be able to get off their chelators if they can so that's the basic story there.

Ahmad: So that's the timing we want to make sure to give patient enough time to be able to get off their key layers. If they can so.

Ahmad: That's the basic story there with Gtx 102, we've had discussions on both MDI and other ways of looking at the endpoints of the FDA.

With GTX 102, we've had discussions about both MDRI and other ways of looking at the endpoints of the FDA and I think they're open to various ways of looking, and I think they showed a lot of flexibility in many ways. Whether we do MDRI now will be just a question of whether we want to press our case on choosing something novel or whether we should stick to picking a traditional single endpoint or two endpoints for the primary, but we're still working through that with the FDA. I think it's been good, but I'm not really worried about our competitor, honestly. Our efficacy will be the driver of what we do. I don't think that our competitor is going to change the outcome on the endpoints. They are behind us at this point and I think the efficacy data they have put out has not been impressive. So, at this point, I think our future is all in our hands. And honestly, I think we have some of the best teams in developing endpoints, methodology around it, and support for it. And nothing in our conversations with the FDA suggests that they're listening to anyone else, particularly in this. They seem to be willing and able and ready to work with us on a final solution on the endpoint.

With GTX 102, we've had discussions about both MDRI and other ways of looking at the endpoints of the FDA and I think they're open to various ways of looking, and I think they showed a lot of flexibility in many ways. Whether we do MDRI now will be just a question of whether we want to press our case on choosing something novel or whether we should stick to picking a traditional single endpoint or two endpoints for the primary, but we're still working through that with the FDA. I think it's been good, but I'm not really worried about our competitor, honestly. Our efficacy will be the driver of what we do. I don't think that our competitor is going to change the outcome on the endpoints. They are behind us at this point and I think the efficacy data they have put out has not been impressive.

Ahmad: I think they are open to various ways of looking at I think they showed a lot of flexibility in many ways.

Emil D. Kakkis: Whether we do MDRI now will be just a question of whether we want to press our case on choosing something novel or whether we should stick to picking a traditional single endpoint or two endpoints for the primary, but we're still working through that with the FDA. I think it's been good, but I'm not really worried about our competitor, honestly. Our efficacy will be the driver of what we do. I don't think that our competitor is going to change the outcome on the endpoints. They are behind us at this point

Ahmad: We do amarin, MDI and that will be just.

Ahmad: A question, whether we want to press our case on using something novel or whether we should stick to picking a traditional single endpoint or endpoints for the primary but we're still working through that with FDA I think it's been good but not really worried about the competitor honestly, our efficacy will be the driver of what we do.

Ahmad: I don't think that there are competitors going to change the outcome on the endpoints.

Ahmad: They are behind us at this point and I think the efficacy data they've put out has not been impressive so.

Dagon Ha: and I think the efficacy data they have put out has not been impressive. So, at this point, I think our future is all in our hands. And honestly, I think we have some of the best teams in developing endpoints, methodology around it, and support for it. And nothing in our conversations with the FDA suggests that they're listening to anyone else, particularly in this. They seem to be willing and able and ready to work with us on a final solution on the endpoint. Thank you. One moment for our next question, and that will come from the line about Dagon Ha with Stiefel. Your line is open. 

and I think the efficacy data they have put out has not been impressive. So, at this point, I think our future is all in our hands. And honestly, I think we have some of the best teams in developing endpoints, methodology around it, and support for it. And nothing in our conversations with the FDA suggests that they're listening to anyone else, particularly in this. They seem to be willing and able and ready to work with us on a final solution on the endpoint.

So, at this point, I think our future is all in our hands. And honestly, I think we have some of the best teams in developing endpoints, methodology around it, and support for it. And nothing in our conversations with the FDA suggests that they're listening to anyone else, particularly in this. They seem to be willing and able and ready to work with us on a final solution on the endpoint.

Ahmad: At this point I think our futures on our hands and honestly I think we have shown the best team in developing endpoints methodology around it and support for it and nothing in our conversations with the FDA suggests that they're listening to anyone else, particularly in this they seem to be willing enable and ready to work with us on a final solution on the <unk>.

Ahmad: Points.

Operator: Thank you. One moment for our next question, and that will come from the line about Dagon Ha with Stiefel. Your line is open.

Speaker Change: Thank you one moment our next question.

Speaker Change: And that will come from the line of Dae Gon Ha with Stifel. Your line is open.

Dagon Ha: Great, good afternoon. Thanks for taking our questions. I'll just ask two on GSD-1A. I guess the first one is, Emil, can you shed some more insight on the cornstarch reduction? So we've heard from some Docs that sleeping through the night is also as important, if not more important, than the reduction itself. So when you think about the outcome here, what do you consider a clinically meaningful level of cornstarch reduction? And what data will you provide to address the sleeping aspect for the physicians? And then, kind of sticking with GSD-1A, can you talk about the training and monitoring of these investigators to ensure the cornstarch reduction is done appropriately versus just slower than expected out of caution? Thanks so much.

Speaker Change: Great. Good afternoon, thanks for taking our questions I'll just ask two on <unk>.

I guess the first one is can you shed some more insights on the cornstarch reduction. So we've heard from some docs that sleeping through the night is also as important if not more important than the reduction itself. So when you think about the outcome here what do you consider clinically meaningful level of cornstarch reduction.

Emil D. Kakkis: So we've heard from some Docs that sleeping through the night is also as important, if not more important, than the reduction itself. So when you think about the outcome here, what do you consider a clinically meaningful level of cornstarch reduction? And what data will you provide to address the sleeping aspect for the physicians? And then, kind of sticking with GSD-1A, can you talk about the training and monitoring of these investigators to ensure the cornstarch reduction is done appropriately versus just slower than expected out of caution? Thanks so much.

Speaker Change: And what data will you provide to address the sleeping aspect for the physicians and then kind of sticking with <unk> can you talk about the training and monitoring of these investigators to ensure their cornstarch reduction is done appropriately versus just slower than expected out of caution. Thanks. So much.

Emil D. Kakkis: Good, I'll deal with the first question, and then maybe Erik, you could deal with the second question about the training of the site and so forth. So we haven't set a minimum threshold of change for cornstarch because we agree with you that what is probably more important than the actual reduction is whether the patients are critically dependent on cornstarch to survive because the problem with cornstarch is not taking cornstarch, the problem is that each patient lives each day with a gun to his head, thinking, if I forget to take cornstarch, I could die. That is a horrible burden to live with and have to take something every three hours. So, what we know from our Phase I-II study is that many patients were able to have no cornstarch at night, and their glucose levels were maintained. They did not drop to zero; they were maintained and supported.

Speaker Change: Good.

Speaker Change: I'll deal with the first question and then maybe Eric you can deal with the second question about the training on site so forth.

Eric Harris: So we haven't set a minimum threshold of changed requirements, Josh because we agree with you that.

Speaker Change: What is probably more importantly, actual reduction is whether the patients are critically dependent on cornstarch to survive because the problem with corn starch is not taking cornstarch. The problem is that each patient lives each day with a gun to his head thinking if I forget to take cornstarch I could die as a horrible burden to live with and have to take something every.

Speaker Change: Three hours.

Speaker Change: What we know from our phase one two.

Speaker Change: Eddie is it patients.

Speaker Change: Many patients were able to have no cornstarch at night and their glucose is were maintained they did not drop to zero. They were maintained and supported so what data will we have we will looking at primary clinical.

Eric Schmidt: So what data will we have? Well, we're looking at the primary clinical and statistical significance of cornstarch reduction. We'll also look at the number of cornstarch administrations they take, whether they're taking it at night, we'll have tedious glucose monitoring, which allows us to monitor glucose control during the night, which will also be something we'll be looking at. So in addition to corn starch, you'll hear about the other characterizations of corn starch dependency, which I think are an important part of the story. And it's an important part of why the amount of reduction we're seeing is transformational for patients where they feel like they can go out of the house and exercise without feeling that they're going to get hypoglycemia and drop somewhere, and we've had many patients tell us they feel safe now that that's not gonna happen to them, and many who don't take starch at night and sleep through the night. So I think those are all aspects of what will come out with the phase three data to help provide a clinical meaningful argument in addition to the quantitatives around cornstarch reduction. Now, Erik, maybe you can provide a little more on the training and how we're doing this with sites.

Speaker Change: Statistical significance of Cornstarch reduction will also look at the number of cornstarch administrations, they take whether theyre, taking at night will have.

Speaker Change: Tedious glucose monitoring, which allows us to monitor glucose control during the night, which will also be something we'll be looking at so in addition to the cornstarch Youll hear about the other characterization of the cornstarch dependency, which I think are important part of the story and is important part why the amount of reduction we're seeing is transformed for patients where they feel.

Eric Schmidt: And it's an important part of why the amount of reduction we're seeing is transformational for patients where they feel like they can go out of the house and exercise without feeling that they're going to get hypoglycemia and drop somewhere, and we've had many patients tell us they feel safe now that that's not gonna happen to them, and many who don't take starch at night and sleep through the night. So I think those are all aspects of what will come out with the phase three data to help provide a clinical meaningful argument in addition to the quantitatives around cornstarch reduction. Now, Erik, maybe you can provide a little more on the training and how we're doing this with sites. Yeah, to your point, training and monitoring are very important here.

And it's an important part of why the amount of reduction we're seeing is transformational for patients where they feel like they can go out of the house and exercise without feeling that they're going to get hypoglycemia and drop somewhere, and we've had many patients tell us they feel safe now that that's not gonna happen to them, and many who don't take starch at night and sleep through the night. So I think those are all aspects of what will come out with the phase three data to help provide a clinical meaningful argument in addition to the quantitatives around cornstarch reduction. Now, Erik, maybe you can provide a little more on the training and how we're doing this with sites.

Speaker Change: They can go out of the house and exercise without feeling that they're going to get hyperglycemia and drops somewhere and we've had many patients tell us they feel safe now that that's not going to happen to them and many who don't take starch at night and sleep through the night so.

Speaker Change: I think those are all aspects of what will come out with the phase III data to help provide the.

Speaker Change: The clinical meaningful argument in addition to the quantitative around cornstarch reduction.

Speaker Change: No Eric maybe you can provide a little more on the the training and how we're doing this with sites.

Erik Harris: Yeah, to your point, training and monitoring are very important here. We really did want to rely on our study team's principal investigators who gained a lot of experience during the Phase 2-1 part of this program to continue on as trial sites for the Phase 3. Because of the double-blind nature of the Phase 3 study, we also wanted to build an independent group of experts and physicians truly, the biggest experts in GSC1A who aren't participating in clinical trial sites to really work with the sites and guide them to make sure we're doing this consistently and safely.

Eric Harris: To your point, but training and monitoring is very important here.

Arlinda Lee: We really did want to rely on our study team's principal investigators who gained a lot of experience during the Phase 2-1 part of this program to continue on as trial sites for the Phase 3. Because of the double-blind nature of the Phase 3 study, we also wanted to build an independent group of experts and physicians truly, the biggest experts in GSC1A who aren't participating in clinical trial sites to really work with the sites and guide them to make sure we're doing this consistently and safely. One moment for our next question. And that will come from the line of June Lee with Truist Securities. Your line is open. 

We really did want to rely on our study team's principal investigators who gained a lot of experience during the Phase 2-1 part of this program to continue on as trial sites for the Phase 3. Because of the double-blind nature of the Phase 3 study, we also wanted to build an independent group of experts and physicians truly, the biggest experts in GSC1A who aren't participating in clinical trial sites to really work with the sites and guide them to make sure we're doing this consistently and safely.

Speaker Change: Really did want to rely on.

Eric Harris: Study team's principal investigators have gained a lot of experience during the phase one part of this program to continue on as trial sites for the phase three.

Speaker Change: Because of the double blind nature of the Phase III study. We also wanted to build an independent group of expert physicians truly the biggest experts in <unk>, who aren't participating in clinical trial sites.

Speaker Change: Really work with the sites and guide them to make sure we're doing that consistently and safely.

Operator: One moment for our next question. And that will come from the line of June Lee with Truist Securities. Your line is open.

Speaker Change: One moment for our next question.

Speaker Change: And that will come from the line of Joon Lee with Jewish Securities. Your line is open.

Emil D. Kakkis: Hi, good afternoon. This is Mehdi on for June. I have two questions. Could you please provide some clarification on the patient mix that you are envisioning for phase three? Would you exclude UPD patients or patients with prior experience with ASOs? And the other question is on [inaudible]: what gives you confidence that a potential chronic dosing would be underlabeled for this treatment? Thank you. Yeah, so you're speaking of GTX 102, correct?

Unknown: Hi, good afternoon. This is Mehdi on for June. I have two questions. Could you please provide some clarification on the patient mix that you are envisioning for phase three? Would you exclude UPD patients or patients with prior experience with ASOs? And the other question is on [inaudible]: what gives you confidence that a potential chronic dosing would be underlabeled for this treatment? Thank you.

Arlinda Lee: Hi, Good afternoon. This is maybe for June.

Arlinda Lee: Two question could you please provide some.

Arlinda Lee: Clarification on the patient mix that you're envisioning for phase III would you exclude.

Arlinda Lee: <unk> patients.

Arlinda Lee: Or like patients with prior experience with <unk>.

Arlinda Lee: The other question is on <unk>.

Arlinda Lee: What gives you confidence that.

Arlinda Lee: Central chronic dosing would be on the label for treatment.

Emil D. Kakkis: Yeah, so you're speaking of GTX 102, correct?

Thank you, yes, so you're speaking of GTA flow too correct.

Arlinda Lee: Yes.

Unknown: Yeah. 

Arlinda Lee: Yes.

Arlinda Lee: So for.

Emil D. Kakkis: For the genotypes, we're gonna stick to the genotypes we have been studying, which is the deletion type, which is 70% of the patients. The UPD and these set of patients wouldn't be in the randomized controlled phase 3 but our intent is to provide a basket study where we'll look at a cohort of those type patients, open label to help look at their efficacy and provide support for conclusion on the label. But they won't be part of phase three because, as a habit and method within the company, we don't expand genetic types or types of patients who haven't been treated if we haven't studied them already in phase two, so phase three will be all deletion types. Since those are the most severe patients improving benefit in the most severe patients which is on path to build support efficacy with smaller studies that deal with the other types. Now, patients who have prior experience, for example, patients who have been in the Roche program, we've had a number of Roche patients inquire, the challenge is very complicated right now, particularly for those that have safety events in another ASO to drop into a Phase III study. It's not something we would do.

Emil D. Kakkis: For the genotypes, we're gonna stick to the genotypes we have been studying, which is the deletion type, which is 70% of the patients. The UPD and these set of patients wouldn't be in the randomized controlled phase 3 but our intent is to provide a basket study where we'll look at a cohort of those type patients, open label to help look at their efficacy and provide support for conclusion on the label. But they won't be part of phase three because, as a habit and method within the company, we don't expand genetic types or types of patients who haven't been treated if we haven't studied them already in phase two, so phase three will be all deletion types. Since those are the most severe patients improving benefit in the most severe patients which is on path to build support efficacy with smaller studies that deal with the other types.

For the genotype, so we're going to stick to the <unk>, we have been studying which is the deletion tie of which 70% of the patients COPD and missiles patients wouldn't be.

Arlinda Lee: In our randomized control phase III.

Arlinda Lee: Our intent is to provide a basket study, where we will look at a cohort of those type patients.

Arlinda Lee: Open label to help look at their efficacy and provide support for conclusion on the label.

Arlinda Lee: But they won't be part of phase III, because we as a habit and method within the company, we don't expand Jack types.

Arlinda Lee: Types of patients we haven't treated if we haven't studied them already in phase III. So it'll phase III will be all deletion type.

Arlinda Lee: So those are the most severe patients improving benefiting the most severe patients I think puts on path to be able to support efficacy with smaller studies to deal with the other types.

Emil D. Kakkis: Now, patients who have prior experience, for example, patients who have been in the Roche program, we've had a number of Roche patients inquire, the challenge is very complicated right now, particularly for those that have safety events in another ASO to drop into a Phase III study. It's not something we would do. We're going to look at ways to look at access for those patients going forward in our program. We just haven't done it yet. We still have to work out our safety and efficacy before we take on those complexities, but there are certainly patients interested in crossing over at this point in time. So, remind me, the last question you had was on which program?

Now patients who had prior experience for example patients who've been on the Roche program. We've had a number of Roche patient inquire. The challenge, it's very complicated right now, particularly for those that had safety events and another ASR to drop into a phase III study its not something we would do we're going to look at ways. While we can do to look at access for those patients.

Emil D. Kakkis: We're going to look at ways to look at access for those patients going forward in our program. We just haven't done it yet. We still have to work out our safety and efficacy before we take on those complexities, but there are certainly patients interested in crossing over at this point in time. So, remind me, the last question you had was on which program? I believe it was on chronic dosing for OI.

We're going to look at ways to look at access for those patients going forward in our program. We just haven't done it yet. We still have to work out our safety and efficacy before we take on those complexities, but there are certainly patients interested in crossing over at this point in time. So, remind me, the last question you had was on which program?

Arlinda Lee: Going forward in our program, we just haven't done it yet we still have to work out our safety efficacy when we take on those complexities, but theres certainly patients interested in crossing over at this point in time.

Arlinda Lee: So remind me the last question you had was on which program.

Arlinda Lee: I believe it was on chronic dosing for Oi.

Unknown: I believe it was on chronic dosing for OI.

Arlinda Lee: Prior to dosing for ROI Okay.

Emil D. Kakkis: Chronic dosing for OI, ok. Why do we believe we can get chronic dosing? Well, we know that you probably need it. First of all, osteoporosis and [inaudible] are very different diseases. They're very different diseases, particularly the age of the patients, the state of their bones, and the biology of their bone disease. What we know from the asteroid study that was conducted by Mirio is that when they took them off [inaudible] and put them on just bisphosphonates, they were losing bone marrow density. Their bones were turning back around the direction they'd gained. It's clear that you need chronic dosing. What we know now from treating patients chronically, because we had, including one kid that we showed you, 17 months of treatment, is that they continue to gain ground and do better and better. So everything we said in the OI indication, their bones are different, and particularly, they're younger, and they have an induction effect from their genetic disease that makes them different. By stimulating, we're able to maintain their bone marrow density or corrode it further and what we do believe is there may be a point at which we need to move to maintenance dosing where you don't need to make their bones more dense. At that point, we'll look at going into a less frequent maintenance dosing regimen.

Arlinda Lee: Why do we believe we can get chronic dosing well, we we know that you probably need it first of all occupiers coenosteum in Austria and perfect are very different diseases.

Emil D. Kakkis: They're very different diseases, particularly the age of the patients, the state of their bones, and the biology of their bone disease. What we know from the asteroid study that was conducted by Mirio is that when they took them off cetrusimab and put them on just bisphosphonates, they were losing bone marrow density. Their bones were turning back around the direction they'd gained.

Arlinda Lee: Theyre very different diseases, particularly the age of the patient subset of their bone and the biology of their bone disease. What we know from the asteroid study that was conducted by Mario is that when they took them off the <unk> Mab and put demand just bisphosphonates. They were losing bone mineral density their bonds were turning back around.

Arlinda Lee: Round the direction. They gained its clear that you need chronic dosing, what we know now from treating patients chronically because we had including one kid that we showed you 17 months of treatment as they continue to gain ground and do better and better.

Emil D. Kakkis: It's clear that you need chronic dosing. What we know now from treating patients chronically, because we had, including one kid that we showed you, 17 months of treatment, is that they continue to gain ground and do better and better. So everything we said in the OI indication, their bones are different, and particularly, they're younger, and they have an induction effect from their genetic disease that makes them different. By stimulating, we're able to maintain their bone marrow density or corrode it further and

Arlinda Lee: We said in the <unk> indication their bonds are different and for particularly they are younger and they are have an induction effect from their genetic disease that makes them different by stimulating we're able to maintain their bone mineral density or grow it further and while we do believe there may be a point at which we need to move.

Emil D. Kakkis: what we do believe is there may be a point at which we need to move to maintenance dosing where you don't need to make their bones more dense. At that point, we'll look at going into a less frequent maintenance dosing regimen. One moment for our next question. And that will come from the line of Yaron Werber with TD Cowen, your line is open.

what we do believe is there may be a point at which we need to move to maintenance dosing where you don't need to make their bones more dense. At that point, we'll look at going into a less frequent maintenance dosing regimen.

Maintenance dosing, where you don't need to make their bones more dense and at that point.

Arlinda Lee: Sure.

Arlinda Lee: Look at going into a less frequent maintenance dosing regimen.

Operator: One moment for our next question. And that will come from the line of Yaron Werber with TD Cowen, your line is open.

Speaker Change: One moment for our next question.

Speaker Change: And that will come from the line of Yaron Werber with TD Cowen Your line is open.

Unknown: Great. Thanks. This is Brendan on for Yaron. First, just another quick one on Sanfilippo. I understand talks with FDA are still ongoing, but just wondering when you think you might know and be able to make a decision on timing for regulatory filing and whether based on how those talks are going you expect that could happen this year. And then just really quickly on GST1A, I wanted to see how soon after the Q2 readout you expect to be able to file. Has FDA really given you any confirmation on how long they want you to follow these patients after that primary endpoint, just to understand durability or what have you, just before you get that submitted? Thanks very much. 

Speaker Change: Great. Thanks. This is brendan on for your own.

Emil D. Kakkis: First, just another quick one on Sanfilippo. I understand talks with FDA are still ongoing, but just wondering when you think you might know and be able to make a decision on timing for regulatory filing and whether, you know, based on how those talks are going, you expect that could happen this year. And then just really quickly on GST1A, I wanted to see how soon after the Q2 readout you expect to be able to file. Has FDA really given you any information on how long they want you to follow these patients after that primary endpoint, just to understand durability or what have you, just before you get that decision? Very good

Brendan: First just another quick one on sanfilippo.

Brendan: I understand talks with a key are still ongoing but just wondering when you think you might know and be able to make a decision on timing to regulatory filing and whether based on how those talks are going you expect that could happen this year.

Brendan: And then just really quickly on <unk>.

Brendan: Wanted to see how soon after the Q2 readout you expect to be able to file.

Brendan: Giving you really any information on how long they want you to follow these patients after that primary endpoint just to understand durability or what have you just before you get that submitted thanks very much very good.

Emil D. Kakkis: So, for MPS 3A, the workshop coming up I think will be an important touch point, and I'd expect that after that, I would assume this first half will have a read on whether we can file off the biomarker-based data. I will tell you that we've collected almost enough clinical data to be able to file off clinical data alone. However, we think it's more meaningful to be able to get an accelerated approval for the biomarker, but we should know this first half, the workshop being an important moment, but the follow-up meeting that may occur with the review division then will let us know what our path is. Either way we can find a way forward for MPS3A, we just think it's better for the field, both us and the field, if we are able to get approval and open the door now for treating ultra rare diseases. For GST-1A readout, we haven't put a timeline for filing.

Emil D. Kakkis: So, for MPS 3A, the workshop coming up I think will be an important touch point, and I'd expect that after that, I would assume this first half will have a read on whether we can file off the biomarker-based data. I will tell you that we've collected almost enough clinical data to be able to file off clinical data alone. However, we think it's more meaningful to be able to get an accelerated approval for the biomarker, but we should know this first half, the workshop being an important moment, but the follow-up meeting that may occur with the review division then will let us know what our path is. Either way we can find a way forward for MPS3A, we just think it's better for the field, both us and the field, if we are able to get approval and open the door now for treating ultra rare diseases.

Brendan: <unk> the workshop coming up I think it will be important touch point and I'd expect that after that I would assume this first half will have a read on whether we could file off of the biomarker based data I will tell you that we've collected almost enough clinical data to be able follow up clinical data alone. However, we think it's more meaningful to.

Brendan: <unk> accelerated approval on the biomarker, but we should know this first half the workshop being an important moment, but the follow up meeting that may occur with the review Division then we'll we'll let US know what our path is either way, we can find a way forward for MTS III, We just think it's better for the field.

Brendan: Both us and the field, if we are able to get accelerated approval and opened the door now treating more ultra rare diseases.

Emil D. Kakkis: For GST-1A readout, we haven't put a timeline for filing. We have noted our plan to bring manufacturing in-house, which will require some time, but we are confident that will be an important part of what we have to do but we'll have to meet with FDA to understand more precisely what is expected in all the different packages, the CMC package and the rest of it, and so that will help determine what happens. But the data are positive, which we expect, we'll be working to move toward a filing as diligently as we can, given the parameters I've stated.

Brendan: <unk> readout, we haven't put a timeline for filing we have noted our plan to bring the manufacturing in house, which will require some time, but we are that will be an important part of what we have to do.

Emil D. Kakkis: We have noted our plan to bring manufacturing in-house, which will require some time, but we are confident that will be an important part of what we have to do but we'll have to meet with FDA to understand more precisely what is expected in all the different packages, the CMC package and the rest of it, and so that will help determine what happens. But the data are positive, which we expect, we'll be working to move toward a filing as diligently as we can, given the parameters I've stated. One moment for our next question. And that will come from the line of Kristen Kluska with Cantor Fitzgerald. Your line is open.

We have noted our plan to bring manufacturing in-house, which will require some time, but we are confident that will be an important part of what we have to do but we'll have to meet with FDA to understand more precisely what is expected in all the different packages, the CMC package and the rest of it, and so that will help determine what happens. But the data are positive, which we expect, we'll be working to move toward a filing as diligently as we can, given the parameters I've stated.

Brendan: But we'll have to go and meet with FDA to understand from a previous meeting more precisely what is expected in all the different packages the CMC package and the rest of it.

Brendan: And so.

Brendan: That will help determine what happens but.

Brendan: We are at.

Brendan: If the data are positive, which we expect will be working to move toward a filing as diligent as we can given the parameters I appreciate it.

Speaker Change: One moment for our next question.

Operator: One moment for our next question. And that will come from the line of Kristen Kluska with Cantor Fitzgerald. Your line is open.

Speaker Change: And that will come from the line of Kristen <unk> with Cantor Fitzgerald. Your line is open.

Kristen Kluska: Hi everyone, thanks for taking my questions. So with the phase 2 [inaudible] data guided for the second half of the year, I think that puts you at a mean of at least a year and a half worth of follow-up. So I wanted to ask if there's anything that you're going to be looking for beyond fracture prevention, which of course is the essential goal? Then also to your comments earlier about chronic dosing, what do you think about in OI and chronic dosing in general, if there could be further improvement or even prevention of further impact as it relates to some of the other features of OI, such as the deformities, the bone structure, et cetera?

Kristen: Hi, everyone. Thanks for taking my question, so with the faith curious in cheese and update our guidance for the second half of the year I think that puts you at nee, Nina or at least a year and a half.

Kristen: First a follow up I wanted to ask if there's anything that you are going to be looking for beyond that you're preventing which of course is essential goal. But then also to your comments earlier about sort of thing.

Emil D. Kakkis: Then also to your comments earlier about chronic dosing, what do you think about in OI and chronic dosing in general, if there could be further improvement or even prevention of further impact as it relates to some of the other features of OI, such as the deformities, the bone structure, et cetera? Thank you. Yeah, so you're right. I think they were probably in that range for a year and a half. And if you could see like the patient we described who had 17 months of treatment, he wasn't using a wheelchair anymore, and he's running around and playing.

Then also to your comments earlier about chronic dosing, what do you think about in OI and chronic dosing in general, if there could be further improvement or even prevention of further impact as it relates to some of the other features of OI, such as the deformities, the bone structure, et cetera?

Kristen: What do you think about an OIS chronic dosing in general if there could be further improvement or even preventing further impact as it relates to some of the other features.

Kristen: Such as the deformities, Shropshire et cetera. Thank you.

Emil D. Kakkis: Thank you. Yeah, so you're right. I think they were probably in that range for a year and a half. And if you could see like the patient we described who had 17 months of treatment, he wasn't using a wheelchair anymore, and he's running around and playing. I think that's kind of what we're hoping for is to look at those secondary clinical signs that not only have reduction of fractures, but people feel better, are more active, and still not have fractures. So we're going to look for that clinically meaningful side of the story as well in those patients.

Speaker Change: Yes, so youre right I think we're probably in that range, a year and a half and if you could saw like the patient. We described that had 17 months of treatment.

Speaker Change: He wasn't using wheelchair anymore and he is running around and playing I think that's kind of what we're hoping for is to look at those secondary clinical signs that not only a reduction of fractures, but people feel better or more active and still not having fractures. So we're going to look for that clinical meaningful side of the story as well in those patients.

Emil D. Kakkis: I think that's kind of what we're hoping for is to look at those secondary clinical signs that not only have reduction of fractures, but people feel better, are more active, and still not have fractures. So we're going to look for that clinically meaningful side of the story as well in those patients. Our thinking, and this relates to the maintenance dosing, is that if we improve the vulnerable densities sufficiently so that they stop having fractures or have very few fractures, then we expect two things to happen. We should be able to go to maintenance dosing where we give [inaudible] every two or three months that allows us to maintain the bone marrow density that they have and not lose ground. But we'd also expect that

I think that's kind of what we're hoping for is to look at those secondary clinical signs that not only have reduction of fractures, but people feel better, are more active, and still not have fractures. So we're going to look for that clinically meaningful side of the story as well in those patients.

Our thinking, and this relates to the maintenance dosing, is that if we improve the vulnerable densities sufficiently so that they stop having fractures or have very few fractures, then we expect two things to happen. We should be able to go to maintenance dosing where we give [inaudible] every two or three months that allows us to maintain the bone marrow density that they have and not lose ground. But we'd also expect that when you stop having fractures, you will stop having progressive deformity. And in particular, the place we're most interested in is in the spinal column. The spinal column degeneration is absolutely the

Our thinking, and this relates to the maintenance dosing, is that if we improve the vulnerable densities sufficiently so that they stop having fractures or have very few fractures, then we expect two things to happen. We should be able to go to maintenance dosing where we give [inaudible] every two or three months that allows us to maintain the bone marrow density that they have and not lose ground.

Speaker Change: Our thinking and this relates to the maintenance dosing is that if we improve the viral density sufficiently that they stop having fractures have very few fractures and we expect two things to happen, we should be able to go to maintenance dosing, where we give.

<unk> Mab every two or three months that allows us to maintain the momentum they have and not lose ground.

Speaker Change: <unk>.

Speaker Change: We'd also expect that when.

Emil D. Kakkis: when you stop having fractures, you will stop having progressive deformity. And in particular, the place we're most interested in is in the spinal column. The spinal column degeneration is absolutely the

But we'd also expect that when you stop having fractures, you will stop having progressive deformity. And in particular, the place we're most interested in is in the spinal column. The spinal column degeneration is absolutely the the most devastating part of OI, particularly Type 3s and 4s, the ones that end up in wheelchairs, their lives are devastated. Preventing the vertebral fractures, which we hope to be able to see at that point in time, would be the kind of thing that would prevent the deformity of their spines, the decline in spinal function, and becoming wheelchair-bound. Those are the kind of things that can change the future. It's partly why we're running the COSMIC study in the two- to four-year-olds to try to capture that result.

Speaker Change: When you stop having fractures that you will stop having progressive deformity and in particularly the place. We're most interested in is in the spinal column the.

Speaker Change: The spinal column degeneration is absolutely the most.

Emil D. Kakkis: the most devastating part of OI, particularly Type 3s and 4s, the ones that end up in wheelchairs, their lives are devastated. Preventing the vertebral fractures, which we hope to be able to see at that point in time, would be the kind of thing that would prevent the deformity of their spines, the decline in spinal function, and becoming wheelchair-bound. Those are the kind of things that can change the future. It's partly why we're running the COSMIC study in the two- to four-year-olds to try to capture that result.

Speaker Change: Devastating part of Oi, particularly type threes and for the ones that are a wheelchair zelizer devastated.

Speaker Change: <unk> stated.

Speaker Change: Preventing the FERC <unk> fractures, which we hope to be able to see at that point in time would be the kind of thing that would prevent the deformity of their spines.

Speaker Change: The decline in spinal function in the wheel, becoming wheelchair bound those are the kind of things, which are can change the future. It's partly why we're running the cosmic study in the two to four year old to try to capture that results when we.

Emil D. Kakkis: So when we head to a filing for approval, we can establish a new standard of care that you need to be treating OI patients with [inaudible] at a young age to help prevent the deformities going forward. So hopefully, the Cosmic Study will add to that question that you've asked about changing deformities. If you can do that, it could be that you could stop OI type threes and fours from being wheelchairs-bound, and what a terrific result that would be. And that's what we think is possible with what we've seen so far.

Speaker Change: <unk> to a filing for approval.

Speaker Change: We can establish a new standard for care that you need to be treating <unk> patients with the <unk> at a young age to help prevent the deformity is going forward. So hopefully the cosmic study will add to that question that you asked about changing deformities. If you can do that it could be that you could stop Oi type III enforcer, ending wheelchair bound and water.

Speaker Change: Terrific result that would be and Thats, what we think is possible with what we've seen so far.

Salveen Richter: And that's what we think is possible with what we've seen so far. One moment for our next question, and that will come from the line of Salveen Richter with Goldman Sachs. Your line is open. Hi, this is Lydia on for Salveen.

And that's what we think is possible with what we've seen so far. One moment for our next question, and that will come from the line of Salveen Richter with Goldman Sachs. Your line is open.

And that's what we think is possible with what we've seen so far.

Operator: One moment for our next question, and that will come from the line of Salveen Richter with Goldman Sachs. Your line is open.

Speaker Change: One moment for our next question.

Speaker Change: And that will come from the line of Salvia Richter with Goldman Sachs. Your line is open.

Unknown: Hi, this is Lydia on for Salveen. Thanks so much for taking our question. So we just have one on UX701, could you just help us frame the clinical update expected this year, specifically around how much proof of concept we could expect here? Thanks so much. 

Lidia: Hi, This is lidia on for solving thanks, so much for taking our question. So I just have one on <unk> hundred one could you just help us frame the clinical update expected this year, specifically around how much proof of concept we could expect here. Thanks, so much.

Emil D. Kakkis: Thanks so much for taking our question. So we just have one on UX701, could you just help us frame the clinical update expected this year, specifically around how much proof of concept we could expect here? Thanks so much. 

Emil D. Kakkis: Yeah, so the proof of concept, the information you're going to get is five patients at three doses, right? So it's still a relatively small sets of data. What we'd be looking to see is whether we can eliminate the need in at least some patients for chelators. That is, we can remove their chelators and still maintain urinary [inaudible] that is, we can replace the chelators. The second thing, can we restore copper distribution?

Emil D. Kakkis: Yeah, so the proof of concept, the information you're going to get is five patients at three doses, right? So it's still a relatively small sets of data. What we'd be looking to see is whether we can eliminate the need in at least some patients for chelators. That is, we can remove their chelators and still maintain urinary [inaudible] that is, we can replace the chelators.

Lidia: Yes so.

Speaker Change: The proof of concept the information youre going to get our five patients at three doses right. So still relatively small set the data what will we be looking to see if can we.

Eliminate the need and at least some patients for key later.

Speaker Change: That is we can remove their key later then still maintain year end copper that is we can replace the key layers the second thing.

Emil D. Kakkis: The second thing, can we restore copper distribution? That is a place where the gene therapy can exceed what you obtain with chelators because we didn't get into the Wilson gene therapy business just to replace chelators, just to get rid of a treatment. We got in there because we think you can have a more profound beneficial treatment that restores copper distribution as well as detoxification. So we'd want to be able to show that both those things are happening. If we can show that both those are happening in patients at the optimal dose and done with safety, it sets us up for immediately rolling out a phase 3 study at that dosing regimen that will allow us then to potentially [inaudible]. The stronger the benefit of the copper distribution on their outcomes, then the more likely the drug will become adopted by a larger fraction of Wilson patients. If it's great at removing the toxicity, then it could be that 23% of the patients that are not tolerating chelators very well would benefit.

Can we restore copper distribution that is the place where the gene therapy we.

Emil D. Kakkis: That is a place where the gene therapy can exceed what you obtain with chelators because we didn't get into the Wilson gene therapy business just to replace chelators, just to get rid of a treatment. We got in there because we think you can have a more profound beneficial treatment that restores copper distribution as well as detoxification. So we'd want to be able to show that both those things are happening. If we can show that both those are happening in patients at the optimal dose and done with safety, it sets us up for immediately rolling out a phase 3 study at that dosing regimen that will allow us then to potentially [inaudible]. The stronger the benefit of the copper distribution on their outcomes, then the more likely the drug will become adopted by a larger fraction of Wilson patients. If it's great at removing the toxicity, then it could be that 23% of the patients that are not tolerating chelators very well would benefit. Our expectation, though, is it could be more beneficial than you might imagine, given what's known about chelators

That is a place where the gene therapy can exceed what you obtain with chelators because we didn't get into the Wilson gene therapy business just to replace chelators, just to get rid of a treatment. We got in there because we think you can have a more profound beneficial treatment that restores copper distribution as well as detoxification. So we'd want to be able to show that both those things are happening. If we can show that both those are happening in patients at the optimal dose and done with safety, it sets us up for immediately rolling out a phase 3 study at that dosing regimen that will allow us then to potentially [inaudible]. The stronger the benefit of the copper distribution on their outcomes, then the more likely the drug will become adopted by a larger fraction of Wilson patients. If it's great at removing the toxicity, then it could be that 23% of the patients that are not tolerating chelators very well would benefit.

Speaker Change: It can exceed what you obtained with key layers, because we didn't get into the Wilson gene therapy business just to replace key later just to get rid of a treatment.

Speaker Change: We got in there because we think you can have a more profound beneficial treatment that restores copper distribution as well as detoxification. So we'd want to be able to show that both those things are happening. If we can show that both of those are happening patients at the optimal dose and done with safety.

It sets us up for immediately rolling a phase III study at that dose and regimen that will allow US then to potentially.

Speaker Change: Yes.

Speaker Change: Okay.

Speaker Change: <unk> the stronger the benefit of the copper distribution on their outcomes and the more likely the drug will become adopted by a larger fraction of Wilson patients.

Speaker Change: We're great at moving the toxicity.

Speaker Change: And then it could be the 23% of the patients that are not tolerant keloid very well that it would be beneficial.

Our expectation, though, is it could be more beneficial than you might imagine, given what's known about chelators and that will open the door to having a larger fraction of Wilson patients that would respond. So it will give us at least the beginning framing of those two aspects of Wilson disease. But remember, it's only five patients per group, so we cannot expect to have definitive clinical outcomes results in that grouping to tell us the answer. But with a phase three study following that, we'd have enough patients in there to start to say something more about the clinical meaningfulness or the secondary neurologic effects otherwise that you might obtain by having restoration of copper distribution. One moment for our next question, and that will come from the line of Yigal Nochomovitz with Citi. Your line is open.

Expectation, though there could be more beneficial than than you might imagine given what's known about key letters and that will open the door to having a larger fraction Wilson patients that would respond. So it will give us at least the beginning framing of those two aspects of the Wilson disease, but.

Emil D. Kakkis: and that will open the door to having a larger fraction of Wilson patients that would respond. So it will give us at least the beginning framing of those two aspects of Wilson disease. But remember, it's only five patients per group, so we cannot expect to have definitive clinical outcomes results in that grouping to tell us the answer. But with a phase three study following that, we'd have enough patients in there to start to say something more about the clinical meaningfulness or the secondary neurologic effects otherwise that you might obtain by having restoration of copper distribution. One moment for our next question, and that will come from the line of Yigal Nochomovitz with Citi. Your line is open. Hi, this is [inaudible] on for Yigal. 

and that will open the door to having a larger fraction of Wilson patients that would respond. So it will give us at least the beginning framing of those two aspects of Wilson disease. But remember, it's only five patients per group, so we cannot expect to have definitive clinical outcomes results in that grouping to tell us the answer. But with a phase three study following that, we'd have enough patients in there to start to say something more about the clinical meaningfulness or the secondary neurologic effects otherwise that you might obtain by having restoration of copper distribution. One moment for our next question, and that will come from the line of Yigal Nochomovitz with Citi. Your line is open.

But remember it's only five patients per group. So we cannot expect to have definitive clinical outcomes results in that grouping to tell us.

The answer but with the phase III study following that we'd have enough patients in there to start to say something more about the clinical meaningfulness or the secondary neurologic effects, otherwise that you might obtained by having restoration of copper distribution.

Speaker Change: One moment for our next question.

Yigal Levin: And that will come from the line of Yigal know John Levin with Citi. Your line is open.

Unknown: Hi, this is [inaudible] on for Yigal. Thanks for taking my question. I had a follow-up on an earlier Angelman discussion. I guess as you're thinking through the various scenarios between a more novel endpoint for Phase 3 versus a more traditional endpoint, I'm curious how you think the expansion data you're planning on sharing with us here might capture the potential for a more novel endpoint. And if you lean towards the more novel end of the spectrum and you take that to regulators, is there maybe the potential that you need to generate additional data beyond this cohort before you start the phase three? I'm just curious how you're thinking about that. Thanks.

Cuba: Hi, Tim. This is also Cuba on for Yigal. Thanks for taking my question I had a follow up on earlier Angelman discussion.

Yigal Dov Nochomovitz: Thanks for taking my question. I had a follow-up on an earlier Angelman discussion. I guess as you're thinking through the various scenarios between a more novel endpoint for Phase 3 versus a more traditional endpoint, I'm curious how you think the expansion data you're planning on sharing with us here might capture the potential for a more novel endpoint. And if you lean towards the more novel end of the spectrum and you take that to regulators, is there maybe the potential that you need to generate additional data beyond this cohort before you start the phase three? I'm just curious how you're thinking about that. Thanks.

Speaker Change: Just as we're thinking through.

John Levin: Area scenarios between a more novel endpoint for phase III versus a more traditional end point.

Cuba: I'm curious how you think the expansion data.

Cuba: On sharing with US you might capture.

Cuba: For a more novel endpoint.

Cuba: If you lean towards more novel end of the spectrum.

Cuba: That's our regulators is there maybe potential that you need to generate additional data beyond this expansion cohort to submit before you start the phase III I'm, just curious how you're thinking about that thanks.

Emil D. Kakkis: Yeah well, our focus, I mean, I think our focus in terms of endpoint choice is the main ones we've already shown that we've tested before and we're adding to. We're not necessarily expecting brand new endpoints to come out, but we'll be dependent primarily on what we see. The thing that will happen in the study though is that we'll get a large number of patients loaded the same way, which we haven't had, which will give us a better, a more precise estimate of the change we see and make it more reliable, not wishful thinking, but to see a large number of patients showing a very similar pattern of results. Our goal expectations are from the endpoints, we've talked about five domains, which Bailey was for three of those domains and two other endpoints for behavior and sleep.

Emil D. Kakkis: Yeah well, our focus, I mean, I think our focus in terms of endpoint choice is the main ones we've already shown that we've tested before and we're adding to. We're not necessarily expecting brand new endpoints to come out, but we'll be dependent primarily on what we see. The thing that will happen in the study though is that we'll get a large number of patients loaded the same way, which we haven't had, which will give us a better, a more precise estimate of the change we see and make it more reliable, not wishful thinking, but to see a large number of patients showing a very similar pattern of results.

Speaker Change: Yes, well our focus.

Speaker Change: Our focus in terms of endpoint choices give me the main ones, we've already shown that we tell.

Speaker Change: Before and we're adding to our we're not necessarily expecting a brand new endpoints to come out, but so it will be dependent on primarily what we see the thing that will happen in the steady though is that we will get a large number of patients loaded the same way right, which we haven't had which will give us a better a more precise estimate.

Speaker Change: <unk> of the change, we see and have it be more reliable not.

Speaker Change: Not wishful thinking but to see <unk>.

Speaker Change: Large number of patients showing a very similar pattern. A result, our goal expectations are from the endpoints, we've talked about five domains, which the Bailey was for three of those domains in two other endpoints for the behavior and fleet those are going to be the core of five domains that we're going to be working with there'll be other assessments are fine.

Emil D. Kakkis: Our goal expectations are from the endpoints, we've talked about five domains, which Bailey was for three of those domains and two other endpoints for behavior and sleep. Those are going to be the core five domains that we're going to be working with. There will be other assessments for fine motor and expressive communication, but the five we've talked about will be the main drivers. So I don't really think there's gonna be a point where we're going to start fresh with a new endpoint to restart over. That's not something we need to do.

Emil D. Kakkis: Those are going to be the core five domains that we're going to be working with. There will be other assessments for fine motor and expressive communication, but the five we've talked about will be the main drivers. So I don't really think there's gonna be a point where we're going to start fresh with a new endpoint to restart over. That's not something we need to do.

Speaker Change: Motor and express the communication, but the five we've talked about will be the main drivers.

Speaker Change: I don't really think theres going to a point, where we're going to start fresh with a new endpoint to restart over that's not something we need to do we think we have enough data among the ones. We know they come up with a good conclusion and structure the endpoints in a way that gives us the best insight in how the drug works in.

Emil D. Kakkis: We think we have enough data among the ones we know to come up with a good conclusion and structure the endpoints in a way that gives us the best insight into how the drug works and gets regulatory agreement. But we certainly wouldn't want to start off fresh and restart the discussion. We do believe we'll have enough to make that conclusion with the agency. One moment for our next question. And that will come from the line of Jeff Hung with Morgan Stanley. Your line is open.

We think we have enough data among the ones we know to come up with a good conclusion and structure the endpoints in a way that gives us the best insight into how the drug works and gets regulatory agreement. But we certainly wouldn't want to start off fresh and restart the discussion. We do believe we'll have enough to make that conclusion with the agency.

Speaker Change: Regulatory agreement, but we certainly wouldn't want to start off fresh and restart the discussion. We do believe we'll have enough to make that conclusion with the agency.

Operator: One moment for our next question. And that will come from the line of Jeff Hung with Morgan Stanley. Your line is open.

Speaker Change: One moment for our next question.

Speaker Change: And that will come from the line of Jeff Hung with Morgan Stanley. Your line is open.

Jeff Hung: Thanks for taking my question. For UX111, you mentioned that you've collected almost enough clinical data to file off the clinical data alone, what length of long-term follow-up do you need to accurately measure potential for improved development with sustained HS normalization? How should we think about the time course for development?

Jeff Hung: Thanks for taking my question for you ex 111, you mentioned that you've collected almost enough clinical data to file off the clinical data alone what length of long term follow up do you need to accurately measure potential for improved development with sustained Hs normalization, how should we think about the time course for development.

Speaker Change: Okay.

Emil D. Kakkis: Well, this is one of the areas for discussion with the agency. Originally, they told Aviona and, in our discussions, had a requirement to see at least patients reach age five years. However, we've been able to show that between 24 months and 60 months, between that period, there is the most rapid decline normally in natural history. And then if you look at the estimated yearly change in development and the trajectory of development, you can readily distinguish patients during that period. We have a number of patients now that have already gone past 60 months or five years, but between 48 and 60, there are a number of others that are also showing good development. And we think the combination of those patients may already be enough clinically to demonstrate the benefit, which was part of that update. We're working to understand in our new analysis we showed this estimated yearly change in its relationship to area under the curve exposure, helps provide better insight into how to understand the trajectory of development over time. And we think this means we can interpret better what's happening between, let's say, 30 months of age and 60 months of age to know what the trajectory of a patient with [inaudible] who's untreated is and what the trajectory of someone who has adequate heparin sulfate reduction. And so those will be what we'll be pressing for.

Speaker Change: Well. This is one of the areas for discussion with the agency and originally they had told that beyond and in our discussions had.

Speaker Change: Our requirement to see at least patient reach age five years.

Speaker Change: However, we've been able to show that.

Speaker Change: That between 24 months and 60 months between in that period. There is the most rapid decline normally natural history and then if you look at the estimated yearly change of development and the trajectory of development you can readily distinguish patients during that period, we have a number of patients now that have already gone pass.

Emil D. Kakkis: And then if you look at the estimated yearly change in development and the trajectory of development, you can readily distinguish patients during that period. We have a number of patients now that have already gone past 60 months or five years, but between 48 and 60, there are a number of others that are also showing good development. And we think the combination of those patients may already be enough clinically to demonstrate the benefit, which was part of that update. We're working to understand in our new analysis we showed this estimated yearly change in its relationship to area under the curve exposure, helps provide better insight into how to understand the trajectory of development over time. And we think this means we can interpret better what's happening between, let's say, 30 months of age and 60 months of age to know what the trajectory of a patient with [inaudible] who's untreated is and what the trajectory of someone who has adequate heparin sulfate reduction. And so those will be what we'll be pressing for.

Speaker Change: 60 months or five years, but between 48 60, there are a number of others are also showing good development and we think the combination of those patients may be already enough clinically to demonstrate the benefit which was part of that update.

Speaker Change: But.

Speaker Change: We're working to understand and our new analysis. We showed on this estimated yearly change and its relationship to area under the curve exposure.

Speaker Change: To provide better insight into how to understand trajectory of development over time, and we think this means we can interpret better what's happening between let's say 30 months of age 60 months age to now what does the trajectory of a patient with sample lethal this untreated and west.

Speaker Change: Dejectory of someone who has adequate heparin sulfate reduction and so those will be what we'll be pressing for but even just patients from 48 to 60 months minimum $40 60 months, we already have clinical data, saying that drug is effective. So it is another way for us to go forward, but far more valuable.

Emil D. Kakkis: But even just patients from 48 to 60 months, a minimum of 48 to 60 months, we already have clinical data saying the drug is effective. So it is another way for us to go forward, but far more valuable to get an accelerated approval, include all the data and all the patients, and accept the 48 to 60 minimum treatment data as simply evidence toward the reasonably likely [inaudible] standard. One moment for our next question. And that will come from the line of Joseph Schwartz with Lyrinc. Your line is open.

But even just patients from 48 to 60 months, a minimum of 48 to 60 months, we already have clinical data saying the drug is effective. So it is another way for us to go forward, but far more valuable to get an accelerated approval, include all the data and all the patients, and accept the 48 to 60 minimum treatment data as simply evidence toward the reasonably likely [inaudible] standard.

Speaker Change: To get an accelerated approval.

Speaker Change: All of the data and all the patients.

Speaker Change: And accept the 48% to 60 minimum treatment data is simply evidence towards the reasonably likely to predict standard.

Operator: One moment for our next question. And that will come from the line of Joseph Schwartz with Lyrinc. Your line is open.

Speaker Change: One moment for our next question.

Speaker Change: Yes.

Speaker Change: And that will come from the line of Joseph Schwartz with Leerink. Your line is open.

Unknown: Hi, all. Thanks for taking our questions. This is Will on for Joe today. So just two quickly from us, both on Angelman. Previously, it was noted that you would expect to see more of an effect as compared to the prior data cut, given the higher doses in the expansion cohort so I just wanted to make sure that this is still the expectation. And then also, for Angelman, we often hear that these patients are constantly gaining skills, and there may be some increased hope in the community, which could lead to a placebo response. So, just wondering what strategies can help mitigate a potential response in a pivotal trial. Thank you. 

Speaker Change: Hi, all thanks for taking our questions. This is will on for Joe today. So just to quickly from US both on Angelman. So previously it was noted that you expect to see more of an effect as compared to the prior data cut given the higher doses in the expansion cohort I just wanted to make sure that this is still the expectation and then also for Angela.

Emil D. Kakkis: So just two quickly from us, both on Angelman. Previously, it was noted that you would expect to see more of an effect as compared to the prior data cut, given the higher doses in the expansion cohort. So I just wanted to make sure that this is still the expectation. And then also, for Angelman, we often hear that these patients are constantly gaining skills, and there may be some increased hope in the community, which could lead to a placebo response. So, just wondering what strategies can help mitigate a potential response in a pivotal trial.

And we often hear that these patients are constantly gaining skills and there may be some increased hoping to community, which could lead to a placebo response. So just wondering what strategies can help mitigate a potential response in a pivotal trial. Thank you.

Emil D. Kakkis: Thank you. So our expectation was that loading at higher doses would accelerate the improvement relative to what we've seen. We haven't changed our view on that. The thing I would say is, remember that in the phase two data we showed you from extension, we went all the way out to 500 days of treatment, right? So the magnitude effect you see at 500 days is not going to be the same that you're going to see at 170 days, but we do expect that the higher load dose and the larger number of patients should allow us to verify that we're seeing a real effect. Now, with regard to the placebo response, I think the longer-term data already show you that there is not a placebo response because they continue to gain ground. The placebo effect doesn't go on forever, It goes on for a while, but people eventually recognize something's not happening.

Speaker Change: Thank you so.

Speaker Change: Our expectation that loading at higher doses that the improvement should be accelerated relative to what we have seen.

Speaker Change: We haven't changed our view on that the thing I would say is remember that in the phase two data. We showed you for extension we have win all the way out to 500 days of treatment right. So the magnet effect you see at 500 days is not going to be the same that youre going to see a 170 days, but we do expect that the higher low dose.

Emil D. Kakkis: The thing I would say is, remember that in the phase two data we showed you from extension, we went all the way out to 500 days of treatment, right? So the magnitude effect you see at 500 days is not going to be the same that you're going to see at 170 days, but we do expect that the higher load dose and the larger number of patients should allow us to verify that we're seeing a real effect. Now, with regard to the placebo response, I think the longer-term data already show you that there is not a placebo response because they continue to gain ground. The placebo effect doesn't go on forever, It goes on for a while, but people eventually recognize something's not happening.

Speaker Change: And the large number of patients that should make us allow us to verify that we're seeing a real effect now with regard to the placebo response.

Speaker Change: The longer term data already show you that there is not a placebo response, because they continued to gain ground. The placebo effect doesn't go on forever. It goes on for a while then people eventually recognize something's not happening, but they are able to see linear continued gain of ground over time, it's clearly beyond what you would see with the placebo effect in the phase III, though you have to worry what youre thinking.

Emil D. Kakkis: But to be able to see linear or continued gain of ground over time is clearly beyond what you would see with a placebo effect. In a phase three, though, you have to worry about what you're thinking, well, what if people are optimistic? What we are doing, and a lot of the key endpoints is to use third-party psychologist evaluators, like for the [inaudible]. The third-party evaluator is looking at the kid doing things. While the patient report may have some impact, they are looking for the kid to do things, so that helps provide some objectivity that we're seeing the kid actually do things, and it's not just wishful thinking. That said, our expectation is to have a large enough effect and a large enough population of patients to be able to power past the placebo effect.

Speaker Change: Well, what if people are optimistic.

Speaker Change: What we are doing and one of the key endpoints used third party.

Third party psychologist evaluated like for the Bally The third party valuation looking at the Kid doing things while at patient report may have some impact they are looking for the kid to do things. So that helps provide some objectivity that we're seeing the kid actually do things in stock just wishful thinking.

Emil D. Kakkis: While the patient report may have some impact, they are looking for the kid to do things, so that helps provide some objectivity that we're seeing the kid actually do things, and it's not just wishful thinking. That said, our expectation is to have a large enough effect and a large enough population of patients to be able to power past the placebo effect. In addition, the longer timeframe we've been talking about, which is maybe 250 days or 330 days should be well past the normal window of what a placebo would be. I think when you look at how many domains are improving in patients, 2 to 5 domains improvement in most of the patients,

While the patient report may have some impact, they are looking for the kid to do things, so that helps provide some objectivity that we're seeing the kid actually do things, and it's not just wishful thinking. That said, our expectation is to have a large enough effect and a large enough population of patients to be able to power past the placebo effect.

Speaker Change: That said our expectation is to have a large enough effect and a large enough population of patients to be able to power path.

In addition, the longer timeframe we've been talking about, which is maybe 250 days or 330 days should be well past the normal window of what a placebo would be. I think when you look at how many domains are improving in patients, 2 to 5 domains improvement in most of the patients, it will become evident to people who are responding and who are not responding. And so the issue you raised is certainly one of importance, and we've been thinking a lot about it. But I do think the magnet effect, and the length of time are factors which will help reduce the risk of a placebo response clipping or impairing the results of that study.

<unk> effect. In addition, the longer timeframe, we've talking about which is maybe 250 days of 330 days.

Speaker Change: Should be well past the normal window, what placebo would be.

Speaker Change: I think when you look at how many domains are improving in patients two to five domains improvement in most of the patients.

Emil D. Kakkis: it will become evident to people who are responding and who are not responding. And so the issue you raised is certainly one of importance, and we've been thinking a lot about it. But I do think the magnet effect, and the length of time are factors which will help reduce the risk of a placebo response clipping or impairing the results of that study.

It will become evident to people who is responding who is not responding.

Speaker Change: So the issue raised is certainly one of importance and we've been thinking a lot about it but I do think the magna affect the length of time of factors, which are hub.

Speaker Change: Reduce the risk of a placebo response clip.

Speaker Change: Clipping or comparing the results of that study.

Operator: And one moment for our next question. And that will come from the line of Jack Allen with Baird. Your line is open. Alright, thank you so much for taking the questions. I have two quick ones.

Operator: And one moment for our next question. And that will come from the line of Jack Allen with Baird. Your line is open.

Speaker Change: One moment for our next question.

Speaker Change: And that will come from the line of Jack Allen with Baird. Your line is open.

Jack Allen: Alright, thank you so much for taking the questions. I have two quick ones. The first one has to do with the commercial products, namely Dojolvi and Crysvita. I know there's some seasonality in the fourth quarter numbers, but when you analyze the fourth quarter numbers, it seems like you're already at the lower end of guidance. I was hoping you could provide some more color as it relates to how we should think about the growth of those two products over the course of 2024. And then, on GSD1A, any thoughts on your early market research here? Is there a subset of patients that are more severe that could be asked to early adopt gene therapy here?

Jack Allen: Alright. Thank you so much for taking the questions I have two quick ones. The first of all the commercial products, namely <unk> <unk> and Christina.

Emil D. Kakkis: The first one has to do with the commercial products, namely Dojolvi and Crysvita. I know there's some seasonality in the fourth quarter numbers, but when you analyze the fourth quarter numbers, it seems like you're already at the lower end of guidance. I was hoping you could provide some more color as it relates to how we should think about the growth of those two products over the course of 2024. And then, on GSD1A, any thoughts on your early market research here? Is there a subset of patients that are more severe that could be asked to early adopt gene therapy here? That's for GSD-1A.

The first one has to do with the commercial products, namely Dojolvi and Crysvita. I know there's some seasonality in the fourth quarter numbers, but when you analyze the fourth quarter numbers, it seems like you're already at the lower end of guidance. I was hoping you could provide some more color as it relates to how we should think about the growth of those two products over the course of 2024. And then, on GSD1A, any thoughts on your early market research here? Is there a subset of patients that are more severe that could be asked to early adopt gene therapy here?

Jack Allen: There is some seasonality in the fourth quarter numbers, but when you annualize out the fourth quarter numbers and it seems like you're already at the lower end of guidance I was hoping you can provide some more color as it relates to how we should think about the growth of those two products over the course of 2024 and then on GSD <unk>.

Jack Allen: Any thoughts on your early market research. There is there a subset of patients that are more severe that could be asked to early adopt a gene therapy here.

Emil D. Kakkis: That's for GSD-1A.

Jack Allen: That is <unk>.

Emil D. Kakkis: Yeah. Okay. So, with Dojolvi and Crisvita, guidance is always an art form but our view is that we're continuing to see something close to 20% growth. Dojolvi may be a little slower because some of the territories we just have we are responding to main patient sales. I think Eric made that clear.

Jack Allen: Yeah.

Emil D. Kakkis: Okay. So, with Dojolvi and Crisvita, guidance is always an art form but our view is that we're continuing to see something close to 20% growth. Dojolvi may be a little slower because some of the territories we just have we are responding to main patient sales. I think Eric made that clear.

Jack Allen: Yes.

Jack Allen: Okay.

Jack Allen: So with digital and Chris fee guidance as always.

Jack Allen: Farm, but our view is that we're continuing to see something close to 20% growth to Shelby may be a little slower because some of the territories. We just have we're responding named patient sales I think Eric made that clear.

Emil D. Kakkis: We're in the territories that we're commercializing, and we're continuing to see the 20% growth rate. I don't think there is any issue with this. We're trying our best to provide guidance and give street numbers we feel confident in achieving. And I think looking at a 20% growth rate is, I think, still an excellent growth rate. So the lumpiness, Q4s, in these patterns with Latin America have been a recurring theme. It is what it is. I think, ultimately, it swings up and down. I think the fourth quarter tends to be higher as there is some buying before the winter months and before the new year. But it's just something that we're always gonna have to manage overall. So we have to smooth it out and come up with guidance that makes sense but I feel good about the guidance we have and a 20% growth rate should be excellent.

Jack Allen: In the territories that we're commercializing, we're continuing to see the 20% growth rate.

Jack Allen: I don't think there is any issue with this we are trying our best to navigate guidance then give.

The street numbers, we feel confident in achieving.

And I think looking at <unk> growth rate I think is I think still excellent growth rates. So the lumpiness Q4s in Q in these patterns with Latin America have been a recurring theme. It is what it is I think ultimately it's just it swings up and down I think fourth quarter tends to be higher or there's some.

Jack Allen: Buying before the winter months and before.

Emil D. Kakkis: But it's just something that we're always gonna have to manage overall. So we have to smooth it out and come up with guidance that makes sense but I feel good about the guidance we have and a 20% growth rate should be excellent. With regard to GSD-1A, 81% of the patients have a severe genotype or null-like genotype, right? 81%. So the vast majority of patients are severe. There's some milder ones, but the majority are severe.

But it's just something that we're always gonna have to manage overall. So we have to smooth it out and come up with guidance that makes sense but I feel good about the guidance we have and a 20% growth rate should be excellent.

Jack Allen: The new year, but.

Jack Allen: And it's just something that we're always going to have to manage overall.

Jack Allen: We have to smooth it out and come up with guidance. It makes sense, but I feel good about the guidance, we have 20% growth rate should be excellent.

Jack Allen: With regard to <unk>.

With regard to GSD-1A, 81% of the patients have a severe genotype or null-like genotype, right? 81%. So the vast majority of patients are severe. There's some milder ones, but the majority are severe. And so we'd look at the population being more homogeneous in that regard than many of our gene therapy diseases that we study. So at this point, I would look at most of the patients being highly dependent on starch, having a very severe phenotype, and probably in the greatest need and most danger from that disease in terms of crashing and dying suddenly.

Jack Allen: 81% of the patients have severe.

Jack Allen: Severe genotype or no like genotype rate, 81%. So it's the vast majority pages are severe theres some milder, but the majority are severe and so we'd look at the population being more homogeneous in that regard than many of our gene therapy.

Emil D. Kakkis: And so we'd look at the population being more homogeneous in that regard than many of our gene therapy diseases that we study. So at this point, I would look at most of the patients being highly dependent on starch, having a very severe phenotype, and probably in the greatest need and most danger from that disease in terms of crashing and dying suddenly. And one moment for our next question, and that will come from the line of Ed Arce with H.C. Wainwright. Your line is open. 

And so we'd look at the population being more homogeneous in that regard than many of our gene therapy diseases that we study. So at this point, I would look at most of the patients being highly dependent on starch, having a very severe phenotype, and probably in the greatest need and most danger from that disease in terms of crashing and dying suddenly.

Jack Allen: <unk> disease that we study.

Jack Allen: So at this point I would look at most of the patients being highly dependent on starch, having very severe phenotype and probably in greatest need most danger from that disease in terms of crashing and dying suddenly.

Speaker Change: And one moment for our next question.

Operator: And one moment for our next question, and that will come from the line of Ed Arce with H.C. Wainwright. Your line is open.

Speaker Change: And that will come from the line of Ed Arce with H C. Wainwright Your line is open.

Unknown: Hi, good afternoon everyone. This is Thomas asking a couple of questions for Ed. Thank you for taking our questions. So just for GTX-102 and Angelman, among the 20 patients in the expansion cohort, can you tell us what some of the longest treatment durations that these patients have been on in the Phase I-II study? And also, what are some additional endpoints that investors can focus on compared to the previous data set? Thank you. 

Speaker Change: Hi, Good afternoon, everyone. This is Thomas Yip, asking a couple questions for Ed.

Taking my questions.

Thomas Yip: For Gtx 102 and Angelman.

Thomas Yip: Among the patients in the expansion cohort.

Thomas Yip: Can you tell us what are some of the longest.

Thomas Yip: The current duration that these patients have been in the phase one two study and also what are some additional endpoints.

Thomas Yip: <unk> focus on compared to the previous statements.

Thomas Yip: Okay.

Thomas Yip: I heard the extension core youre asking from the ones, we presented how long they go out.

Emil D. Kakkis: I heard the expansion cohort. You're asking from the ones we presented how long they go out. By the time we get to the end of phase two, we'll have patients who have had two years of treatment, probably, but it'll be somewhere between a year to two years of treatment of exposure for all those patients so quite a long time. And we had patients, a good chunk of patients were already beyond day 504 at the Analyst Day meeting, so I think, actually, that's a good thing, shows you that chronically exposed accumulating drug doses are not gonna cause a safety problem in this disease. So I think that's an important part of the safety profile that we can keep doing these treatments and not have an issue. Restate your second question because I didn't quite catch it.

Thomas Yip: <unk>.

Thomas Yip: By the time, we get to end of Phase II, we will have patients who have had two years of treatment, probably but it'll be somewhere between a year or two years of treatment of exposure for all of those patients so quite a long time.

Emil D. Kakkis: And we had patients, a good chunk of patients were already beyond day 504 at the Analyst Day meeting, so I think, actually, that's a good thing, shows you that chronically exposed accumulating drug doses are not gonna cause a safety problem in this disease. So I think that's an important part of the safety profile that we can keep doing these treatments and not have an issue. Restate your second question because I didn't quite catch it. I think the second question was about additional endpoints that they should be considering, beyond perhaps what we've already discussed at Analyst Day. Well, we have a lot of different ones we're looking at, but I think the ones we've talked about, the [inaudible] the core, either the Angel Severity Assessment for behavior or sleep, or an alternative behavior and sleep scale could be used.

And we had patients, a good chunk of patients were already beyond day 504 at the Analyst Day meeting, so I think, actually, that's a good thing, shows you that chronically exposed accumulating drug doses are not gonna cause a safety problem in this disease. So I think that's an important part of the safety profile that we can keep doing these treatments and not have an issue. Restate your second question because I didn't quite catch it.

Thomas Yip: And we have patients a good chunk of patients were already beyond age Dave $5 four at the analyst day meeting so.

Thomas Yip: I think actually that's a good.

Shows you that chronically exposed accumulating drug doses are knocking it caused the safety problem in this disease. So I think thats an important part of the safety profile that we can keep doing it but I don't have an issue.

Speaker Change: Restate your second question, because I didn't quite catch it.

Speaker Change: I think the second question was about additional endpoints that they should be considering.

I think the second question was about additional endpoints that they should be considering, beyond perhaps what we've already discussed at Analyst Day. Well, we have a lot of different ones we're looking at, but I think the ones we've talked about, the [inaudible] the core, either the Angel Severity Assessment for behavior or sleep, or an alternative behavior and sleep scale could be used.

Unknown: I think the second question was about additional endpoints that they should be considering, beyond perhaps what we've already discussed at Analyst Day.

Speaker Change: Beyond perhaps what we've already discussed and IC.

Well, we we have a lot of different ones, we're looking at but I think the ones, we talked about the Bailey our core.

Emil D. Kakkis: Well, we have a lot of different ones we're looking at, but I think the ones we've talked about, the [inaudible] the core, either the Angel Severity Assessment for behavior or sleep, or an alternative behavior and sleep scale could be used. Those are two alternatives. They're scales we've used before. We've seen them before, we just didn't have them in the most recent extension data. So we'll get a little more information on those alternative ways of doing it. I would say to you in our discussion with the FDA, they were highly flexible with us, calling out questions and just pulling up like a few key questions on those endpoints and relying on those for the endpoint. They showed great collaborative flexibility and not rigidity with regard to choosing those endpoints. And so within our existing data set, we can even just pull out questions, for example, and hone in on those questions and use those in particular for behavior or sleep. So our goal would be not to go with new things we haven't seen before, but to look at what we have and pull out the best data sources that are sensitive to the change and are clinically meaningful for patients in coming up with those additives. But there won't be any brand new things you've never seen or that we don't have any data on.

Speaker Change: <unk>.

Speaker Change: The either the Angel severity assessment for behavior or.

Speaker Change: Our sleep or an alternative behavior of sleep scale could be used those are two alternatives. There are scales. We've used before we've seen them before we just haven't.

Emil D. Kakkis: Those are two alternatives. They're scales we've used before. We've seen them before, we just didn't have them in the most recent extension data. So we'll get a little more information on those alternative ways of doing it. I would say to you in our discussion with the FDA, they were highly flexible with us, calling out questions and just pulling up like a few key questions on those endpoints and relying on those for the endpoint. They showed great collaborative flexibility and not rigidity with regard to choosing those endpoints. And so within our existing data set, we can even just pull out questions, for example, and hone in on those questions and use those in particular for behavior or sleep. So our goal would be not to go with new things we haven't seen before, but to look at what we have and pull out the best data sources that are sensitive to the change and are clinically meaningful for patients in coming up with those additives. But there won't be any brand new things you've never seen or that we don't have any data on.

Emil D. Kakkis: We just haven't, We didn't have them in the most recent extension data. So we'll get a little more information on those alternative ways of doing it. I would say to you in our discussion with FDA, they were highly flexible with us, calling out questions and just pulling up like a few key questions on those endpoints and relying on those for the endpoint. They showed great collaborative flexibility and not rigidity with regard to choosing those endpoints. And so within our existing data set, we can even just pull out questions, for example, and hone in on those questions and use those in particular for behavior or sleep. So our goal would be not to go with new things we haven't seen before, but to look at what we have and pull out the best data sources that are sensitive to the change and are clinically meaningful for patients in coming up with those additives. But there won't be any brand new things you've never seen or that we don't have any data on.

Speaker Change: We haven't didn't include we didn't have them in the most recent extension data. So we'll get a little more information on those alternative ways of doing it I would say to you in our discussion with FDA.

Speaker Change: We're highly flexible to us calling out questions and just pulling up like a few key questions on those endpoints and relying on those for the endpoint they were.

Speaker Change: Zinc showed great collaborative flexibility and not rigidity with regard to choosing those endpoints and so within our existing dataset. We can even just pull out questions for example, and hone in on those questions and use those for particular for behavior sleep. So our goal would be not to go with new things, we haven't seen before but too.

Speaker Change: Look at what we have and pull out the best data stores Theyre sensitive to the change and are clinically meaningful for patients and coming up with those that data, but there won't be brand new things, you've never seen or that we don't have any data on.

Operator: Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Joshua Higa for any closing remarks. Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at ir@ultragenyx. Thank you for joining us. Thank you all for participating. This concludes today's program. You may now disconnect. 

Operator: Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Joshua Higa for any closing remarks. Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at ir@ultragenyx. Thank you for joining us.

Operator: Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Joshua Higa for any closing remarks.

Speaker Change: Thank you I'm showing no further questions in the queue. At this time I would now like to turn the call back over to Joshua Hager for any closing remarks.

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

Speaker Change: Thank you all for participating. This concludes today's program you may now disconnect.

Speaker Change: Okay.

Speaker Change: [music].

Speaker Change: Okay.

Speaker Change: Good.

Speaker Change: [music].

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

Speaker Change: Okay.

Speaker Change: Thank you.

Speaker Change: [music].

Speaker Change: Sure.

Speaker Change: [music].

Operator: Thank you all for participating. This concludes today's program. You may now disconnect.

Speaker Change: Okay.

Speaker Change: Yes.

Speaker Change:

Speaker Change: [music].