Q2 2024 Ultragenyx Pharmaceutical Inc Earnings Call

Good afternoon, and welcome to the Ultragenyx Second Quarter 2024 Financial Results Conference Call.

Speaker Change: Vice President of Investor Relations. Please go ahead.

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

Speaker Change: Thank you. We have issued a press release detailing our financial results, which you can find on our website at Ultragenyx.com.

Speaker Change: Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Erik Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and Erik Crombez, Chief Medical Officer.

Speaker Change: 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.

Amy: Please refer to the risk factors discussed in our latest SEC filing. I'll now turn the call over to Amy. Thanks, Josh. And good afternoon, everyone.

Amy: We've had an incredible first half of the year and look forward to sharing more with you today. On the commercial front, our strong revenue performance puts us on a trajectory to outperform our prior projections. And so we're raising our total revenue guidance range. And we're happy with what this means for access to our drugs globally. And Eric and Howard can share more on the revenue details. Within our clinical pipeline, we've meaningfully advanced our late-stage programs through multiple positive data readouts and successful and critically important regulatory interactions on the data front.

Emil: Thanks, Josh, and good afternoon, everyone. We've had an incredible first half of the year and look forward to sharing more with you today.

Speaker Change: On the commercial front, our strong revenue performance puts us on a trajectory to outperform our prior projections, and so we're raising our total revenue guidance range. We're happy with what this means for access to our drugs globally, and Eric and Howard can share more on the revenue details.

Speaker Change: Within our clinical pipeline, we have meaningfully advanced our late-stage programs through multiple positive data readouts and successful and critically important regulatory interactions.

Amy: In addition to the positive results we shared earlier this year on both UX111 in Sanfilippo syndrome and GTX102 in Angevin syndrome, we recently announced positive phase 3 results from the DTX401 gene therapy for the treatment of patients with glycosidase disease type 1a and additional long-term positive phase 2 results from the UX143 antibody for the treatment of patients with osteogenesis imperfecta.

Erik: on the data front.

Emil Kakkis: For GTS 1 and 2 for Angeman Syndrome, we announced the successful completion of an end of phase 2 meeting with the FDA where we aligned on phase 3 study design and key endpoints to be evaluated. Our teams have been working with our study sites to initiate our global phase 3 study by the end of this year. On UX111 for Sanfilipo Syndrome Type A, we also reached agreement with AHC on a path forward to seek accelerated approval.

Speaker Change: For GTX-102 for Angeman Syndrome, we announced the successful completion of an end-of-phase-2 meeting with the FDA where we aligned on phase 3 study design and key endpoints to be evaluated. Our teams have been working with our study sites to initiate our global phase 3 study by the end of this year.

Speaker Change: On you, what's 111 for Sanfilepal Syndrome Type A.

Emil Kakkis: The FDA has agreed that cerebral spinal fluid heparin sulfate is a reasonable surrogate endpoint to support submission of a BLA supported by our clinical data to date. Our next step is to finalize the details of our submission with the agency in a pre-relay meeting, and we intend to submit this DLA later this year or early next. Collectively, this puts us in a position to have multiple regulatory marketing submissions and key clinical data readouts over the next six to 18 months, which is extraordinary.

Speaker Change: We also reached agreement with the agency on a path forward to seek accelerated approval. The FDA has agreed that cerebral spinal fluid heparin sulfate is a reasonable surrogate.

Speaker Change: Collectively, this puts us in a position to have multiple regulatory marketing submissions and key clinical data readouts over the next 6 to 18 months, which is extraordinary.

Emil Kakkis: I spent my career developing therapies for rare diseases, and I can tell you I've never seen a rare disease company with the breadth and depth of opportunities we have ahead of us, nor with our ability to move all these things forward. These achievements are the direct result of our excellent execution across the company from our committed employees and our best-in-class approach to rare disease drug development. It's a very exciting time for Ultragenyx.

Emil Kakkis: I'll now turn the call over to our Chief Commercial Officer, Erik Harris, to provide an update on the momentum across our commercial portfolio that has led us to raise our total revenue guidance for the year. Thank you, Emil, and good afternoon, everyone. I'll start with Chris Vita's performance in the United States.

Erik Harris: I'll now turn the call over to our Chief Commercial Officer, Erik Harris, to provide an update on the momentum across our commercial portfolio that has led us to raise our total revenue guidance for the year.

Erik Harris: Thank you, Emil, and good afternoon, everyone. I'll start with Chris Vita's performance in the United States.

Erik Harris: The demand for CRISPR in the U.S. remains strong in Q2 2024. Approximately 60% of the initial forms came from adult patients and were prescribed by community physicians, with over 40 new prescribers in the quarter. This is encouraging given adult penetration is in the low 20s and implies Crispita has ample room to continue growing. We are confident in our full-year U.S. revenue projections, given the strength of the underlying demand. Moving to CRISPR-Vita in Latin America, where we lead commercialization, our LATAM team delivered another successful quarter by adding approximately 60 new patients to CRISPR-Vita, totaling over 620 patients on reimbursed therapy since launch. Brazil is the largest market in Latin America and continues to drive the majority of revenue in the region.

Speaker Change: The demand for CRISPR in the U.S. remains strong in Q2 2024. Approximately 60% of the start forms came from adult patients and were prescribed by community physicians, with over 40 new prescribers in the quarter.

Speaker Change: This is encouraging, given adult penetration is in the low 20s.

Speaker Change: and implies Prospita has ample room to continue growing. We are confident in our full year U.S. revenue projections, given the strength of the underlying demand.

Speaker Change: Shifting to CRISPR-Vita in Latin America, where we lead commercialization, our LATAM team delivered another successful quarter by adding approximately 60 new patients to CRISPR-Vita, totaling over 620 patients on reimbursed therapy since launch.

Erik Harris: That said, we are beginning to see more meaningful contributions from countries like Argentina and Mexico, supported by underlying patient demand. As I mentioned on previous earnings calls, we expect quarter-to-quarter variability in LATAM revenue due to uneven ordering patterns, but remain confident in the underlying demand growth for our product. Moving on to Djovi, growth of new START forms remains strong. In the U.S., we added approximately 30 START forms and 30 patients on reimbursed therapy, resulting in approximately 520 reimbursed patients since launch. The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults.

Speaker Change: That said, we are beginning to see more meaningful contributions from countries like Argentina and Mexico, supported by the underlying patient demand.

Erik Harris: The number of new prescribers continues to grow, adding approximately 10 new prescribers in Q2 2024, with half of them writing more than one prescription. For Djovi, across Europe and the MENA region, revenue is currently driven by named patient sales requests. There are approximately 215 patients treated under MPS across 12 countries in the region. The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the EMEA region, including the Middle East.

Erik Harris: The number of new prescribers continued to grow, adding approximately 10 new prescribers in Q2 2024, with half of them writing more than one prescription.

Speaker Change: For Djovi, across Europe and the MENA region, revenue is currently driven by named patient sales requests. There are approximately 215 patients treated under MPS across 12 countries in the region.

Erik Harris: The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the AMIR region, including the Middle East.

Erik Harris: As I have said before, 2024 is an important launch year for Keystone. In the AMIA region, we added approximately 60 new patients in the second quarter who are being treated through MPS and regular reimbursement processes where we have approval. In Japan, the launch is starting, but it has already gained meaningful contribution following regulatory approval in January and pricing and reimbursement approval in April. The team there has done an excellent job to map and identify a majority of patients in the country and has processed 35 initial forms through the second quarter of 2024. In our territories, we continue to receive positive feedback from the HOFH physician and patient community.

Erik Harris: In Japan, the launch is starting but has already gained meaningful contribution following regulatory approval in January and pricing and reimbursement approval in April .

Erik Harris: The team there has done an excellent job to map and identify a majority of patients in the country and has processed 35 start forms through the second quarter of 2024.

Erik Harris: And they are all very excited to have EFKISA as a treatment option. We expect demand for EFKISA to continue growing as we bring this important therapy to patients with HOFH. Overall, Q2 2024 was a strong quarter for Ultragenyx. As expected, the second quarter bounced back from the first quarter seasonality, leading to $147 million in total revenue.

Erik Harris: Overall, Q2 2024 was a strong quarter for Ultragenyx. As expected, the second quarter bounced off the first quarter seasonality, leading to $147 million in total revenue.

Howard Horn: The broad strength across the commercial portfolio through the first six months of the year put us on a trajectory that gives us confidence we will exceed the guidance range that we established at the beginning of the year. With that, I'll turn the call over to Howard to share more details on our financial results for the quarter and guidance for the year. Thanks, Eric. And good afternoon, everyone.

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

Howard Horn: I'll start by briefly summarizing our financials that were reported in our press release earlier today. As Erik noted, we reported $147 million in total revenue for the second quarter of 2024. Presvita contributed $114 million, including $67 million from North America, $40 million from Latin America and Turkey, and $6 million from Europe. Jolvi revenue in the second quarter was $19 million.

Howard Horn: Thanks, Eric, and good afternoon, everyone. I'll start by briefly summarizing our financials that were reported in our press release earlier today.

Howard Horn: As Erik noted, we reported $147 million in total revenue for the second quarter of 2024.

Howard Horn: Prospita contributed $114 million, including $67 million from North America, $40 million from Latin America and Turkey, and $6 million from Europe .

Howard Horn: If Kisa revenue in the second quarter was $8 million, and Metsevi revenue in the second quarter was $6, our total operating expenses in the second quarter were $263 million, which included R&D expenses of $162 million, SG&A expenses of $81 million, and cost of sales of $21 million. Operating expenses included non-cash, stock-based compensation of $39 million. In the second quarter, the net loss was $132 million, or $1.52 per share. As of June 30, 2024, we had $874 million in cash, cash equivalents, and marketable securities, which included net proceeds of $381 million from our offering in June. Net cash used in operations was $77 million for the second quarter and was $268 million in total for the first half of the year.

Howard Horn: The Jolby revenue in the second quarter was $19 million, Kieser revenue in the second quarter was $8 million, and Metsevi revenue in the second quarter was $6 million.

Howard Horn: SG&A expenses of $81 million and cost of sales of $21 million.

Howard Horn: Operating expenses included non-cash, stock-based compensation of $39 million.

Howard Horn: In the second quarter, net loss was $132 million, or $1.52 per share.

Howard Horn: As of June 30, 2024, we had $874 million in cash, cash equivalents, and marketable securities, which included net proceeds of $381 million from our offering in June .

Howard Horn: Net cash used in operations was $77 million for the second quarter and was $268 million in total for the first half of the year.

Howard Horn: As we discussed on our May call, there is seasonality in the first quarter because it includes items like the payment of annual bonuses. Our guidance for 2024 net cash use and operations remains unchanged, and is expected to be less than $400 million for the year. Moving to Revenue Guidance. We are increasing our range for total revenue, which is now expected to be between $530 and $550 million for the year. This reflects strong performance and trajectory across all of our products, including Prospita globally and the launch of Ivkiza in our territory.

Howard Horn: Our guidance for 2024 net cash use and operations remains unchanged and is expected to be less than $400 million for the year.

Howard Horn: Accordingly, we are targeting Prisvita revenue to be towards the upper end of our existing range of $375 million to $400 million, which includes all regions and all forms of proceeded revenue to Ultragenyx. Specifically, it includes CRISPR product revenue from Latin America and Turkey, and cash and non-cash royalties from North America and Europe. We continue to expect Jolby revenue to be between $75 and $89.

Speaker Change: Specifically, it includes Crispida product revenue from Latin America and Turkey and cash and non-cash royalties from North America and Europe.

Howard Horn: We continue to expect the Jolvi revenue to be between $75 million and $89 million.

Erik Crombez: With that, I'll turn the call over to our CMO, Erik Crombez. Thank you, Howard, and good afternoon, everyone. The first half of the year has seen a number of important clinical catalysts for UX111 for the treatment of MPS3A. For example, we announced data demonstrating clinically significant reductions in heparin sulfate that correlated with improved long-term cognitive function. This was followed up by our announcement in June that we reached agreement with the FDA that CSF heparin sulfate can be used as a surrogate endpoint for accelerated approval. We expect to finalize details of our filing package at a pre-BLA meeting later this year with the goal of filing the BLA around the end of 2024.

Erik Crombez: For DTX-401, for the treatment of GSD-1A, we announced positive top-line data from the phase three study that showed that treatment with DTX-401 resulted in a statistically significant reduction in daily corn starch intake at week 48 with maintenance of strong glucose control. Results from the study will be discussed with regulatory authorities at a pre-BLM meeting in the second half of 2024. For UX143, for the treatment of osteogenesis imperfecta, we announced 14-month data from the Phase II portion of ORBIT that showed treatment with cetrusimab resulted in a sustained 67% reduction in annualized fracture rate and persistent median annualized fracture rate of zero.

Howard Horn: Thank you, Howard, and good afternoon, everyone.

Speaker Change: The first half of the year has seen a number of important clinical catalysts. For UX111, for the treatment of MPS3A, we announced data demonstrating clinically significant reductions in heparin sulfate that correlated with improved long-term cognitive function.

Speaker Change: This was followed up with our announcement in June that we reached agreement with the FDA that CSF pepper and salt aid can be used as a surrogate endpoint for accelerated approval.

Speaker Change: We expect to finalize details of our filing package in a free BLA meeting later this year with the goal of filing the BLA around the end of 2024.

Speaker Change: for DTX-401 for the treatment of GST-1A.

Speaker Change: We announce positive top-line data from the Phase 3 study.

Speaker Change: that showed that treatment with DTX-401 resulted in a statistically significant reduction in daily cornstarch intake at week 48 with maintenance of strong glucose control.

Speaker Change: Results from this study will be discussed with regulatory authorities in a pre-BLM meeting in the second half of 2024.

Speaker Change: for UX143 for the treatment of osteogenesis imperfecta.

Erik Crombez: There were also continued substantial improvements in bone mineral density with a mean increase from baseline of 22% and a mean improvement in z-score of 1.25 for GTX-102 for the treatment of Angelman syndrome. In April, we shared additional phase one, two data from the expansion cohorts that showed rapid and clinically meaningful improvements across multiple domains. These improvements were consistent or exceeding those of the dose escalation cohort data at day 170. We also shared that additional long-term data and dose escalation cohorts showed increasing and sustained clinical benefits through day 758.

Speaker Change: There were also continued substantial improvements in bone mineral density with a mean increase from baseline of 22% and a mean improvement in z-score of 1.25.

Speaker Change: For GTX-102 for the treatment of Angelman Syndrome, in April we shared additional Phase 1-2 data from the expansion cohorts that showed rapid and clinically meaningful improvements across multiple domains.

Speaker Change: These improvements were consistent or exceeding those of the dose escalation cohort data at day 170.

Speaker Change: We also shared that additional long-term data in dose escalation cohorts showed increasing and sustained clinical benefits through day 758.

Erik Crombez: There's been a lot of news flow in the space recently, and we feel very good about the ability of GTX-102 to improve the lives of patients affected by this disorder. We continue to see patients in the Phase 2 portion of the study developing new skills across multiple domains with no new serious adverse events, and we believe we are in a strong position as we advance Phase 3 startup activities. Last month, we completed a successful end of phase two meeting with the FDA, where we agreed on the design for a global 48-week blinded randomized sham-controlled phase three study.

Speaker Change: There's been a lot of news flow in the space recently, and we feel very good about the ability of GTX-102 to improve the lives of patients affected by this disorder.

Speaker Change: We continue to see the patients in the Phase 2 portion of the study developing new skills across multiple domains with no new serious adverse events. And we believe we are in a strong position as we advance Phase 3 startup activities.

Speaker Change: Last month we completed a successful end of Phase 2 meeting with the FDA where we aligned on the design for a global, 48-week, blinded, randomized, sham-controlled Phase 3 study.

Erik Crombez: We expect to enroll approximately 120 patients between 4 and 17 years of age who have a full UBE3A deletion. The primary endpoint will be improvement in cognition assessed by Bayley's 4 cognitive raw score. The study will also include a key secondary endpoint of a multi-domain responder index evaluating cognition, receptive communication, behavior, gross motor, and sleep.

Speaker Change: We expect to enroll approximately 120 patients between 4 and 17 years of age who have a full UBE3A deletion.

Emil Kakkis: Individual secondary endpoints were also discussed and aligned with the FDA for the domains of communication, behavior, motor function, and sleep. Phase 3 study-startup activities have been ongoing for some time, and now that FDA alignment is in place, we are focused on initiating the study by year-end. The ongoing Phase 2 study includes 25 states across 8 countries, which allows us to respond to the significant global demand for sites to participate in the study and for these sites to gain experience with GTX-102.

Speaker Change: Individual secondary endpoints were also discussed and aligned on with the FDA for the domains of communication, behavior, motor function, and sleep.

Speaker Change: Phase 3 study-startup activities have been ongoing for some time, and now with FDA alignment, we are focused on initiating the study by year-end.

Emil Kakkis: With start-up activities already in progress and alignment with FDA and design, we are on track to begin enrollment in our Phase III study by the end of this year. While this initial phase 3 study will focus on patients with full deletions, who represent the majority of patients with Angelman syndrome, we are also planning to initiate an open-label study to evaluate GTX102 for the treatment of patients with other genotypes and in other age groups in 2025. We expect to enroll both studies in parallel and plan to include both sets of data in a future BLA application. I'll now turn the call back to Emil to provide some closing remarks. Thank you, Eric.

Speaker Change: With start-up activities already in progress and alignment with FDA and design, we are on track to begin enrollment of our Phase III study by the end of this year.

Speaker Change: While this initial phase 3 study will focus on patients with full deletions,

Speaker Change: who represent the majority of patients with Angelman syndrome. We are also planning to initiate an open-label study to evaluate GTX-102 for the treatment of patients with other genotypes and in other age groups in 2025.

Speaker Change: We expect to enroll both studies in parallel and plan to include both sets of data in a future BLA application.

Speaker Change: I'll now turn the call back to Emil to provide some closing remarks.

Emil Kakkis: In the first part of the year, we've made significant progress advancing our clinical pipeline, and we've performed well globally in the commercialization of core products. I'll close quickly by summarizing our key clinical catalysts for the rest of the year. For GTX-102 for Angelman syndrome, we're working to initiate the phase 3 study by the end of the year, and we plan to share updates on how the phase 2 patients are doing over time.

Emil Kakkis: Thank you, Erik.

Emil Kakkis: In the first part of the year, we've made significant progress advancing our clinical pipeline. We've performed well globally on the commercialization of four products. I'll close quickly by summarizing our key clinical catalysts for the rest of the year.

Speaker Change: For GTX 102 for Angelman Syndrome, we are working to initiate the Phase 3 study by the end of the year and over time, plan to share updates on how the Phase 3 patients are doing as they continue receiving maintenance doses.

Emil Kakkis: Our long-term data is far superior to any other data presented on ASLs for Angelman to date, and this puts us in an excellent position for the future of that program. For the Phase 3 portion of the UX143 Orbit Study, there are two interim analyses planned, with the first anticipated by year-end or early 2025. The first analysis will have a stringent threshold of p-value less than or equal to 0.001.

Speaker Change: For the Phase 3 portion of the UX143 Orbit Study, there are two interim analyses planned with the first anticipated by year-end or early 2025.

Speaker Change: The first analysis will have a stringent threshold of p-value less than or equal to 0.001. If the threshold is not met, a second interim analysis will occur a few months later, followed by a final analysis at 18 months.

Emil Kakkis: If the threshold is not met, a second interim analysis will occur a few months later, followed by a final analysis at 18 months. The first interim analysis will not be reported to the company by the Data Monitoring Committee unless the data have met this very stringent threshold. It is important for steady integrity to run these analyses very carefully and rigorously.

Speaker Change: The first interim analysis will not be reported to the company by the Data Monitoring Committee unless the data have met this very stringent threshold. It is important for steady integrity to run these analyses very carefully and rigorously.

Emil Kakkis: In the event of an interim analysis that clears the threshold, we would share that outcome, but top-line results would not be announced immediately, as the study would require patients to complete their final visits over a couple months, and then there is time to collect and prepare the data for a formal analysis. For UX701 for Wilson disease, we expect to share stage one data in the second half of the year. In this dose finding stage, a data readout will be prompted once the last patient in cohort 3 has been on therapy for six months or more, followed by some additional time to collect and analyze all of the data.

Emil Kakkis: In the event of an interim analysis that clears the threshold, we would share that outcome, but top-line results would not be announced immediately, as the study would require patients to complete their final visits over a couple months

Speaker Change: For UX701 for Wilson disease, we expect to share stage 1 data in the second half of the year. In this dose finding stage, a data readout will be prompted once the last patient cohort 3 has been on therapy for 6 months or more, followed by some additional time to collect and analyze all of the data.

Emil Kakkis: All of these are very exciting catalysts, and while the teams are executing on these clinical programs, we will also be working on two BLA submissions, one for UX111 for SAMHSA Lipo Syndrome, which is expected around the end of the year, and the other for DTX401 for collection and storage disease type 1A, which is expected in 2025. Ultragenyx is at an incredible inflection point.

Speaker Change: All of these are very exciting catalysts, and while the teams are executing on these clinical programs, we will also be working on two BLA submissions.

Speaker Change: One for UX111, for Sanfilippo Syndrome, which is expected around the end of the year, and the other for DTX401 for Duplex and Stroke Disease Type 1A, which is expected.

Emil Kakkis: Over the next 12 to 18 months, we expect to have filed two BLAs, provided phase three data on UX143, and should be well on our way to initiating the GTX102 phase three study. All the while, we're generating meaningful revenue growth that's now expected to be between $530 and $550 million this year. With that, let's move on to your questions. Operator, please provide the Q&A instructions for the syndrome data update. We also saw quite a few other data updates from both Ionis and Roche.

Speaker Change: in 2025. Ultragenyx is at an incredible inflection point. Over the next 12 to 18 months, we expect to have filed two BLAs, provide phase 3 data on UX143, and should be well on our way to the GTX102 phase 3 study.

Speaker Change: All the while we are generating meaningful revenue growth that is now expected to be between $530M and $550M this year. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Speaker Change: Thank you very much. At this time, we will be conducting a question and answer session.

Speaker Change: If you would like to ask a question today, please press star then 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue.

Speaker Change: Press star and then 2 if you would like to remove yourself from the question queue.

Speaker Change: The first question that we have comes from Gena Wang of Barclays, please go ahead.

Emil Kakkis: Emil, what are your latest thoughts, you know, regarding the competitive landscape and the read-through to your trial design, especially if we're looking at the loading dose frequency and also the endpoints such as expressive communication for Bayley? Hey Will, is your line muted? We can't hear you.

Eric: All right, looks like we're having maybe a little bit of technical difficulty, and we've lost Emil's line. Eric, are you able to help out with that question? Yep, thanks. And certainly, we've been following along the important data updates that were released around the time of ASF. So certainly feel very good about where we stand looking more closely at the data both from Roche and importantly from IONIS. We, as we've mentioned, had a very successful end of Phase 2 meeting with the FDA, and we really have locked in our plans for Phase 3, as we're looking forward to the first patient by the end of the year.

Eric: We have done some thinking on loading doses and reducing from 4 to 3 loading doses, which also gives us the ability to increase our dose and drive to higher doses in a shorter period and really get to, you know, a data readout for that Phase 3 in under one year. Again, you know, looking across all of the important domains we've been talking about collectively in the MDRI and individually as secondary endpoints, we're seeing great movement across all of those domains. We are moving forward with cognition raw scores as our primary endpoint, but we are certainly looking at expressive communication as an important secondary endpoint. Blowing back,

Speaker Change: as secondary endpoints. We're seeing great movement across all of those domains. We are moving forward with cognition raw scores for our primary endpoint but certainly looking at expressive communication as an important secondary endpoint.

Eric: Yeah, Eric took care of the call. Gena, was there any follow-up there that you had for Emil? Sure. Yeah, so regarding the Wilson data in the second half of this year, maybe, you know, how many more patients and what kind of data beyond biomarkers you will share with us. Well, there are a total of 15 patients, 5 in each cohort, so it'll be 15 patients' worth of data, 5 at each dose level. It'll be primarily biochemical.

Speaker Change: Hello, I'm back.

Speaker Change: Yeah, Eric took care of the call. Gena, was there any follow-up there that you had for AMAL? Sure, yeah, so maybe regarding the Wilson data in second half this year, maybe, you know, how many more patients and what kind of data beyond biomarker you will share with us?

Eric: There's not enough patients in there to have a lot of clinical information, right? you know, so it'll be focused on copper, copper levels. Transcripts provided by Transcription Outsourcing, LLC. Gene Therapy Working Well, we certainly have an early indication. And that was where he heard it.

Speaker Change: Distribution levels and other aspects of Cochrane metabolism. I think will give us an understanding of is the gene therapy working well. We had certainly an early indication and that was very encouraging. So primarily focus on the biochemical part of the story at this point.

Eric: So we'll primarily focus on the biochemical part of the story. Great, thank you. Hey Salveen, I'm not sure if your line is muted, so we can't hear you. Hi, can you hear me now?

Speaker Change: Great, thank you.

Speaker Change: The next question we have comes from Salveen Richter of Goldman Sachs. Please go ahead.

Salveen: Loud and clear, Salveen, go ahead. Oh, so sorry about that. Thank you for taking my question. Could you help us understand how you look at OI with regard to, how you look at OI with regard to the phase two data translating to phase three here? And particularly as these patients see improvements, how that kind of impacts the rate of fractures here for the population and your assumptions around that in the phase three trial.

Salveen Richter: Hi, can you hear me now?

Salveen: Well, I think what we've shown with the 14-month data was, in fact, that the bone marrow density continues to increase dramatically, and the p-value got much smaller, so remember, that's looking at all the patients, not just the median. Unknown Attendee, Translating to Phase III, We know from the data we have on a few placebos that they do not see bone marrow density improvement during this period of time, so there will be no placebo effect from that. With regard to fractures, fractures are dependent on both disease severity and also environmental factors, like what the patient is doing.

Speaker Change: P-Value is declining substantially. It tells you all the patients are moving toward a reduction in fractures. So we feel the effect is very large. In terms of translating to Phase III,

Speaker Change: We know from the data we had on a few placebos that they do not see bone marrow density improvement during this period of time, so there will be no placebo effect from that.

Emil Kakkis: Our expectation is that patients when they feel better could start doing more work, but what we have seen is patients that have gotten stronger and been on treatment for a longer period of time will have falls and not have fractures, so we feel pretty confident that the strength of bones is such. Commentary Transcripts are provided by Transcription Outsourcing, LLC. 2013 Transcription Outsourcing, LLC. All rights reserved. Transcription Outsourcing, LLC

Speaker Change: What we have seen is patients that have gotten stronger and been on treatment for a longer period of time will have falls and not have fractures, so we feel pretty confident that the strength of bones is such too.

Davey Du: But we do think that the transcripts provided by Transcription Outsourcing, LLC. Did I hit on the thing you were most interested in, Salveen? That's really helpful. Thank you. Hey, good afternoon, guys. Thanks for taking my questions. Hope I'm coming off okay. Can you guys hear me?

Speaker Change: We do think that the way patients feel and their activity will bode well for supportive clinical data on how the patients are doing, which I think will support the value of the product and its clinical meaningfulness.

Speaker Change: Hit on the thing you are most interested in, Salveen.

Salveen Richter: That's really helpful, thank you.

Salveen Richter: Please go ahead.

Salveen Richter: Hey, good afternoon guys. Thanks for taking my questions. Hope I'm coming off okay. Can you guys hear me?

Davey Du: Loud and clear, Davey Du. Awesome. So maybe just revisiting or maybe rewording Gena's earlier question. Emil, coming out of that ASF, and we certainly have some details around the different domains and their impact by the ASOs, I guess now that the phase three trial design is set, is there a certain strategy you have in terms of maximizing GTX 102's product differentiation as you feel about the other ASO coming through fairly quickly?

Speaker Change: Now that the Phase 3 trial design is set...

Speaker Change: Is there a certain strategy you have in terms of maximizing GTX-102's product differentiation as you feel about

Davey Du: And then, just maybe, a little bit tangential here, but I was wondering if you guys ever thought about using an Omaya Reservoir for GTX 102, just thinking about intrathecal administration and its affiliated side effects. I mean, would an Omaya Reservoir be like a lifecycle management strategy where you can get more of the drug a bit more safely, perhaps with greater potency? Thanks so much.

Speaker Change: the other ASO coming through fairly quickly. And then...

Speaker Change: Just maybe a little bit tangential here, but I was wondering if you guys ever thought about using an OMAYA reservoir for GTX-102, just thinking about intrathecal administration and its affiliated side effects,

Speaker Change: I mean, would an Omaya Reservoir be like a lifecycle management strategy where you can get more drug a bit more safely perhaps with greater potency? Thanks so much.

Emil Kakkis: Thanks, Dagon. So, on the first... I think the thing that's most important about looking at our data is that we actually are showing long-term data and showing the Bayley 4-off cognition in the double-digit range for the majority of patients. If you look long enough, so we were showing two years plus of data. I haven't seen any of that from anyone.

Speaker Change: Thanks, Dagon. So on the first.

Emil Kakkis: So for right now, we're the only program that's showing that kind of data. Our drug is more potent than the other drugs. We're operating in the 5 to 14 milligram range, far below that.

Speaker Change: Our drug is more potent than the other drugs. We're operating in the 5 to 14 milligram range, far below that. That tells you the science of what we've been talking about is right.

Emil Kakkis: That tells you the science of what we've been talking about is right. The targeted region that we have padded is more potent and more effective, so we believe we'll differentiate on superior efficacy, and I'm waiting to see other data from people that will actually match what we have. (Inaudible) An OMY is one thing. It is certainly an invasive approach. It has its upsides and downsides. There are also companies that make lumbar catheter-type devices, which would have catheters inside, Access, which is a much simpler procedure than a lumbar puncture through a port.

Speaker Change: The targeted region that we have padded is more potent and more effective. So we believe we'll differentiate on superior efficacy. And I'm waiting to see other data from people that will actually match what we have.

Speaker Change: With regard to your point, I think it's a good point. I think...

Speaker Change: One of our philosophies in Rare Pearls is that we first make things work and then we make them easy. Our goal is to get a drug, approved drug.

Speaker Change: for this Angelman syndrome as soon as possible. But then we'll look at how do you make this easier for patients or more potent.

Speaker Change: And Omiya is one thing. It is certainly an invasive approach. It has its upsides and downsides. There are also some things that make lumbar catheter type devices, which would have catheters inside which you can

Speaker Change: [inaudible]

Emil Kakkis: So certainly those are things we can do as lifecycle management. Those are things we will consider. And we as a company never sit still. If we get approved, we're still going to be constantly looking for ways to improve the patient experience, improve the efficacy, and continue to drive forward with the best possible outcome. So we feel like we're in a great position, and after ASF, I haven't seen anything that tells me otherwise.

Speaker Change: We feel like we're in a great position and after ASF I haven't seen anything that tells me any differently.

Emil Kakkis: Fair enough. Thank you very much and congratulations on the progress. The next question we have comes from Tazeen Ahmad of Bank of America. Please go ahead.

Speaker Change: Fair enough. Thank you very much and congrats on the progress.

Speaker Change: Thanks.

Speaker Change: Thank you. The next question we have comes from Tazeen Ahmad of Bank of America. Please go ahead.

Tazeen Ahmad: Hi, good afternoon, thanks for taking my question. On Wilson, you're talking about doing that interim stage one readout. And maybe Emil, I wanted to get a sense of, initially, your thought was that you would have a readout on the first half and then move, a couple of times, to the second half of the year. Just curious about the reason for the delay and then once we do see that data, what should we expect as the next steps in the development of that program?

Tazeen Ahmad: Hi, good afternoon. Thanks for taking my question.

Tazeen Ahmad: On Wilson, you're talking about doing that interim stage 1 readout, and maybe Emil, I wanted to get a sense on, initially your thought was that you would have a readout on the first half and then it moved.

Speaker Change: I'm curious about the reason for the delay, and once we do see that data, what should we expect as next steps in the development of that program?

Tazeen Ahmad: Yes, so Tazeen, thank you for the question. I think one of the first things is that finishing out cohort three took longer, and we ended up having a patient that qualified, and something happened, and we had to end up dragging out the last patient, and so that was part of one of the problems. One thing we saw in cohort one day that we did put out, is that it actually took more time. It wasn't; it took more than six months to see the effects of the drug. It's a transporter for copper.

Emil Kakkis: Yes, so Tazeen, thank you for the question. I think one of the first things is that to finish out the cohort three took longer and we ended up having a patient that qualified and something happened and we had to end up dragging out the last patient and so that was part of one of the problems.

Speaker Change: One thing we saw in the cohort one day that we did put out is that it actually took...

Emil Kakkis: It's not gonna behave like some of our enzymes, so we're learning a little about it. So our take was we need at least six months of data from the last patient in. And that's what the timing is. And you have to add on to that time to clean the data.

Speaker Change: It's a transporter for copper. It's not going to behave like some of our enzymes, so we're learning a little about it. So our take was we need to go at least six months of data from the last patient in, and that's what the timing is. And you have to add on to that time to clean the data. It is an international-based 2-3 study.

Emil Kakkis: It is an international phase two, three study. Fix the analyses and put it out. So we felt it's important to get this right and make good decisions, and so that's where it is. But we're encouraged by the early data we saw, and I think there is a gene therapy treatment for Wilson on the horizon, and we'll continue to put that data forth and come up with our plan for heading into phase three. Thanks, Operator.

Speaker Change: Repair the analyses and put it out. So we felt it's important to get this right and make good decisions. And so that's where it is, but

Speaker Change: We're encouraged by the early data we saw and I think there is a gene therapy treatment for Wilson on the horizon and we'll continue to put that data forth and come up with our plan for heading into phase three.

Kristen Kluska: Next question, please. The next question we have comes from Kristen Kluska of the Council of Fitzgerald. Please go ahead. Hi, congrats on a great quarter. On Citrusumab, I wanted to ask you if there are any benefits this drug could potentially show as it relates to the pain these patients experience. Is there a reason to think that both reducing the fractures and putting down better bones has the potential to have an impact on pain?

Speaker Change: Operator, next question please. Thank you Salve. The next question we have comes from Kristen Kluska of Council of Fitzgerald. Please go ahead.

Kristen Kluska: On Citrusumab, I wanted to ask if you think that there are any benefits this drug could potentially show as it relates to the pain these patients experience. Is there reason to think that both reducing the fractures and putting down better bones has the potential to have an impact on pain?

Emil Kakkis: Yes, our impression from the phase two patients... Tazeen Ahmad, Yigal Nochomovitz, Christopher Raymond, Gena Wang, Anupam Rama, Christopher, Transcripts provided by Transcription Outsourcing, LLC. Patients having much more activity, not needing wheelchairs, not being as afraid of physical activity. So we have confidence that stronger bones will reduce micro-fractures and will improve pain.

Speaker Change: Yes, our impression from the phase two patients...

Speaker Change: Particularly, with their increased activity, they're feeling better. They're having less pain. And while we look talk about fractures all the time, OI patients have weak bones. And what that means is lots of micro fractures. So, if they do some heavily strong activity, they'll feel terrible the next day because they probably induced a bunch of micro fractures.

Speaker Change: So, it's not a single point fracture. What we can see from the patients treated at the one-year point or beyond...

Speaker Change: Patients having much more activity, not needing wheelchairs, not being as afraid of physical activity. So we have confidence that stronger bones will reduce micro fractures and will improve pain.

Emil Kakkis: And so we are evaluating both pain, quality of life, and other measures in the study. And it's a large enough study that should help us power those endpoints. So we think it's one of the ways that we'll make Shuzumab, a really important therapy for OI. And then just on that point, I know people sometimes ask if you're feeling better and you're doing more activities, does that open the door to any potential fracture risks?

Speaker Change: And so we are evaluating both pain, quality of life, and other measures in the study. And it's a large enough study that should help us power those endpoints. So we think it's one of the ways that will make, I think, Sertuzumab a really important therapeutic pro-line.

Emil Kakkis: But maybe on the other end of that spectrum, if people are exercising and doing more activity, could that help even further slow down any type of bone loss or density loss? Thank you again.

Speaker Change: If people are exercising and doing more activity, could that help even further slow down any type of bone loss or density loss? Thank you again.

Emil Kakkis: I think you certainly could increase fracture risk. We did have a patient who started doing sports again and did have a fracture. But I'm not the one to tell a patient, "You feel great now, so don't do anything with that, right?" It's just not rational to think that.

Speaker Change: Yeah, it's a very good point. I think we certainly could increase fracture risk. We did have a patient who started doing sports again and did have a fracture, but I'm not the one to tell a patient, you feel great now, now don't do anything with that, right? It's just not rational to think that. What I will say,

Emil Kakkis: What I will say is, Thanks, Emil. The next question we have comes from Anupam Rama of J.P. Morgan. Please go ahead. Hi everyone, this is Priyanka on behalf of Anupam.

Speaker Change: It's these patients, if you're sedentary, you or I sit in our bed and we don't do enough.

Speaker Change: So the exercise they do will actually stimulate their bones to lay down the bone where their bone is weakest. It will actually enhance their bone strength further. So I think it will have a beneficial effect for them to be more active.

Anupam Rama: Just a quick question from us. For UX111, even though the BLA filing will be based on available data, are there any gating factors for the BLA filing later this year or early next year? Well, the one thing we need to make sure is that the CNC put together with our contract manufacturer, they're doing an excellent job. This is Andelin, they're derived from the Nationalwide Children's People. They know their stuff, they do good work.

Speaker Change: Well, the one thing we need to make sure is that the CMC put together with our contract manufacturer.

Speaker Change: They're doing an excellent job. This is Andelin. They're derived from the Nationwide Children's People. They know their stuff. They do good work.

Anupam Rama: And so we feel we're pretty much on track to get where we need to go. But that would be one thing that has to be in line. We had a discussion with the agency about exactly what needs to be in a BLA, and the agency has shown the proper flexibility on what needs to be now and what can be added later. I think right now I don't see any gating factors. It is a lot of work putting a BLA together.

Emil Kakkis: And, but we're, we're expected to get there this year. Thanks so much for taking our question. Operator, next question please. Thank you. The next question we have comes from Joon Lee of Trace Securities. Please go ahead.

Speaker Change: Thanks so much for taking our question.

Speaker Change: Operator, next question please.

Joon Lee: Hey, congrats on the strong quarter, and thanks for taking our questions. During Biogen's conference call this morning, when asked why they did not opt into Ionis' Angelman program, Biogen implied that the data may not have crossed the preset go-no-go threshold. Knowing what you know about the competing ASO from what's been publicly disclosed, in what ways do you think GTX 102 may be a better option for patients than Ionis 582?

Speaker Change: Knowing what you know about the competing ASO from what's been publicly disclosed, in what ways do you think GTX102 may be a better option for patients than Ionis 582? In other words, as patients consider enrolling for EIDA-GTX,

Emil Kakkis: In other words, as patients consider enrolling in either GTX 102 or Ionis' study, what would be the selling point for your program? Thank you. Well, I think I am sure Biogen is considering looking at all the data that are publicly available since we show substantially higher levels of Bayley-Fork condition achievement. Over longer periods of time, steady growth, and in multiple domains, in fact. I think that's a strong data set compared to what we've seen from our Ionis. The competitor is a limited amount of data.

Speaker Change: Over longer periods of time, steady growth and in multiple domains, in fact, I think that's a strong data set. What we've seen from our Ionis competitor is a limited amount of data.

Emil Kakkis: Transcribed by https://otter.ai, I'm sure that Biogen has the capability to understand what the data look like and how to compare them, and they made their choice. It seems unlikely to me that they wouldn't have opted in if they had a product that was equal to ours. Thank you. Thank you. The next question we have comes from Maury Raycroft of Jeffreys. Please go ahead.

Speaker Change: through six months, so

Speaker Change: Thank you.

Speaker Change: Thank you. The next question we have comes from Maury Raycroft of Jefferies. Please go ahead.

Maury Raycroft: Hi, thanks for taking my question. And I'll ask one about Wilson's disease. For your upcoming update, you're assessing global copper metabolism by biomarkers. What would be considered a win, or what magnitude of change do you need to see to advance to phase three? Or what scenarios could require further optimization?

Maureen Raycroft: Hi, thanks for taking my question.

Emil Kakkis: Thanks, Maury. I think... With Wilson, to have an effective gene therapy, I think it's necessary to see patients be able to get off standard of care, right? And maintain free copper levels and urinary copper excretion that indicates that they are now detoxifying copper through the proper pathway, right?

Speaker Change: Thanks Maury, I think.

Emil Kakkis: So first off, we have to be able to replace chelators as a way to detoxify copper. Secondly, we'd like to see some significant improvement in the majority of patients in copper distribution, that is, ceruloplasmic copper levels, which are generally very low in these patients and are the source of copper. I think that copper deficiency is...

Speaker Change: that indicates that they are now detoxified copper through the proper pathway, right? So, first off, we have to be able to replace chelators as a way to detox.

Speaker Change: Copper. Secondly, we'd like to see some significant improvement in the majority of patients in copper distribution, that is the ceruloplasm copper levels, which are generally very low in these patients and are the source of copper

Speaker Change: to the brain and other places, and in many patients we think that copper deficiency is

Speaker Change: Contributor to the Wilson Phenotype. So those are the two things we're looking for, a substantial improvement in copper distribution over their background baseline, particularly in those patients where it's low, and the ability to remove standard of care and maintain toxicity control.

Emil Kakkis: Toxicity Control. Got it. That's helpful. Thanks for taking my question. Thank you. The next question we have comes from Joseph Schwartz of Leering Partners. Please go ahead. Hi all, this is Will on behalf of Joe.

Speaker Change: Got it. That's helpful. Thanks for taking my question.

Speaker Change: Thank you. The next question we have comes from Joseph Schwartz of Leering Partners. Please go ahead.

Joseph Schwartz: Thanks for taking our question. Congratulations on the progress this quarter. One for us on GTX 102.

Speaker Change: Hi all, this is Will on for Joe. Thanks for taking our questions and congrats on the progress this quarter.

Will: One for us on GTX-102, outside of the study design and endpoints, just wondering if the FDA has provided any color on the bar of success for approval, and along the same lines, can you remind us of our understanding of what a clinically meaningful benefit would be on the Bayley-4 endpoint? Thank you.

Emil Kakkis: Outside of the study design and endpoints, just wondering if the FDA has provided any color on the bar of success for approval. And along the same lines, can you remind us of our understanding of what a clinically meaningful benefit would be on the Bayley-4 endpoint? Thank you. Well, first off, they agreed to a continuous variable analysis for the BLE-4, right? So there was no set threshold established or required.

Speaker Change: Well, first off, thank you.

Speaker Change: They agreed to a continuous variable analysis for the Bay Leap War, right? So there was no set threshold.

Emil Kakkis: They felt that a continuous variable approach was the right way, so they didn't require responder analysis. We do have a responder as part of the MDRI. I want to be clear about that. While we picked Bayley 4 as the primary endpoint, the other endpoints are part of the story and the value of it as we see it through the eyes of the MDRI. So there's a combination of factors that is a change in life for patients. So I'd look at the bigger picture. The Bayley-Forskor score itself doesn't tell the whole story.

Speaker Change: Established or acquired, they felt that a continuous variable approach was the right way, so they didn't require responder analysis. We do a responder as part of the MDRI.

Speaker Change: which will support the clinical need for this. So that's what they've required of us. They haven't set any numbers. In our mind, if we can show what we've already seen in phase two, which is...

Speaker Change: Achieving a majority of patients into the double-digit range of Bayley-4, that's...

Speaker Change: Essentially twice.

Speaker Change: What is considered a statistically significant improvement in the Bayley score, I think that's quite important, but I want to be clear about it, while we picked Bayley 4 as the primary, the other endpoints are part of the story, and the value of it, as we see it through the eyes of the MDRI, is this combination of factors that is a change of life for patients,

Emil Kakkis: Knowing a patient sleeps well, is not falling down as much, the behavior is calmer, is understanding language, and spoken language instructions better are all things that are changes of life for patients at home, and we think some of these things have multiple domains of improvement that are going to tell you why this drug would be important for patients. So we can replicate that in phase three. And based on what we've already shown you in phase two, I think we're in good shape. Thank you, Salve.

Speaker Change: So I'd look at the big picture. The Bayley-Forst score itself doesn't tell the whole story. Knowing a patient sleeps well, is not falling down as much, the behavior is calmer, is understanding spoken language instructions better. These are all things that are a change of life for patients at home.

Speaker Change: and we think some of these data have multiple domains of improvement are going to tell you why this drug would be important for patients. If we can replicate that in phase 3, what we've already shown you in phase 2, I think we're in good shape.

Yaron Werber: The next question we have comes from Yaron Werber of TD Cohen. Please go ahead. All right, thanks for including us as well. Maybe I just have a one-on-one follow-up.

Salve: Thank you, Salve.

Speaker Change: The next question we have comes from Yaron Werber of TD Cohen. Please go ahead.

Yaron Werber: All right, thanks for including us as well. Maybe I just have a one-on-one follow-up. Emil, maybe just an angel in the 48-week end point.

Emil Kakkis: Emil, maybe just on Angelman, the 48-week endpoint, can you give us a little bit of a sense of what kind of a delta in terms of powering are you kind of hoping to see and planning to see in Phase 3? And is there going to be a longer look as a secondary endpoint? And then just on GSD-1A, you know, we're beginning to get questions kind of about what's feasible in terms of the commercial opportunity here. I think you've kind of talked about the price being, let's say, just, you know, in the mid sort of $1 million or so.

Yaron Werber: Can you give us a little bit of a sense, what kind of a delta in terms of powering are you kind of hoping to see and planning to see in the Phase 3?

Speaker Change: and is there going to be a longer look as a secondary endpoint?

Speaker Change: And then just on GSD-1A, you know, we're beginning to get questions kind of how to think about what's feasible in terms of the commercial opportunity here. I think you've kind of talked about price being, let's say, just, you know, in the mid sort of $1 million or so. I don't want to speak for you, but how big of a market can we think here? Thank you.

Emil Kakkis: I don't want to speak for you, but how big of a market can we think of here? Thank you. Great.

Emil Kakkis: So, 48-week data, we actually, if you look at our April AAN, Academy of Neurology, Jack? We actually put a slide on powering in there showing we're well above the 90 percentile, even if you assume the placebo group had three times the, Natural History Control Group GFD-1A Commercial Opportunity For the patients, the exact amount of cornstarch is less the issue, then the fear of dying if they miss their doses, the brittle nature of their disease, and what we're seeing with these patients is a change in their outlook on They are no longer highly dependent on cornstarch to survive.

Speaker Change: Great. So...

Speaker Change: The 48-week data, if you look at our April AAN, the Academy of Neurology deck, we actually put a slide on powering in there, showing we're well above 90 percentile, even if you assume the placebo group had three times

Speaker Change: So, three times the natural history or three or four times the natural history, we still had well more than 90% power. In fact, with the typical...

Speaker Change: Natural History Control Group, in fact we would be well above 95% power, so it is very well powered to see the effect sizes we're seeing right now, which we're into the double-digit range

Speaker Change: And when you talk about 48 weeks, one of the reasons we went longer is we felt you accumulate more improvements and that made it a better story overall.

Speaker Change: So that's the powering on Angeman.

Speaker Change: With regard to GSE-1A Commercial Opportunity, I think the thing to recognize is...

Speaker Change: For the patients, the exact amount of cornstarch is less the issue than the fear of dying if they miss their doses, the brittle nature of their disease.

Speaker Change: and what we're seeing with these patients.

Speaker Change: is a change in their outlook on what's happening to them because

Emil Kakkis: We think our data in phase three, because of the blinding and the inability to tell patients and doctors what their sugars were, didn't get us as strong a reduction as we've seen, and we are seeing an extension, but we know that number will get better and better as their physiology changes. But the effect of feeling better and having a change of life is very much there. We think there's a high urgency about this disease. I think people hate living with a gun to their head, waiting to die.

Speaker Change: They are no longer highly dependent on cornstarch to survive. We think our data in the Phase 3, because of the blinding and the inability to tell patients and doctors what their sugars were.

Speaker Change: didn't get us as strong a reduction as we've seen and we are seeing an extension, but

Speaker Change: We know that number will get better and better as their physiology changes, but...

Speaker Change: The effect of feeling better and having a change of life is very much there. We think there's a high urgency in this disease.

Emil Kakkis: And the cornstarch is just a representation of that risk that occurs to them every day, with regard to the urgency that exists. So we think it will be highly desired in the patient population, and we expect patients to want to get dosed. And we think that's the key to gene therapy success commercially has been, what's the level of patient urgency? That's defining what's been happening. With regard to pricing, we certainly have not put out pricing at this point. It's a bit too early.

Speaker Change: I think people hate living with a gun to the head, waiting to die, and the corn starch is just a representation of that risk that occurs to them every day, and it's nothing like some of the other diseases.

Speaker Change: with regard to the urgency that exists. So we think it will be highly desired in the patient population and we expect patients to want to get your dose and we think that's a key to gene therapy success commercially has been what's the level of patient urgency that's been defining what's been happening.

Emil Kakkis: We have said in the past that pricing in the $1 million to $2 million range is possible. I think price points have gotten even higher for some programs, but we haven't set down what our plan is, and we're going to look carefully at this and come at it, but I think GST-1A is a very reasonable and important opportunity. I think it will do well, and I think it will be an important new therapy.

Speaker Change: With regard to pricing, we certainly have not put out pricing at this point. It's a bit too early. We have said in the past that pricing in the $1 to $2 million range is possible.

Speaker Change: I think price points have gotten even higher for some programs.

Speaker Change: We haven't set down what our plan is. We're going to look carefully at this and come at it, but I think GST-1A is a very

Speaker Change: Reasonable and important opportunity. I think it will do well.

Speaker Change: Perform more like some of the other programs where there's high levels of urgency.

Emil Kakkis: I expect it to, Transcript by Rev.com Page of Thank you so much. The next question we have comes from Jeffrey Hung of Morgan Stanley. Please go ahead. Hi, this is Michael Riad. I'm here with Jeff Hung.

Salve: Thank you, Salve.

Speaker Change: The next question we have comes from Jeffrey Hung of Morgan Stanley . Please go ahead.

Michael Riad: Thank you for taking our question. Going back to cetrusmeb and thinking about that cycle of fractures leading to bone deformation and then loss of activity, what factors do you think play a role, a bigger role in the treatment course? Is it age or OI type?

Michael Riad: Hi, this is Michael Riad. I'm here with Jeff Hung. Thank you for taking our question. Going back to cetrusumab and thinking about that cycle of fractures leading to bone deformation and then loss of activity, what factors do you think play a bigger role in the treatment course? Is it age or OI type?

Speaker Change: I mean if you think about like the profiles such as MAB, do you view it as like a broadly better option for most pediatric patients regardless of type, whereas for adults you'd expect more OI type dependent penetration? Thank you.

Emil Kakkis: I mean, if you think about the profile of cetrusmeb, do you view it as a broadly better option for most pediatric patients regardless of type, whereas for adults, you'd expect more OI, type-dependent penetration? Thank you. Well, you know, I think each patient can have a reason to be treated. It may be different. If you're a type three patient. Tazeen Ahmad, Yigal Nochomovitz, Christopher Raymond, Gena Wang, Emil Kakkis, Yaron Werber, [inaudible] Probably the sphere half that population.

Speaker Change: Thank you. Bye.

Emil Kakkis: You know, I think each patient is going to have a reason to be treated. It may be different. If you're a type 3 patient or type 4 with a really severe bone disease,

Speaker Change: and you're treated when you're one or two years old.

Speaker Change: Our hope, and we will see what the phase 3 data show, is that we could be transformed in terms of stopping fractures, stopping vertebral compression.

Speaker Change: and not basically destroying your skeleton before you're three or four years of age and ending up in a wheelchair. So that would be what you could do when you're treating kids who are young. However, when they're old, even if you're in a wheelchair because you have deformed bones, you're still fracturing, you're still in pain all the time.

Speaker Change: Being able to stop being in pain by stopping fracturing, even if you can't change deformation, is still highly valuable in an adult with type 3 or 4.

Speaker Change: for Type 1.

Emil Kakkis: And so, all of these people will have enough fractures where, at any age, young or old, it's going to be beneficial. They don't have as much deformation, but being able to be comfortable participating in sports or activities you might not have been doing before, I think will get Type 1 treated. There may be some Type 1 who are milder, don't have as many fractures, and there might not be as much addressable need in those patients.

Speaker Change: Probably the sphere half of that population.

Emil Kakkis: We'll have enough fractures where at any age, young or old, it's going to be beneficial. They don't have as much deformation.

Speaker Change: But being able to be comfortable.

Speaker Change: Participating in sports or activities you might not have been doing before, I think will

Speaker Change: will get type 1's treated. There may be some type 1's who are milder, don't have as many fractures and there might not be as much addressable need in those patients. So we would expect all type 1's. What I can say from the data we've shown you though, the type 1's do really well on the treatment as do the type 3's and 4's. So we expect that we'd have a

Emil Kakkis: So, we would expect all Type 1s. But from the data we've shown you, though, the Type 1s do really well with treatment, as do the Type 3s and 4s. So, we expect that we'd have a good penetration of all three types, as well as at all ages, because we think there's a reason to treat at any point in life and with any of these.

Emil Kakkis: Good penetration of all three types, as well as in all ages, because we think there's a reason to treat at any point in life and with any of these diseases.

Emil Kakkis: Thank you. I appreciate that. I'm out of color.

Speaker Change: Thank you. I appreciate that. I'm out of color. And then for Angelman, I just want to circle back to something. So obviously, we saw like competitor data that showed good responses up to six months, and the phase three is out to 48 weeks. But that makes the phase one to giving a bit of a more unique insight into those longer term benefits.

Speaker Change: So I was just wondering how that data, like, do you think it can be used for evaluating that more like durable clinical aspect and like the developmental gains that have been achieved?

Emil Kakkis: And then for Angelman, I just want to circle back to something. So obviously, we saw competitor data that showed good responses up to six months, and phase three is up to 48 weeks. But that makes phase one to give a bit of a more unique insight into the longer-term benefits. So I was just wondering how that data, like you think it can be used for evaluating that more like durable clinical aspect and like the developmental gains that have been achieved? Are you asking about our data or someone else's data? I didn't quite understand.

Speaker Change: Are you asking about our data or someone else's data? I didn't quite understand. I'm asking about like the phase 1-2, like how that phase 1-2 data, especially like the longer term data can... Your data? Yes.

Emil Kakkis: I'm asking about phase 1-2, like how that phase 1-2 data, especially the longer-term data, can help... Yes. Well, I think what's important about the long-term data is to see patients continue to gain ground. They don't plateau; they continue to gain ground.

Emil Kakkis: Yeah. Well, I think what's important about the long-term data is to see patients continue to gain ground. They don't plateau. They continue to gain ground.

Emil Kakkis: Tazeen Ahmad, Yigal Nochomovitz, Christopher Raymond, Gena Wang, Anupam Rama, Kristen Kluska, Maury Raycroft, Joseph Schwartz, Emil Kakkis, Yaron Werber, Jeff Hung, Camille Bedrosian, Laura Chico, Aaron Olsen, Joori Park, Howard Horn, Dagon Ha, Howard Horns, Ultragenyx Pharmaceutical Inc. The other point I would make is that Functioning better It does take time for kids to learn things right, just like growing up, you had took time to learn them right, so there's a developmental component, particularly in receptive communication, [inaudible] from the control group, get the drug approved, but the long-term...

Emil Kakkis: which tells you that 48 weeks is only one point on a longer journey where these kids are going. Where they can go is still unclear. How much better could they get?

Emil Kakkis: The other point I would make is that while you get a brain to start

Emil Kakkis: Functioning better. It does take time for kids to learn things, right? Just like growing up, you had to take time to learn them, right? So there's a developmental component, particularly in receptive communication,

Speaker Change: [inaudible]

Speaker Change: We feel that 48 weeks is a good time point to capture enough improvement to demonstrate the shift.

Emil Kakkis: Continued improvement will be why patients stay on drugs and why the product will penetrate the population if it's successful and feasible. Thank you so much for answering our questions. Thank you. The next question we have comes from Jack Allen of Baird. Please go ahead.

Emil Kakkis: from the control group gets drug approved, but the long-term and continued improvement will be why patients stay on drug.

Emil Kakkis: and why the product will penetrate the population if successful in phase 3.

Speaker Change: Thanks so much for answering our questions.

Speaker Change: Thank you. The next question we have comes from Jack Allen of Baird. Please go ahead.

Jack Allen: Great, thanks so much for doing the questioning. Congratulations on all the progress over the quarter. I wanted to ask about citruzumab, I guess there are a few little parts to this question.

Jack Allen: Alright, thanks so much for doing the questioning. Congratulations on all the progress over the quarter.

Emil Kakkis: The first of which, I was wondering what we should expect as we look towards the second half of the year and the presentation of additional data for citruzumab. It looks like the BMD and Z-scores are continuing to improve over time. Do you expect to provide additional color as it relates to differences in fracture rates over time with citruzumab and how that correlates with the biomarkers we're looking at there? And then I also just wanted to follow up and ask about any comments as it relates to enrollment in the ORBIT study and the types of patients you're seeing in that trial versus the Phase II portion of that study. Sure.

Speaker Change: I wanted to ask on citrusmab

Emil Kakkis: I guess a few little parts of this question. The first of which, I was wondering what we should expect as we look towards the second half of the year and the presentation of additional data for CitrusMab

Speaker Change: It looks like the BMD and Z-scores are continuing to improve over time.

Emil Kakkis: Do you expect to provide additional color as it relates to differences in fracture rates over time with cetrusimab and how that correlates with the biomarkers we're looking at there? And then I also just wanted to follow up and ask about any comments as it relates to that enrollment in the ORBIT study and the types of patients you're seeing in that trial versus both phase two.

Emil Kakkis: So with regard to the second half, we haven't set a plan now, a particular set of data that we might present or not. I mean, honestly, right now, our goal is to crank up phase three and to be prepared as necessary to file a BLA if [inaudible] has continued to do extremely well, and it's very encouraging, and it's been transformative. So we definitely think that's true.

Emil Kakkis: portion of that study.

Emil Kakkis: Sure, so with regard to the second half, we haven't set a plan now.

Emil Kakkis: A particular set of data that we might present or not. I mean, honestly, right now our goal is to crank phase three and to be prepared as necessary to file a BLA if

Emil Kakkis: We're able to hit an interim but I would right now I'm not sure if we will put out more data but the patients clearly have continued improvement over time and 14 months is certainly not the end of the story they continue with the patient have been on the 17 to 24 months

Emil Kakkis: have continued to do extremely well and it's very encouraging and it's been transformative. So, we definitely think that's true. We may put it out at some point in time, but I think most people are eyes already turned toward interim analyses in 2025. So, we haven't committed to more data yet.

Emil Kakkis: We may put it out at some point in time, but I think most people's eyes are already turned toward interim analyses in 2025, so we haven't committed to more data yet. In regard to the ORPIT type of patient... We did enroll more Type 3s and 4s, but we didn't output up the ratio, but in the first... In the phase 2 study, we had 17 type 1's and 7 type 3's and 4's, and it's, [inaudible] Patients in Most Need.

Emil Kakkis: With regard to the ORPIT type of patients...

Emil Kakkis: We did enroll more Type 3s and 4s. We now put up the ratio, but in the first...

Speaker Change: Phase 2 study we had 17 type 1's and 7 type 3's and 4's and it's...

Emil Kakkis: A significantly larger type 3s and 4s in the ORBIT study, which is what we wanted. We wanted to get more severe patients that had more fractures, that had more medical need.

Emil Kakkis: and we were able to enroll a number of those. I think actually the phase 2 data stimulated them to get involved because before they were apprehensive when they saw data then the doctors started putting in their most

Emil Kakkis: So there is a little bit of shift there, but I don't think it'll be substantially different in what we see compared to our Phase II data. Got it. Thanks so much for that context. Maybe just one brief follow-up. I know you get a lot of questions on how to think about the powering of the ORBIT study.

Emil Kakkis: There is a little bit of a shift there, but I don't think it will be substantially different in what we see compared to our Phase II data.

Emil Kakkis: But in that context, what were your expectations for enrollment when you set out to enroll the phase three portion of ORBIT? And, I guess, did you enroll potentially more severe patients than expected? Any thoughts on how that may impact power?

Emil Kakkis: Well, we originally started with the 195 patient study, and then when we saw our first look of data at six months, it was pretty clear that Fracture reduction of 67% is way past what's needed. We brought that down to 150. Which is not a huge difference in power, frankly, but we wanted to keep it at that large because you want to get enough type 1s, type 3s, and 4s to look at the subsets, right?

Emil Kakkis: And you also have P's and adults, right? So you have to look at the age subsets, right? So the number 150 you can look at as the overall power, but I also look at it as having enough of each group to be able to look at their data and understand the benefit of young or old or type 3s, 4s, or 1s. So that was one of the drivers in maintaining the number 150.

Emil Kakkis: And you also had peds and adults, right? So you have to look at the age subsets, right? So the number 150 you could look at as the overall powering, but I'd also look at it as having enough of each group.

Emil Kakkis: I think with the fracture reduction rate and assuming a higher fraction rate in the study, there was plenty of power. We could have made the study smaller. But I think when you try to cover the types and the severities in the age groups... What we did, I think, was a good design that captured the amount of data across all types of the line.

Emil Kakkis: Thanks so much for the call out, and congratulations on all the progress. Thank you. Thank you. The next question we have comes from Liisa Walter of RBC. Please go ahead.

Liisa Walter: Thank you.

Speaker Change: Thank you. The next question we have comes from Liisa Walter of RBC. Please go ahead.

Liisa Walter: Oh, great. Thanks for taking our question. This is Liisa on behalf of Luca.

Liisa Walter: Oh, great. Thanks for taking our question. This is Liisa on for Luca. This question is for Emil. More of a big picture question. Wondering if we can get your thoughts on the future of the Rare Pediatric Disease Voucher Program.

Liisa Walter: It sounds like this is set to expire on September 30th unless it is reauthorized by Congress. So if it's not reauthorized, how might this affect rare disease drug development going forward? Any caller there would be much appreciated. Thanks so much.

Emil Kakkis: This question is for Emil, more of a big picture question. I was wondering if we can get your thoughts on the future of the Rare Pediatric Disease Voucher Program. It sounds like this is set to expire on September 30th unless it is reauthorized by Congress. So if it's not reauthorized, how might this affect rare disease drug development going forward? Any color there would be much appreciated.

Emil Kakkis: Yes, so the sun setting of being able to get them, being able to apply for new ones.

Speaker Change: It's happening later this year and through next year. For us as a company, there should be two PRVs available to us if we file for UX111 and DTX401. We should be able to get two. So for us, it doesn't affect us in the short term in our own financial planning.

Emil Kakkis: Thanks so much. Yeah, so the downside of being able to get them to be able to apply for new ones in the long run. PRV vouchers really change the equation of what happens in some of the ultra-rare diseases. And for us, we've sold two vouchers, something like $170-$180 million of additional cash for Ultragenyx that's had a major impact on our ability to develop other rare disease drugs. We've submitted that information. We're highly supportive of the PRV. We think there's bipartisan support on the Hill, and there's rarely that for almost anything.

Emil Kakkis: In the long run,

Emil Kakkis: The PRV vouchers really change the equation on what happens in some of the ultra rare diseases and for us we've sold

Emil Kakkis: We've sold two vouchers.

Emil Kakkis: Something like $170-$180 million.

Emil Kakkis: of additional cash for orthogenetics has had a major impact on our ability to develop other rare disease drugs. We've submitted that information. We're highly supportive of the PRV. We think there's bipartisan support on the Hill, and there's rarely that for almost anything. So right now, I feel that it will get done, but.

Emil Kakkis: So right now, I feel that it will get done. You know, it hasn't happened yet, and election year is a crazy time to do things, but we think it's something that... You know, it doesn't matter with regard to what party you are if you have a rare disease. So we hope the PRB will get the support we're certainly providing. Thanks, Operator. Can we go to the next question? The next question we have comes from Liisa Bayko of Evercore ISI. Please go ahead. Hi, this is streaming for Liisa.

Emil Kakkis: It hasn't happened yet and election year is a crazy time to do things but we think it's something that Rare doesn't...

Emil Kakkis: It doesn't matter with regard to what party you are if you have a rare disease. So we hope the PRB will get some support. We're certainly providing it.

Emil Kakkis: Thanks, operator. Can we go to the next question?

Speaker Change: The next question we have comes from Liisa Bayko of Evercore ISI. Please go ahead.

Liisa Bayko: Thanks so much for taking our questions. We noticed that MGEN is running an open-label phase three study for rhomosalzumab and OI, and they have indicated that if the phase three study is positive, they may have an opportunity to pursue approval and launch an OI. So we're just wondering what implications it would have for cetrusumab if MGEN decides to pursue approval in OI? Thank you. Hi. Well, that's news to us. They've already given us intellectual property access, so I don't think they've had that much interest in it.

Liisa Bayko: Hi, this is streaming for Liisa. Thanks so much for taking our questions.

Liisa Bayko: So, we noticed that MGEN is running an open-label phase 3 study for Romosazuma and OI, and they have indicated that if the phase 3 study is positive, they may have an opportunity to pursue approval and launch an OI.

Speaker Change: So we're just wondering what implications do you think it would have for the Truth-O-Map if Amgen decides to pursue approval in OI? Thank you.

Emil Kakkis: As a biologic for them, osteoporosis is a huge indication. It's growing. There's a big shift toward anabolic agents for osteoporosis. I really think that's their focus.

Emil Kakkis: Hi, well that's news to us. They've already given us the intellectual property access, so...

Emil Kakkis: With regard to OI, we've seen their Phase II data, and we understand their dosing from published comments in clintrials.gov or the European version of it. Right now, they're getting substantially less bone marrow density at the dose levels they're using. So we're a superior treatment in terms of our bone marrow density improvement, and we will then be superior in... (inaudible) An unclear story. What they've done in phase three is not optimized.

Emil Kakkis: Published comments in the ClinTrials.gov or the European version of it.

Emil Kakkis: Right now, they're getting substantially less bone marrow density at the dose levels they're using, so we're a superior treatment in terms of our bone marrow density improvement, and we will then be superior in

Emil Kakkis: or fracture reduction. So I think you should look at this as.

Emil Kakkis: Please draw and ignore the presentation for OI. And so I really don't have any concerns right now because we know our data is far superior. For them to get to our data, they would have to change their dosing dramatically from phase three, which is not likely to happen at this point. So at this point, I think they will be inferior to us, and I think that will be a factor. Now, could they use a higher dose of Romo?

Emil Kakkis: An unclear story. What they've done in their Phase 3 is not optimize the drug nor the presentation for OI.

Speaker Change: and Coke.

Emil Kakkis: I really don't have concerns right now because we know our data is far superior. For them to get to our data, they would have to change their dosing dramatically from phase 3.

Emil Kakkis: which is not likely to happen at this point, so.

Emil Kakkis: At this point, I think they will be inferior to us, and I think that will be a factor. Now, could they use a higher dose of Romo? Potentially, but then the differentiation in regard to pricing goes away if you have to give five times.

Emil Kakkis: Potentially, but then the differentiation in regard to pricing goes away if you have to give five times or eight times more drug to match our dosing level. So we feel like we're in a good position, and I haven't heard anything from Anjan about this before. I believe that osteoporosis is in their main space. Transcript by Rev.com Page of, That's helpful. Thank you. Thank you. Ladies and gentlemen, we have reached the end of our question and answer session, and I would like to turn the call back to Joshua Higa for closing remarks. Please go ahead, sir.

Speaker Change: We're in a good position. I haven't heard anything from Angen before. I believe that the osteoporosis has been their main space for it and hasn't been listed as part of their rare disease franchise at all.

Speaker Change: So, I'd be surprised if they're changing that.

Speaker Change: That's helpful. Thank you.

Joshua Higa: Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at irultragenyx.com. Thank you for joining us. Thank you. Ladies and gentlemen, that concludes today's conference. Thank you for joining us. You may now disconnect your lines.

Joshua Higa: Thank you. Ladies and gentlemen, we have reached the end of our question and answer session, and I would like to turn the call back to Joshua Higa for closing remarks. Please go ahead, sir.

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

Joshua Higa: Thank you. Ladies and gentlemen, that then concludes today's conference. Thank you for joining us. You may now disconnect your lines.