Good afternoon, and welcome to the Ultragenyx Fourth Quarter and Full Year 2022 Financial Results Conference Call. [Operator Instructions] 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 Olson, Senior Vice President of Corporate Strategy and Finance; and Ted Hazinga, 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, and good afternoon, everyone. Some of you may have listened in on my presentation at the recent JPMorgan Healthcare Conference where I talked about our focus for areas for 2023. Over 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 to $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, and 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 US, which will leverage our global commercial infrastructure and capabilities. We acquired global rise 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 Transfer A study. We also exercised 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. And we completed the build-out of our gene therapy manufacturing plant in Bedford, Massachusetts, which…

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 only ran variant. Revenue from Crysvita in our territories grew 34%; Dojolvi grew 41%; and Mepsevii, our ultrarare product grew 29%. The team's efforts are proving rare disease products can generate meaningful revenue growth 5-plus years after launch. 2022 was also the first year where global sales of Crysvita exceeded $1 billion. Crossing the threshold we made possible through the Ultragenyx team's efforts that led to approximately $700 million in total product sales across North America and Latin America and also the efforts of key our caring 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 into harder-to-reach community clinics where more than 50% of our start forms are generated. With combined Kyowa Kirin and Ultragenyx build 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…

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 31, 2022, totaled $363 million, Crysvita revenue in Ultragenyx territories was $258 million, including $215 million in the North American profit share territory and net product sales of $43 million in other regions. Total royalty revenue related to the sales of Crysvita in the European territory $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 31, 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 noncash stock-based compensation expense of $130 million and a onetime R&D expense of approximately $75 million related to our acquisition of GeneTx. For the year ended December 31, 2022, net loss was $707 million or $10.12 per share. We ended the year with approximately $900 million in cash, 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 be 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 read the recap the 2023 clinical catalyst.

Thank you, Aaron. I'll summarize the catalysts 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. If unique maximum stimulates more osteoblast 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, and we expect to share these data in transition to the Phase III in mid-2023. Separately, we are playing 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 the 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, 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 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 GSDIa 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.

[Operator Instructions] Our first question comes from the line of Gena Wang from Barclays.

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? And then for the osteogenesis imperfecta, in the midyear update, how would you use, first, can you remind us the 2 doses used in the obvious Phase II portion? And how would you use the biomarker response enable mineral density to establish those algorithm for Phase III portion?

Great. Thank you, Gena. So in the Angelman, we have been, of course, evaluating higher doses and through a dose titration period. We haven't put out what doses we are using, but we've established some doses that we believe have an appropriate benefit risk that we'll be using 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 doses in both children from ages five to adults to 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 antibodies using pharmacokinetic analysis to achieve the optimal results. So we'll look at the concentrations of drug in the young and the old, and we'll also look at the biomarkers for bone production P1NP, and we'll have also some bone marl density data as well, and 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? So 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 and -- 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, at least our expectation based on bone disease we've treated in the past.

[Operator Instructions] And our next question comes from the line of Chris Ramsey from Piper Sandler.

Just one question on a collaboration that I don't think I've heard you guys talk about. So Enozyme 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, this asset would seem to be something that would, I would think, fit in within your wheelhouse developmentally. Just kind of curious if you had any thoughts on this collaboration and maybe 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?

Yes. We work with a lot of companies on the issue of diagnosis and not just 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 Indesign is doing and others with regard to new opportunities for rare diseases. But at this point, we have on our plate all we need to manage and -- but finding patients and working with our partners and others in the field is something we do routinely.

And our next question comes from the line of Joon Lee from Truist.

With 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, growing bones where too much bone formation could lead to potential safety issues, maybe hearing loss, for example.

So 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. And while if you had a genetic defect of sclerostin, you might get these problems the ability for us to knock down the level of cost to the degree required, I think, is very different from a genetic deficiency state. Secondly, I would say, the patients 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. And based on the asteroid study where we -- the treatment was stopped and we looked at resorption, it looks like we can establish, let's say, 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. But let's face it, right now, these patients are suffering every day. Their bones are disintegrating and that's first order of business, but we'll always watch out for managing the effect of our drugs going forward. But at this point, we're not concerned about it in the beginning of this program.

And our next question comes from the line of Yigal Nochomovitz from Citi.

So obviously, we are getting a lot of questions lately on the OI program and romo comes up quite a lot in that conversation, which obviously, as you know, is anti-sclerostin. So if you could help us with the quick elevator pitch on why setrusumab is differentiated from romo, and why your antibody will be the preferred option potentially NOI? Answer

Sure. First of all, romo 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. And secondly, by optimizing the dosing regimen, we'll be able to treat patients in an optimal way as a rare disease company will also be able to support patients specifically. So the combination of the dose, the regimen and support programs will differentiate setrusumab from what out there at romo right now. So those are some of the factors, I think, that will be important.

And just a follow-up on Gena's earlier question regarding the dose selection for the OI study that you're going to 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-old when you're comparing head-to-head versus the post?

Well, 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.

And our next question comes from the line of Tazeen Ahmad from Bank of America.

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? And how many patients do you think there are in the U.S. and abroad. And 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, Tazeen. So with Sanfilippo IIIa, 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. And our view was there wasn't really. The other program in lifetime, 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. But really, there isn't another, I think, effective AAV gene therapy out there that's at the stage that says. So our feeling was that this would be the lead program and had the best efficacy that I've seen from at least a biomarker standpoint. So that was our decision. With regard to the population of the world, there's probably a few thousand patients, but the -- 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 was 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 clearly the optimal benefit happens when you treat Young. So I would look at it that way. What I was saying 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 is doing right now, we think essentially every sample patient won't want to get treated because the other…

And our next question comes from the line of Jeff Hung from Morgan Stanley.

I guess for setrusumab, you talked about the two doses what kind of incremental benefit would you expect or want to see with the 40-milligram per kilogram dose over the 20? And then can you talk about the feedback that you've been hearing on the launch of Evkeeza in Europe?

So with setrusumab, we haven't set precise criteria. We really want to look at the gradations of drug concentration and drug effect as we go along. But to give you a rough idea, if there were -- if doubling the dose gave you 10% more bone production. I don't think it's worth it. But if it gave you 50% more bone production, then I would say that's worth it. So 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 compassionate use requests and patients treated. And I think that we're excited about potential in [indiscernible] 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 and -- so if we can get it reimbursed and get access out there, I think we will see a strong uptick because there is great interest in it. And part of the reason we decided to partner with Regeneron on the program in the first place.

Our next question comes from the line of Salveen Richter from Goldman Sachs.

This is Tommy on for Salveen. So 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?

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 branders around liver or immune response, etcetera. So it will be primarily a biochemical kind of look at both glucose control as well as release of glycogen fragments. So 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. So it will be a first indication of what we can achieve in terms of metabolic correction based on -- primarily biochemical misers.

And our next question comes from the line of Maury Raycroft from Jefferies.

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 five to 25. But are you breaking out what proportion are older versus younger?

Yes. So for -- what we'll have is for those 24 patients will have all their data through at least two months, including the last patients in. For some of the patients that were started last year will have maybe six months of data, which will include BMDs that were done at interim time points. So that will be kind of a broad set of data. We will look at different age groups, and we haven't decided how much we need to disclose. We'll have -- 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.

Our next question comes from the line of Dae Gon Ha from Stifel.

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? And any update to the time line of FDA submission of the package for the protocol harmonization?

Yes. The patients, as we said before, a resolved essentially resolved the problems they had. I think that we're continuing to evaluating him. He's not redosed yet. We have to wait until his 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 and the second question was on -- yes. So we're planning that discussion shortly, and we'll be presenting how to approach moving ahead with expansion cohorts in the U.S. And we're expecting a good meeting. We think we've gotten good responses through discussions with them lately and I feel like there's an opportunity to move ahead. But 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.

And our next question comes from the line of Liisa Bayko from Evercore.

Could you run through just with the change in -- 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 the profit split, that would be helpful.

Yes. So 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.

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. So 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. And so we feel 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 don't want to say to that.

No, that was well summarized. Thanks, Emil.

[Operator Instructions] Our next question comes from the line of Anupam Rama from JPMorgan.

Two quick ones from me. Following up on Tazeen's question on UX111 and MPS III has been meeting with the FDA been calendared? And maybe walk us through the scenarios that could play out here. And if you are able to go with an accelerated path forward for that program, is there any read-through to your broader gene therapy programs. And then 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 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.

Yes. Normally, with regulatory authority discussions, we don't precisely put out the exact timing of meetings and events that degree the meeting is set, and we're planning to meet with them shortly. But does 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 that is predictive. And we believe in our public discussion with Peter Marks and in other settings as the heparan sulfate marker may be possible as the primary, which would allow us to file earlier than waiting for the clinical data. So 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. And so that will come relatively soon. And we'll let you know as soon as we know what the answer is to that question. It doesn't mean the program is -- 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 in a capital efficient way as possible because we do have a lot on our plate. So 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 Bailey were better with the higher dose groups and with the lowest dose group at two mg in the U.S. So that was the dose-dependent piece. And we've said that patients seem to improve over time, and that's the time-dependent piece. So 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 Bailey scores and language and sleep. And 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.

And our next question comes from the line of Joel Beatty from R W. Baird.

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. And I'm not sure Aaron would have anything more to say. But I think you can always expect some lumpiness particularly with Latin America because the orders come in burst and off and on. And so it's a little bit harder to predict. It's just part of the nature of the rare disease business. But 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 establishes 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. So demand remains strong. That said, we do experience some seasonality in ceasing 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 changeable insurance process. So it just takes a little longer on to get on. But we remain confident in the underlying demand and which is why we reaffirmed our guidance.

And our next question comes from the line of Yaron Smith from Cowen.

This is Brendan [ph] on for Yaron. Sorry, if you just answer my phone call for just a second. But for Crysvita, I noticed Q4 sales really did jump up a bit. I was hoping you can 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 hold moving forward? And then 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 day to 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 want to put out the data.

Sure. Well I'll answer the agent question first. And then maybe, Erik, you can touch on the Crysvita and the strong Q4 question. So on Angelman, we've been releasing. We've been doing these dose titration costs, which were just relatively small for patient groups. But it's clear we need to have something like at least 10 patients in each group to kind of give us the kind of data that we can do statistics on and at least do enough projection to understand how to power a study. So I'm looking for the announced to have maybe 20 patients or about half of what we need to enroll. That's giving you a rough idea. And now 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 will 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. And for Crysvita Q4, I think it's a pattern we've seen before, Erik. Perhaps you want to add to the pattern.

Yes. We had expected a strong second half of the year as 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 of educational meetings and programs. And I think consistently growing demand throughout the year was one of the main factors driving the strong Q4.

So it's a bit of a rebound out of the hampered first part of the year, but it generally has been strong in Q4.

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.

Ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.