Good afternoon, welcome to the Ultragenyx's fourth quarter and full year 2022 financial results conference call. At this time, all participants are in listen-only mode. At the end of the prepared remarks you will have the 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, Executive Director and Head 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, Erik Harris, Chief Commercial Officer, Camille Bedrosian, Chief Medical Officer, Aaron Olsen, Senior Vice President of Corporate Strategy and Finance, and Ted Huizenga, Chief Accounting Officer. I'd like to remind everyone that during today's call we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil. Thanks, Josh. Good afternoon, everyone. Some of you may have listened in on my presentation at the recent JP Morgan Healthcare Conference, where I talked about our focus for areas for 2023. Over the last year, we completed several strategic investments, aligned our teams and resources around the highest value-generating programs for the company. This year we'll continue to focus on operational efficiency while generating data from our key clinical programs in Angelman, osteogenesis imperfecta, and our pivotal gene therapy studies. In 2022, we generated more than $350 million of global revenue in our fifth year as a commercial company. This year we expect revenue to be in the $420 million-$450 million range from our four products across five indications. We expect a steady revenue growth to continue as the existing products are still in relatively early phases of commercialization. At the same time, the investments made over the last few years have positioned us to drive meaningful value from large opportunity programs like GTX-102 for Angelman and UX143 for osteogenesis imperfecta. We have more recently bolstered our business with additional strategic steps. Specifically, we secured a license and collaboration agreement to commercialize Evkeeza for clinical homozygous familial hypercholesterolemia in countries outside of the U.S., which will leverage our global commercial infrastructure and capabilities. We acquired global rights to UX111 in AAV gene therapy for the treatment of Sanfilippo syndrome from Abeona based on the strength of the pivotal marker data and clinical data generated in the Transpher A study. We also excised our option to acquire GeneTX following interim data from the phase I/II of GTX-102 for the treatment of Angelman syndrome. The GeneTX acquisition gives us full control over that program. We completed the build-out of our gene therapy manufacturing plant in Bedford, Massachusetts, which is expected to begin production this spring. This facility and our manufacturing capabilities grant us the ability to better control the timing, cost, and scale of the production of our gene therapies, establishing us as a commercial-ready gene therapy company. Within our pipeline, we made strong progress over the past year in addition to progressing our Angelman program. We initiated a pivotal phase II/III program for UX143 in OI and have completed enrollment of the phase II portion of the study. We advanced DTX401 into pivotal Phase III study for GSDIa and have enrolled the last patient into the baseline screening period. We also initiated a Phase III study of DTX301 in OTC, where we have randomized and dosed the first patient in this study with additional patients in the baseline screening period. We initiated and dosed patients in the pivotal seamless study of UX701 for Wilson disease. As a commercial company with growing revenue in a diverse late-stage clinical pipeline, we recently evaluated ways to improve our operating efficiencies. We will focus on leveraging our established global infrastructure, actively managing expenses and headcount to drive value from the commercial launches and execute on our most important clinical programs. With that, I'll turn the call over to Erik to provide more specifics on the commercial programs and their successes last year. Thank you, Emil, and good afternoon, everyone. 2022 was an important year for the commercial and field teams. Across all the products, they delivered 35% year-over-year growth, overcoming some of the early challenges presented by the Omicron variant. Revenue from Crysvita in our territories grew 34%. Dojolvi grew 41%. Mepsevii, our ultra-rare product, grew 29%. The team's efforts are proving rare disease products can generate meaningful revenue growth 5+ years after launch. 2022 was also the first year where global sales of Crysvita exceeded $1 billion. Crossing the threshold was made possible through the Ultragenyx team's efforts that led to approximately $700 million in total product sales across North America and Latin America, also the efforts of Kyowa Kirin in Europe and Asia. Since launching Crysvita in April 2018, we have established a strong base of business that we expect will continue to grow as we transition the primary commercialization responsibilities to Kyowa Kirin in April of this year. In the U.S., we added approximately 110 start forms in the fourth quarter and approximately 90 patients on reimbursed therapy, along with 50 new unique prescribers. These metrics are nearing their pre-pandemic levels and support the 26% annual revenue growth in this region. This is particularly impressive as the team has shifted efforts to finding adults in the harder to reach community clinics where more than 50% of our start forms are generated. With combined Kyowa Kirin and Ultragenyx field teams in Q4, we have started to reach many more prescribers in the community and raising awareness of XLH, which has helped us in our patient find efforts. In Latin America, Crysvita continues to grow, supported by additional regulatory and reimbursement approvals and also from steady demand in the pediatric and adult setting. We ended 2022 with approximately 300 patients on reimbursed therapy in this region. We expect this will continue to grow as more and more prescribers see the benefits their patients experience from Crysvita. As is common in this region, ordering patterns drive some quarter-to-quarter variability in revenue, the underlying demand continues to grow at a steady pace. In 2023, we updated the regions for which we will issue Crysvita guidance. This does a better job of representing the broad reach of Crysvita and the total revenue to Ultragenyx. At the beginning of the year, reaffirmed today, we issued guidance of $325 million-$340 million for Crysvita in North America, Latin America, and Europe. This is inclusive of all types of revenue, whether profit share, royalty, cash or non-cash. Compared to 2022 for the same regions and types of revenue, this range represents between 16%-22% growth. Turning now to Dojolvi, where I'll begin with the team's work in the U.S. In 2022, we were encouraged by truly strong patient demand. We ended the year with approximately 425 completed start forms with approximately 375 patients on reimbursed therapy. The number of unique prescribers continues to grow, now with approximately 190 healthcare providers writing at least one prescription for Dojolvi. In 2023, we will be focused on continuing to educate healthcare providers on the benefits of the dose titration supported by our clinical studies to assure patients are able to achieve optimal dose titration. In Europe, demand for Dojolvi continues to be led by the named patient in early access programs, particularly in France and Italy. We have also begun to see requests come in from Germany, Austria, and certain Middle East countries. In Latin America, we are continuing to work through the process, leveraging our existing infrastructure to expand across the region. In Brazil, Dojolvi is currently approved, and we are working through the process to get full reimbursement approval from the Ministry of Finance. We also anticipate additional country regulatory filings in the region later this year. Across all regions, we expect 2023 Dojolvi revenue to be between $65 million and $75 million, reaffirming the range we announced last month. This represents between 17% and 35% growth over 2022. At the beginning of the year, we also issued guidance for total revenue, which we are reaffirming today. The range of $425 million-$450 million represents 20%+ growth versus 2022. It includes estimates for Crysvita and Dojolvi that I just mentioned and also includes Mepsevii and Evkeeza. With that, I'll turn the call to Aaron to share more details on the financial results for the quarter. Thanks, Erik. Earlier today, we issued a press release that included financial results for the quarter, which I will briefly summarize. Company revenue for the 12 months ended December 31st, 2022 totaled $363 million. Crysvita revenue in Ultragenyx territories was $258 million, including $250 million in the North America profit share territory and net product sales of $43 million in other regions. Total royalty revenue related to sales of Crysvita in the European territory was $22 million. Dojolvi revenue for 2022 was $56 million. Mepsevii revenue for the same time period was $21 million. Our total operating expenses for the year ended December 31st, 2022 were $1 billion, which included R&D expenses of $706 million, SG&A expenses of $278 million, and cost of sales of $28 million. Operating expenses for the year include non-cash stock-based compensation expense of $130 million, and a one-time R&D expense of approximately $75 million related to our acquisition of GeneTX. For the year ended December 31st, 2022, net loss was $707 million or $10.12 per share. We ended the year with approximately $900 million in cash equivalents and marketable securities. In 2023, our net uses of cash are expected to decrease significantly as we leverage our established infrastructure and continue to grow the top line. This will be enabled by financial discipline, revenue growth, and operational focus on our late-stage clinical portfolio. While these improvements in net cash use will be partially offset by the portion of our Crysvita North America royalty that will now go to our financing partner, we are confident that the continuing strength of our business fundamentals will allow us to drive towards profitability in the coming years. Now I'll turn the call back to Emil to briefly recount the 2023 clinical catalyst. Thank you, Aaron Olsen. I'll summarize the catalyst from our broad and diverse clinical portfolio before we open up for the Q&A. Starting with UX143 for osteogenesis imperfecta, setrusumab's anti-sclerostin mechanism provides a unique dual action to address the body's maladaptive response to the bad collagen. Its unique mechanism stimulates more osteoblasts to mature into bone-making cells and makes those cells increase their bone production while also limiting bone resorption. The phase II portion of the study has been fully enrolled. We expect to share these data and transition to the phase III in mid-2023. Separately, we are planning to initiate a young pediatric study that compares setrusumab to bisphosphonates to assess total fractures in a younger patient population, which have a much higher fracture frequency. Next, GTX-102 in Angelman syndrome. We are continuing to see encouraging signs of clinical activity across the patients who have been dosed under the amended and expanded access protocols. We recently began screening patients in both expansion cohorts and expect to provide the next data update based on a larger number of patients in the program later this year. Turning to the gene therapy programs. With UX111 for Sanfilippo syndrome, we're expecting to have a meeting with FDA in the first half of 2023 to discuss a plan to file for accelerated approval based on a biomarker endpoint. For DTX401 for GSDIa, we enrolled the last patient in the baseline screening period for the pivotal study earlier this year. Once this patient has been dosed, the 48-week clock will begin, and we expect to share this phase III data in the first half of 2024. DTX301 for OTC deficiency dosed the first patient in the phase III study earlier this year. We anticipate enrollment in this study will increase momentum as more patients make it through the baseline screening period. UX701 for Wilson disease, enrolling patients in the dose-finding stage. We expect this to be complete mid-2023, with the data on safety and initial signs of clinical activity expected in early 2024. Finally, UX053, our mRNA program for GSD III, has completed enrollment in the single ascending dose cohorts of the phase I/II study, and we expect to have these data in the first half of 2023. Based on these analyses and other work, we'll then review our plans for the next steps in the program. I founded Ultragenyx in 2010. 13 years later, we have four commercial products and are approaching revenue of $450 million. We also have one of the most robust late-stage clinical pipelines in rare diseases. We're now poised for the next phase of the company, with growing revenues fueling our development of new pipeline priorities. In the coming years, a growing revenue base, financial discipline, and larger indication opportunities will allow us to reach profitability while also leading the future of rare disease medicine. With that, let's move on to your questions. Operator, please provide the Q&A instructions. Certainly. Ladies and gentlemen, if you have a question at this time, please press star one one on your telephone. If your question has been answered and you'd like to remove yourself from the queue, simply press star one one again to remove yourself from the queue. We ask that you please limit yourself to one question and one follow-up. You may get back into the queue as time allows. Our first question comes from the line of Gena Wang from Barclays. Your question please. Thank you for taking my questions. I will ask one question each for Angelman program and also osteogenesis imperfecta. For Angelman program, what are the doses you selected for the expansion cohort A and B? For the osteogenesis imperfecta, in the mid-year update, first, can you remind us the two doses you used in the ORBITIA phase II portion? How would you use the bone biomarker response and the bone mineral density to establish dose algorithm for phase III portion? Great. Thank you, Gena. In Angelman, we have been, of course, evaluating higher doses and through a dose titration period. We haven't put out what doses we're using, but we've established some doses that we believe have an appropriate benefit risk that we'll be using in the expansion in both loading patients and in their maintenance levels. We've put some information out of the range of doses that we've been trying, but we'll put out more information when we have it on the exact doses we're using. With regard to osteogenesis imperfecta, we're comparing two doses in both children from ages 5 to adults at 25, and we're comparing 20 to 40. Our expectation is that the younger children may need more drug in order to get enough concentration of antibody using pharmacokinetic analysis to achieve the optimal results. We'll look at the concentrations of drug in the young and the old, we'll also look at the biomarkers for bone production, P1NP. We'll have also some bone marrow density data as well. The goal is to compare those and determine, do we need to use a higher concentration of drug in the younger patients to achieve the optimal effect or not? Look at this as dose tuning rather than dose finding. We know the dose. The question is, do we need to go a little higher in the younger patients? You'll get a little read on what this drug does in young patients at that time, which I think will be more responsive patients than the older patients that have been treated before. That's at least our expectation based on bone disease we've treated in the past. Thank you. Thanks, operator. Next question. Certainly. Once again, if you have a question at this time, please press star then one. One moment for our next question. Our next question comes from the line of Chris Raymond from Piper Sandler. Your question please. Hey, thanks. Just one question on a collaboration that I don't think I've heard you guys talk about. Inozyme today mentioned that they just started a collaboration with you guys to find misdiagnosed ENPP1 patients. It seems XLH seems to overlap, maybe phenotypically with that disease. Emil, you know, this asset would seem to be something that would, I would think fit in within your wheelhouse developmentally. Just kinda curious if you had any thoughts on this collaboration and maybe, you know, any thoughts on the drug itself, especially in light of the data that these guys had at least top line today, and how you're thinking about this relationship going forward. Yeah, well, we work with a lot of companies on the issue of diagnosis, and not just Inozyme, other companies. We're all trying to help find patients and share that information with each other. At this point, we are not planning on bringing any more products into our portfolio, and we continue to watch the field, including what Inozyme is doing and others with regard to new opportunities for rare diseases. At this point, we have on our plate all we need to manage. Finding patients and working with our partners and others in the field is something we do routinely. Great. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Joon Lee from Truist Securities. Your question please. Hi. Thanks for taking our questions. you know, as we await, the biomarker data for setrusumab, is there a level of bone formation you wouldn't want to exceed? Are there potential safety issues, particularly in young patients with growing bones, where, too much bone formation could lead to potential safety issues, maybe, hearing loss, for example? Thank you. Yeah, thank you. The question is whether you can stimulate too much bone growth and kind of impinge nerves like in hearing or otherwise. I think the truth is these patients are very deficient in their bone production, so we're starting from a place of deficiency. While if you had a genetic defect of sclerostin, you might get these problems, the ability for us to knock down the level of sclerostin to the degree required, I think is very different from a genetic deficiency state. Secondly, I would say the patient are beginning at a position of very deficient bone quantity. As we treat them and grow, we'll look at after we've improved their bone strength at a point of establishing a maintenance dosing. Based on the ASTEROID study where treatment was stopped and we looked at resorption, it looks like we can establish a less frequent maintenance dosing once we get patients fully loaded and having their bone strength improved, which I think would mitigate, for example, if there was a long-term risk of that kind. Let's face it, right now, these patients are suffering every day. Their bones are disintegrating, that's first order of business. We'll always watch out for managing the effect of our drugs going forward. At this point, we're not concerned about it in the beginning of this program. Next question. Thank you. One moment for our next question. Our next question comes from the line of Yigal Nochomovitz from Citi. Your question please. Hi, Emil, team. Thank you for taking the question. Obviously, we are getting a lot of questions lately on the OI program, and romosozumab comes up quite a lot in that conversation, which obviously, as you know, is an anti-sclerostin. If you could help us with a quick elevator pitch on why setrusumab is differentiated from romosozumab and why your antibody will be the preferred option potentially in OI. Thanks. Sure. For first of all, romosozumab was designed and developed for treatment of osteoporosis and approved and labeled in that area. What we're going to be doing is dose optimizing for the osteogenesis imperfecta indication, not the osteoporosis indication. They have a limit of 12 months of treatment. We will not have that limit. We will be able to have chronic dosing, which will be very important in this disease, which is lifelong. Secondly, by optimizing the dosing regimen, we'll be able to treat patients in an optimal way. As a rare disease company, we'll also be able to support patients specifically. The combination of the dose, the regimen, the support programs will differentiate setrusumab from what would out there at romosozumab right now. Those are some of the factors I think that will be important. Okay. Just to follow up on Gena's earlier question regarding the dose selection for the OI study that you're gonna read out in the middle of the year. Once you select that dose, will that be the same dose that is used in the younger patients in the two to five-year-olds when you're comparing head-to-head versus bisphosphonates? If that dose, for example, turns out to be higher, if 20 isn't the dose, it needs to be higher, we'll then adapt that over to the other study dose as well. We would expect to. Okay. Got it. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Tazeen Ahmad from Bank of America Securities. Your question please. Hi, good afternoon. Thanks for taking my questions. Emil, I just wanted to follow up maybe on the opportunity in Sanfilippo syndrome for UX111. Can you just remind us what the competitive landscape looks like today? How many patients do you think there are in the U.S. and abroad? Then a quick follow-up on your manufacturing facility on the new one, would that support all of your gene therapy programs going forward? Thanks. Thanks, Tazeen. With Sanfilippo 3A, one of the decisions we had to make in picking up the program was whether there was a very good option around that we could do just as well. Our view was there wasn't really. The other program with Lyfegen, they are actually, they're going out of business. This product was better than that product, I think, from a standpoint of biomarker reductions in effect. There is a lentivirus approach, which I think has its own challenges. It's fairly early on. Really there isn't another, I think, effective AAV gene therapy out there that's at the stage that says... Our feeling was that this would be the lead program and had the best efficacy that I've seen from at least the biomarker standpoint. That was our decision. With regard to the population, the world, there's probably a few thousand patients, but you have to think of this as a little bit more of an incident population, right? Because the best effect appears to be in kids that are under two years old, so it's a little bit like Zolgensma. They need to be young to get the best benefit. Would we treat older patients? Perhaps. It depends on what happens in the regulatory process. I think there may be benefit in older patients, but it's clear the optimal benefit happens when you treat young. I would look at it that way. What I would say to you about this gene therapy and unlike some of the other diseases where there are other treatments, if we add a gene therapy that's doing what we believe we see it's doing right now, we think essentially every Sanfilippo patient would wanna get treated because the other options are just none at this point in time. It has the kind of devastating impact that you have with SMA, and I think the adoption rate would be very high if we can get it approved promptly. Now, the other question was the manufacturing plant and capacity. The plant has two suites. It can run 30 runs a year. One suite is operating right now. We can operate a second suite. [30] runs a year gets a lot of what we need done. I don't know that it will handle 100% of the needs because it depends on which just programs you're talking about to achieve that. Our plan had always been to have some hybrid, some contract manufacturing and some of our own. If necessary, we do have a green space, a greenfield plant space next to our plant that we could double the plant further. Right now, I think 30 runs will take us a long way in the future. If we're at that high level success rate, treating that many gene therapies, we can then invest in expanding that capacity further. It will take us a long way with, for what we need at the moment. Thank you. One moment for our next question. Our next question comes from the line of Jeffrey Hung from Morgan Stanley. Your question, please. Thanks for taking my question. I guess first to setrusumab, you talked about the two doses. What kind of incremental benefit would you expect or wanna see with the 40 milligram per kilogram dose over the 20? Can you talk about the feedback that you've been hearing on the launch of Crysvita in Europe? Thanks. With setrusumab, you know, we haven't set precise criteria. We really wanna look at the gradations of drug concentration and drug effect as we go along. To give you a rough idea, if doubling the dose gave you 10% more bone production, I don't think it's worth it. If it gave you 50% more bone production, then I would say that's worth it. If that gives you kind of a rough idea, I think that would be what we would be looking for, is something more meaningful to warrant spending and giving that much more drug. With regard to Evkeeza, we've had tremendously positive feedback from doctors on it, both in Europe and we've had a few compassion use requests and patients treated. I think that we're excited about the potential in HoFH. It's really the first really good drug that doesn't depend on the LDL receptor at all and can be given just as a monthly IV. If we can get it reimbursed and get it, get access out there, I think we will see a strong uptake 'cause there is great interest in it, and it's part of the reason we decided to partner with Regeneron on the program in the first place. Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs. Your question, please. Hi. Thanks so much for taking our questions. This is [Tommy] on for Salveen. For the UX053 data coming this year, can you remind us what some of the details here are in terms of duration, number of patients, and any bars or benchmarks where you would see a positive signal? Thank you. Certainly. The UX053 program is an mRNA LNP that's producing this enzyme that will help restore glycogen metabolism. We'll be looking for changes in biomarkers and glucose release and biomarkers of glucose fragments that are accumulating, as well as safety parameters around, you know, liver or immune response, et cetera. It'll be primarily a biochemical kind of look at both glucose control as well as release of glycogen fragments. Those two things should help us get an idea about dose. These are all single-dose patients that were escalated at single dose, ascending dose kind of cohort. It'll be a first indication of what we can achieve in terms of metabolic correction based on primarily biochemical measures. Thank you. One moment for our next question. Our next question comes to the line of Maury Raycroft from Jefferies. Your question please. Hi. Thanks for taking my questions. I was wondering for the setrusumab phase II update, can you clarify if you'll have all patients at each of the two doses, and the age range is 5-25, but are you breaking out what proportion are older versus younger? Yeah. What we'll have is for those 24 patients, we'll have all their data through at least two months, including the last patients in. For some of the patients that were started last year, we'll have maybe six months of data, which will include BMD that were done at entering interim time points. That'll be a kind of a broad set of data. We will look at different age groups, and we have to decide how much we'll do and we need to disclose. We have ages that are distributed around the age range that will allow us to look at different ages and use both PK and the biomarker modeling to try to determine whether we need to increase the drug exposure at the lower doses. Got it. Thank you. One moment for our next question. Our next question comes from the line of Dae Gon Ha from Stifel. Your question, please. Hi, good afternoon. Thanks for taking our questions. maybe a question on GTX-102. can you maybe provide any updates on the scoliosis patient? Has that patient resolved fully to continue receiving the dose? Any update to the timeline of FDA submission of the package for the protocol harmonization? Thank you so much. Yeah. The patient, as we said before, had resolved, essentially resolved the problems he had. I think that we're continuing evaluating him. He's not redosed yet. We will wait until his protein levels have resolved, which we will do at intervals and measure, but we're encouraged how that's gone. The second question was on? Harmonization with FDA. Yeah. We're planning that discussion, you know, shortly, and we'll be presenting, you know, how to approach moving ahead with expansion cohorts in the U.S. You know, we're expecting a good meeting. We think we've gotten good responses to discussions with them lately, and I feel like there's an opportunity to move ahead. We still need to have that formal discussion in order to open up the protocol in the U.S., which we think will be important in being able to rapidly expand the study and put us in position to get a large enough amount of data to be confident about designing a phase III. Thank you. One moment for our next question. Our next question comes from the line, Liisa Bayko from Evercore ISI. Your question, please. Hi there. Thanks for taking my question. Could you run through, just with the change in, to the, to the royalty, can you just remind us of that and how you're seeing kind of the net profit from that changing? Is the royalty somewhat equivalent to what you'd be getting from a profit split? That'd be helpful. Thank you. Yeah. To be clear, you're talking about the switch from a profit share with our partner, Kirin, to the royalty period. Is that correct? That's what you're talking about? Yes, exactly. Yes. Thank you. Well, in general, that crossover will essentially be even. There won't be a significant change really. The way we structured it originally made was actually pretty well modeled in terms of predicting what our share should be. The 29%, the top tier of the royalty will cover and expect to cover some commercial costs. We are sharing some costs with them, but at this point, if you look at the total picture of how the profit share was designed and how this is, it's pretty flat, pretty similar. We feel, you know, very good that you wouldn't see a significant step-off or change in the revenue stream. I don't know if there's anything more, Aaron, you'd want to say to that. No, that was well summarized. Thanks, Emil. Thank you. Thank you. One moment for our next question. As a reminder, ladies and gentlemen, if you do have a question at this time, please press star one one on your telephone. Our next question comes from the line of Anupam Rama from JPMorgan. Your question please. Hey, guys. Thanks so much for taking the questions.Two quick ones from me. Following up on Tazeen's question on UX111 and MPS III, has the meeting with the FDA been calendared? Maybe walk us through the scenarios that could play out here. If you are able to go with an accelerated path forward for that program, is there any read-through to your brother gene therapy programs? Question two, maybe could you expand on the statement in the press release that with GTX-102, there continues to be a dose and time-dependent clinical activity in the population? And, you know, maybe if you could provide any type of color on what type of benefit you're seeing over what time period, that would be helpful. Thanks so much. yeah, normally with regulatory authority discussions, we don't precisely put out exact timing of meetings and events to that degree. The meeting is set, and we're planning to meet with them shortly. The point of the meeting is that the FDA had already agreed on a clinical endpoint and with a longer period of time to evaluate. However, of late, they have started showing some acceptance of heparan sulfate as a biomarker that is predictive. we believe in our public discussion with Peter Marks and in other settings that the heparan sulfate marker may be possible as the primary, which would allow us to file earlier than waiting for the clinical data. Our discussion will focus on can we use heparan sulfate of the particular high quality assay that's being used for purposes of filing, with a commitment to complete the clinical follow-up data, of course, to verify the clinical benefit. That will come relatively soon. We'll let you know as soon as we know what the answer is to that question. It just means we can go a little faster. If we can go faster, it just allows us to file earlier. We still have to set up the CMC manufacturing pieces of the program, and we're trying to run that as in a capital efficient way as possible because we do have a lot on our plate. In GTX-102, we disclosed that there was some dose and time-dependent differences. We have actually mentioned this before. When we put out information earlier, we had talked about the fact that the quantitative endpoints around the Bayley were better with the higher dose groups than with the lowest dose group at 2 mgs in the U.S. That was the dose-dependent piece. We've said that patients seem to improve over time, and that's the time-dependent piece. It's information we've been seeing. It's in the main drivers are the ones we've already disclosed, which are, we're talking about in the Bayley scores in language and sleep. You know, we're evaluating multiple things and looking at many things, but we feel good about the pattern of response we're seeing with both dose and time dependent, and that's why we're moving into expansion cohorts. Thank you. Once again, if you have a question, please press Star then one. One moment for our next question. Our next question comes from the line of Joel Beatty from RW Baird. Your question please. Great. Thank you. For revenue, are there any seasonal effects from Q4 of last year and Q1 of this year to be aware of? Well, there are always seasonal effects, but I think actually, I think we did well last year in terms of hitting our marks. I'm not sure if Erik would have any more to say, but I think you can always expect some lumpiness, in particular with Latin America because the orders come in bursts and off and on, so it's a little bit harder to predict. It's just part of the nature of the rare disease business. I think things are well. Erik, did you have anything else to add on lumpiness? You covered it as far as, Latin America is concerned. I mean, I think it's important to recognize that we've had steady growth over the last five years for Crysvita. It's established as the gold standard for treatment of XLH, and we expect it to continue to grow as we've seen consistent increases in key performance indicators such as patient finding, start forms, reimbursed patients and unique prescribers. Demand remains strong. That said, we do experience some seasonality in phasing ordering patterns in Q4 and Q1, which has been consistent year-over-year if you look back over the previous years. Q1 being a little lighter, as expected as patients work through the reauthorization and change of insurance process. It just takes a little longer for them to get on. We remain confident in the underlying demand and which is why we reaffirmed our guidance. Thanks, Erik. Thank you. One moment for our next question. Our next question comes from the line of Yaron Werber from Cowen. Your question please. Hi, guys. This is Brendan on for Yaron. Thanks for taking the questions. Sorry if you just answered this. My phone cut out for just a second. For Crysvita, I noticed the Q4 sales really did jump up a bit. I was hoping you could maybe give us any color as to what was really underlying that just in Q4 relative to Q3, and if this is kind of some trends that you're expecting to hold forward or hold moving forward. I just wanted to ask on Angelman. I know there's a lot of questions here on dosing and things like this, but can you just give us a sense of what we could expect in the next data readout in terms of really how many patients you're thinking to include, whether they'll include them from the expansion cohorts and maybe over how long? Really kind of just trying to get a sense of where the internal bar is for you all in terms of when you wanna put out the data. Sure. I'll answer the Angelman question first, and then Erik, you can touch on the Crysvita and the strong Q4 question. On Angelman, you know, we've been doing these dose titration codes, which were just relatively small for patient groups. It's clear we need to have something like at least 10 patients in each group to kinda give us the kinda data that we can do statistics on and at least do enough projection to understand how to power a study, you know. I'm looking for the analysis to have maybe 20 patients or about half of what we need to enroll. That's giving you a rough idea. In addition, we would have the patients we've already treated who will have been titrated in maintenance mode, and I would expect that would be the kind of volume of data that would allow us to accurately project what phase III would look like, which is I think what investors ask for us, is to have confident data that will allow them to see the future for the program in a phase III program. So that's that. For Crysvita Q4, I think it's a pattern we've seen before. Eric, perhaps you wanna add to the pattern. Yeah. We had expected a strong second half of the year, we were hampered in early 2022 with the Omicron variant. We saw continued increase in patient volumes in the offices as they opened up more and more, as well as participation in live educational meetings and programs. I think, you know, consistently growing demand throughout the year, was one of the main factors driving the strong Q4. Yeah. It's a bit of a rebound out of the hampered first part of the year, but it generally has been strong in Q4. [Sid?] All right. All right. Thanks, guys. Thank you. This does conclude the question and answer session of today's program. I'd like to turn the program back to Joshua Higa for any further remarks. Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at ir@ultragenyx.com. Thank you for joining us. Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.