Good afternoon, and welcome to the Ultragenyx Fourth Quarter and Full Year 2023 Financial Results Conference Call. . At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call.

It is now my pleasure to turn to Josh -- turn the call to Joshua Higa, Vice President of Investor Relations..

Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, Chief Medical Officer.

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

Thanks, Josh, and good afternoon, everyone. In 2023, we generated significant momentum across our commercial and clinical programs that have set us up for Catalyst bridge 2024.

On the commercial front, we progressed international regulatory and reimbursement negotiations across our marketed products, continuing to add to new approvals and positive reimbursement decisions. This geographic expansion along with growing demand in our existing markets put us in position to maintain our trajectory of robust year-over-year growth.

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

On UX 143 for osteogenesis imperfecta, the interim Phase II data showed substantial increases in bone real density and Z score after just six months of treatment. This led to a 67% reduction in analyzed fracture with 20 of the 24 patients showing no radiographically confirmed fractures at six months.

On GTX-102 for Angelman syndrome, data from the long-term extension cohorts Phase I/II study demonstrated clinically meaningful improvements across multiple neuro-developmental domains, including cognition, receptive communication, growth motors, behavior and fleet.

These data show we can repeatedly dose GTX-102 for much longer than one year with acceptable safety profile. On UX701 for Wilson disease, the data we presented showed four or five patients in the lowest dose cohort have begun tapering their standard of care, including two who are completely off key letters and/or zinc therapy.

While still early for the UX701 program, we are encouraged by the data we have observed. Our momentum is continuing into 2024 with multiple clinical development updates.

Last week, GTX-102 was granted priority medicine or PRIME designation by the European Medical authority based on the positive early clinical data from the long-term extension cohorts and the potential of GTX-102 to address the unmet need for our treatment in this disease. The clinical data we've shared with The Street, along with positive U.S.

and European regulatory interactions give us confidence that we will be able to navigate the development path for this program. For UX-111 in San Filippo A syndrome, we released Phase III data last week from extension of newly treated patients at the WORLD Symposium Annual Research Meeting in San Diego.

The results we shared demonstrated treatment with UX-111 resulted in rapid and sustained decreased levels of heparan sulfate in the cerebrospinal fluid and the sustained reductions in CSF heparan sulfate exposure over time was correlated with improved long-term cognitive development.

Our discussions on an accelerated approval pathway with the FDA are ongoing, and we continue to believe there's a strong case to be made in this program. Looking ahead, we are entering 2024 in a robust financial position with $777 million on the balance sheet, including proceeds from our equity offering in the Q4 that raised $326 million.

We're also continuing to focus our spend and resources on the key clinical programs that will drive value for our company, many [indiscernible] in the coming months. Our Chief Medical Officer, Eric Crombez will view more of these updates in his section.

There's a lot to look forward to as we continue our efforts to lead the future of rare disease medicines. Now I'll turn the call over to our Chief Commercial Officer, Erik Harris, to provide an update on our commercial efforts last year that led to a 20% revenue growth in 2023..

Thank you, Emil, and good afternoon, everyone. I'll start with Crysvita's performance in North America. I want to remind everyone that on April 27, 2023, we successfully transitioned the promotion of Crysvita in the U.S. to Kyowa Kirin and that Crysvita will continue to generate growing revenue for our company.

During the transition period, the Ultragenyx field team continued to find patients from community physicians, while introducing key accounts to Kyowa Kirin field teams. Our patient support services team supported the transition of patients from the Ultragenyx hub to the Kyowa Kirin hub to ensure continuity of treatment and reimbursement.

In 2023, the smooth transition and additional field resourcing helped support the growing demand for Crysvita in the U.S. and Canada. In fact, there were approximately 500 start forms generated in 2023 from a continually growing base of unique prescribers and patients on reimbursed therapy.

The success we saw in 2023 and has led us to further amend our agreement with Kyowa Kirin that will allow our experienced field team from Ultragenyx to continue to support Crysvita in the U.S.

through this year with a robust demand from 2023, a fully transitioned patient support services hub and the support of Ultragenyx' focused field team, we feel confident that 2024 will be another strong year for Crysvita in North America. Shifting to Crysvita in Latin America.

We finished the year with over 500 new patients on reimbursed therapy, which included approximately 50 new patients who began commercial therapy in Q4 of 2023. Over the course of the year, we added approximately 200 nations to our growing base of patients on commercial therapy.

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

In Latin America, we expect quarter-to-quarter variability in revenue driven by uneven ordering patterns but remain confident in the underlying demand growth for our products. These combined efforts across our global organization generated 2023 Crysvita revenue of $328 million, which is a 17% increase compared to 2022. For Dojolvi in the U.S.

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

In Latin America, we are making steady progress in finding patients despite the lack of newborn screening in the region while expanding access for Dojolvi to more patients.

Most recently in Mexico, Dojolvi was approved by the HCA for inclusion in the National Medicine Compendium, which is an important step toward increasing reimbursed patients in 2024.

Across the EMEA region, the Dojolvi is driven by named patient sales request as we continue to deepen the awareness of LC-FAOD with key stakeholders through our medical teams. Though the majority of current requests are coming from France, we are seeing an increased demand throughout Europe and the Middle East.

In 2023, the teams generated $71 million in Dojolvi revenue, which is 27% growth compared to 2022. Lastly, on FSA, we continue progressing steadily across our launch markets in EMEA, Canada and Japan. In EMEA, European HTAs have provided infusion with positive clinical recommendations and we are working through the reimbursement processes.

On December 18, we received approval from the European Commission for an expanded indication for Evkeeza in children aged five years and older with HOFH. This approval further validates the drug's clinical value and expands the addressable patient population in the EMEA region.

In Canada, both HTA bodies, CIS and NS have provided positive clinical recommendations for Evkeeza. The team is prepared -- is preparing to accelerate the public reimbursement process with the Canadian authorities in the coming months. In the meantime, we are working to give private payers on board to expedite reimbursement.

The initial uptake on the start forms has been steady since Health Canada's approval. In Japan, we received regulatory approval on January 18 and pricing discussions are underway with Japanese authorities. Following reimbursement approval, we expect to launch Evkeeza in Japan next quarter.

The team is busy educating the physicians on the Evkeeza-label and identifying appropriate patients who could benefit from the treatment. Building on the success in 2023, we expect continued strong performance across our portfolio in 2024. Crysvita will continue to drive the majority of the revenue followed by Dojolvi and Evkeeza.

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

Thanks, Erik, and good afternoon, everyone. I'll focus on full year corporate financials since we just covered our individual product performance. Starting with total revenue. For 2023, we reported $434 million representing 20% growth over 2022.

Total operating expenses for the year were $1 billion, which included R&D expenses of $648 million, SG&A expenses of $310 million and cost sales of $45 million. Operating expenses included noncash stock -- noncash stock-based compensation of $135 million. For the year, net loss was $607 million or $8.25 per share.

As of December 31, we had $777 million in cash, cash equivalents and marketable securities. In 2023, net cash used in operations was $475 million, which was higher than forecasted due to timing of when certain receipts and payments landed around year-end.

Our 2024 net cash used in operations is expected to be less than $400 million which is consistent with the guidance we provided last month. We are also reaffirming the 2024 revenue guidance ranges we stated last month. Total revenue is expected to be between $500 million and $530 million, which represents 15% to 22% growth versus 2023.

Crysvita revenue is expected to be between $375 million and $400 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. Specifically, it includes Crysvita product revenue from Latin America and Turkey and the cash and noncash royalties from North America and Europe.

Our Crysvita guidance range represents 14% to 22% growth versus 2023. Dojolvi revenue is expected to be between $75 million and $80 million, which represents 3% to 13% -- excuse me, 6% to 13% growth versus 2023.

Our Dojolvi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to name patient requests. With that, I'll turn the call to our CMO, Eric Crombez, who will provide an update on our key clinical data readouts expected this year..

Thank you, Howard, and good afternoon, everyone. In addition to the UX-111 Phase III data that we presented at the WORLD Symposium last week, we have a number of important clinical data readouts planned for 2024.

These include GTX-102 expansion cohort data to be presented mid-first half, DTX401 Phase III data in the second quarter, then UX701 dose-finding data, and finally, UX-143, longer-term follow-up data from the Phase II part of the ongoing Phase II/III study.

For UX-143, there is also the potential for the Phase III study to read out pivotal data from the first interim analysis around the end of the year. We have set a strict p value of 0.001 for un-blinding for this first interim analysis.

This means that the alpha spend is effectively 0 while providing the opportunity to end the study early if the data are compelling and the primary endpoint is met. We have also built in a second interim and final analysis for the study that would occur in 2025.

We Regardless of the timing, the reduction in the annualized fracture rate that we saw in the Phase II study and shared at ASBMR last year gives us confidence that we will see a clinically meaningful and statistically significant reduction in clinical fracture rate in the Phase III study.

Shifting now to the two near-term data readouts for GTX-102 and DTX401. I'll start with GTX-102 for the potential treatment of Angelman syndrome and the Phase II expansion cohort data that we expect to share in the next few months. The first part of the study included a dose escalation stage to understand initial safety and efficacy.

Last October, at our Analyst Day event in New York, we disclosed longer-term extension data, demonstrating clinically meaningful improvements across multiple domains for the patients in these extension cohorts.

We also showed the first ever developmental milestones that many of these patients have achieved to highlight the clinical meaningfulness of these changes. Earlier last year, we began dosing a larger number of patients in expansion cohorts to further study the dose regimen that we intend to evaluate in a Phase III trial.

These expansion cohorts include higher loading doses and enrollment was completed at the end of last year with 53 patients enrolled globally. The upcoming expansion cohort data in mid-first half of this year will focus on the 20-plus patients who have been on therapy for at least 170 days.

We intend to present safety and efficacy data in a similar format to what was shown at Analyst Day, specifically showing domain by no main changes with comparisons to natural history. With higher loading doses and a greater number of patients, we expect to verify the meaningful efficacy that was presented at Analyst Day.

These data will inform dose selection and evaluation period for the Phase III study. Our discussions with the FDA on Phase III planning continue to go well, and we anticipate that the expansion data will support an end of Phase II meeting in mid-2024, which will enable Phase III study start up later in 2024.

The next near-term data readout is for DTX401 and our investigational gene therapy for the treatment of glycogen storage disease type Ia. We have one of the largest late-stage gene therapy pipeline, and this will be our first Phase III data readout.

All of the patients in the Phase I/II demonstrated a clinically meaningful response to DTX401 that has proven durable with the earliest treated patients entering their fifth year of follow-up.

In the randomized, placebo-controlled Phase III study, we expect to see patients with clinically meaningful and statistically significant reductions in cornstarch therapy. We expect to unblind and share top line data from the DTX401 Phase III study in the second quarter of this year.

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

Thank you, Eric. We've made incredible progress across the clinical pipeline, which sets us up for a number of data catalysts this year. I'll close by summarizing those catalysts, everyone get a better sense of what to expect. As Eric mentioned, in the next few months, we'll share the expansion cohort data from the GTX-102 Phase II study.

This is expected to be followed by the top line Phase III DTX401 data in the second quarter. Next, we plan on sharing the UX701 for Wilson disease Stage one data in mid-2024. This will be data from the three dose escalation cohorts that recently dosed the last patient.

Closing with UX-143 for osteogenesis imperfecta, we expect to share longer-term Phase II data in the second half of the year. Enrollment in the Phase III studies is going well, and we are on track to complete enrollment with approximately 150 patients in the Orbit study around the end of the first quarter.

The compact study is also enrolling well and is on track to enroll approximately 50 patients or more around the same time or just after. 2024 is an important year for Ultragenyx.

We'll continue expanding global access to our commercial products, bringing these important therapies to more and more patients is expected to generate more than $500 million in revenue and support our path toward profitability.

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

[Operator Instructions]. Our first question will come from the line of Gena Wang with Barclays..

I have one question regarding the GTX-102 in Angelman and one for setrusumab.

So for GTX-102, you received the prime designation, what is the early feedback regarding approval path and the Phase III trial design? And have you met with the FDA also regarding the Phase III trial design? And for setrusumab, how will long-term Phase II data in the second half '24 will inform the first interim for obvious Phase III before year-end '24..

Very good. Thanks, Gena, for the question. So the prime designation was just a presentation of the data that we've seen so far. And basically recognize the close of data we saw. We have not settled on a Phase III plan with the European authorities that's something to become. With regard to the FDA the prime designation will have no influence on the FDA.

We have initiated our conversations with FDA. We've had good discussions. We're making good progress, and we feel comfortable about putting together a plan when we have our Phase II data in hand when we meet them with end of Phase II, but we're encouraged by the discussion and think there's a way forward in terms of finalizing the plan for Phase III.

We have said just for reference that we're planning the Phase III to be around 100 to 120 patients in a randomized double-blind trial design, and the FDA knows that. And I think that's a traditional design. I don't think there should be any problem with European authorities either with that basic design.

So we'll get the Phase II endpoint -- I mean, Phase III endpoint settle as we move through getting all the data. With setrusumab Phase I data will tell us a little more about the fracture reduction rate over a longer period of time.

It appeared from before there were very few fractures after the 5, 6, seven month of treatment, and we'll get a lot more patients now out further to give us a good sense of the level of reduction over longer periods of time. And that will help us understand the true maximum effect that we might see on fracture reduction.

Since the fracture reduction is up already at the 67% estimate rate that puts us in good position to potentially have a positive interim. It will depend on the variation we see in patients.

But we felt that, that level of efficacy and any higher efficacy would put us in a position to potentially being able to end the study sooner if we have profound highly statistically significant results. We could have a very good result that we still not hit that standard, and we'll have another interim and final in 2025.

So we're very encouraged about setrusumab in the path forward. And the Phase II data shall help us see how great it is and understand a little bit more about the path forward..

One moment for our next question. And that will come from the line of Maury Raycroft with Jefferies..

Based on the totality of your Angelman data so far, including data from your natural history longitudinal study.

As you think about a Phase III design, do you have a sense of what the optimal time frame is to assess efficacy and what age group could show maximum benefits?.

Yes. So if you look at the study data we put out last year at Analyst Day, we've continued to gain ground over time, right? So it looks like going a little longer, like day 170 is early. And if you look at day 254, the data looks much stronger. And our view is it could be anywhere from around day 254 to day 330.

Somewhere in that range is the likely time frame we would do the study. Obviously, the longer it is, that means the more time on placebo. It gives more time for separation of the groups, but it's somewhere in that time frame. And the Phase II data will help us try to figure out what's the right number.

I'd want to do the study, not a long longer than it needs to be meaningful for found results. In terms of age, I think right now, our plan is to continue with the same age range we're using in the Phase II, the 4- to 17-year-old early on, people thought only young patients would respond, but we've been seeing good responses in older kids, too.

So I don't think that should limit we shouldn't need to limit that in order to get the best efficacy. I think we conclude that whole group four to 17 in our Phase III design. Our expectation though is to do a separate study, an open-label study to help look at younger kids, potentially older kids and the other generic types to fill out the data set.

With the main Phase III study, we expect to be 4- to 17-year-old and be somewhere between 250 days to 330 days long..

And one moment for our next question. And that will come from the line of Anupam Rama with JPMorgan..

Maybe just a quick one for me. What was the feedback on the 111 program MPS III program update at WORLD? And where are you there with the FDA discussions in terms of what are the push-pull levers here on like an accelerated approval process in meeting..

Well, in the meeting there, we had really positive feedback from people because I think the extended data is continuing to show good developmental progression among the longer treated patients. That's consistent with the heparan sulfate and being predictive of good clinical outcomes.

And so we're encouraged and there's been a number of people using the HF marker and showing similar predictive value. So FDA has been going on for a while. I think Peter Marks has been very encouraged with the idea that we should be moving with biomarker than the workshops planned organized by Reagan Udall, February 21.

And which will look at heparan sulfate across multiple programs.

We feel the data there should encourage the FDA to take the stand of accepting heparan sulfate as a reasonably likely to predict clinical benefit marker and start doing solid approvals in the MPS brain disease area, which if it happens, I believe, will help us move forward in other rare genetic disorders, particularly that affect the brain.

So I think we're encouraged about the progress forward on the workshop, the data we released, the data others have released tell us that we have a handle on how to treat MPS disease and particularly MPS-IIIA and that's a good thing because there hasn't been a single trend for MPS brain disease approved today..

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

Sorry for the background noise. I have a couple just on 701 for Wilson. You've changed the readout time line. I think originally it was first half, and now you're saying it's mid-2024.

Is just that -- is that just nomenclature or was there a reason for a slight time shift? And then I guess going back to Angelman, a question that we've been getting a lot of recently is with relation to the composite endpoint that we've talked about that includes measures, including Baily and CGI, but have you had detailed discussions with FDA on using that composite endpoint.

And I think the main question around that is coming from the potential of a competitor to have their own Angelman data around the same time as yours.

And how that might affect the FDA's viewpoint of using a more traditional endpoint?.

Okay. So the time line and Wilson has done on the last patient role. We enrolled the last patient cohort just early this year. We want to give them enough time at least six months to kind of have an opportunity to titrate their key layers, get through the whole treatment process and titrate key layers.

So it's slightly off from different from where we have but not meaningfully. So that's the timing. We want to make sure to give patients enough time to be able to get off their key layers if they can. So that's the basic story there. With GTX-102, we've had discussions on both MDI and other ways of looking at the endpoints of the FDA.

And I think they're open to various ways of looking, and I think they showed a lot of flexibility in many ways. Whether we do MDRI now will be just a question whether we want to press our case on using something novel or whether we should stick to picking a traditional single endpoint or two endpoints for the primary.

But we're still working through that with FDA. I think it's been good. But I'm not really worried about the competitor. Honestly, our efficacy will be the driver of what we do. I don't think that there -- a competitor is going to change the outcome on the end points. They are behind us at this point.

And I think the efficacy data they put out has not been impressive. So at this point, I think our future is all in our hands. And honestly, I think we have some of the best team in developing endpoints, methodology around it and support for it.

And nothing in our conversations when the FDA suggests that they're listening to anyone else, particularly in this. They seem to be willing and able and ready to work with us on a final solution on the endpoint..

Thank you. One moment for our next question. And that will come from the line of Dae Gon Ha with Stifel..

I'll just ask two on GSD1a. I guess the first one is, Emil, can you shed some more insights on the cornstarch reduction. So we've heard from some docs that sleeping through the night is also as important, if not more important, than the reduction itself.

So when you think about the outcome here, what do you consider a clinically meaningful level corn starch reduction? And what data will you provide to address the sleeping aspect for the physicians? And then kind of sticking with GSD1a.

Can you talk about the training and monitoring of these investigators to ensure the cornstarch reduction is done appropriately versus just slower than expected out of caution?.

I'll deal with the first question, then maybe Eric, you could deal with the second question about the training of the sites and so forth.

So we haven't set a minimum threshold of change for cornstarch because we agree with you that, what is probably more important than the actual reduction is whether the patients are critically dependent on corn starch to survive. Because the problem with cornstarch is not taking cornstarch.

The problem is that each patient lives each day with a gun to its head thinking, if I forget to make cornstarch, I could die, as a horrible burden on live with and have to take something every three hours.

So what we know from our Phase I/II study is that patients -- many patients were able to have no cornstarch at night and their blue pulses were maintained. They did not drop to 0. They were maintained and supported. So what data will we have? Well, we're looking at primary clinical -- statistical significance and cornstarch reduction.

We'll also look at the number of cornstarch administration they take, whether they're taking at night, we'll have tedious glucose monitoring, which allows us to monitor glucose control during the night, which will also be something we'll be looking at.

So in addition to the cornstarch, you will hear about the other characterization of the cornstarch dependency, which I think are an important part of the story.

And it's an important part why the amount of reduction we're seeing is transformed for patients where they feel like they can go out of the house and exercise without feeling that they're going to get hypoglycemic can drop somewhere. And we've had many patients tell us they feel safe now that that's not going to happen to them.

And many who don't take starch at night and sleep through the night. So I think those are all aspects of what will come out with the Phase III data to help provide the clinical meaningful argument in addition to the quantitative around corn start reduction.

Now Eric, maybe you can provide a little more on the training and how we're doing this with sites..

Yes. To your point, the training and monitoring is very important here. We really did want to rely on our study teams, principal investigators who gained a lot of experience during the Phase III part of this program to continue on as trial sites for the Phase III.

Because of the double-blind nature of the Phase III study, we also wanted to build an independent group of experts physicians truly the biggest experts in GSD1a who aren't participating in clinical trial sites to really work with the sites and guide them to make sure we're doing this consistently and safely..

And one moment for our next question, and that will come from the line of Joon Lee with Truist Securities..

This is Mahdi on for Joon. I have two questions. Could you please provide some clarification on the patient mix that you are envisioning for Phase III, would you exclude UPD patients or like patients with prior experience with ASOs.

And the other question is on setrusumab, what gives you confidence that a potential chronic dosing would be on the label for this treatment?.

Yes. So you're speaking of GTX-102. Correct. So for the gene types, we're going to stick to the gene times we have been studying, which is the deletion type, which is 70% of the patients, the UPD and misses patients wouldn't be in the randomized control Phase III.

But our intent is to provide a basket study where we'll look at a cohort of those type patients open label to help look at their efficacy and tried support for conclusion on the label, but they won't be part of Phase III because we -- as a habit and method within the company, we don't expand genetic types of patients we haven't treated if we haven't studied them already in Phase II.

So it will -- the Phase III will be all deletion type. So those are the most severe patients, improving benefit in the most severe patients, I think, puts us on path to be able to support efficacy with smaller studies to deal with the other types. Now patients who had prior experience, for example, patients have been on the Roche program.

We've had a number of Roche patient acquirer. The challenge is very complicating right now, particularly for those that had safety events and another ASO to drop into a Phase III study. It's not something we would do. We're going to look at ways what we can do to look at access for those patients going forward in our program.

We just haven't done it yet. We still have to work out our safety net and efficacy we take on those complexities. But there's certainly patients interested in crossing over at this point in time.

And so remind me the last question you had was on which program?.

I believe its chronic dosing product dosing for OI..

chronic dosing for OI. Okay. Why do we believe we can get chronic dosing? Well, we know that you probably need it. First of all, osteoporosis and osteogenesis imperfecta are very different diseases. They are very different diseases, particularly the age of the patients, the state of their bone and the biology of their bone disease.

What we know from the asteroid study that was conducted [indiscernible] is that when they took them off the setrusumab and put them on just bisphosphonates, they were losing bone real density, their bones were turning back around the direction they gained. It's clear that you need chronic dosing.

What we know now from treating patients chronically because we had, including one kid that we showed you, months of treatment as they continue to gain ground and do better and better.

So everything we say said in the OI indication, their bones are different, and for particularly they're younger and they have an induction effect from their genetic disease that makes them different. By stimulating, we're able to maintain their bone all density or [indiscernible] further.

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

And one moment for our next question. And that will come from the line of Yaron Werber with Cowen..

This is Brendan on for Yaron. First, just another quick one on San Filippo. I understand talks with if you are still ongoing. But just wondering when you think you might know and be able to make a decision on timing to regulatory filing and whether based on how those talks are going to expect that could happen this year.

And then just really quickly on GSD1a. I wanted to see how soon after the Q2 readout you expect to be able to file.

Has FDA given you really any confirmation on how long they want you to follow these patients after that primary endpoint, just to understand durability or what have you, just before you get that submitted?.

So for MPS IIIA, the workshop coming up, I think, will be an important touch point. And I'd expect that after that, I would assume this first half will have a read on whether we could file off of the biomarker-based data. I will tell you that we've collected almost enough clinical data to be able to follow up clinical data alone.

However, we think it's more meaningful to built et approval in the biomarker, but we should know this first half.

The workshop being an important moment, but the follow-up meeting that may occur with the review division, then will let us know what our path is either way we can find a way forward for MPS IIIA, we just think it's better for the field, both us and the field if we are able to get accelerated approval and open the door now to treating more ultra-rare diseases.

For GSD1a readout, we haven't put a time line for filing. We have noted our plan to bring the manufacturing in-house, which will require some time, but we are -- that will be an important part of what we have to do.

But we'll have to go and meet with the FDA to understand from a pre-BLA meeting more precisely what is expected in all the different packages, the CMC package and the rest of it. And so that will help determine what happens.

But we're -- if the data are positive, which we expect we'll be working to move toward a filing as diligent as we can given the parameters I've said..

One moment for our next question, and that will come from the line of Kristen Kluska with Cantor Fitzgerald..

So with the Phase II setrusumab data guided for the second half of the year, I think that puts you at mean of at least 1.5 years worth of follow-up. So I wanted to ask if there's anything that you're going to be looking for beyond fracture prevention, which, of course, is the essential goal. But then also to your comments earlier about chronic dosing.

What do you think about in OI and chronic dosing in general, if there could be further improvement or even preventing further impact as it relates to some of the other features of OI such as the deformities of bone structure, et cetera?.

Yes. So you're right. I think that we're probably in that range of 1.5 years. And if you could say like the patient we described it had 17 months treatment. He wasn't using wheelchair anymore and he's running around and playing.

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

Our thinking, and this relates to the maintenance dosing, is that if we improve the bone density sufficiently so that they stop having fractures and have very few fractures, and we expect two things to happen.

We should be able to go to maintenance dosing where we give tetrizumab every two or three months, it allows us to maintain the bone density that they have and not lose [indiscernible].

But we'd also expect that when you stop having fracture, you will stop having progressive deformity and in particularly the place we're most interested in is in the spinal column.

The spinal column degeneration is absolutely the most devastating part of OI, particularly type three and 4, the one in the wheelchairs who lives are devastated, preventing the fortrebral fractures, which we hope to be able to see at that point in time would be the kind of thing that would prevent the deformity of their spines, the decline in spinal function and the wheel -- becoming wheelchair bound.

Those are the kind of things which are -- can change the future. It's partly why we're running the COSMIC study in the 2- to 4-year old to try to capture that result.

So when we head to a filing for approval, we can establish a new scanner for care that you need to be treating OI patients with setrusumab at a young age to help prevent the deformities going forward. So hopefully, the case that will add to that question that you've asked about changing deformities.

If you can do that could be that you could stop OI type three and four ending wheelchair-bound and what a terrific result that would be, and that's what we think both what we've seen so far..

One moment for our next question. And that will come from the line of Salveen Richter with Goldman Sachs..

This is Lidia on for Salveen.

So we just have one on UX701, could you just help us frame the clinical update expected this year, specifically around how much proof of concept we could expect here?.

Yes. So the concept -- the information you're going to get are five patients at three doses, right? So it's still a relatively small set to data.

What we'd be looking to see is can we eliminate the need in at least some patients for chelators that as we can remove their chelators and still maintain urinary copper that is we can replace the chelators, the second thing is can we restore copper distribution, that is a place where the gene therapy can exceed what you obtain with chelators.

Because we didn't get into the Wilson gene therapy business just to replace chelators letters just to get rid of a treatment. We got in there because we think you can have a more profound beneficial treatment that restores copper distribution as well as detoxification. So we'd want to be able to show that both of those things are happening.

If we can show that both of those are happening, patients at the optimal dose is done with safety, it sets us up for immediately rolling a Phase III study at that dose and regimen that will allow us then to potentially work with the disease.

The stronger the benefit of the copper distribution on their outcomes and the more likely the drug will become adopted by a larger fraction of Wilson patients. If it's we're great at moving the toxicity. And then it could be the 20%, 30% of the patients that are not tolerant chelators very well that it would be beneficial.

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

But remember, there's only five patients per group. So we cannot expect to have definitive clinical outcome results in that grouping to tell us the answer.

But with the Phase III study, following that, we'd have enough patients in there to start to say something more about the clinical meanfulness or the secondary neurologic effects, otherwise, that you might obtain by having restoration of copper distribution..

One moment for our next question. And that will come from the line of Yigal Nochomovitz with Citi..

This is Ashu Kumar on for Yigal. I had a follow-up on earlier Angelman discussion. I guess as you're thinking through the various scenarios between a more novel end point for Phase III versus a more traditional endpoint.

I'm curious how you think the expansion data, you're planning on sharing with is you might capture the potential for a more novel end point.

And if you lean towards the more novel end of the spectrum and you take that to regulators, is there maybe potential that you need to generate additional data beyond this expansion cohort to submit before you start the Phase III? I'm just curious how you're thinking about that..

Yes. Well, our focus -- I mean, I think our focus in terms of endpoint choice is going to be the main ones we've already shown that we've tested before and we're adding to. We're not necessarily expecting a brand new endpoints to come out. But -- so it will be dependent primarily on what we see.

The thing that will happen in the study though is that we'll get a large number of patients loaded the same way, right, which we haven't had, which will give us a better or more precise estimate of the change we see and have it be more reliable, not wishful thinking, but to see a large number of patients showing a very similar pattern of result.

Our goal expectations are from the end points, we've talked about five domains, which the daily was for three of those domains and two other endpoints for the behavior and sleep. Those are going to be the core five domains that we're going to be working with. There will be other assessments for fine motor and express and communication.

But the five we've talked about will be the main drivers. So I don't really think there's going to be a point where we're going to start fresh with a new endpoint and restart over. That's not something we need to do.

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

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

For UX-111, you mentioned that you've collected almost enough clinical data to file off the clinical data alone.

What length of long-term follow-up do you need to accurately measure potential for improved development with sustained HS normalization how should we think about the time course for development?.

Well, this is one of the areas for discussion with the agency. Originally, they had told Abeona and in our discussions had a requirement to see at least patients reach age five years. However, we've been able to show that between 24 months and 60 months, between in that period, there is the most rapid decline normally in natural history.

And then if you look at the estimated yearly change in development and the trajectory of development, you can readily distinguish patients during that period. We have a number of patients now that have already gone past 60 months or five years. But between 48 and 60 there are a number of others that are also showing good development.

And we think the combination of those patients may be already enough clinically to demonstrate the benefit, which was part of that update.

But we're working to understand in our new analysis, we showed on this estimated yearly change in relationship to area on the curve exposure helps provide better insight into how to understand trajectory of elements over time.

And we think this means we can interpret better what's happening between, let's say, three months of age and 60 months of age to know what is the trajectory of a patient with sample to that's untreated. And what's the trajectory of someone who has adequate heparan sulfate reduction. And so those will be what we'll be pressing for.

But even just patients from 48 to 60 months, a minimum of 48, 60 months, we already have clinical data saying the drug is effective.

So it is another way for us to go forward, but far more valuable to get an accelerated approval to include all the data and all the patients and accept the 48 to 60 minimum treatment data is simply evidenced toward the reasonably likely predict standard..

One moment for our next question. And that will come from the line of Joseph Schwartz with Leerink..

This is Will on for Joe today. So just to quickly from us both on Angelman. So previously, it was noted that you expect to see more of an effect as compared to the prior data cut, given the higher doses in the expansion cohort.

I just want to make sure that this is still the expectation, and then also for Angelman, we often hear that these patients are constantly gaining skills and there may be some increased hope in the community, which could lead to a placebo response.

So just wondering what strategies can help mitigate a potential response in a pivotal trial?.

Thank you. So our expectation that loading at higher doses that the improvement should be accelerated relative to what we've seen. We haven't changed our view on that.

The thing I would say is, remember that in the Phase II data we showed you from extension, we went all the way out to 500 days of treatment, right? So the magnitude effect you see at 500 days is not going to be the same that you're going to see at 170 days.

But we do expect that the higher load dose and should -- and the large number of patients that should make us allow us to verify that we're seeing a real effect. Now with regard to the placebo response, I think the longer-term data already show you that there's -- it's not a placebo response because they continue to gain ground.

The placebo effect doesn't go on forever. It goes on for a while then people eventually recognize something is not happening. But be able to see linear continued gain of ground over time is clearly beyond what you would see with the placebo effect. In the Phase III, though, you have to worry what you're thinking, well, what if people are optimistic.

What we are doing and a lot of the key endpoints, use third-party psychologist evaluators like for the Bailey, the third-party value are is looking at the kid doing things. While the patient report may have some impact, they are looking for the kid to do things.

So that helps provide some objectivity that we're seeing the kid actually do things and it's not just wishful thinking. That said, our expectation is to have a large enough effect and the large enough population of patients to be able to power past a placebo effect.

In addition, the longer time frame we're talking about, which is maybe 250 days or 230 days should be well past the normal window of what placebo would be.

I think when you look at how many domains are improving in patients, two to five domains improvement in most of the patients it will become evident to people who's responding and who's not responding. And so the issue raised is certainly one of importance and we've been thinking a lot about it.

But I do think the negative effect, the length of time are factors, which will help reduce the risk of a placebo response clipping or impairing the results of that study..

One moment for our next question. And that will come from the line of Jack Allen with Baird..

I have two quick ones. The first of all, as the commercial products, namely Dojolvi and Crysvita. I know there's some seasonality in the fourth quarter numbers. But when you analyze out the fourth quarter numbers, it seems like you're already at the lower end of guidance.

So I was hoping you could provide some more color as it relates to how we should think about the growth of those two products over the course of 2024? And then on GSD1a, any thoughts on your early market research here.

Is there a subset of patients that are more severe that could be asked to really adopt a gene therapy here?.

That's for GSD1a?.

Yes..

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

We're in the territories that we're commercializing, we're continue to see the 20% growth rate I don't think there is any issue with this. We're trying our best to navigate guidance and give the Street numbers we feel confident in achieving. And I think looking at 20% growth rate, I think, is I think, still excellent growth rate.

So the lumpiness, Q4s in these patterns with Latin America have been a recurring theme. It is what it is. I think, ultimately, it's just -- it swings up and down. I think Fourth quarter tends to be higher.

Is there some buying before the winter months and before the new year? But -- and it's just something that we're always going to have to manage overall. So you have to -- we have to smooth it out with guidance that makes sense, but I feel good about the guidance we have and 20% growth rate should be excellent.

With regard to GSD1a, 81% of the patients have severe genotype or no like genotype, right, 81%. So the vast majority of patients are severe. There are some milder but majority are severe. And so we'd look at the population being more homogeneous in that regard than many of our gene therapy disease that we study.

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

And one moment for our next question. And that will come from the line of Ed Arce with H.C. Wainwright..

Good afternoon. This is Thomas here asking a couple of questions for Ed. So just for GTX-102 and Angelman, amount patients in the expansion cohort.

Can you tell us what are some of the longest current duration that these patients have in the Phase III study? And also, what are some additional endpoints that investors can focus on compared to the previous days..

I heard the extension cohort. You're asking from the ones we presented how long they go out. The -- by the time we get to end of Phase II, we'll have patients who have had two years of treatment probably, but it will be somewhere between a year to two years of treatment of exposure for all those patients.

So quite a long time and we have patients -- a good chunk of patients who are already beyond age day 504 at the Analyst Day meeting. So I think actually that's a good -- shows you that chronically exposed accumulating drug doses are not going to cause the safety problem in this disease.

So I think that's an important part of the safety profile that we can doing these treatments and I have an issue. Reestate your second question because I didn't quite catch that..

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

I see. Well, we have a lot of different ones we're looking at. The ones we talked about, the Bailey or the core, the either the Angelman severity assessment for behavior or sleep or an alternative behavior or sleep scale could be used -- those are two alternatives their scales the scale we've used before. We've seen them before.

We haven't didn't include -- we didn't have them in the most recent extension data. So we'll get a little more information on those alternative ways of doing it.

I would say to you in our discussion with the FDA, they were highly flexible to us calling out questions and just pulling up like a few key questions but endpoints and relying on those for the endpoint. They were I think showed great collaborative flexibility and not rigidity with regard to choosing those endpoints.

And so within our existing data set, we can even just pull out questions, for example, and hone in on those questions and use those for particular for behavior sleep.

So our goal would be not to go with new things we haven't seen before, but to look at what we have and pull out the best data sources that are sensitive to the change and are clinically meaningful for patients in coming up with those agent, but there won't be brand new things you've never seen or that we don't have any data on..

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

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

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