Ultragenyx Pharmaceutical Inc. Price & Performance (RARE)

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 Amel. 2024 was a pivotal year for the company as we advanced six late stage programs in serious genetic conditions most without any approved therapies. While also expanding access and growing revenue from our four commercial products worldwide.

In the middle of the year, we increased our guidance for total revenue and now confirm that we exceeded the upper end of that range for 2024. After filing our first BLA for Sanfilippo's gene therapy earlier than planned, we now expect to have a second BLA for GSD1a gene therapy submitted to the FDA in mid-twenty twenty five and if both are approved, we would have six commercial products on the market. Combine that progress with the expected Phase three data on UX 143 in osteogenesis imperfecta, and expected full enrollment of our Phase three for GHGX two for Angolan syndrome we're set for a strong year of value creation greater than any year in our company's history Our international growth in 2024 was particularly impressive We successfully launched EvKisa in Europe, Canada and Japan, while broadening access to our other commercial therapies in Latin America, Canada and Turkey, have also been working within these regions to establish clinical trial sites prepare drug submissions with regulatory authorities and bring our therapies into more geographies through name patient programs. We're looking forward to another year of strong global revenue growth and 2025, supported by multiple products in launch mode globally.

This progress sets us firmly on a path forward full year GAAP profitability in 2027. In January, I discussed in-depth our priorities for this coming year, so I will use our time today to focus on our UX-one 11 program for Sanfilippo syndrome, which has the potential to be our next approved product.

In our first commercial gene therapy program Last week, we presented important new clinical data at the World Symposium in San Diego that were also included in our BLA submission last December We filed for accelerated approval based on the substantial and sustained decrease in levels of heparin sulfate and supraspinal fluid or CSFHS following treatment with UX-one hundred and eleven CSF HS is what I call a disease caused biomarker because it's directly responsible for disease pathology and progression. It's not just a random measure associated with disease, it is the disease. These new data show the sustained reduction in CSF HS exposure is statistically associated with significant continued growth in the Baylee three cognitive raw score for the sub domains of cognition, receptive communication and expressive communication, when compared to natural history data we show a decline during this age period. Importantly, we also saw that older children with more advanced disease at time of treatment we're able to retain clinically meaningful functional abilities, including communication, ambulation, self feeding, while in treatment with 11 when the Bailey score is not an effective measure. As we stated in the release, we know from caregivers, clinicians, and others that stabilizing disease so that a child can retain or even slow down the loss of key skills like walking independently, communicating and self feeding, has profound impact on their quality of life The early we treat, the better is the long term outcome and in the long run, newborn screening will identify patients at birth and potentially enable an optimal treatment outcome.

Whether treatment from birth or later in life, these gains or retention of function with UX-one hundred and eleven treatment are remarkable compared with the progressive loss of function expected in these patients These results give us give me confidence that UX-one hundred and eleven will be a successful product once approved with the potential to make a meaningful difference for patients with Sanfilippo syndrome type A and their families. Our US-one hundred and eleven program also serves as a strong example of how we are leading and driving changes for the field. Our progress in San Felipe and the progress of other companies in the MPS field is made possible by FDA's willingness to accept CSF HS as a primary biomarker endpoint Last February, we joined patient advocates, regulators academics and industry representatives in a workshop hosted by the Reagan Udall Foundation to discuss qualifying biomarkers in support of rare disease regulatory pathways. This was an opportunity to take decades of work by academic research and clinicians in neuropathic MPS diseases have put together a body of information to provide a support for leveraging accelerated approval to change the paradigm for drug development in these diseases. Given my long history working on treatment for MPS diseases, including four of the five currently approved enzyme therapies in The U. S, was an incredible achievement and opens up the possibility of accelerated development for broader the broader rare disease community, especially those impacted by metabolic diseases of the brain.

We're pleased and thankful to see the FDA's folks on the rare disease over the past year with the advancement of first to ever treatments, some of which were at risk of being shelved entirely, We will continue our advocacy and engagement efforts to advance rare disease regulatory policy. With that, I'll turn the call over to our Chief Commercial Officer, Eric Harris, to provide a more detailed update on the progress across our commercial portfolio. Thank you, Emil, and good afternoon, everyone. 2024 was a strong year for the PROSPHETA franchise. Both the Kiowa Kirin team in The U. S, Canada and Europe and our team in Latin America and Turkey delivered outstanding results and led to the revenue beat, raise and beat that Aimo mentioned earlier. I'll start with Crysvita in Latin America.

Where we lead the commercial operations.

In 2024, our team generated approximately two ninety start forms, that led to approximately two fifty patients on reimbursed therapy. [indiscernible] We now have approximately seven fifty patients on commercial products in the region as the team continues to exceed our expectations. Similar to what we saw in The United States, once doctors in Latin America see how well their patients are doing on therapy, They frequently write prescriptions.

For their other patients.

Growth in the region has accelerated following successfully negotiating reimbursement from the Brazilian and Mexican authorities.

Two largest payers in the region. And continued expansion in other South American countries In The U. S, our partner, Kiawa Kirin, is leading commercialization and had a strong fourth quarter driven by growing underlying demand.

Over the course of the year, the number of start forms generated exceeded our expectations as did the number of patients on reimbursed therapy. We believe this confirms there are still a large number of patients who could benefit from this therapy and gives confidence there are still meaningful meaningful opportunities to grow this product. Moving on to DeJovi. Growth of new start forms in the fourth quarter continued to steadily increase. In 2024, our team generated approximately 120 start forms that led to approximately 105 new patients on reimbursed therapy across The U. S. This brings the total since launch in 2020 to almost five seventy five patients on reimbursed therapy. The split between continues to be approximately sixty five percent PEDs and thirty five percent adults.

The number of new prescribers continued to grow in the fourth quarter with approximately half writing more than one prescription.

For DeJovi across the EMEA region, revenue is a result of name [indiscernible] There are over two fifty patients treated under NPS across 14 countries in the region.

The majority of demand is in France, but we are receiving an increasing number of requests from other countries in the EMEA region including The Middle East.

The demand for this product is quite strong in this region especially given We are not actively marketing the therapy and simply responding to named patient requests. I'll close with a few comments on FKESA. Which we have been launching outside of The U. S. Over the past year or so. In the EMEA region, we have patients from all of the major countries, including France, Italy, Germany, Austria, The Middle East.

We now have treated approximately one hundred and ninety patients across 14 countries.

Is a result of our commercial commercialization efforts or responding to named patient requests as we continue to successfully navigate the country by country pricing negotiations.

In Japan, the team continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. We expect Japan to contribute more meaningfully to the total revenue as we launch Epkezza and our future programs in this As I have mentioned previous earnings calls, we continue to expect quarter to quarter variability in revenue. Primarily due to uneven ordering patterns for Crysvita and Latin America. We remain confident in the growing underlying demand for all of our products around the world. Our teams were excited to deliver strong results in 2024 and we are looking forward to potentially commercializing two or three new products in the coming year or so. In The U. S, our inborn areas of metabolism team that is currently commercializing DEJOVY and MEZSEVI look forward to being able to promote UX 111 and DTX401.

As transformational gene therapies once approved, For UX-one 43, we will need to build out the U. S. Team in preparation for and we will be able to use our deep institutional knowledge from our successful Crysvita launch where there is 90% overlap in call points.

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

Thanks, Eric, and good afternoon, everyone. I'll focus on full year 2024 corporate results and our 2025 guidance. Starting with total revenue, For 2024, we reported $560,000,000 representing 29% growth over 2023. Crysvita contributed $410,000,000 including $249,000,000 from North America dollars 135,000,000 from Latin America and Turkey, and $26,000,000 from Europe.

In total, this represents 25% growth over 2023. If you focus on Latin America and Turkey, where we are responsible for generating sales, this represents 78 growth over 2023. Turning now to Dijolvie, it contributed $88,000,000 which represents 25% growth over 2023. [indiscernible] And mepsebi contributed 30,000,000 as we continue to treat patients in this ultra rare indication. Total operating expenses for the year were $1,100,000,000 which included R and D expenses of $698,000,000 dollars SG and A expenses of $322,000,000 and cost of sales of 77,000,000 Operating expenses included non cash stock based compensation of $158,000,000 For the year, net loss was $569,000,000 or dollars or $6.29 per share.

As of December 31, we had $745,000,000 in cash, cash equivalents and marketable securities. 2024, net cash used in operations was $414,000,000 Importantly, in 2025, we expect reduced net cash used in operations compared to 2024. As you remember from prior years, we typically use more operating cash in the first quarter than in the other three quarters. Because it includes items like the payment of annual bonuses. This year, the first quarter will also include $45,000,000 in payments for two milestones that were achieved in the fourth quarter of twenty twenty four. One for the initiation of our Angelman Phase three study and one for a sales milestone for Evkeiza. We will continue to prioritize expense management and focus our investments on the execution of our upcoming commercial launches Shifting to revenue guidance for 2025, total revenue is expected to be between $640,000,000 which represents 14% to 20% growth over 2024. Drivers include increasing demand for our products in Latin America, continued penetration of the pediatric and adult XLH markets in The U. S, and growth from EKISA in Europe and Japan. Crysvita revenue is expected to be between 600 or excuse me, $460,000,000 and $480,000,000 which includes all regions and all forms of Crysvita revenue to Ultragenyx Ultragenyx.

This range represents 12% to 17% growth over 2024. As a reminder, in the first quarter of the year, we restart at the lowest tier of our royalty structure North America. The JOLVY revenue is expected to be between $90,000,000 and 100 which represents 2% to 14% growth over 2024. As in prior years, our DeJolby projections represent a blend of faster growth in countries where we commercialize, and lower growth in countries where we respond to name patient [indiscernible] With that, I'll turn the call to our CMO, Eric Krombets. Who will provide an update on our key clinical data readouts expected this year. Thank you, Howard, and good afternoon, everyone. I'll provide some brief operational updates on our late stage programs and review our upcoming clinical milestones. Starting with 43 for the treatment of osteogenesis imperfecta. The Phase three Orbit study is progressing well and the safety profile is similar to what was observed in Phase two. Based on the Phase two data we previously shared, we are confident significant reduction in annualized fracture rate at either the second interim analysis or the final analysis The Orbit and Cosmic studies will both have an interim analysis mid year after all patients have been on therapy for at least twelve months and the alpha spend for each study will be 0.01.

Study analysis in the fourth quarter. Moving to GTX-one hundred and two for the treatment of Angelman syndrome. Enrollment in the Phase three ASPIRE study is going well.

And we are on track to complete enrollment in the second half of this year.

Based on the strong interest from physicians and patient and with our team's commitment I have confidence that we will be able to enroll the planned 122 patients in less than one year.

In parallel, we are also working to initiate our Phase twothree study, AURORA, that will study younger and older patients Once this protocol is through the regulatory process, we will share a Shifting now to our gene therapy programs and starting with U. S. 111 for the treatment of MPS IIIA. Expect to receive confirmation of our BLA acceptance shortly. This will also confirm our PDUFA date, which we expect to be in the second half of the year. The biomarker data and the newly presented clinical improvements in multiple [indiscernible] who otherwise face a [indiscernible] I look forward to completing this work and to the launch of our first gene therapy product. Next, DTX401 for the treatment of glycogen storage disease Type 1a. Work on the BLA filing is going well and we are on track for FDA submission mid year.

We have talked about the decision to move manufacturing for this program to our facility in Bedford, Massachusetts while this required some additional work and time, it enabled far greater control over the manufacturing process improved quality and reduced costs.

Finally, I'll touch on DTX-three zero one for the treatment of ornithine transcarbamylase deficient As noted in our press release today, we have completed enrollment in the Phase III study with a total of 37 patients randomized one to one to placebo or DTX-one.

We did amend the Phase three protocol to allow a blinded comparison production primary endpoint through week 36 and will now evaluate the reduction in removal of standard of care after unblinding given the reluctance of patients and doctors to stop alternate pathway medication This reluctance stresses the severity of this disease with the irreversible damage caused by high ammonia levels and the need for a one time treatment option that is establishes the normal ability of the urea cycle to metabolize ammonia. The primary endpoints are unchanged and are one, response as measured by change in twenty four hour ammonia levels during the first thirty six week blinded period compared to placebo patients and two percent of responders who were able to remove all This responder endpoint will now be assessed across the whole group of patients, including placebo crossover patients for up to sixty four weeks. The new design increases the power of the study by assessing ammonia early where reductions occur rapidly and then assessing the diet and drug removal by evaluating all patients compared to the baseline in the longer follow-up period. Changes allow us to reduce costs and to shorten the overall timeline ending enrollment at thirty seven patients and making the study more patient centric.

The protocol amendment reflects the real time feedback we heard from patients and physicians about the fear of removing life saving treatments in a blinded placebo controlled study.

As a patient engaged company, we need to hear their concerns during trial conduct and now have made a better trial design with their feedback. I'll now turn the call back to Emil to provide some closing remarks.

In 2025, we'll continue building on the outstanding clinical and commercial to transform into a leading rare disease company [indiscernible] commercial financial engine that supports its clinical pipeline. We have a number of near term catalysts, which Eric has already covered next expect to have three potential approvals in the next year or so. As the company, LTX has arrived, we are creating the paradigm for the next generation of rare disease companies changing the future for rare disease patients. With that, let's move on to your questions. Operator, please provide the Q and A instructions.

Thank you. We will now be conducting a question and answer session. We ask that you limit yourself to one question and one follow-up. Our first question comes from the line of Tazeen Ahmad with Bank of America. Please proceed.

Hi guys. Thanks for taking my question. So mine is going to be on OI and how we should be thinking. I think you've you've talked about this many times, but, Emil, if you could give some color about your confidence in the second interim read being sufficient to stop the study versus needing to go to the third interim? I know you've expressed overall confidence in the trial design and the likelihood of success.

But we'd like to hear your thoughts about how you're thinking about the importance of the study being stopped at the second interim?

Great. Well, we believe the second certainly has a much greater chance of of hitting than the first one because it's a 0.01 threshold and because patients will have had at least twelve months of treatment to allow the group to separate. So there's certainly greater confidence in the second interim But we feel confident one way or another the trial is going to end and we'll be successful this year. Just we've been watching the Phase two patients. They're doing great and we feel very good about how Phase three conduct is going. So we have more confidence in second interim than we did in the first. But it's either second interim or in the study, but we have a product that's going to work and we're excited about that product and bringing it to OI patients. Thanks, operator. Let's move to the next question.

Thank you.

Our next question comes from the line of Salvin Richard with Goldman Sachs. Please proceed. Good afternoon. Thanks for taking my question. Just a follow-up to the first one here.

Maybe help us understand if it doesn't hit on the second interim, what would those reasons be or what are the risks to that? And then how long would we have to wait for the final analysis? Thank you.

Well, we said the second will be midyear. For it not to hit at twelve months, usually in rare disease that have to do with amount of variation in the number of fracs fractures. If there's a lot of variation, there's a wide range of patients baseline fracture rates because we have some type three, four and then type one patients. Large variation could could create some a challenge, but I think that so far we feel like the trial is proceeding as expected. So if it doesn't hit in the second interim, we'd expect to release data by the end of the year. On the final assessment for the trial.

Our next question comes from the line of Anupam with JPMorgan. Please proceed. Hi, guys. This is Priyanka on for Anupam. Thanks for taking our question. Question. Once Orbit hits, will you immediately prepare to file or wait for the Cosmic Analysis to finish and add it to the application? Thanks.

If Orbit hits, first of all, we will have the data clean and locked in and there won't be a need to follow any for any longer. So it will be more quickly to reach final analysis and to file. And so compared to interim mouse one, there's probably just a one quarter delay in filing off the quarter two. So it should come more quickly after that. At that result. Thanks, operator. Let's move to the next one.

All right. Our next question comes from the line Jenna Wang with Barclays. Please proceed. Thank you. Sorry, I will ask another OI question. Given the study complete enrollment on 05/01/2024, is it fair to assume June, July timeframe you should share the second interim update? And then how would you communicate with the investor in the case the study didn't hit the stats? And in the case the study hits stats, Would you need extra time to analyze the data and therefore share the update a little bit later.

Yes. So we will be managing the second room like the first. DMC will meet and looks at the data and if they don't inform us that it hit, then we know it didn't hit And we will expect to communicate the street where we're at at that point in time. You asked whether Fair to consider June, July, I guess that's possible but we haven't set the time we said mid year. Is in that range, but we're not committing to an exact time We're trying to keep you guessing a little bit, Gina. Did I miss, did I get your questions?

Yes. So if you hit it, that means like share with us a little bit later since you would need to take a few more weeks to analyze the data?

Yes. Because the database is locked, we would the BMC would see the data, we would find out it hit, we would then get to online and look at the date ourselves and and relatively sooner after that we would expect to put out results It won't be like the first time where we had it to go two months more, remember we had to take two more months. We should be relatively quicker. To come out with the actual result, top line results anyways.

Thank you. Our next question comes the line of Yaron Weber with TD Cowen. Please proceed.

Great. Thank you. So I also shockingly have a 143 question.

In the ORBT study, are you stratifying the remind us Type one, three and four between the two arms? And then secondly, when you look at the primary of fracture rates, do you have a secondary looking fracture rates by type underlying type? Thank you. Yes. So in general, we do stratify, but it's mainly for overall fractures and its age. But I'll let Eric talk about the way we're approaching it.

Yes. So, because the primary point is annualized fracture rate, you want to stratify by fracture rate.

So while that definitely will kind of encompass the different types there, the strict stratification is based on fracture rate coming into study.

So Type II IV may have a higher fracture, but we're focusing on that Doing it by the 3s and 4s and 1s, we didn't it didn't look like that was going to be the right way to go as fracture rate was a better way. So we are also looking at ages. So there's an age balance between the groups. And regarding the other endpoints, We are looking at total fractures, not just the fractures minus fingers, toes, skull, those total fractures are an endpoint and the subset between subtypes, I'm sure we'll do analysis sensitivities in that in there, but it's not a formal secondary endpoint.

Our next question comes from Yigal Novovitz Please proceed. Hi, this is Rina on for GAL. Thanks for taking my question.

I just wanted to ask one on OI. I was just wondering if at the point of hits, whether it be the second interim or the final, if we would learn maybe retrospectively like any kind of retrospective analysis you'd share on how close the studies were to hitting at either the first interim the second interim?

Steve wants to tell you what what happened at IE1 or IE2 later Yes, like personal bets with other investors about that to trying to settle. I don't know if we would show with the other end and we haven't decided that. I think what matters if the study hits the study work and the drug works. And I'm right now I'm not committing whether we're going to show all the little bits and pieces of what happened. We're pretty comfortable that look, we if you look back, we presented Phase two data remember at six months. And showed you a 67% reduction with a P value of 0.04. And then we did the same group of patients, but now at fourteen months, [indiscernible] [indiscernible] But now the ATA P value was 0.0014.

That is a reasonable model for what would be going on here that the groups have set [indiscernible] So I'd look at that Phase two data we've already shown you as kind of a model for what's going on. But right now, we put out data, we'll put out the data we have and I don't know if we'll put out the rest to settle scores Thank you. Our next question comes from the line of Maury Raycroft Please proceed.

Hi, this is Faizdin on for Maury.

Just to clarify an earlier you mentioned that if the second interim hit do the final analysis quickly. So just wondering if you to supplement the final data package with the eighteen months data or not.

If we hit at the second interim, then the package will include all those patients with at least twelve months of data The range that would be like from twelve, there are some patients at that point would have twenty months it's twelve to twenty months of exposure time. So it's a pretty long period of time actually. It's almost two years. In all patients. So twelve that will be I think plenty I didn't mention someone asked about orbit or I mean cosmic earlier. COSTMIC will be evaluated in parallel and but we won't close out CLOSMIC if Orbit doesn't hit. If Orbit hits, then we'll we'll look at cosmic but the data will be ready to be looked at. But we wouldn't stop COSMIC if Orbit doesn't hit We need Orbit in order to file But we wouldn't hold out filing to get eighteen month data. We'd file with the data we had and we've had that discussion with the FDA.

Got it.

Thank you. Our next question comes from the line of Jun Yee with Tuohy Securities.

Thank you for taking our questions.

If the OI study goes to completion in 4Q, does that implies that the magnitude of Is that Of the set, sorry, may not be as great as expected. And in that case, how competitive would cetrusimab be compared to bisphosphonate?

Actually, it would not mean it's not as great. You remember, earlier when we had six month data and a fourteen month data in Phase two, they both had sixty one percent reduction in fractures What it has to do is the two lines have to separate. So the biggest reason that there's too much variation and those variations might cause a delay but the actual rate separation could very well be sixty seven percent. It's just you have a lot of patients that may have ten fracs of the year or one fracture year in the same study and some of the ones may not have fracture for example, and then during for whatever reason, So it's really more about separating the two groups but I don't think it necessarily tells you what the percent reduction is. We think if you listen to some of the KOLs that 50% or greater reduction of fracture is considered really important. And frankly, when we look at patients after a year fifteen, sixteen months of therapy. We've had some or longer they are many of them are not fracturing at all at some point. So we feel very comfortable that the long term outcome here is greatly reduced fractures whatever the number is.

But I think the biggest issues the variation in how much fractions are occurring in each group wide range that probably exists that will impact how the study reads out We are using co variables to manage that variation, but that would be the number one reason. So I don't think you can conclude the drug is not working well if we go to the end. Remember the original plan here was to do a two year The only reason we felt we could go sooner is because the percent reduction was higher than we thought and that the speed of response was faster. Those are the things that give us confidence that we can go earlier But we've been moving this up from eighteen months to two year study right, down to what we're talking about now, which is a twelve to eighteen month timeframe. So eighteen months is still a win. And I feel confident whichever one happens that we have a drug that will be far better than bisphosphonates and certainly the best treatment for OI that's available Thank you. Our next question comes from the line of Jeff Hung with Morgan Stanley. Please proceed.

Thanks for taking my question. I just wanted to clarify, make sure I understood correctly. You talked about how the Phase two data and the 0.014014.

But just first, with the Orbit Phase two portion hit with the second interim analysis criteria? And if not, how were the baseline fracture rates different from the Phase two portion? Thanks. Yes. So what I said was the Phase two data at six months last patient in we had 0.04 and then with fourteen month data, we had 0.0014 Right. So that was the difference. You're asking how close is that Well, the Phase two patients are fairly similar in terms of the criteria for fractures are the same. They're made up of type I, III's and IV's. There's Phase III has somewhat more three's and four's. But not a dramatic difference. So it's a very comparable population, age range, types included, and baseline fracture requirements. So I think that those are reasonable ways to look at what Phase three should be happening.

And so the only question has to do with how the variation in in the population, how big is it and how much it moves in the timeframe I think data from Phase two are a reasonable model. For what's happening.

Okay. That's helpful.

Thank you. Our next question comes from the line of Joseph Schwartz with Leerink Partners. Please proceed.

This is Will on for Joe. Thanks for taking our question. Progress this quarter. I have one on OI and then a follow-up on UX-one 11. So just first for OI, wondering if you could provide any more color on the characteristics of the patients in the Phase two that had fractures while they were on treatment? Do we know the subtype of these patients? And how does that impact your thinking about the Phase three, which has just as you said a few more severe patients? Thank you. Okay. So the Phase II, the patient that fracture is surprisingly, they were not necessarily Type 3s and 4s only. They were There were 17 Type 1s and they were some of the ones that had fractured were Type 1s. So it's not like having type three to four has made more fractures fracture rates, but the ones that did have fractures were not necessarily like only Type 3s and 4s. For example, it was I think they're mostly Type 1s, if I recall. So there's no, I would say, a pattern there that would tell you something about how face three. I think actually there's no pattern of what was probably more impressive as how much all three types respond very comparably in bone mineral density improvement I think that was the most interesting thing that we saw.

So you had a follow-up with 111? Great. Yes. Thank you. Yes, just on 111, since it's going to be the first gene therapy launch for you guys, how are you thinking about pulling learnings from other programs or experiences that had success or maybe not weren't that successful in the commercial rollout? And how does this kind of set you up for other gene therapy launches down online, including four zero one? Thank you.

A very dynamic commercial organization and we're used to launching new things and this has never been treated before. So we've essentially done every single time. I'll let Eric say a few words if you'd like, but the we are going to be looking at what everyone is doing for sure. And our goal will be to get our work with payers upfront get to understand the value proposition, the data we have in hand and allow them and hopefully to create as rapid and prompt a pattern of review and approval because urgency and time really matter for these kids to the six month delay is not allowable. This is very severe disease. So I would look at SKUX-one hundred and eleven as being more like Zolgensma and SMA in terms of life or death and no alternative treatment. Do think there's an urgency. I think the payers will respect that. We just need to make them aware of it. And I don't know Eric, is there anything simple thing you can touch on or how we're going about their launch?

Yes, we've been in close contact with the treatment center potential treatment centers because remember, we're in with those customers now with [indiscernible] And so we're learning a lot about the coordination that will be required between the patients and the physicians for delivery of the gene therapy [indiscernible] we're ready. We'll be ready to go. And we'll certainly want to learn for successful launches of Olganza and there's a lot of people out there that have that knowledge and I think there's an advantage now coming out now with several products out there and knowing what works, what hasn't. And I think the truth about rare disease about gene therapy launches is all about urgency. Diseases don't have a treatment that's good, lethal, Their adoption is going to be much faster and we think UX-one hundred and eleven fits that mold like [indiscernible] So we're looking forward to a good launch and we're excited about the opportunity of treating this disease. They've been Sanflu patient waiting forever for something and this the first time it's actually happening and I know there grateful and excited about finally something being done for their kids.

Thank you. Our next question comes from the line of Kristen Kulska with Cantor Fitzgerald. Please proceed. Hey, everyone. This is Rick Miller on for Kristen. Thanks for taking our questions. We're going to mix it up a little bit and ask about OTC deficiencies. Just to better understand the amended protocol that you talked about today, when the patients in the Phase three are in the initial thirty six week blinded period, are they still eligible for titrating down on ammonia scavengers and diet control? Or would that just be an op [indiscernible] [indiscernible] have based on what a meaningful reduction in ammonia look like and how this correlates with normalizing some of the clinical effects you see Sure. Well, we already have treated a lot of patients and know that none of them wanted to reduce. So we kind of know during the line of period none of them would reduce. So we're if we have the option or not, it doesn't matter. The truth is it's a little cleaner if no one would, but since they have it, it doesn't matter. So we're going to look at ammonia baseline roll to later. What we know is we allowed up to 200 micromole in the study So there will be a number of patients that have significantly elevated ammonias, which on a chronic basis are not good.

And these ammonias we're talking about are twenty four hour curves, right? So they're during twelve hour cycle that go up and down So we expect from our Phase two data that should drop within six weeks. And very rapidly drop to normal range. So we'd expect that the patients that have high ammunities are clearly abnormal range at [indiscernible] Should normalize. And that's why we think we'll have a lot of power. So I think the degree of ammonia change in those that are elevated will be clearly from cognitive impairing type range and into a normal range where you expect greater clarity of thought and function. We'll be monitoring those things as well. The problem, of course, with removing their drugs is they're so afraid of because it can happen suddenly that we're just reserving that to after they get them blinded. And so we'll actually have the same endpoints and really the same trials, just that we'll unwind people after thirty six weeks and then they can start titrating And but we'll get blinded data, controlled blinded data for that period, which we think will be clinically meaningful ammonia reductions don't know if there's anything else I missed, Eric, that you'd add.

Well, I would just draw the parallels.

To GSE1A. I mean, we had a lot of reluctance there in the blinded period to to be aggressive with reduction of corn starts, but once all patients rolled over to long term follow-up in an unblinded setting. We saw further reduction in all patients and very closely mimicking what we saw in the Phase two. So think we're confident we'll see something similar here in this Phase three and get much closer to a duplication of what we saw on the Phase two was done in an un blinded manner.

And the percent responders is complete response, so they have to get off their drug and diet control to be considered complete responder, which is what the FDA I think having all patients be assessed that way, I think is a will help the power of the study because it's actually more patients and doing it within patient comparison is a lot more powerful than doing it to group comparison. [indiscernible] Thank you. Our next question comes from the line of Luca Isak with RBC Capital. Please proceed.

Great. Thanks so much for taking my question.

I guess we'll revert back to the mean here and maybe ask a question on OI. What's the latest thinking on duration of therapy Assuming that the trial is successful, do you think that the FDA will cap the duration of therapy to twelve months as they have done for thrombocystinib immunosupporosis? Or do you think this will be chronic dosing with no cap? So that's one. And then second, very quickly, can you just remind us why for Angelman, running a shame control trial is the better way to go versus a placebo controlled trial? Thanks so much. Sure. So on the duration, it's one of the first things we did in taking over the program is does not make the assumption that twelve months makes any sense for these patients. And what we are learning already is that the assumption that twelve months that the treatment stopped working essentially you don't need to go longer that you then lock it in with the fossil. That model is true for maybe 80 year old women with osteoporosis. But when you're talking about these kids, their bones want to absorb. The kids that [indiscernible] delta stop treatment before that were OI patients in the Asteroid study started losing ground.

And it's pretty clear to us that OI is just different And when we look at patients long term treated, they continue to gain ground in BMD for quite a bit of time And our view is that we should be treating till optimal clinical effect and our expectations that will become a chronic treatment it's possible down the road that they get could go to maintenance therapy where they get less frequent dosing But it's pretty clear that one year is you're not done after one year and that most of these kids probably need at least two years continuous therapy, if not and chronic therapy is our expectation. So we'll FDA is aware of that, that concept that change and we'll have to help them [indiscernible] think the data we have is already telling us that that's right. That the patients are continuing to benefit When you have a bone marrow density for example, it's minus two to minus four Z score, the gain a lot of ground in one year, They're continuing to gain ground in the second year clearly, linearly. [indiscernible] we're very comfortable that we're making the right call here.

And it's one thing that's important as a company that we don't just follow the what everyone says. We're looking at what's really going on at the science and the science says these kids need to get treated longer. And we're going to continue to do that. We'll work with the agency in long term Would there be a maintenance later perhaps? But I think at this point we're talking about product therapy for this disease. That's the best way to probably maintain the right balance of bone production versus bone resorption, which they need that constant stimulation to make that set point, right? Now like an osteoporosis patient, which they are officially trying to up their bone production but they don't have an intrinsic problem like these kids do, right? So when you have an underlying gen cause, I think it's just a different biologic situation and we think chronic treatment is the right answer.

Second question on Angel then. [indiscernible] actually proposed placebo originally. The FDA at the time said there as [indiscernible] potentially unethical to have to do sham treatment or placebo treatment We opted not and we'd heard something similar from EMA, so we opted to go with the sham just because we felt there was an ethical regulatory burden there that we have to go through, not them, just them, just them, but IRBs. But I think you could do the study either way. I don't think it's going to matter Sham has more work, right?

Yes. I mean, the real difference between sham and CSF.

So that really the practical difference that you're seeing.

In the sham design. In the sham design. So it's really not a big significant difference between the two designs. But don't need to administer artificial CSF Great.

For that. It's a little bit more work to do, Sham, but it is we felt I didn't want to battle uphill with IRBs or EMA or other regulatory authorities regarding the issue of ejecting placebo and going having every injection be an injection in these kids. So but I don't think it's going to matter and won't make a difference in the meaningful meaning of the treatment. We feel comfortable that the design is going to get us where we need to go.

Super helpful. Thanks so much. Thank you.

Our next question comes from the line of Bishav Bhakal with Evercore ISI. Please proceed.

Hi, thanks for taking the question.

A question on the variability in OI In your work preparing for the trial and assumptions you talk about any sort of registry or database views you got on variability? Is there some way to describe that? And I guess, is there a trend like if a patient has fracture, are they more or less prone to a fracture in a certain period of time? I just would love some color around that. Thank you so much.

Well, we know from our Phase two baseline data that there was a pretty wide range. There were patients who had 0.7 or one fracture a year and I think they're up as high as six or seven. Fractures a year. Is that right, Eric? [indiscernible] that's a pretty wide range of baseline fractures. We know in the younger patients, they tend to have more fractures So if you talk about the really young ones, the younger you go, the more fracture they have. So those are the factors. Age particularly and that wide range, then you have to imagine that you have to power the study to reduce fractures across a wider array of change. So we think that we're well powered to do that in the design and if you look at what happened in Phase two over after a period of time really the majority of the patients have not had any more fractures, stop having fractures completely. [indiscernible] and certainly as we put in our deck there have been one of the doctors said they've not seen a single Fragility fracture since starting strezumab. So we're comfortable that we're going to be able to show the delta.

I was just saying if you asked me why would Interim two not work, well, it's a question of variation is usually the thing in these studies. We feel comfortable that with enough time they will separate and you'll get a an important result for this disease.

Thank you. Our next question comes from the line of Ed Akerstrom with H. C. Wainwright. Please proceed. Hi, good afternoon, everyone. This is Thomas Yip asking a couple of questions for Ed.

You so much. So perhaps switching gears or 102, as you work to finalize the sign for the Phase [indiscernible] Can you discuss some factors between the two patient population that would differentiate the study from ASPIRE and then taking a bigger picture overall strategy of 102 do you also expect AURORA would have data to supplement BOA that we expect based on the prior data [indiscernible] 2026.

Okay.

So on GNT162, the main study to remind everyone the main study is as far as is focused on deletion patients ages four to 17. Which is the same population we studied in Phase two. So the AURORA study is simply to support labeling across different age groups and different genotypes. For under four, we'll have some patients treated open label. We'll look at the same endpoints but just show does under two under four year old patients they respond comparable than we saw in our Phase two or in what's in Phase three. And this Our experience in rare disease world that you can expand the label for age simply by treating a small number of patients in an open label format and collect data that's comparable to your blinded set.

For the We will also do that for some older patients. For the non the non deletion types, we'll look at patients in the main range and the point will be the same to look at the different genotypes collect enough patients to show it's safe to give it to them and that using comparable endpoints we can demonstrate a magnitude effect that is comparable In our experience, that kind of data would allow us to support labeling So our intent is to have cut of data from Aurora in time for BLA filing but we will probably still continue to collect data in Aurora during the review process in case the agency wanted more. And the other advantage of Aurora is that we can also do it in other territories around the world giving more doctors exposure to the treatment and to gain support for regulatory filings that might occur in other parts of the world. So those are some of the factors of how Aurora will work.

Thank you. Our next question comes from the line of Aaron Weaver with TD Cowen. Please proceed. Yes. Thanks for taking my follow-up. I just got a couple, Emil.

The first one on 04/2001, so given that you're fully enrolled now and the primary is the thirty six weeks, And then you're on blind, is there a chance that we'll get the data that the first sort of the primary is this And then secondly, I think I misheard, but I just want to double check.

It sounds like you're saying in Cosmic, you'll do an interim analysis now midyear as Well, Is that indeed is that going to be the first intro for that? And I think you mentioned at twelve months, but with a 0.01 alpha, but that was referring to Orbit. I just want to double check the interim analysis on Cosmic. Sure.

So think you're speaking of three zero one for OTC.

Yes, so the 3,060 data could provide data We're not saying when yet.

It depends a little last patient in and having thirty six weeks, etcetera.

But it could be. We haven't provided the exact timing of that data yet [indiscernible] For OI, when we run the interim on the Orbit study, we'll run an interim on COSMIC At the same time, we'll look at Orbit. If Orbit is positive, we'll look at the Cosmic data. If Orbit's positive, then we'll look at Cosmic and it also is being looked at at a 0.01P value. If Orbit doesn't stop, then there's no reason to stop Cosmics this point. So we'll keep them going until we final But we wanted to do them more in parallel. So the idea is to have both trials in the filing, which is the FDA's preference.

And which would give us the full label We also think it gives us labeling against bisphosphonates, right, as well as versus placebo, right? So they both studies add value commercial launch of the program. [indiscernible] Thank you. There are no further questions at this time. I'd like to pass the call back over to Joshua for any closing remarks.

Thank you. This concludes today's call.

If there are any additional questions, please contact us by phone, or at Ultragenyx dot com. Thank you for joining us.