Ultragenyx Pharmaceutical, Inc. Stock

Good afternoon, and welcome to the Ultragenyx Pharmaceutical conference call to discuss the U.S. Food and Drug Administration approval of the AUV for the treatment of the MPS-IIIA, also known as Sanfilippo Syndrome Type A. It is now my pleasure to turn the call over to Joshua Higa, Chief of Staff and Vice President of Investor Relations. Please go ahead.

The U.S. FDA approval of Fayuvi, the first-ever treatment for Sanfilippo syndrome Type A. We appreciate all of you making time to join us this afternoon to discuss this important milestone. A press release with details on this announcement is available on our website, along with an updated corporate presentation. Joining me today are Emil Kakkis, Chief Executive Officer and President; Eric Crombez, Chief Medical Officer; and Erik Harris, Chief Commercial Officer. Howard Horn, Chief Financial Officer, is also on the line for Q&A.

Before we begin, I'd like to remind everyone that today's discussion will include forward-looking statements. These statements involve risks and uncertainties, and actual results may differ materially. Please refer to the risk factors described in our SEC filings. And with that, I'll turn the call to Emil.

Thank you, Josh, and good afternoon, everyone. Earlier today, the FDA approved FAYUVI, the first-ever treatment for Sanfilippo syndrome Type A and our second gene therapy approval in less than a month. This milestone represents our sixth FDA approval overall and further established Ultragenyx is the leader in both rare disease medicine and gene therapy.

Before we discuss in detailed significance of this achievement for our company and the MPS community I want to briefly acknowledge the recent outcome from our Phase III ASPIRE study for GTX-102 for Angeman syndrome. This was truly disappointing for the company and for the Angul community. We expect to provide a more comprehensive update by our next quarterly financial results call. We will address your questions on the annual results and our expense management plans in greater detail at that time.

But for today, we're going to focus on the FAYUVI approval and what it means for children and families with Sanfilippo syndrome type A. Sanfilippo syndrome Type B is 1 of the most heartbreaking diseases I have encountered in my career, -- these children often appear healthy early in life, then my age is 2- to 6-year-old as the disease progresses, they gradually lose their ability to learn, to communicate and engage with the world around them. And after a period of hyperactivity and altered behavior of the children slow down as family watch skills disappear one by one, leading to a bedridden state.

The children eventually die from this devastating disease usually of teenagers. Until now, families and clinicians have had to face this diagnosis without any approved treatment with the potential to stop or slow this inevitable decline. We're here today because parents, avocis clinicians, researchers and organizations across the broader MPS community used to accept that reality. They raised awareness, funded research, participating in clinical studies and never stop fighting for their children. Now thanks to their pre-severance. Families receiving a diagnose of Sanfilippo syndrome Type A can have hope that their children's future may look different.

Ultragenyx was founded to pursue diseases that others overlooked and delivered treatments where none existed before. In 1 month, we've now achieved our consecutive gene therapy approval for 2 severe rare diseases demonstrating not only the strength of our science, but our ability to translate innovation into approved medicines for patients. Even though Ultragenyz was not originally working on Sanfilippo syndrome, we received a call from Abeona CEO, Vish Seshadri. When funding constraints arose despite positive clinical data, Abeona made the pivotal decision to outline the asset to Ultragenyx, ensuring this vein reach the finish line for patients.

When we picked up the program, our team found a way to make it work relentlessly and courageously taking on the task make sure the Procon hand was able to treat kids and getting the program to a BLA filing. It has not been an easy road for us either, but we're gratified that all of this work has enabled us to bring forth the first approved treatment for Sanfilippo Type A.

Developing new therapies is only 1 part of our mission. We've also believed that approval only matters that patients can actually obtain treatment, and we are committed to helping eligible families in the U.S. access FAYUVI as quickly as possible. We also know and have gotten urgent calls for treatment from families elsewhere in the world, also in great need, and we will work on finding a way to treat some patients globally while we seek approval in other regions.

I'll now turn it to Eric Crombez to review the clinical data and Eric Harris to discuss our commercial launch preparations.

Thank you, Emel. Fayuvi is indicated for the treatment of neurologic manifestations of mucopolysaccharidosis Type 3A or Sanfilippo syndrome type A in pediatric patients with preserved neurodevelopmental function. As Emil noted, this is a rare and fatal liposomal storage disease that primarily affects the brain and is marked by neurodegeneration beginning in early childhood. The disease is caused by an enzymatic deficiency which results in the accumulation of heparan sulfate and progressive damage to the central nervous system.

Fayuvi is a single-dose AAV9 gene therapy designed to directly address this underlying enzymatic deficiency. Conceptually, this gene therapy provides the ability to produce fully functioning enzyme in some cells in the brain to break down heparin these cells will then secrete the enzyme that can cross-correct other brain cells, resulting in a decrease in heparan sulfate substrate levels throughout the brain.

The BLA was based on data from the Phase I/II/III Transfer A study and long-term follow-up demonstrating improvements in key developmental domains compared with natural history along with substantial and durable reductions in CSF heparan sulfate.

Clinical data now extends to nearly 8 years of follow-up. -- a was generally well tolerated and maintained a favorable safety profile. The most frequently reported treatment-emergent adverse events for elevation in liver enzymes, which were mostly mild or moderate. While we originally submitted Pause for accelerated approval, the agency recognized the robustness of our clinical data package during the review and granted standard full approval rather than accelerated approval.

Importantly, this approval covers the entire pediatric age range and reflects the deep understanding by the FDA of the unmet need for children and families affected by this disease. Over time, we expect that children will be diagnosed earlier through Newborn screening, enabling the option for early treatment prior to the accumulation of heparin sulfate and irreversible damage to the central nervous system. As well over therapies, we will monitor clinical trial patients and an additional cohort of commercially treated patients in our disease monitoring program through 10 years of follow-up.

The totality of evidence generated throughout development gives us confidence in the potential of Fayuvi to meaningfully alter the course of this devastating the disease. With that, I'll turn the call over to Eric.

Thank you, Eric. First, I'd like to acknowledge where rare privilege it is to have the opportunity to launch new drugs in a month, impacting the lives of patients with significant unmet needs. The approach you heard me reference a few weeks ago, understanding the need of patients and caregivers first remains our guiding principle for the second launch.

Families with children that live with Sanfilippo syndrome type A, understand that this disease is progressive and relentless. Every day matters to preserve precious neurologic function and each day without treatment risks the potential loss of critical skills and abilities. That understanding has shaped our preparation. We are fortunate that both Jim glycos and AUV fall within our inborn errors of metabolism franchise.

So there are significant synergies between our preparations for both gene therapy launches. Based on extensive preapproval engagement with both Medicaid programs and leading commercial plans, it is clear that payers understand the devastating nature of Sanfilippo syndrome Type A and the importance of treating as soon as possible.

Beyond the clinical impact, payers recognize that the lifetime cost of care forge out with Sanfilippo syndrome Type A who can spend years in a bid ridden state can exceed $8 million and that this burden grows as the disease advances. We set the U.S. per patient wholesale acquisition cost of Fayuvi at $3.95 million as the first and only onetime gene therapy treatment for this ultra-rare progressive and fatal neurodegenerative disease with the potential to slow or stack is irreversible decline.

Consistent with our expectations for genglycos, we expect that access in the initial phase of launch for Fayuvi will flow through single-case agreements. Our OtraCare program has a proven history of helping patients and families navigate access to therapies and overcome potential barriers to care. As I shared at the approval of genglycos, we have expanded that offering to include dedicated gene therapy guys who will help families navigate insurance coverage, assist in obtaining treatment support and answer questions about treatment products.

Treatment will be provided through a national network of qualified treatment centers selected for clinical expertise and experience in gene therapy administration. The network is highly synergistic with our footprint for genglycos with many centers planning to offer both treatments, a list of QTCs will be available on fayuvi.com once that website is live in the coming days. As with genglycos, we have established relationships with treating community with the treating community, like families, providers understand that the time is of the essence for these patients and approach treatment decisions with a strong sense of urgency.

So we are expecting a fairly rapid request for treatment. Fayuvi is manufactured entirely within the U.S. at our gene therapy manufacturing facility in Bedford, Massachusetts and at Andelin Biosciences in Columbus, Ohio. We believe we have adequate commercial supply to meet initial demand and we'll continue our efforts to scale manufacturing over time. We expect that the commercial product will be ready to ship to QTCs in approximately 30 to 60 days, consistent with the expectations we shared for gynglycos. This is now our sixth commercial approval and second gene therapy launch.

The infrastructure capabilities and experience we have built in commercializing rare disease therapies are highly applicable across our entire portfolio of approved medicines with purposeful alignment built into our approach for Fayuvi. We have been preparing for these 2 launches for months, and we are excited to begin delivering this treatment to patients.

With that, I'll turn it over to Emil.

Thank you, Eric. This approval carries special personal meaning for me having worked on treatments for MPS diseases for more than 30 years. For the first time, family is affected by Sanfilippo syndrome Type A have an improved treatment option -- after years of advocacy, scientific innovation, unwavering determination from a remarkable community, we have reached a milestone that many ones believe might never come.

Now the work begins to treat as many patients as we can as promptly as we can. Today's approval further values of vision we pursued since our founding of delivering first-ever medicines to patients with serious rare and ultra-rare diseases regardless of scientific or commercial complexity, the approvals of both Fayuvi and Genglacos demonstrates the strength of our platform, our ability to execute and our commitment to leading the future of rarity medicine.

The company received a priority review voucher upon Fayuvi approval, just as we did for Jelco -- the final delivery of this therapy did not come without tremendous difficulties during its development, and we hope this approval will revitalize investment in other ultra-rare gene therapies. Therapy was developed by high-end food and Doug McCarty, during their tenures at Ohio State University, Nationwide Children Hospital and was licensed to Abeona. We thank Dr. Han Fu her laboratory, the development and leadership team at Abeona and so many patients, families and investors have worked tirelessly through so many obstacles over the many years to lead us to this moment of shared success.

We're honored to stand alongside them, and we are committed to ensuring this approval is only the beginning.

With that, we can open the line for questions. Operator, please provide the Q&A instructions.

[Operator Instructions]

Our first question comes from Yigal Nochomovitz with Citi.

Great. Congratulations to meal and team. Very nice to see this. I guess I just wanted to probe a little bit more, if I may, on the label language with respect to preserved neurodevelopmental function. Can you just drill into that a little bit more? What does that mean? How is that exactly defined in terms of Bailey score or specific retained skills or just a physician caregiver judgment?

Yes. I think a good question, Yigal. And one of the really important piece of the story is to let doctors practice medicine. I think the FDA were very sensitive to the fact that there's a range of patients who might want to get treated, and they offered something more general about this. It doesn't say neurocognition, so it's not talking daily scores, a neurodevelopmental and what they're saying is they have some prefer function, meaning in our interpretation, if someone is bedridden and unresponsive that's someone who doesn't have reserve function.

So it's leaving open the definition of what a doctor and parent wants to do with regard to a level of function. Some preserve function, meaning they're able to respond or have some some ability to participate in life. I think it's really important to not be Bailey is not part of it or part of the discussion. So I think the offered an open-ended view of it, but I think we'd all agree that someone who's at end-stage disease is not a good candidate for gene therapy. And the goal is treated as young as possible.

So this issue is more of an issue at the start because as time goes on, we should be newborn screening and treating kids before their H2 Unifor age 1. And we have some kids treated at 6 months have done really well. And I think that's when we got to get to. So right now, they've offered something broad in terms of preserve neurodevelopment function and did not set any testing standards and what that means. And I think it was very thoughtful to the FDA, and I appreciate their thinking through of letting doctors and patients decide for themselves with the right decision on treatment.

Okay. Great. And if I could just do one follow-up for Howard or for you, Anil. Just could you comment on the time lines to monetize what the 2 PRVs, which are important for your cash position?

Well, I'll let Howard answer that one. Yes. Yigal, thanks Same answer is the last time. We will monetize both of them. We'll monetize the first 1 expeditiously. And the second one, when we think the time is right.

All right. Well, congratulations again.

I think is a good market for them. So we expect to be an important addition or cash position at the company puts it in a very good position.

Our next question comes from Anupam Rama with JPMorgan.

Congrats on the approval here. The press release talked about shipping to qualified centers in the next 30 to 60 days. Can you talk a little bit about how many centers of excellence we're talking about here that are equipped for infusions today and how that could grow over time?

Sure. I think Eric will probably Harriers can provide a little bit on that. Are you able to do that, Eric, on the numbers, but there's a few dozen of them already, but it's growing. Eric Harris, did you want to answer?

Yes, sure. There -- overall, there are about 120 or so centers that focus on these areas. But with regards to qualified treatment centers, we have over 25 under contract now, and they are growing daily. I get updates every -- almost every day, it seems like now with us adding another treatment center. And as consistent with what I said during the call, we expected to get to 40 or so by the end of quality of treatment centers by the end of the year, more than enough to meet the initial demand that we're expecting for both products.

And both -- most of the sites are dual size for both Junglicose and for.

Congrats again on the approval, guys.

Your next question comes from Yaron Werber with TD Cowen.

, agents on the approval. It's an important day for patients. This is Steven Inovov your own. -- among the 3,000 to 5,000 patients that you've identified as prevalent within the Sanfilippo Type A community, what based on the neurodevelopmental stage, would you consider the pool that would be most accessible or most -- I suppose, the first logical treatment candidate for Fayuvi?And how many of those patients are identified and present at current qualified treatment centers?

Yes. So right now, we're aware of in the United States, around 300, 400 patients that are potentially within the range. With regard to the development function, obviously, you don't post that routinely, but about their patients. But generally, when patients reach the 10, 11 years old, they start to be at the end of their period for that become bedridden often as teenagers.

So we're talking about patients generally are going to be younger than that in probably less than 10 or 11, more likely, the average age will be more like 5%. But we'd expect there might be patients up to age 10 that might be still in function. We haven't precisely put down the list yet, but there's a lot of patients to treat already around and -- our hope is to treat as many of the ones that are prevalent now and hopefully to enhance the diagnosis of the young ones where the most good can be done before H2 or really before age on -- but we don't have a precise number, but that gives at least enough idea for the U.S. right now.

Got it. And just to confirm that $300 million to $400 million within the range, that range you're referring to is the range of ages that you were just speaking of right?

Yes, it's about that. yes.

Congrats again.

Our next question comes from Maurice Raycroft with Jefferies.

Congrats on the update. For Eric's comment around the expectation for a request for treatment. Is there more color on that providing? What could initial demand look like? And is there more perspective on what that could be for what patient demand for 2026, maybe through 2027 look like?

Well, I'll let Eric answer the second, but we're generally not going to put out forecasted guidance on what's going to happen in the first 6 quarters, that's have been our habit. So we don't want to overstate and create an issue. We are going to work promptly to get as many as we can. We have enough treatment centers up and they continue to add them to service patients. So we do think that the drug is going to do well. That is we think that there's a higher sea treat we have product available, and we expect to do well.

But right now, going to give any precise predictions on the ramp yet. But I realize that's a very important issue for gene therapy because there have been some ones that have done extremely well and some have done very poorly. I don't know, Eric Harris, is there any other color you would provide on that?

Nothing else to add at this particular time. But other than that there's very strong interest from patients and the patient community.

Got it. That's helpful. And maybe just one follow-up for the price. Do you expect that some payers are going to require an outcome space reimbursement arrangement? And what could that look like? Or is this something that you're offering proactively to payers?

I think we expect in May. I don't know, Eric, do you want to comment on the OBA.

We'll be prepared to engage payers regarding OBAs if that is something that we'll get them more comfortable with providing reimbursement. But we're not expecting to have to do that with the majority of the payers.

Your next question comes from Christian Kluska with Cantor.

congrats on this approval and appreciate you taking this program forward so that these patients now have an option. So I wanted to ask on patient identification efforts. I remember a couple of years ago at World, 1 of his themes was looking at different recognition features for different MPS patients to help identify it, and that was before this AI wave. So I'm curious if there are ways you can be creative about trying to find more patients.

Yes. I think there are -- I think the face recognition for Sanfilippo is probably the weakest feature because they have the least effect on the facial features, where for other MPS, there's much more bone effect and, therefore, more facial effect. The big thing really is the early screening for developmental delay, any development of lay or anything to help identify these cases before they've gone too long.

And I think -- the challenge with that, of course, is that wants some development delay, that means they're already having some brain effect going on. The truth is that the best thing is to work on newborn screening and to get it advanced into numerous screening. There is already MPS 1 and 2 newborn screen or on the RUSP, we need to get this added. We have been supporting work to have the same type of enzyme assay that's used for those others to be SKUs for screening. We think that needs to get implemented. I think the rest process needs to change. The committee has come apart right now, but Secretary Kennedy has been nominating putting things on the list on his own without our advisory committee.

We need to get this on that, and we need to get it implemented across the United States. So these kids are getting treated when they're like 6 months old, which I think will give us the best effect. There are some ways to screen symptomatically, but ultimately, it's got to be newer screening, we've got to press for it, and we're actively doing that

Your next question comes from Salveen Richard with Goldman Sachs.

This is Lydia on for Salveen. Congrats on the approval. Could you just speak to the overlap with the prescriber base with your existing commercial franchise and also the sales force that has been deployed for OpGen IPOs?

Certainly. There is a big overlap. The majority are medical gases that make diagnosis. And so there is a very large lab. And I can let in a moment, Eric wants to add a little more about that overlap. So Macrogen, which is what I'm trained as make the diagnosis commonly. There are some cases areas where pediatric neurologists might make the diagnosis for Sanfilippo where there might not be a medical genesis. So those are a couple of the specialties. I don't know if you have anything else to add, Eric Harris, on that.

Yes. And you asked a question about our current field team. As stated with the genglycos launch, this -- this falls right into our inner metabolism franchise. So the same team that has been calling on these centers for years now with -- for both NEVSEVI and DIJOVI -- we'll also continue to call on these same institutions, and we estimate probably 75% or more overlap.

So this will be a highly leveraged franchise that has established relationships with many of these doctors already.

Your next question comes from Eli Merrell with Barclays.

This is Tejas on for Eli. As you begin to launch both of these 2 therapies in the U.S., can you remind us what key metrics you'll provide for the launch like start forms or something similar? And then in terms of the treatment time line, how should we think about the timing between start form and patients eventually receiving drug?

Okay. So with regard to -- we'll be talking about how many QTC centers we have up and running and ultimately, the number of patients that have been treated we could do start forms, but I guess it's really treated is probably more an accurate sense -- and the second question time to treatment, identified a treatment.

Time to treatment will obviously be evolving over time. I mean in the beginning, they're all exceptions and we're waiting for their policies. Eric, do you have anything to say? I think about time to treatment obviously, it matters a lot for Sanfilippo so we don't want to be -- it can't take a long time. We need to drive this along. We've told all the payers, by the way, that needs to be treated like Zolgensma for SMA. Eric, any thought on time to treatment.

Yes. So we have several patients in process right now as they work and consider treatment. And in fact, we've already received some initial start forms for and as we stated, we'll work with the patients and the caregivers through the reimbursement process, and expect these patients to -- we'll expect product to be available within 30 to 60 days, and that's on track.

So I think somewhere in that time frame, we should have our initial treatment of patients for both therapies.

Something like 30 to 60 days to time to treatment. I think with Fayuvi, we're going to want to -- as time gets going, we'll want to make it as tight as possible. And we've actually set up our systems and the the testing that needs to happen and other things to make sure we can move this along as promptly as possible. Thank you for the question. Let's go on to the next question.

Your next question comes from Joe Schwartz with Leerink Partners.

Congrats on the approval. Given the release frames Global Access as a longer-term goal, I was just wondering what's the timing for other territories, in particular, where does the MAA and the EU stand and then can you remind us of the Abeona economics in terms of things like the approval milestone if there is one royalty rate? And is there any sharing of any proceeds from a PRV

Yes, we can comment. I'll let Howard comment on some of that in a moment. Regard to Global Access, we are going to file in a number of countries shortly or have. And we'll probably put out a little more detail a little bit later, but we expect to have to work toward Europe, particularly soon. But we are also seeing many named patient inquiries from the Middle East and other places for Fayuvi.

So we'd also expect to support named patient treatment outside the U.S. in the meantime, while we are also pursuing formal filings and approvals.

Yes, I'll take the Avion economics. And there's more on this in our corporate deck and in our other filings. But the short answer is no sharing of PRV and the commercial milestones, I think, range up to about $30 million or so, and there's a mid- to high single-digit royalty.

Your next question comes from Ben Burnett with Wells Fargo.

This is Tenici for Ben. Congratulations on approval. -- understanding that the target prescribing physician is largely kind of same. But can you please just quantify how much of maybe expenses that will be associated with this launch?

Sure. Well, we're actually leveraging almost everything that's being done and the few things we added for Genglycose will be used here as well. So it's actually a relatively modest incremental spend for us because the field team is already selling those MPSV and that team is already out there and maybe there's a few people. But I would say the expense has been relatively modest. We do have a gene therapy treatment team like the physicians to help manage the ongoing treatment, but that's we already set that up for Gen glycos and they're managing both.

So the true incremental expense would be modest, and it's going to really leverage a lot of what we've done before. So we think this will help it become accretive to us more rapidly with that base cost already being covered.

And congrats again on approval -- thank you.

Next question comes from Maxwell Skor with Morgan Stanley.

Congratulations I was just wondering if you can provide any insights into gross to net, particularly in the early stages of the launch?

We can, sometimes there are obviously a number of government discounts. Howard or Eric, do you want to comment on that? Yes. So what Eric had said earlier is that our WAC price is going to be 3.95 and what we've shared in the past is that our net range is $2 million to $4 million which, of course, may not be all that insightful because it includes the price. We can help sharpen it maybe later, but that at the moment is what we've shared.

Your next question comes from Jack Allen with Baird.

Congrats on the approval. This is Chris on for Jack. Kind of just piggybacking off that last question, commercial opportunity? I know it's early days, but just back of the envelope math, it seems like your projections could be a $1 billion drug. Just your thoughts on that. And then just one on CMC. I know you made some alterations to that in response to the CRL to 111. And just anything from those changes that you think might be able to help.

On the second one, we do sell fish in the same place. So the change we made helped work with each other in terms of CMC. We didn't change the process at this point. The process being run is a relatively smaller scale process. We opted not to try to change process in the middle of here, but we will probably expect to scale the process further as time goes on as we move ahead.

We haven't talked to the commercial opportunity, I would say, we are not thinking of it as a $1 billion opportunity, I think that would be a reach. But we do think it's a substantial opportunity. And as we can say very clearly from history, whatever you're in gene therapy that the size of the opportunity is not necessarily just the patients, the number of patients exactly, but it's the urgency and how many get treated. I think in Sanfilippo, the urgency will be high, though the population is relatively smaller we will actually see a lot of the patients want to get treated and get treated quickly. They're not going to wait and see -- so I do think it's going to be a very reasonable opportunity probably larger than what people think, but I don't think that it's a $1 billion opportunity. I wouldn't want that people to believe that.

And then, Jack, just let me pull a few things together that have been answered in different parts of the day. So 3,000 to 5,000 patients in commercially addressable markets, and we've talked about maybe 1/4 of those in the U.S. WAC price we've talked about in net price, we talked about lack of 3.95% and that's somewhere between 2 and 4 -- we've talked about the fact that we have a pre-existing field force that doesn't really need to be augmented much to get this out there. And we've talked about a PRV coming along with it. So those are building blocks of the model that we've shared with folks.

Got it. And congrats again.

Your next question comes from Laura Chico with Wedbush Securities.

Congratulations to Emil and team on the approval. I guess just 1 -- I don't know if I should direct this towards Eric a little bit, but I'm trying to better understand what is the capacity of these centers to treat? And I believe I heard about 40 centers. But I guess I'm trying to understand, obviously, there is a high urgency to get folks in the door here, but there's also a pretty complicated cases.

So just wondering if you could expand on what happens to get centers up and running and what that capacity looks like.

Yes. Well, I think Erik has told you, we had 25 we're adding them regularly. In fact, some of the first gen glycos patients were at new centers. So we actually have a whole team set up to set up train centers and train them wherever they are. We're not going to be stiff about requiring only certain centers. We made them to be quick as possible. But based on payer issues, region state issues, we have to make sure to be adaptive, and we are planning to be. I don't think capacity of the centers to treat patients is going to be a limiter in our ability to commercialize at all.

I think we've got plenty of QTCs and we will add them as needed, wherever they're needed to make sure we are treating everyone that needs to get treated. So right now, I don't think that the QTC capacity is going to be an issue. I don't know if you have anything else to fares on it.

That's right. I mentioned we've grown more than -- and more than 25 now, expect to get up to 40% or so by the end of the year. We'll keep adding as we move forward with expanded demand. So I don't want you to think we're going to attack the number of treatment centers at 40. We'll continue to expand as needed.

And the last question comes from Ram Selvaraju with HC Wainwright.

This is Jade on for Ram. And congrats on the 2 gene therapy launches. Could you just discuss quickly what real-world evidence data is likely to be collected following the launch in your patients?

Yes. Well, has talked about a lot -- we actually believe in another more all disease monitoring program model, which is a fully sponsored model where we collect accurate high-quality data and support the doctors and the patients and getting that data, which will allow us to do it with great precision and quality limiting missing data.

The FDA has accepted the DMP is now for all 6 of our programs that have been approved as a single post-marketing commitment in which we do all the clinical work. It's a different model than real-world data, but we will collect data in our programs for up to 10 years. But all the patients in the program are on commercial drug. So they don't get drug as part of this program, they get monitored or they get testing done by it. The difference in with real-world data instead of using electronic records and other sources to pull up information. We're able to quantitatively more like a measure individual data.

Now there's no doubt that claims data or other real data will be a supplement to it, but it's not our main focus. We definitely think there's an opportunity to use real-world data as it just won't be the main thrust of our approach to monitoring patients long term.

Great. And just quickly, could you discuss the mild label restrictions on liver function, particularly as pertains to AAV therapies.

Sure, I'll let Erik do that. I think the general view is that all AVs go to the liver. And so you don't want to have a liver that's highly injured so that you don't hurt them. But Eric, do you want to say anything about that?

Eric Columbus?

Yes. Right. Thank you. Yes. So certainly, no restrictions in the indication we always, as Emil said, want to dose patients with relatively healthy levers, but that's not an issue here that wasn't like a screaming issue or something that we really encountered while we are enrolling these trials. So we don't expect it to be an issue at all in the commercial setting either.

The sample patients don't have liver injury. There are some diseases where there is, but they really don't have significant liver injury.

The last question coming from Sami Corwin at William Blair.

This is Josh on for Sami. Congrats on the approval. We were wondering what launch metrics the company plans on sharing? And how soon should we expect those updates?

Yes. So where do you want to put it? We're playing to -- we'll tell you about how many QT centers and how many patients have been treated for both diseases. So that will be it. We'll probably be doing that on our quarterly calls was our expectation. And at points where we're providing revenue numbers will provide revenue numbers. But those would be the metrics right now. I think those are the ones that are important. It should give you a feel for how things are going. By the -- the first call is coming here. I'm not sure there's a lot to be said yet, but we do expect in every quarter to provide qualified treat centers number of patients treated revenue numbers for each program.

This now concludes our question-and-answer session. I would like to turn the floor back over to Joshua Higa for closing comments.

Thank you. This concludes today's call. Please reach out to us at [email protected]. if you have any additional questions. Thanks.

Ladies and gentlemen, thank you for your participation. This does conclude today's teleconference. Please disconnect your lines, and have a wonderful day.

Good afternoon, and welcome to the Ultragenyx Pharmaceutical Conference Call to discuss the U.S. Food and Drug Administration approval of GENGLYCOS known as DTX401 for the treatment of glycogen storage disease type 1a or GSD1a.

[Operator Instructions]

And it is now my pleasure to turn the call over to Joshua Higa, Chief of Staff and Vice President of Investor Relations. Thank you, Joshua. Please go ahead.

Thank you, and good afternoon, everyone. We appreciate you all for making time to join us on such short notice to discuss this important day for Ultragenyx. The press release we issued announcing the approval of GENGLYCOS is available on our website at ultragenyx.com.

Joining me on today's call are Emil Kakkis, Chief Executive Officer and President; Eric Crombez, Chief Medical Officer; Erik Harris, Chief Commercial Officer; and Howard Horn, Chief Financial Officer.

Before we begin, 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 SEC filings.

And with that, I'll turn the call over to Emil.

Thank you, Josh, and good afternoon, everyone. Today is an important day for Ultragenyx and for the GSDIa community. Earlier today, the FDA approved GENGLYCOS, marking Ultragenyx's first gene therapy approval and the fifth approved medicine in our company's history. It is also the first ever FDA-approved treatment designed to address the underlying cause of glycogen storage disease type 1a, representing exactly the type of breakthrough therapy Ultragenyx was built to deliver. This is a day that thousands of people living with GSDIa in the United States and elsewhere and the families and clinicians who care for them have hoped and advocated and thought for over the years.

Until today, the only thing standing between a person living with GSD1a and a life-threatening episode of hypoglycemia was cornstarch taken as a slurry every 3 to 4 hours around the clock, day and night. Now there's an additional treatment with the potential to reduce their dependence on cornstarch and ease the constant burden of care that defines their lives. We're grateful to everyone across the GSDI community who helped make this today possible, and we want to especially thank the patients and families who are participating in our clinical trials.

As a reminder, our randomized placebo-controlled Phase III study met its primary endpoint with a statistically significant reduction in daily cornstarch intake and was also positive in multiple secondary endpoints. Late during the review, the agency decided to consider cornstarch reduction as a surrogate endpoint and so approved GENGLYCOS by accelerated approval pathway. The FDA requested additional evidence to confirm this reduction associated with clinical benefit and improved fasting tolerance over time. We agreed to generate that data through enhancements to our existing disease monitoring program or DMP. And Eric will share some additional details of our post-marketing program when he walks through our clinical data.

Ultragenyx has created to lead the future of rare disease medicine, and that vision goes beyond the moment of approval and into our conduct as a commercial company. We're committed to helping patients access the treatments they need and reduce financial barriers that may stand in their way. GENGLYCOS extends that leadership into gene therapy, and it does so as a medicine we manufacture end-to-end entirely in-house at our gene therapy manufacturing facility in Bedford, Massachusetts.

With that, I'll turn the call over to Eric Crombez and Erik Harris to walk you through our data and launch plans. And finally, Howard Horn to comment on the PRV and our expectations for launch.

Thank you, Emil. The approval of GENGLYCOS fulfills our commitment to provide the first therapy that directly targets the root cause of GSDIa. The reduced reliance on cornstarch demonstrates this liver-directed gene therapy's capability to deliver the necessary transgene to enable patients' livers to break down glycogen and to produce glucose during fasting or metabolic stress. This ability to regulate glucose levels has alleviated the disease burden and mitigated the risk of severe or life-threatening hypoglycemia for these patients.

GENGLYCOS indicated for the treatment of adult and pediatric patients, 8 years of age and older with glycogen storage disease Type 1a who do not have antibodies to AAV8. The BLA was based on data from our Phase III randomized, double-blind, placebo-controlled study, which enrolled 46 patients aged 8 years and older. Results from the Phase III study showed that patients treated with GENGLYCOS reduced daily cornstarch requirements compared to placebo while maintaining glycemic control.

GENGLYCOS was well tolerated with an acceptable safety profile. The most common treatment-related events were transient elevations in liver enzymes that were generally nonserious and managed with a prophylactic corticosteroid regimen. The results across the entirety of the clinical development program, which encompasses data on 52 treated patients over 8 years of follow-up speaks to both the magnitude and to the durability of effect of this gene therapy.

In regard to the post-marketing requirements that Emil referenced, we will collect 2 years of data from 50 commercially treated patients through enhancements to our existing disease monitoring program, evaluating daily cornstarch intake and time to hypoglycemia in a controlled fasting challenge. We will also follow 20 untreated patients who have AAV8 antibodies over the same time period as the control group.

Unlike the Phase III study, this DMP evaluation will be performed in the open-label setting with patients and the physicians receiving real-time glucose measurements. We believe that this will allow for greater cornstarch reduction and improved metabolic control compared to what can be achieved in a blinded study without real-time glucose information available to patients.

As a reminder, the use of a DMP is the strategy that we have used for 4 prior approvals as the sole and comprehensive evaluation of all of our treatments in the post-marketing setting. The GSDIa DMP will collect 10 years of treatment data across clinical study participants and new commercially treated patients. This DMP is already active and enrolling clinical trial patients as they cross over from the Phase III study to long-term follow-up.

With that, I'll hand it to Eric to discuss how we are bringing GENGLYCOS to patients.

Thank you, Eric. As we have approached each launch in our portfolio, our guiding principle has been to start with understanding the needs of the patients and caregivers. The repeated success of this approach has informed our preparation. Supporting patients is at the center of our work. Our UltraCare program has an established track record of helping patients and families successfully navigate access to our approved therapy.

Treatment with gene therapy is a multistep process. So we have adapted our offering with that reality in mind. We have established a new dedicated role called UltraCare Gene Therapy Guides, who will help patients navigate insurance coverage, assist in obtaining treatment support and answer questions about the treatment process. In coordination with providers, treatment will be delivered through a national network of qualified treatment centers, institutions with specialized expertise and training to safely administer gene therapy. We selected our network of centers based on clinical experience with GSDIa and gene therapy administration as well as for a geographic footprint that is rightsized for anticipated demand while minimizing travel burden for patients and their families.

Our teams are being deployed immediately upon this approval to train teams at QTCs on the final label and we'll continue to onboard and train centers to ensure medical readiness on a rolling basis as contracts are finalized. A list of QTCs will be available on genglycos.com once that website is live in the coming days.

As we've mentioned previously, there is roughly 75% overlap in GSDIa providers with the treating community we know well for Mepsevii and Dojolvi. Our commercial organization is already in the field and able to leverage established trusted relationships with key providers.

Shifting to payers. Our work to lay the foundation for quality coverage has been extensive with numerous interactions across state Medicaids and large national payers. Consistently, payers appreciate the severity of GSDIa and associated unmet needs. We are also encouraged that they recognize a reduction in cornstarch dependence as a clinically meaningful endpoint that represents the potential to deliver substantial impact for patients, caregivers and their families. We have set the U.S. per patient wholesale acquisition cost of GENGLYCOS at $2.7 million, reflecting its potential to reduce patients' reliance on cornstarch and enable better metabolic control of glucose.

As Emil emphasized at the outset, we have a strong commitment and track record of supporting patients and families in helping to access our approved medicines, and that approach will extend to gene therapy. Consistent with what's been observed for other newly approved gene therapies, we expect access will flow through single case agreements in the initial phase of launch. We are familiar with an experience in this pathway. So we stand ready to help patients and providers in navigating the process. GENGLYCOS is manufactured entirely in-house at our gene therapy manufacturing facility in Bedford, Massachusetts. We have existing commercial inventory to meet anticipated demand and we'll continue to scale production as the launch continues.

I'll close by reminding you, this is our fifth commercial launch in rare disease. We are leaders in navigating or in some cases, building complex paths from product to patient. Our team brings the experience, agility and most importantly, the commitment for patients as we deliver our first gene therapy in the commercial setting.

With that, I'll turn to Howard to touch on launch expectations.

Thank you, Erik. Consistent with our practice, we plan to provide revenue guidance once we have sufficient visibility into market dynamics, which historically has been approximately 6 quarters after launch. In the interim, we look forward to updating you on metrics such as how our QTC network is growing and ultimately, the number of patients that have been treated. With clear urgency to treat supporting patient demand and our highly leveraged commercial model, we expect GENGLYCOS will make an important contribution to our profitability. Additionally, I can confirm that Ultragenyx received a priority review voucher with GENGLYCOS' approval. We plan to monetize the PRV to bolster our balance sheet and support our path to profitability.

With that, I'll turn it back to Emil to close.

Thank you, Howard. Developing first-ever treatments for rare and ultra-rare disease is why we exist as a company and because we believe we have a responsibility to put the best available science to work for patients and families who are too often left behind. Our teams are prepared to bring a new treatment option for GSDIa to patients that need it. The key characteristic of successful gene therapy launches is related to the urgency of the disease. And GSDIa is an urgent disease with round-the-clock demands on patients every day and night without holiday or break. A gene therapy designed to deliver the missing enzyme is the ideal way to address this severe ultra-rare genetic disease. We look forward to updating you on our progress.

In closing, I want to pause again to reflect the enormity of this milestone. It's a first for us, for our gene therapy manufacturing facility and most importantly, for the GSDIa community. After 50 years of cornstarch as the only available option for patients and their families, it's extraordinarily meaningful to be able to take advantage of the science that exists to deliver an option designed to directly treat the underlying cause of their disease. This approval reflects the work of a remarkable team spanning many years and organizations.

We are deeply grateful to the original team from Dimension Therapeutics who worked on the program and to Janice Chou, who did some of the early research at NIH. We're also thankful to Dr. David Weinstein, whose scientific leadership laid critical groundwork and whose support and was involved in the early clinical trial. We must also thank the patients and families and PIs, investigators who made our clinical studies possible and the myriad of Ultragenyx employees throughout the company who supported this program through development and across the finish line. The collective commitment and perseverance have transformed a scientific vision into a new therapy option for patients.

Operator, please provide the Q&A instructions.

[Operator Instructions] And the first question comes from the line of Anupam Rama with JPMorgan.

Congrats on the approval. Really cool to see. Can you walk us through the segmenting of this GSDIa market? What portion of patients are treated at sort of medical genetics centers of excellence? And how are you defining the various call points here?

Yes. No, it's an interesting question. The majority of the patients are treated by medical genetics patients, doctors. That's where they usually get diagnosed and usually where they're managed, although there are some endocrinologists that do manage the patients. But as I think Eric mentioned, we have about 75% overlap with the doctors we're already seeing. So it's a pretty -- we leverage our commercial footprint pretty well right now, and we're not really concerned about it.

We also have our patient find program, which will go out and find patients who may not be at the centers where we're operating in to discover where they are and help bring them into the fold or add new QTC centers or call points. But right now, we think the majority will be within our catchment area, and we'll always be looking to find those other patients as well. But I do think we can leverage our investment in the field that we've been building over the last few years.

And the next question comes from the line of Yaron Werber with TD Cowen.

Let me add that this is really a terrific milestone. Congrats on this. This is years and years of work. I have maybe just a couple of questions. The first one, Emil, you mentioned [indiscernible] inventory and the confirmatory work as part of the DMP, is that going to be under commercial settings? Or is that going to be under as a clinical study protocol? And then finally, just remind us, this is a big milestone or a derisker for the MPS IIIA program [indiscernible] and what's the overlap?

Yes. So with regard to the inventory, we have asked to cover the launch and what -- the confirmatory 50 patients are commercial patients treated commercially. And as we're treating commercial patients, if we find some patients who have antibodies to AAV8 are not -- can't qualify for treatment, we'll include some of those 20 of those to be in the control group. So we'll conduct that through our DMP program, but they are commercial patients, revenue-generating patients. That allows us to do a larger program and allows us to get more data, and that was, we think, a better way to go. It's a high-quality, fully sponsored trial, though, all of our DMP programs, we don't do registries. We all do DMP for all post-marketing. And it's our way of solving the question of how to get high-quality post-marketing data and put the money where it means something where you can do something with it.

In regard to what it means for MPS-IIIA, the GSDIa is fill finished and produced at the same Bedford plant where 111 is also fill-finish. So there's overlap in the facilities. We can't speak yet to comments about the 111 review, which is ongoing. But the plant is approved now to do fill-finish for GSDIa. So obviously, that has some read-through on the process and conditions that are required to get approval for fill-finish that overlap with the 111 program.

And the next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

It's Ross on for Kristen. Congrats on the approval. Really curious if you guys could provide any color as it relates to kind of the treatment center capacity. And also, how many treatment centers do you expect to have online by the year-end and in 2027?

I'll put a few high-level comments and if Erik wants to give a little bit more color on the number. Our goal with the treatment center is to set up enough centers to be able to accommodate all patients we need, but we also kind of expect that we're going to have to continue adding. We've done a lot of work in building up the network. And we haven't put out the exact number. But Erik, you can provide maybe a little more of where we are on building QTCs?

Yes. Well, I won't give out the exact number. We feel confident we have a sufficient number of QTCs under contract now and expect that to expand very quickly now following approval and with the potential to double by the end of the year. So we'll be able to meet the initial demand. And as I also stated, we'll continue to add treatment centers as demand grows.

And the next question comes from the line of Yigal Nochomovitz with Citigroup.

Congratulations as well on the approval. I just wanted to ask what triggers the full approval? Do you have to wait for the 2 years for the safety and efficacy data from the 50 patients and 20 control? Or does the FDA also want to see some additional duration because you mentioned that you're going to be following these patients for a total of 10 years. And then also, if you could please comment just what percent of the population do you expect would be positive for AAV8 antibodies?

So the commitment to complete 2 years of data for the conversion approval into study endpoints we have studied, the number of doses of cornstarch as well as the time to hypoglycemia between 70 and 54. So those are endpoints we've evaluated. So we are comfortable with that evaluation. But we're going to do it now in open-label treatment format, which will allow the treatment to be implemented, let's say, in a more real-world setting, those 2 years of that.

We will follow patients for 10 years as part of our commitment we do in all of our programs. It's not part of the confirmatory program, right? It's part of our general commitment. And gene therapies in general, have a longer lead time in monitoring for safety in any case. But we as a company commit to investing in these longer-term programs as part of our commitment to these -- the rare disease community.

Regarding the percent of the population, it's varied. It's maybe 1/4 of the patients, but it's around that range. It varies in different areas and regions. So I don't want to give you a precise number, but it's around that range. and we expect it to be similar now. So that's where we are at the current moment.

And the next question comes from the line of Ellie Merle with Barclays.

This is Tejas on for Ellie. Could you just remind us about the plans and timelines for ex U.S.? And then with about 3/4 of that population outside the U.S., how do you see that dollar opportunity shaping up relative to the U.S. given all the different pricing and reimbursement dynamics there?

Tejas, could you give me the first part of your question? I missed something. It just broke up a little bit. The first part of your question again?

Sorry, just on the latest timelines and expectations for ex U.S. approval and then the relative size of the opportunity.

Okay. Yes. So we do expect to commercialize elsewhere. And we think that we're within the worldwide price bandwidth has been successful for other programs. I think it depends on the level of urgency of the disease, in fact, whether we're successful elsewhere. We haven't put out an exact timing. We are planning and we will be filing and have filed in other territories.

The commercial value in U.S. relative to the rest of world, we usually consider the rest of the world as being a larger fraction of the total market. But in gene therapy, that may not be true. The pricing may be have more pressures, and we're going to have to work through that. But we actually think there's already been some price standards set that are above even where we are with this particular ultra-rare disease. And we think we have excellent randomized control data to support it. And so we believe we're going to find a place to be able to commercialize and make substantial revenue ex U.S. as well as U.S. So we're not looking at this as a pure U.S. play. We think we're going to look at it globally.

And we certainly have operations in Europe, Latin America, Japan as well as support of distributorships in other regions like Middle East, et cetera. So we've gotten inquiries from around the world for this disease and getting treated. So I expect there will be demand and important supply and contribution to our future revenue.

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

This is Lydia on for Salveen. Congrats on the approval. Could you just speak to when you expect GENGLYCOS to be commercially available and your expectation for the shape of the early launch curve here? And just the timeline for when patients initially engage with their health care provider to actually getting the treatment?

Yes. So we would expect it to be available within 30 to 60 days from that time frame. There is a process where FDA also releases and that process is ongoing. And -- but we are putting the last pieces together, but we're -- it should be relatively soon. We haven't put forward launch curve or the revenue expectations. We just -- we don't like to do that because we think there is urgent need and a number of patients that want to get treated. But rather than project out, we're going to let the market work and then provide some updates on that. And the last item was about the doctors. Is that right?

Just the timeline from the initial interaction to actually when the treatment would occur.

I see. Well, we don't know you mean how long it takes to have a start form and turn that into a treatment event that -- I'd expect in the beginning, it's all going to be operating off of exceptions, right, of case-by-case exceptions. I don't know, Erik, if that's something you'd want to touch on a little bit here about that process between start form to getting treatment implemented?

Yes. And Emil, I think they also want to know how quickly can you work up a patient to get treated. But let me take the enrollment. Once we receive the enrollment form, we will start working with the patient to navigate the reimbursement process. And as I stated in the opening remarks, they'll take some time to work through their policies for treatment. But we expect, based on our discussions that we've had with them, and they recognize the unmet need and the value that this product brings that we'll be able to get patients approved on a case-by-case basis.

Yes. So the workup part is the main thing they have to get is an anti-AV antibody titer. They have to have the genetic diagnosis, but patients generally have had it already. AAV antibody should not be a particular issue. And then when they get to gene therapy, they don't start any immune modulation or steroids until afterwards. So there's no other preparative effect going on. It's really, I guess, anti-AAV antibody and start form and reimbursement process.

And the next question comes from the line of Maxwell Skor with Morgan Stanley.

Congratulations on the approval. So I see the label asked for steroids in every patient and 6 months of liver monitoring. Is that a hurdle for any of the QTCs? Can you just walk us through how that looks? And yes, any color around that, the monitoring process would be very helpful.

Sure. I'll let Eric add some color, but it's not a big deal. We've been doing this now in the trial. So we have a comfortable plan where we start the steroids on a time basis at 2 weeks and then they're monitored at intervals. I don't know, maybe Eric can provide a little more color. But they're pretty used to this. This is pretty common and standard. I don't think there's any big deal here. And we didn't really have a really major problem with the transaminase. These are relatively lower dose gene therapies. It's not like situations with the very high-dose gene therapies where there's more safety risk. But I don't know, Eric, do you want to provide any color on the steroid regimen and the burden for QTCs?

Yes. No, I think absolutely for systemically administered gene therapy, I think this really is the standard use of steroids that everyone has gotten very comfortable with. Again, important to stress this isn't a significant safety concern for patients. We just really want to use the steroids to control any type of immune response to preserve as much transgene in these hepatocytes as possible. But I think we are very comfortable that these treating physicians will be very comfortable with the use of steroids in this context.

And the next question comes from the line of Raghuram Selvaraju with H.C. Wainwright.

This is Amit on for Ram. Congrats on the approval. I was just wondering on the label contraindicates treatment in severe hepatic fibrosis patients and again using it in patients with preexisting hepatic impairment. What criteria will centers be using to define hepatic impairment? And could you give some color on what proportion of otherwise eligible patients do you expect to lose because of liver findings, if any?

Thank you for the question. I'll let Eric in a moment add a little to that. I don't think we've had that situation. I think it was something that we involved in the trial, and that's why it's being reflected there. But we didn't really have anyone I'm aware of being excluded. I don't think there's any specific criteria. And the idea is that they have very limited liver function or they have really bad liver injury. The question is do you want to put a gene therapy on top of that because of the transient effects of it. But we have not really seen significant issues. So I'm not really concerned about this. But Eric, any thoughts on this liver fibrosis question?

Yes. And again, this is something generally listed for inclusion criteria for liver-directed gene therapy. And that's exactly as Emil said, you want as healthy of a liver as possible when you're dosing with gene therapy. So we didn't encounter any patients who needed to be excluded during the course of the entirety of the development program. I think there's always possible that a patient could have a concomitant disease that could lead to this type of damage. But I think it will -- if anything, it will be a very small number of patients.

And the next question comes from the line of Joe Schwartz with Leerink Partners.

It's Ashleigh on for Joe. Congrats on the approval today. Just one question from us. It seems like patients are mostly severe. So is there any segmentation as to who you guys would consider early adopters? Any color there would be really helpful.

Yes, Ashleigh. So when you look at the genotypes, something like 81% of the genotypes are severe, very low efficiency. There are some that are maybe a little bit enzyme. But the truth is all the patients that are getting diagnosed tend to be severe patients with real disease really very limited. So I don't think that segmentation matter as much. I don't know, Eric, if there's anything you want to add to that segmentation piece. I actually can........

Yes, I know. Absolutely......

Yes, go ahead.

Yes, absolutely. I think with a lot of these inborn errors of metabolism, we do see quite a range of severity in disease. That is not the case with GSDIa. It really is a very consistent phenotype with patients. And I think when we're talking about patients needing cornstarch every 2 to 4 hours around the clock, that is consistent with what we see here. And I think those are patients who are obviously ideal candidates for this. But as Emil mentioned, we really don't see mild patients with GSDIa who don't have that type of cornstarch requirement.

And the next question comes from the line of Ben Burnett with Wells Fargo.

I'll add my congratulations here as well. I wanted to ask, what is your expectation for the adoption curve? Just based on everything you're seeing from a sort of patient finding perspective, just curious if you could speak to your expectations for sort of the rate that you may find patients and sort of the rate that this could grow from a revenue perspective? And should we expect 2026 to be a meaningful year in terms of revenue?

Yes. Very good. Well, look, we -- I'll put it this way. When we ran the trial, did enroll quickly. Like we had demand. It enrolled quickly in different countries. There was urgent demand. And the reason is that there are so many patients who are on this treadmill running and running every day doing this. They want to get off it, right? So you have to think of the urgency of the disease. We found it very urgent. We think there will be significant demand. We have a number of patients found. I think there will be a reasonable degree of urgency why we think it will be a successful launch.

We haven't put forth any numbers because in the beginning, we have to work through reimbursement and policies and exception processes, et cetera. But we would expect some revenue in '26, but I don't want to -- I don't think that's going to necessarily reflect how it will do.

I do think that this is a gene therapy that has no other good solution or treatment, no other specific treatment and for which the patients are on a treadmill that is a crazy 7-day a week, 365-day a year, multiple round the clock, right? You have to imagine yourself in that setting, would you want to get off that thing? Or yes, you probably would. And especially when you imagine that at any time at night, you miss something, you could die if you mess up, right? It's a terrible way to live, and we have a sense of a lot of urgency among patients to do something better.

So we think it will do well. We are not yet able to project out how we think that -- what the numbers will be. But we have a sense from the trials alone that enrollment was not an issue. In fact, when we closed enrollment, we had people upset. They couldn't get in the trial. So I feel that I can feel the demand is there, and we're excited about the potential of treating a number of patients out there as we go commercial.

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

This is James on for Maury. Congrats on the approval. Can you confirm whether the 96-week durability data is reflected in the label? And separately, beyond the 200-plus payer engagements completed as of 2Q, what's the current state of payer coverage policies? And then separately, just a third quick one, how are you thinking about gross to net expectations? Do you expect mid-20% in line with some of the other gene therapies?

Wow, you popped them all in there. I'll let Eric handle the last one on the percent, the gross to net. I think that's what that question was. And we'll talk about payers. First one was -- I'm sorry, what was your first question? I missed it.

96-week data.

Yes, 96 data. Yes, there is some 96-week data in the label related to the 61% reduction in the crossover that's in the label under the clinical trial section. So that's there. Most labels I will point out to you have very limited bit of data. So it's pretty common and rare that you don't see all the data in the label. We do have a publication that's been accepted at proof that will be coming out soon. That paper will have the more complete data and be available.

With regard to the payers, we've done a lot -- there are no policies yet. We've been talking, and I have personally been involved in a number of the pipe presentations. But there are some groups that won't really engage until the approval occurs, but others we haven't had meetings and so forth. So I think they are aware of -- I think they're aware of the urgency and part of my role to help to understand the urgency and severity of the disease. I think we will be operating purely under the exception mode beginning, and then we'll get into getting policies. But because we've been doing this leg work all year long, I think we've prepped a lot of the biggest plans with what this is about, why it's important. And I think that's laid good pipe for having a productive discussion about ultimate policy coverage.

Eric, did you want to talk about the -- I think you're asking about sort of the gross to net kind of expectations and discount. Is that right?

Yes, I'll just make one comment and then turn it over to Howard to talk about the gross to net. And as you stated in your question, we do expect it to be very similar to what you have seen with other gene therapies, where they'll be on a case-by-case basis as they work toward policies. But we fully expect these patients to get access in a reasonable time as they did with other gene therapies.

Howard, do you want to...

Consistent with our past comments about overall average net pricing, I think we've talked in the past about a range of $1 million to $2 million. Given the lack of $2.7 million, I think we should anticipate it to be at the top end of that range or near the top end.

And this now concludes our question-and-answer session. I would like to turn the floor back over to Joshua Higa for any closing comments.

Great. Well, thank you all for joining us on such short notice. If you have any follow-up questions, please reach out via e-mail at [email protected]. Thanks again for joining us.

Thank you, ladies and gentlemen. That does conclude today's teleconference. We thank you for your participation. You may disconnect your lines at this time.

Good afternoon and welcome to the Ultragenyx Second Quarter 2026 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. now my pleasure to turn the call over to Joshua Higa, Chief of Staff and 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 Kakas, Chief Executive Officer and President, Howard Horn, Chief Financial Officer, Eric Harris, Chief Commercial Officer, and Eric Krambes, 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 the second quarter, we continued our pattern of strong execution across the development and commercial organizations. The commercial teams delivered the highest quarterly revenue in the history of the company, which supports our reaffirmed full-year revenue guidance. As they have done in prior quarters, they continue to find new patients and expand access to CRISVITA, Doljolvi, Ebkisa, and Mepsevi around the world. The commercial and field teams are also preparing for our first two potential gene therapy launches, which are anticipated in the coming months. If approved, both these therapies would represent first-ever treatments for disease with significant unmet needs and high urgency to treat. The PDUPA date for DTX 401 for GSD 1A is just a few weeks away.

Patients with GSD1A have to drink a flurry of cornstarch every few hours around the clock, day and night, knowing that a single missed dose could lead to their death. This is a constant reminder of their disease and the severe consequence of missing a dose. In our Phase I, II, and Phase III studies, patients treated with DTX4-1 have been able to significantly reduce the amount and frequency of cornstarch doses to a pre-specified clinically meaningful degree. More importantly, this gene therapy allows patients to have a more normal glucose metabolism, staying in the normal range a larger fraction of the day. The expression of the missing G6PAs enzyme from the DTX401 vector should allow their liver to break down glycogen to produce glucose during times of fasting or metabolic stress. The ability to regulate glucose better has reduced the burden of disease and reduced the potential for rapid decline to dangerous glucose levels. Transitioning now to UX111, I've been in and around the NPS community for many years, and I've seen so many San Felipe patients have to watch helplessly as their children decline and die.

San Francisco syndrome type A has an urgent need to treat, and yet there has been nothing for them. Staphylococcal syndrome is a horrible neurodegenerative disease, and kids are losing brain cells every day. Patients between the age of two and six years progressively lose their cognitive function. By 10 years old or so, they're often bedridden and tube bed and in and out of the hospital for many years. They can end up nonresponsive for the last five or ten years and often die as teenagers. Until now, families have had no option but to watch helplessly as their children decline and die. Based on our clinical data, treatment with UX111 reduces heparin sulfate in these patients and enables them to stabilize and retain cognitive function compared to natural history.

While patients across the industry in the study showed benefits following treatment with UX111, It's also clear that treating earlier demonstrated better results by protecting their brains before they had lost too much function. With a disease like sample evil syndrome, there's no greater as long you wait, the less function you may have. Our development organization under Dr. Krambez, as we're working with regulatory agencies around the world on BLA submissions, both GTX 4 over GSD1A and UX111 for San Felipe O'Ain syndrome. These include preparing the applications, responding to information requests, and supporting facility inspections. This would be a lot for a single BLA. Our team is working simultaneously through the process for two BLAs that have Paducah dates a month apart. We remain confident in the work our teams are doing to support these applications.

Shifting to GTX 102 for Angelin Syndrome, where we have the most advanced clinical ASO program. In the Phase III ASPIRE study, the last patient in has had their 48-week visit. and the teams in the process of cleaning and locking the database. For a global study like this, the process can take months, and we expect to unblind and share top-line results with you in September or October timeframe. With three major catalysts on the horizon, the second half of 2026 is poised to be the most significant period in our company's history. We're positioned to lighting series of potential first for our company, the communities we serve, and the broader field of rare disease medicine, including the first gene therapy approvals for all genetics, the first FDA approvals for two devastating and intractable rare diseases, first late-stage clinical data in the Angelman syndrome. It's a privilege to continue to lead the future of rare disease medicine. We believe the combination of continued growth from our current products, accelerated by contribution from potential upcoming launches and disciplined expense management gives us a clear path to profitability in 2027.

I'll now turn the call over to our Chief Commercial Officer, Eric Harris, who will provide details on the commercial business and launch of its activities in the second quarter.

Thank you, and good afternoon, everyone. As Emil mentioned, we are pleased with our steady, successful commercial execution. and we continue to see the benefit of our global infrastructure across products and regions. As we described on the last call, underlying demand for our products remains strong. But seasonal factors can cause quarter-to-quarter variability in revenue. In the second quarter, we saw the strong rebound in orders that we were expecting, reinforcing our confidence that we are on track to deliver against our four-year guidance. Starting with Chris Vita in North America, where our partner KKC is commercializing, we continue to see steady growth in the underlying demand. years post-launch, it's extremely gratifying to continue to see the steady addition of new patients starting this therapy. In Latin America, Cursita performance was strong in the second quarter, supported by the combination of continued pacing growth and and timing of regional orders, including Brazil and Argentina.

Approximately 50 patients began commercial therapy in the quarter, bringing the total number of patients on Chrisleeda to 1,000 in the region. As discussed, we expect that ordering patterns will continue to create some quarter-to-quarter variability. We are confident that the underlying demand will continue to grow steadily. In Turkey Eye, there are over 100 patients being treated with CRISPR-VITA through the NAME Patient Program. It has been the case in other countries. There is accelerating demand as HEPs and patients see the benefits this transformative therapy offers. Shifting now to DeJovey, the trend of steady growth continues.

In North America, our team generated approximately 30 stock forms in a quarter, and we now have approximately 675 patients on reimbursed therapy. In Europe, approximately 300 patients are being treated through named patient or early access programs, with notable growth in the MENA region following marketing authorization approval in Kuwait. We also recently began treating patients with the Jovi in Japan. following its listing on the National Health Insurance Drug Price List. We are off to a strong start in demand, reinforcing our belief that this country represents another meaningful opportunity for continued growth over time. FQIESA continues to be an important and growing contributor to our revenue base. In our territories outside of the United States, we are responsible for commercialization. There are more than 500 patients across 25 countries receiving FKESA.

Our teams continue to navigate country-by-country reimbursement, support early access, and convert appropriate patients to reimburse therapy. Beyond the individual product performance, the real strength of this business is the the scale, reach, and experience of our global commercial infrastructure. Rare disease commercialization requires deep market-by-market expertise to inpatient find reimbursement navigation, and field execution. That is what our global team provides every quarter and giving us high confidence that we will be prepared for the next potential use. I'll close briefly with a couple of comments on the teams engagements with payers, we've been pleased that they recognized the significant unmet need associated with both diseases. and understand the particular urgency to treat and Sanfilippo syndrome. the foundation necessary to support and minimize for eligible patients. We've been building toward these potential launches for years. We stand ready to add these products to our existing portfolio and expand our mission of helping patients with rare disease.

With that, I'll turn the call to Howard to share more details.

on our financial results and guidance. Thank you, Eric, and good afternoon, everyone. I'll focus on our second quarter financial results, guidance for the year, and provide a few comments on our path to profitability. Starting with revenue, revenue for the second quarter of 2026 was $214 million. CRISVITA contributed $156 million, $94 million from North America. 54 million from Latin America and Turkey, and 8 million from Europe, which were consistent with the anticipated quarterly timing and trends Eric just mentioned. The Jolby contributed $27 million, consistent with our expectation for SETI demand growth. And Pisa contributed $21 million, representing 50% growth over the second quarter of 2025 as the moon continues to build following launches in our territories outside of the United States.

And Mepcevi contributed 10 million as we continue to treat patients in this ultra-rare indication. Total operating expenses for the quarter were $289 million, which included cost of sales of $34 million and combined R&D and SG&A expenses of $255 million. Total operating expenses included $34 million of non-cash stock-based compensation. For the quarter, net loss was 92 million, or 90 cents per share. June 30, we had $406 million in cash, cash-equipped and marketable securities. Net cash used in operations for the quarter was 97 million, a significant decrease from the first quarter and consistent with the expectations we discussed on our last call. As noted in our press release, we are reaffirming our financial guidance for revenue and combined R&D and SG&A operating expenses.

Finally, I want to share a few thoughts on how we plan to achieve our path to profitability in 2027. There are three primary factors. First, continued double-digit revenue growth from our current products plus contributions from our potential upcoming launches. Second, continued expense discipline and strategic capital allocation to support our launches as outlined in our operating expense guidance. And third, incremental non-dilutive capital to bolster our balance sheet for monetization of the priority review vouchers associated with DTX 401 and UX 111, if approved.

With that, I'll call to our Chief Medical Officer, Eric Crumbas. Thank you, Howard, and good afternoon, everyone. I'll start with GTX102, or apazumersin, our antisense oligonucleotide for the treatment of Angelman syndrome. As Emil mentioned, and something that I am sure you are tracking closely, we are approaching the phase three Aspire data readout expected in the September or October timeframe. The Aspire study is a randomized, double-blind, sham-controlled study that enrolled patients with a full maternal UBE3A gene deletion and their criteria for success are well defined. In the 48-week study, the primary statistical alpha is split between the Bayley-4 cognitive raw score at 80% and the multi-domain responder index, or MDRI, at 20%. This is not a hierarchical evaluation, meaning both endpoints tested in parallel.

If the Bayley cognition endpoint reaches a P value equal or less than 0.04, or if the MDRI reaches a P value equal or less than 0.01, we will have a statistically successful phase three study. We designed and powered the study to hit both endpoints, but we do not need both endpoints to achieve statistical significance in order to have a successful study. across the Phase I-II program, patients have now been on continuous therapy for an average of three years for the longest approaching five years, which represents the most significant and mature data set in the field. These patients continue to demonstrate meaningful improvements across multiple development domains while maintaining a consistent safety profile. The Phase I-II open-label single-arm data demonstrates substantial clinical benefit, well beyond what might be considered with placebo, though it is in an open-label single-arm. setting. We believe that the long-term experience beyond the first year of treatment remains even more important as we evaluate the potential for GTX102 to provide meaningful benefit with chronic dosing in the commercial setting. shifting to UX143 or citruzumab, our monoclonal antibody for the treatment of osteogenesis imperfecta. At the end of last year, we shared the results from the phase three orbit and cosmic studies. While neither study hit statistical significance for the primary endpoints of annualized fracture reductions, we did see clear signals of biologic activity, statistically meaningful improvements in bone mineral density and patient reported outcomes, and meaningful reductions in fractures in certain bones and in patients with higher fracture frequencies.

Since then, we have continued analyzing the data and have had discussions with regulators in the U.S. and U.K. Based on the discussion with the MHRA, we believe that a new randomized study may be needed before they would consider reviewing an application for approval. The FDA indicated openness to considering alternative approaches to fracture analysis, and we will need additional conversations with them to further define what additional clinical data would be needed to support a potential BLA. I'll now turn the call back to Emil to provide a reminder of our catalyst for 2026 and some closing remarks.

Thank you, Eric. I'll close with a few of the important catalysts we have later this year. The full list can be seen in the corporate deck posted to our website. Starting with DTX-401 for the treatment of Glycine Stored Disease Type 1a, will we continue to work with FDA ahead of our PDUFA action date of August 23rd? Next, UX111 for the treatment of Sanfilippo syndrome, similar to DTICS401. We continue to work with FDA ahead of the PDUFA action date of September 19th. And lastly, GTS1 and 2 for the treatment of Angelman syndrome, where we're on track to read out top-line phase three data from the ASPIRE study in the September or October timeframe. The second quarter reinforced the continued strength of our global commercial business and our expertise in developing first-ever medicines for patients with rare diseases. We are ready for potential launches, continue to execute across the portfolio, and are approaching a set of milestones that could meaningfully expand our impact for patients and with X-rays of growth for ultragenics.

With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Thank you. And at this time, we'll be conducting a question and answer session. Please limit yourselves to one question and one follow-up question for each time you enter the queue. To ask a question, press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. And our first question comes from Kristen Kluska with Kantor Fitzgerald.

Please state your question.

Hi, good afternoon. Congrats on a really strong quarter. For Angelman Syndrome, was hoping you could provide a little bit more context on these endpoints, specifically if the FDA has signed off whether one endpoint or not would be sufficient for filing, and then also understanding what's clinically meaningful, understand that these both endpoints were powered for success, but were they also powered to show results that the community would deem clinically acceptable? Thank you.

We had our discussion with the FDA on the sharing of primary alpha, and that was agreed to in our NFA2 involved discussions on the two endpoints. So sharing of alpha means that either endpoint can be positive in their analysis. We are powering based on the effects we've seen, but we think a five or six point change, for example, in the Bayley should be sufficient to achieve significance, and that would be the six point level is considered clinically meaningful. For the MDRI, it only scores if there's clinically meaningful results, that is each shift. which domain improvement requires a threshold of clinical meaningfulness. And in that, previously we've seen, if you remember in phase two, about two domains net positive that were in the clinical meaningful range. So because of the design, we would see MDI would be positive only with clinically meaningful results. So at this point, we feel comfortable about the two endpoint approach, and we think the powering will be positive with clinical and lethal results based on our plan.

We will see the data when they come.

Thanks, operator. Let's move to the next question. Thank you, John. I'm going to go ahead and take the next question.

Your next question comes from Yaron Werber with TD Cowan. Please state your question.

Great. Thanks so much. So maybe on the MDRI endpoint, which I think has generated some confusion from investors, as you notice, it's the first and most important secondary, but it's really a co-primary. And it's not been used before in Angelman, but you've used it in some of your other MPS disorders. Can you talk about the level of sensitivity and whether it's a better endpoint than cognition, just given that it's a co-primary? Thank you so much.

Yes, the MDRI approach simply captures efficacy across multiple domains using a clinically meaningful threshold in order to capture any positive results. What we're saying is any of, let's say, five or six endpoints, if there's a clinically meaningful change in a patient, we count that and add up all those clinically meaningful changes together. We used it previously in the MEPSAVI program, which it was significant in our 12-patient trial. In our analyses published in our paper, the MRI was, for example, tenfold more powerful to detect change in an enzyme replacement therapy trial compared to individual endpoints, right? That's what we published before. So, we think it's substantially more sensitive when you look at the ANGIV and Phase II data, Even in the 15-patient trial, we show substantial power with p-values less than 001, even in small study. So it's more powerful because we capture more efficacy in it. So its sensitivity is very good, but its meaning is greater, and it's one of the reasons we want it.

It's not just sensitivity. able to show through five important domains for handling what a drug is doing, I think it's a better assessment of what a drug does in a disease as complex as Angman, as you know, because you've worked in the area. So we think it's just a better way of describing. However, it is new and it's different, but we're confident it's clinical mean for this. and its power in detecting change in diverse complex disorders like Angelman syndrome.

Thank you. Your next question comes from Yigal Nukomovitz with Citi. Please state your question.

Yes, hi. How are you? I just wanted to ask with regard to the filing plans, are you going to file on the data coming up in September, October, or the additional study and additional genotypes will also support the Angelman's genotype? Can you just comment on the order of operations with regard to what data sets will be included? Thank you.

we're going to do about filing. It's something under consideration, and at this point, we're not going to describe what our plan is. We're collecting data in all the types in our program. Our expectation is to get approval in all the types, but we won't discuss at this point what our filing timeline is. Thank you.

Thank you. Thank you. Your next question comes from Maury Raycroft with Jefferies. Please state your question.

Hi, congrats on the quarter, and thanks for taking my question. I'll ask one on Angelman as well. Wondering if there have been any cases of lower extremity weakness or neuroinflammation based on DMC feedback during the study, and how are you setting expectations on this for the top-line disclosure? And I guess what's the latest you can say on the dropout rate from the pastry?.

Yes, we usually don't describe all the details and operation of the study, and honestly, the safety and efficacy will have to get evaluated together. The study has never stopped or had any issue during its conduct. It's continued smoothly through. So there's been no safety issue to cause a problem that stopped the study. So I would say we're comfortable where we are. I think we don't expect to see a different safety profile from what we've seen before.

going forward. And do you want to comment on the discontinuation rate that we saw? Yes, well,.

We wouldn't comment on that. It's also part of study conduct at this point. If you look past the Phase II program, we've had very few, and usually it's north towards the beginning, but among patients that get, let's say, after six, eight, seven, eight months, we had a very good persistence of those patients long-term.

Got it. Thank you. Your next question comes from Ellie Merle with Barclays. Please state your question.

Hey guys, thanks for taking my question. Another two on Angelman. So first, I guess, what are your latest expectations for the placebo arm performance on MDRI and the Bayley Cognition Score, and your confidence that there won't be a placebo effect? And then second, I guess, if you show a trend on both endpoints, but do not reach statistical significance. Curious how you would approach that with the regulators in terms of a potential filing. Thanks.

Great. We have talked about the placebo effect before. I think in the Bailey cognitive where we have both natural history and randomized data from another study. the effect has been one point or less in the Bayley Cognitive. So it doesn't change and honestly, But the placebo effects usually don't happen in things like a Bayley score because the patient is not cognitive of what the change should be. It can happen if you're using patient and parent input, but in this case, we think it's likely to see a perceived effect for the Bayley. In the MDRI, we're looking at multiple different endpoints. It is possible that some of those could change. However, we think that the threshold of clinical meaningful change means just a little bit of change from biased view things wouldn't score.

It has to be a really pretty big change before you can score. So I think that should filter out, I would call, random placebo changes. So at this point, we feel both. I don't think placebo effect would be an issue. It is neurology though, I always say, and we always have to consider we learn things, but we think we've designed it to manage any placebo effect and both endpoints. Thank you. Your next question comes from...

Thanks. The next question comes from Anupam Rama with JPMorgan. Please state your question.

Hey, guys. Thanks so much for taking the question. And could you just clarify your comments a little bit on GTX 102 and Bailey? I think you said you needed a five to six point change to kind of hit stats relative to placebo. I think that's the first time you've kind of really quantified that. So I'm assuming that's raw score, right? But using GSV, if I remember back to your Facebook, phase two, you showed a similar-ish effect, right, in phase two. So I was just wondering if you could clarify those comments. Thanks so much.

I wasn't saying that's the threshold for powering. I was saying that a 5-6 point is a meaningful change, and we are powered to detect that average change. That's what I meant to say. I didn't mean to say we're only powered for that threshold. We are well-powered to detect anything that would be considered clinically meaningful in that range. In the data we put out recently, we said it was near 10 score when you combine all the data together at one year. But, you know, we would, if you look at all the various sets of the data, it's in that range that we would expect the data to be. and what I'm saying is we're powered, whatever we would detect should be a clinically meaningful change, and we're confident we can do that.

Great. Thanks for the clarification. Your next question comes from Jack Allen with Baird. Please state your question.

Great. Thanks for taking the questions. And congrats on the progress made over the course of the quarter. I'll keep the train rolling here as it relates to GTX 102. And I wanted to ask a quick clarifying question around the allocation of alpha. I understand on the call and on the more recent calls you've been discussing how you have a 80% allocation of alpha to the baby for cognition endpoint. and a 20% allocation to MDRI. But I was looking at the completion of enrollment press release from July of last year, and I think it was a 90-10 alpha allocation there. And I'm just curious if there was a change to the statistics between the completion of enrollment and the potential readout here, and what educated that change? Thank you.

Yes, our current plan is to do 80-20. 90-10 are very similar. I don't really think they're materially different. We decided to make it 80-20. There was no particular date or other reason for it. It was just our take on the split between the two. It doesn't, I don't think, meaningfully change things, but the MDI is very powerful. We think 10 or 20% is probably adequate for that.

And we had given Adrian 90% to the Bailey. In our discussion with FDA, that was the split we had, but they're comfortable with what we are proposing at this point. Thanks for coming.

question comes from Allison Bratzel with Piper Sandler. Please, to your question.

Hey, good afternoon and thanks for taking the question. Just a clarification on citruzumab. I think in the prepared remarks you said FDA had indicated openness to alternatives to the fracture analysis, but you need to further define what would be needed for a BLA. Could you just clarify that? fileable package from the existing COSMIC and ORBIT data set, and just how important is that open label extension data that's being generated now, and just what's the next point you would be able to update the street on FDA interactions and the path forward in the U.S.? Thanks.

Yes, our comments were basically around the type of fractures and type of patients that we were talking about with regard to what fracture analysis they would want. What we said, though, is that, you know, Our discussions suggest some additional clinical data will be required, and we need to define what that is, which is not fully defined yet. And so we cannot state at this point whether extension data alone or whether there's any additional data required at this point in time. All right. We are discussing with them. I think they've been very open to a discussion and a path forward, and we just need to come up with a good plan to get us to that fileable package.

Thank you. Your next question comes from Maxwell Score with Morgan Stanley. Please state your question.

Great. Thank you very much for taking my question. So another on Angelman. With centralized raters, have you seen a reduction in variability in the blinded baseline data compared to the phase 1-2? Thank you.

Well, we have not personally looked at the data, so we're not aware. We don't look at the blinded aid at the management level. The team would be doing that. We would expect these reviewers which are highly professional and consistent, would help reduce overall study variation. That was the importance of it, to control it, to absolutely make sure that a changing evaluator or variable quality and experience at different locations might cause a problem. So it was our attempt to control the endpoint. But I can't tell you at this point the effect of that.

I believe it is the kind of thing that will help assure consistency and give us the best less noise in the program. But right now we don't have any data to tell you that.

Great. Thank you. Your next question comes from Tazin Ahmad with Bank of America. Please state your question.

Hi, guys. Thanks for taking my questions. On the financial front, how are you feeling about where you are with your cash balance and any potential need to do any kind of financing? Related to that, how should we be thinking about the investment needed for the upcoming launches that you have for your two programs for 401 and 111, assuming that both of them do get approved on time. And then lastly, can you just remind us of what you think the market size for each of those two indications could be?.

Sure. Well, I'll let Howard go through the cash financing piece, but I'll touch on the market size first. So, for DTX 401, GFE 1A, we think there's about 6,000 in the developed approachable world, which means around 1,500 to 2,000 in the US. And for San Felipe syndrome, there's 3,000 to 5,000 globally, but inside the U.S., there's probably, you know, we think of it as 20 or 25% of that. The addressable population will depend on what the label says, but we are looking at patients that are generally going to be probably more likely under 10 than over 10. Those are roughly where we are in population currently. I'll let Howard talk about the financials. Yes, thanks.

So first on the investments, I guess I'll remind folks of the guidance we gave for combined R&D and SG&A, and it was all based on this year or next year versus 2025. So this year was flat to down low single digits, and in 27 it's a decrease of at least 15%. And both of those were inclusive. of the launch investments we're planning to make for 111 and 401. So there is new money going in there. I think also important to note is that those programs fall into a sales structure or a bag that we already carry. So it's a highly leveraged situation. So it's targeted investments. So that's an answer to that part of the question.

And then with regard to cash balance, we were reported $436 million as of the end of the quarter. And as it relates to fundraising plans, our focus is on monetization of PRVs. Upon approval, our intent would be to monetize our GTX 401 PRV and also the UX111 PRV.

Thank you. Your next question comes from Ben Burnett with Wells Fargo. Please state your question.

Hey, thank you. Congrats on the quarter and congrats on the good CRISPR-BIDA number. I wanted to ask about citrusumab and just follow up. I'm just curious, have any of the regulatory agencies that you've spoken with, have they indicated a willingness to use or rely on bone mineral density as sort of a determinant of efficacy? Or do they still also need to see efficacy be determined?.

be defined in some way in terms of fracture rate. Thanks, Ben. That's a good question. At this point, there hasn't been the kind of proof for BMD's predictive value for fractures as there has been for osteogenesis. I'm sorry, for osteoporosis, where it has been accepted. And so we're still in the point of proving it. There is a question of whether the underlying bone disease creates that connection. We have evaluated, we believe it does, but at this point, we're looking at fracture endpoints of some form as the primary way to get approval. using BMD.

I think we all agree BMD demonstrates the profound activity of this drug in these patients, you know, with a whole D-score gain in a year is a profound improvement in their bone. So it gives us confidence, and I think the regulators are also confident that the drug is doing something meaningful. But right now there's, I would say, except the BMD as a primary for approval, it's not yet been enabled.

Thank you. Your next question comes from Salveen Richter with Goldman Sachs. Please state your question.

Hi, this is Lydia on for Selveen. Thanks so much for taking our question and congrats on the progress. Just as a follow up to a previous question on Angelman related to the lower extremity weakness, has FDA provided any sort of threshold on what would be acceptable on the safety front, particularly as it pertains to that lower extremity weakness? Thanks so much.

No, no thresholds provided or any limit. In fact, I believe in our final conversation, I'm not sure if Eric, you want to say something to this. We really have not had much concern, at least MFH2 is little at all. Eric, what's your take on the FDA? I don't think we've had any limits provided to us or like how much, you know,.

maximum could be incurred or something. Yes, no, exactly. During our end of phase two meeting, there was no discussion on lower extremity weakness. And, you know, as I said, we maintain a consistent safety profile.

Yes, so I think our sense from them is that we've gotten past the issue with them, and I think we're in good shape. So we have not had discussions further.

Your next question comes from Luca Isi with RBC Capital Markets. Please state your question.

Hi, team. This is Shelby on for Luca. Maybe on GSD1A, with the PDUFA just weeks away, could you provide any color on your level of confidence headed into that decision and talk about how the review has progressed? And I guess specifically whether there's been any information requests from the FDA and are there any additional manufacturing inspections that you need to clear before the decision date? Any color there, much appreciated. Thanks.

Sure. Well, yes, we have obtained information requests during the review for both CMC and clinical, and we've been answering them. We can't provide an answer yet during progress. Things are underway like that. We feel the review has gone, proceeded normally, and we feel like we're in good shape. However, we can't predict to you what the FDA's actions are. They will have to do it. But at this point, everything we have been doing is answer their questions and move in.

normal fashion forward. Your next question comes from Laura Chico with Wedbush. Please state your question.

Thomas Yip Good afternoon, everyone. This is Thomas Yip, on for Laura. One question from us. So of the 300, 400 San Filippo patients that are identified in the U.S., how many are likely within the age range that you expect the label to support and are clinically appropriate to treat? And then also, what's the incidence rate for new patients being captured on an annual basis? Thank you.

Are you talking for San Felipe syndrome? Yes, that's right, San Felipe. Yes, I thought you were mentioning San Felipe.

So, we haven't put out precise numbers yet on the prevalence, exact prevalence or diagnosed prevalence of patients. We know that the incident rate appears to be about 1 in 100,000 or about 30 to 40 new kids diagnosed per year. So, if you imagine that they're living until their teenage years, you can get a sense for what the number of what the prevalent number is like, right? Does that make sense? We have treated patients up to, I think, eight or nine years old in the trial. We don't know what age range will be in the labeling, but we've shown even in the older patients that we stabilize function with regard to ambulation, feeding, communication at the state they're in when we are able to treat them. So we think there's a justification for treating patients that age, but we don't know what the label will be. But there's this meaningful population of patients in that age range out there and we have a sense it's a lot of urgency in wanting to get treated. So hopefully that gives you at least a feel for it.

Understood. Thank you so much for taking the question.

Your next question comes from Joe Schwartz with Learing Partners. Please state your question.

Thanks. I have a two-part question on Angelman. In phase 1.2, were there particular Bailey cognition items or skill clusters that appeared most sensitive to APA's or NIRSA's? And are those the same skills you expect to drive separation in Aspire? And then, relatedly, because Aspire's primary endpoint removes caregiver input requires the child to demonstrate skills during a single testing session. How should we think about the risk that meaningful home-based gains might not be fully captured by the Bayley Cognition Assessment?.

Good. So, let's start with the last one. The Bailey cognition has a relatively small number of caregiver assessments, and our endpoint team's assessment is that it shouldn't have a material effect on the raw scores at this point. So, we're not concerned about that. So, let's talk about the MDR areas. The areas we studied and presented before in our slides have all been the same ones that we're using. So, the five domains are Bayley cognition, with a threshold set by the Bayley people. We also have communication score, receptive communication for the Bayleys. a sweep score and we have a behavior scale, ABC behavior score, and finally a motor score which is either the ASA or the Bailey.

But those are the five domains. Those domains are ones we saw as meaningful improvement and the ones that are of importance to patients. All of them are contributing. If you look at the prior descriptions where we've shown the heat map, I think you can see all the endpoints are contributing pretty significantly. So it's really not one or another But for sleep, for example, there are patients who have a very big effect of sleep because they're very sleep-deprived kids. Other kids don't have sleep problems where you might not see it. But if you look across those endpoints, we see contribution from all of those endpoints that are built into the MRI. So there's no one or other that's, let's say, say, driving the majority of what the MRI feels, this will see.

So this is why the MRI is so powerful. If you have multiple endpoints all contributing, you gain a lot more power when you're capturing efficacy from all areas of the patient's benefit.

Thank you. Your next question comes from Gavin Clark-Gartier with Evercore SI. Please state your question.

Hi, this is Yixiong for Gavin. Thanks for taking our question. So just a follow up on the Angioman Phase 1-2 study. Looks like the study originally enrolled 74 patients. And efficacy we have seen so far is based on the 40 patients cohort. And the last quarter you mentioned, based on the most recent data cut off, there are 53 patients that has reached the 12-month milestone. Can you remind us when do you plan to share those data? And also, like, especially for the efficacy part, if the data has been consistent with the earlier cohort? Thank you.

All right, well, you're talking about different colors and time, and it depends on whether you're talking about the titration group or we're talking about the expansion group. Those are the two groups. In the most recent release, we talked about all the patients who had been on therapy, and we have a few people who left early on in the study. And the combination data we presented at the last conference, we talked about the combination last quarterly call was including all the people together. We present on the expansion, which wasn't everything, but we mentioned the last call, which was the near 10 score on all patients together combined for the daily cognition was the most complete set of data that had at least a year of treatment So that's included in that data. We are not planning to put out more phase two data at this point because we because we are where we are with the Phase III program. But I hope that gives you a feel for it. What I would say is we presented previously, for example, A and B cohort. that cohort is very similar to what we're seeing, we think, is in the Phase III.

Basically, it's from the same centers that are in the international study. So at this point, we feel comfortable that we have learned from Phase 2. We have disclosed to you as an adequate assessment of the patients in the countries and at the sites that we are using in Phase 3.

Thank you. Your next question comes from Raghu Ram Savaraju with HC Wainwright. Please state your question.

This is Ahmed on for thank you for taking our questions. I was wondering if you could give some color to the launch readiness for the next two products. And when do you expect the, how do you see the timing to first fade infusions? And how sensitive is the 2027 profitability target to slower than expected ramp?.

products. Thank you. Okay. I will, let me touch on it, then I'll let Eric talked about launch radius and maybe you can talk about profitability. We are absolutely driving to ensure that we can get patients treated as promptly as possible because there are a number of patients that really urgently want to be treated. So we're setting up to do that because we already have two products in the space of inborn errors. We already have a team in the field. We already are operating. we're going to prepare to build out with a more moderate measure of addition. But maybe Eric, you could talk about what we're doing in QTC and how we're going to help assure patients get infusion.

promptly as we can. Yes, just to add on something that you said, that we've been preparing now for a few years upon the initial filings. And there's about a 75% overlap with the Joel B. and Mefsevi with the institutions in the healthcare providers that we'll be calling on. So we'll be able to leverage our current infrastructure, which we expanded to meet the demands of our previous commercial products. And I just want to also emphasize this will be our fifth and sixth launches. So we've successfully launched four products previously. So we certainly know what we're doing and we'll be prepared. We have a number of QTCs already under contract and we'll be expanding that as we prepare in our final preparations for commercialization.

You'll be ready to go when we get launched. We'll be. Good.

And then maybe last to your question about the sensitivity of profitability to the launches. You heard my comments earlier on the call about the different factors that play into profitability. We haven't been more specific on the exact contribution from launches, but we do imagine one as part of profitability. But I think the important thing to remember is that there's lots of levers get to a profitable year. And so it's not as though every launch is a must. And that's a fortunate place to be in where we have lots of different revenue sources and lots of different ways to manage our allocation of capital.

Thank you. Thank you. And at this point, we have reached the end of the question and answer session. I will now turn the call over to Joshua Higa for closing remarks.

Thank you. This concludes today's call. If there are additional questions, please reach out to us by phone or at IR at Ultragenyx.com. Thank you for joining us.

Thank you. All parties may now disconnect. Have a good day.

This live transcript is auto-generated without human intervention or review.

[Call has ended.]

All right. Welcome back, everyone. Today, we have the pleasure of speaking with Emil Kakkis, President and CEO of Ultragenyx.

Emil, maybe to start, just to level set, you are sitting in front of key Phase III Angelman data in the second half of the year on the potential path to profitability in 2027. So in that context, how is RARE positioned from here in the second half of the year and then over the next few years? And what are the company's key priorities?

Certainly. We -- certainly happy to be here and be talking with you today. We started the year off with a difficult problem of missing an OA -- OI in Phase III, and that was tough, but we have a lot more than OI in the program in the company. And so Angelman is the big driver for what people are most interested in. It's the biggest upside product. We've done a lot of work in preparing for that Phase III. And we put out some data at the last quarterly call, which talked about the long-term Phase II data.

But that Phase II data shows that patients continue to gain ground over a 3- to 4-year period, they have durable effects and that the safety is excellent, and there's no cumulative safety concerns or issues arising. And it also tell you something even more important which affects us commercially. And that patients and parents are reason -- are interested in keeping, getting intrathecal infusions every 3 months for years for their kid to see the benefit they're getting. And there's very few parents that keep going for intrathecal injections for a drug for no reason, right? So it tells you something that people are staying on the treatment that tells you this is a viable treatment that's really helping their kids and it's worth it. So that's what we got out of that.

We did a lot of work on our Phase III and operationally, which was bringing forth sites that we had already tested in that Phase II study. So we knew they could do the test. We knew what the patients were like, and we had ironed out any particular executional issues. We brought in a third-party tester for the Bayley testing score, which is one of the primary endpoints to make sure that was done into perfection. And we've supported the sites as needed now to be able to handle the workflow and workload. And so it's gone well, and we're really excited about being able to enroll in 6, 7 months and to now be looking at patients finishing the study.

We have already had patients finished and crossover, and we continue doing that process. Last patient in was last July, for 8 weeks takes to sometime this June, July. And then there will be some weeks to months of cleaning, walking, preparing and analyzing data before we release. We haven't put out a specific time line but I think we're in a very good position with the Phase II data showing us long-term durable benefit, long-term gain and a Phase III study that's been executed well.

And finally, we've added the Aurora study, which will look at the older and the younger patients and the other genotypes to fill out the story together, I think, putting us in a good position. It puts us about a year ahead of everyone else, and I think we're pretty encouraged. So that positioned us well for big upside. But if you talk about revenue and cash, the 2 gene therapies probably have a more immediate impact. We've been investing in the launch of both programs expensing product that we've created and put on the shelf. And some of our burn left couple of years has been to make products sitting on the shelf. So it's not burned that's gone. It's sitting there as a product.

When we -- our PDUFA dates are in August and September, so far, reviews are going fine. And if we get both approvals, we will have 2 PRVs we'd expect, which have been selling for very significant sum of money, which will add to our cash balance sheet and put us in a good position. But in addition to that, we'll be launching most of those programs. And Sanfilippo is an urgent disease and of course, there are many patients interested in getting treated. And so we had a lot of inquiries both in the U.S. plus also ex U.S. It's a lot more like Zolgensma for SMA, right, in terms of the urgency. And we think that will drive uptake fairly quickly for Sanfilippo syndrome.

For GSDIa, it is an urgent disease, maybe not as urgent as Sanfilippo. They're not losing their brain, but the idea of taking starch every few hours forever is tough for patients and they want to get off that treadmill and put away some of the fear they have that every day they could die if they miss a dose of their starch. So both of those, I think, are programs that will do well and I think our gene therapy franchise is not valued at all, I think, currently.

And so if you think about that much cash brought in plus the revenue, the swing between this year and next year will be very substantial and put us in a position to launch Angelman well, but finish '27 with a potentially profitable year. with 3 new products launched and then other products in late-stage development, which I think put us in a really good position for the company going forward.

So I look at this year, if we get to third, fourth quarter, it's been kind of transformative for the future of the company. And I think on top of the base business, which is earning the mid-$700,000 -- $700 million range, has been growing by 20% a year the last few years, I think we're well set up with a global company to take advantage of those 3 products launching globally and which we own the full rights to. I think that puts us in a position to really transition to profitability, but more past it. And so I feel good about where that is.

It would have been nicer to start with a positive OI study this year, but we take the challenges that are put before us, it is biotech and it is hard. So I feel good about where we're going. And I feel like I think it should be a good year for us. And I think at our current valuation, I think it should be a clear opportunity for people. Sorry for taking a very long period of time.

No, thank you for laying all that out. I guess maybe just quickly on the path to profitability before we dig into Angelman and some of the other pipeline products. You have 2 potential PRVs that you mentioned. I guess how do you plan to kind of time the monetization of those to kind of bridge that gap to profitability potentially in '27?

Well, we certainly plan to sell both of them, and the exact timing could depend a little bit on what makes sense. Certainly, we could sell 1 this year and 1 next year to manage the burn. But I would -- I think Howard and I will talk through it, but I don't think we want to overthink it. I think cash in the balance sheet are what we need to do. But you could look at how that affects profitability next year. I'd also point out Angelman's positive. That's another potential PRV which could be in 2027. So that itself could put us where we want to be.

And I would say to you, we could do it this year or next year but if we are able to achieve $200 million for each of those, which is what people have been getting close to at this point, it's a substantial increase from where we were modeling in our own plans. But with the reauthorization, another third one, right, could potentially bring us $500 to $600 million total to the balance sheet. It's a pretty big deal without any dilution.

I think that puts us in a good place from where we started the year. With the quarter, we had $534 million. If we add that on top of the gains in revenue, it puts us in a very good position to maintain an adequate balance sheet and hit profitability in the time frame we're looking at with additional cost controls we've put into place.

All right. Maybe just digging into Angelman ahead of the Phase III data in the second half as you laid out. what do you need to see from the primary endpoint of Bayley-4 cognition in order to see a successful study? And then what are the kind of key risks here?

Well, we have looked at the modeling of the power of that endpoint before. The data we just put out in Phase II suggests that at 12 months, we could see somewhere close to 10 points of improvement. I think we modeled a smaller number than that. But with the standard deviation we saw, we were seeing 80% or 90% power or greater, depending on what you assume for the control group. If you assume what we see in natural history or in studies, then we have 90-plus percent power if you assume the background could be 2 to 3x higher a little bit less than that.

But the history of control groups, whether it's the levodopa trial in renal or the natural history study, they really haven't gained more than 1 point on Bayley. And so we feel pretty comfortable that there isn't going to be a big placebo effect going on there. And therefore, I think we're well at above 90% power to detect the magnitude of change we're seeing. So I think we're in a good place. So we've put out a little more data on this power before, but we feel comfortable with the strength of the study.

That said, it is neurology. Neurology is always hard. There's always things that go wrong or things that go off and so we have to be conscious of that. And we put in the multi-immune responder for 2 reasons: one, it's a more powerful assessment of all the domains that are affected, and I think a better alignment of what patients are thinking they're not thinking about one endpoint. None of us think about any disease we have is one point to point. We all think of multiple problems, right? And so the MDRI is better aligned with what patients think about what are the big 5 issues that affect their kid.

But also importantly, it's a very powerful analysis tool and gives us more power. So if there were any problem with Bayley, MDRI, it's more powerful and capture more endpoints which help balance out if there's any risk. We're allocating 20% power to the MDRI, 80% of the Bayley, 20% is enough for the MDRI to be successful. It doesn't need very much power. We to be able to beat that level readily. So that's how we've designed it. We hope that it will help put us in a better position to win one way or another. And if one or the others possibly, we believe we'll still be able to file for approval with that. We expect both to be positive.

All right. And then I guess maybe just taking a step back, could you just talk to the rationale for choosing the primary endpoint of Bayley-4 cognition as opposed to receptive communication, which is what Ionis has selective for their Phase III study?

Yes. I think they picked expressive probably?

Yes, expressive communication.

Yes. I think their argument was that expressive communication is what parents want, but I would argue, I don't think parents want their kids to start talking but not having any thinking. That maybe what's happening already for us with teenagers, but -- sorry, bad joke. There's no one here to laugh anyways, but -- no. So you can't have anything without cognition. So the idea that parents want, I think that the -- if you look at the cognition at the core, we think it's the most fundamental function. FDA has expected it. But I would say to you, we're evaluating all the other endpoints as well, we can look at all of them.

We'll look at expressive. We'll look at receptive. But expressive does take time to evolve and it also can be dependent a little bit on how much training for education. I think it'd probably work better if you're doing more work on edge game kids to help them develop their language skills. But I think all of these things are important. So we pick Bayley-4 as being a more fundamental function. There's also a history we're also using it in the Sanfilippo program is something FDA neurology is familiar with. Those are some factors.

But I would look at it as defining what's the most important disease. It's what we need for regulatory process. But what patients will see is that endpoint, secondary end points, MDRI, we'll see the whole thing. And I think patients can understand endpoints, whether they're primary secondary honestly does not really matter to patients. They want to know what's happening and they're not going to pay attention to the regulatory rubric of statistical plans.

You touched on this briefly already, but just given the one point improvement seen in natural history historically and then the 10-point improvement that you saw in the Phase I/II, I guess, what's your level of confidence that the sham control arm in the Aspire study will not exhibit a significant placebo effect that could kind of compress the treatment effect size?

Well, the main reason is the type of endpoint it is and the type of patient we're dealing with. Angelman patients will be gaining function, but they don't necessarily have the understanding they're in a trial but they don't really know what's going on. So it's a little -- the placebo effect depends on you knowing something and having some belief in something, but that's not really going to happen. Now we don't -- we exclude all caregiver input, where the carryover could have that placebo effect. They know, but that's being excluded. So we think that will help.

The other thing is that this is assessed by a third-party psychologist; not the parent, not the doctor, third party. So the value of that is they're more objective. They're not connected to the family. They don't know the family. They just are doing the testing. Does that make sense? So there I think, going to be a little bit more objective in their professional side. So those are the things we're doing to help control for it. But if you look at the randomized placebo-controlled trials that have been done with the Angelman, which is the one levodopa trial, for example, that was placebo-controlled, there was no Bayley placebo effect observed. So that's not a not a natural history study, an actual trial. It didn't occur in that study.

That's helpful. Maybe just quickly on safety. In the Phase I/II study, there were some cases of lower extremity weakness. Do you believe that these have been mitigated via the use of the Trendelenburg flush in the Phase III?

Yes. We believe it has been. We think the issue we are having based on the MRIs and everything else is pretty clear that there was local concentration of drug that was causing local chemical attrition. As long as the patients are put in tenor and the drug driven cranially to allow for rapid mixing. We seem to have eliminated that. And so we feel pretty comfortable, and we have patients now for 5 years on drug up to 5 years, not having a problem. So if it's really a chemical -- it was a drug related effect, it would have -- it should have either accumulated or recurred, but I think it was very much an administration localized effect. I think we've managed it through these changes.

And as you mentioned, you're also running the Aurora study in additional age groups and non-deletion genotypes. Can you talk about the regulatory filing strategy once you have this data in hand? And then also your level of confidence in that data set, given this is a more heterogeneous population?

Yes. So the Aurora study will help broaden the label past deletion, as you mentioned, includes missense UPD, ICD-type patients. It also includes under age 4 and over age 18. And so the idea is here to cover the rest of the -- we haven't put forth what our filing strategy was going to be. We'll have our Phase III data, we'll have Aurora data, and we'll come up with our exact planning. But the 4 to 17 age group deletion, we think, is the majority of the market or in that range and so forth. There are going to be some adult with Angelman. We'll get to them, but what we do for the filing right now is still to be finally decided. But we think it's most important to get the major market. And the Aurora study will give us knowledge about the rest of it.

And if that study is not that big but shows a trend, do you think that will be enough to get that -- the broader label?

Well, I think that it depends a little bit on what we're seeing. We are looking at MDRI in that study, by the way, in those end points. And those -- it's pretty powerful. So when we had even 12 or 13 patients before and after comparison MRI, we saw strong significance. So it's pretty powerful with that tool, not just in one point. We are looking at daily the really young ones, of course, But I think the methodology will make it a little better for us. Now, MDRI, you might say. Well, is not blinded, how does that hurt you, but the value of MDRI in a non -- in an unblind situation or open label is that you don't count anything else with a really big change, right?

If it's a little change, like a little bias, you're not sure, that won't count. You have to have a big change. So the MDRI has a natural filter for small changes. The only thing that counts are big changes. So if they get better, they're getting better in a big way I think you can be more confident that, that is something real, right, as opposed to something that's just biased on how they're using the tool. So those are some features. I think it will be enough. I think in the past, it has been enough.

In Crysvita, for example, when we originally filed that program, we had our trials were in the 5 to 12, and there was this older patient trial. But we didn't have any older than age 5. But we submitted 4 patients with data under age 5, 4 total. We had 13 who had been treated but 4 with 6 months of data. But we're able to extend the label with the excellent 5 to 12 data and with supportive data just for patients for 6 months, and we were extending the label down to age 1 in that filing, right? So it's open label support of extending the data in the age group. So we've recently done that very thing and was successful. And it was really only 4 patients, but the 4 looked very good. They fit, the safety looked fine, the 13 got doses, drug work the same.

So I do believe that it has to look good in those patients. If it's not distinctively clear that it's working, then maybe it won't work, but it will work if it works the same it has been working and does well in the MDRIs, I think we'll be pretty confident that we can put that forth and allow the adaptation. We specifically decided not to put patients through another randomized controlled trial because to put all these subtypes, all these smaller subtypes in the randomized trials for each type would have created a lot of cost and put a lot of burden.

We put the burden on a group of kids from 4 to 17 to prove the effect of this drug. And for those kids, we just show the fact again, we don't have to prove the relationship because we've already shut proven that this is a cause and effect relationship, if that makes sense. And now we just need to prove that they have the effect and they have safety.

Got it. Maybe we'll pivot to the upcoming gene therapy launches, the first of which is in the next couple of months, potentially. Could you just talk to the early launch dynamics for both of those, both GSDIa and then Sanfilippo syndrome type A, including maybe pricing? And then also which patients you think will be early adopters here?

Yes. And so first, of course, you assumed that we get approved so I appreciate your optimism to talk about launch and launch dynamics. We always have to give the FDA a to-do, that they have something to say for us before we launch. We feel like review is going fine, but we will see. We will get done. Now the launch dynamic for the 2 are probably similar. I think for Sanfilippo is probably the easiest one to talk about. Sanfilippo syndrome is a horrible neurodegenerative disorder, and kids are losing brain cells every week, right, that they wait. They have no other treatment. And between the age of 2 and 6, they lose a lot of the developmental function. By 10 years old, they're bedridden and they may stay in the bedridden state with G-tubes and in out of the hospital, nonresponsive for 5 or 10 years, right? So it's an absolutely horrible situation.

There is no parent in that situation that would not want to get treated as soon as possible, even if there are 5 or 6 because they can keep -- we've had patients in that age range who may have lost speech already but are walking, feeding themselves, interacting with the family, who have stabilized. And we've shown 5 patients that were older that stabilized their function, and they continue to participate with their family and continue to self-feed, walk and so forth. So we think the therapy can work in that group, but the younger the patient, the better outcome, right, and we think there'll be a great urgency. The longer you wait, the less function you may have.

So we think that one will -- by now, it will be urgent and once approved, there'll be people crying when they get treated promptly. And we're hearing about patients now. They're very active in social media, but we're also hearing -- getting inquiries from Europe about mainly patient treatment, and the Middle East as well. So we think there's a lot of interest in the first-ever treatment for neurodegenerative disease. I think it's a pretty easy call. And the treatment is a relatively safe 3e13 infusion dose. So it's not a very high dose and we don't have the kind of complex safety issues that you've seen with some of the others. So there's really -- the downside effects, I think, are modest compared to the potential benefit. So that's the dynamic for Sanfilippo.

But for GSDIa, it's an urgent disease. It's not like your brain is going, you can survive on cornstarch treatment to keep yourself, but it is not a great survival. It is a difficult life because you're taking starch every few hours, all day, all night, about a pound of starch a day. I don't know if you can imagine eating a pound of starch. It's like makes you sick thinking about it, right? Well, they feel sick doing it, by the way. They do not feel good. They're all like induced type 2 diabetics. So imagine you're making yourselves sick but you have to keep doing it because you're trying to avoid running low and you don't know when you're going to run low.

It's like the opposite of diabetes. You're trying to keep your sugar up but you have the worst problem is that the drugs don't -- the starch start and doesn't last very long, so you have to keep taking it, keep taking it. And if you don't wake up at night, you could end up with a very low glucose, comatose or not wake up or die. That is a scary thing to live with. So there is a substantial urgency. And when we were rolling this trial, we had people want to get in.

And we even had a problem in 1 country that they didn't review it very quickly, and we enrolled before this country got started so we canceled enrollment. Parents were -- patients were so upset. They call the regulators who called us and demanded we opened the trial to let their kids in and we couldn't do it. We've spent all the spots. But it tells you something, I've never had regulator call us and demand that we open a trial in their country. Never had that happen, right? That's how intense the feeling was. So I know there's urgency. If you deal with that problem every single day, every few hours, you think about that. And you have to know that if I don't drink the starch, I have a gun to my head and I might go off, if I forget to do it. Just think about that stress of feeling that way. We want to get off that, if you can.

So we think GSD1 will do well. There's more patients with GSD1in the prevalent population than in Sanfilippo though they have similar maybe incidents, but the prevalence maybe 1,500 or more in the U.S. for GSDIa and for Sanfilippo, there's maybe 300 or 400 patients around in the United States. So urgency is very high. We think both programs will do well. We think there will be -- we feel good about the potential for these programs to achieve meaningful revenue for us. They may not be like other programs, but if approved, we think they will be successful gene therapy products and I think it will be supportive of the whole field of AAV gene therapy.

I guess maybe just in Sanfilippo, given there is no standard of care currently, how do you think about patient identification and whether there might be a headwind there trying to find those patients?

Well, I think the challenge is finding them early enough to have the best benefit -- I feel I can't go on without water. The truth is you really need newborn screening to capture patients early because you really want age 1 or age 2. The methodology for newborn screening is the same methodology we already have approved for MPS-I and MPS II, which are being implemented in newborn screening because MPS IIIA is comparable and there's a method. So it's not hard to implement. It could be implemented. It should be, but the newborn screening control system, the fact that this committee is not operating. So we have to work through especially the candidate to help bring forth the need to start newborn screening.

In the meantime, what we're looking is to help support and make sure that patients are being included in panels for developmental delay or other early signs that you would express in Sanfilippo. Some patients are getting diagnosed earlier because of that, that any kind of development delay is being evaluated. But we need to get newborn screening down, make sure panels are being used for those early developmental patients. And then user network connection among the area of doctors just to make sure that we're finding as many as we can. But I agree with you, it's one of the pieces. Right now, I've said we found about 300 to 400 patients with Sanfilippo already found in the United States. And we know the age ranges, et cetera, of the patients out there.

Will all patients get treated? Later-stage patients, maybe not. If they're very advanced, not responsive, the parent need to decide if it's not right and we don't know what the label will do. We have a few people up to age 8 or 9 in the trial. So we know that range could be readily expected in the label. Whether it will go beyond that, we couldn't be sure. I think patients starts emulating it before. It's probably a range that makes sense. We'll have to negotiate what the labeling shows but on the patients we found, I think that will keep us busy enough with supply for the time being.

I guess on that note, could you just speak to the capacity at your Bedford manufacturing plant and whether you have capacity to meet the expected demand for the first maybe 12 months of launch?

Well, because unfortunately or unfortunately, because of the delay, we've been accumulating more commercial products. So while the launch last year would have been more of supply constrained where our supply is continuing to increase and we've been running continuously, the drug substance is actually made at our a contract manufacturer in Ohio, and we do the fill/finish at Bedford for Sanfilippo program. So that program is continuing to run continuously and build a supply. And we think we should have plenty of supply to handle the demand based on what we think we need for the first 12 months.

For GSDIa, we're doing both drugs at the drug product. Again, we should have enough supply to handle the need. Of course, there are more prevalent patients with that disease, but we have enough for what we expect to be the population that will get treated in that time frame.

Maybe just on commercial efforts. I think you've mentioned before that you plan to leverage the existing Mepsevii and Dojolvi sales force, given that these are gene therapy launches, could you just speak to the investments being made to manage the high-touch requirements of a gene therapy launch and the long-term patient monitoring that's required?

Well, there are several things we're doing. From the patient services side, we're creating a gene therapy guide. It's one of our patient services group that become point for helping coordinate all the different functions that are going on. We've created a separate group of the gene therapy treatment group, which is physician experts who are going to guide/qualify treatment centers on both treatment and immune modulation or co-medication management so that they have an expert at hand at all times to help them.

Our commercial team is also creating the qualified treatment centers who will be prospectively trained and ready to go at launch. And so those things, there's a few extra people that are in the gene therapy treatment group. There's been some support for the MSLs required. And the patient services group will be set with some specialized people to help handle the unique needs. So there are a few places we need to bolster on top of the existing commercial group to manage specifically a gene therapy.

The supply chain is also a bit different. And so it's quality, because we're going to be -- we have flat pricing as expected. So that means every group of weight is its own code and has to be packed. So you actually have to create a supply chain that can handle creating a product for each patient's weight in real time. So there's some people in the quality supply chain people who have to be able to do that. The idea is that we will have flat pricing for the gene therapy across the age groups. And so there is some logistics involved in doing that. So there are some places we have to do, but it's not a big lift, not as big a lift as getting here.

Got it. Maybe just with the last few minutes, anything else you'd like to highlight from the pipeline? And then also if you could just quickly touch on setrusumab and whether you've completed those additional analyses of the Phase III data and whether there's a path forward potentially in some subgroups or age ranges?

Well, we've done quite a bit of analysis. So we talked about some of it at JPMorgan in the pediatric subgroup. We certainly see excellent improvement from advancing really in every one, but we saw improvements in pain, physical function, vertebral functions or in other areas. So we've done a lot of analysis on that. I think we wanted to do it carefully and thoroughly, and there will be discussions with regulators around pathway. We'll probably put out information on what that pathway is later in the year before we come out with Angelman data. Somewhere in that time, we should have some understanding.

So we made a decision what we're doing, we'll know them. The goal is to try to find a way with existing patients and ongoing treatment to be able to come up with a path to filing. We can always do another randomized trial, we're trying to avoid that, which is a multiyear kind of a thing. We have a lot of data. We have 2 randomized trials and other patients ongoing treated. So we hope we're going to work with regulators and coming up with an idea. We think the drug is working, but of course, it didn't hit the primary and secondary fracture endpoints. So that's a factor that will always be an issue for us to solve.

Anything else in the pipeline that you'd like to touch on?

Well, we've been incredibly productive. We have OTC Phase III that was positive at will be ongoing with Wilson Cohort 4 coming. Those are in play. But we also have some things we've held back. And if we hit our marks on our gene therapy approvals and launches, we have a program for creatine transport efficiency we've had for a while. It's a prodrug of creatine, a really cool drug that we've made ourselves. It's actually a ring pro drug, we have 2 clips, but we can deliver creatine to the brain traditionally. And that's a very large market disease, maybe 30,000, maybe 50,000 patients, no treatment at all male and female both have infected symptoms that could come to the clinic. And we're having some support from the patients who are moving that forward.

We also have a gene therapy for CDKL5 deficiency. You might think another gene therapy why there's a neuro disease intractable seizures like we used to be called a typical Rett syndrome. So like Rett, we expect it could have dramatic effects. They're propelling the Rett programs forward. We think it's another good one. I just want to be clear, we are an engine of innovation. We have incredible number of products we put and those INDs have been sitting and waiting for the opportunity. So we need to create the value, get the value and drive forward and put some of these programs in play and show that we can be the most productive rare disease company in the business.

All right. With that, thank you so much for joining us. I guess that's just the time here.

I'm one of the biotech analysts here at BofA. Our next presenting company is Ultragenyx. And here with me are Howard Horn, Chief Financial Officer; and Josh Higa, Head of IR. Thank you for joining us, guys.

So I think there's a lot going on at the company. I think most people are familiar with it, but maybe we can start with a quick overview of the company, kind of your commercial products, and you have a very busy second half of the year. So maybe you can highlight some of the key catalysts coming up.

Sure. Glad to, and thank you for having us. So Ultragenyx is a next-generation rare disease company on a pathway to profitability in 2027. We have 4 commercialized products, and we are estimating between $730 million and $760 million in revenue this year. We are hopeful to have 2 approvals and launches of 2 gene therapy programs this year. And the other data event people are waiting for is our Phase III data in Angelman that we talked about coming out in the second half of the year. So yes, it's a very busy year.

All right. Great. Maybe we can start with a quick question on the commercial side. So you recently reported earnings. I think there was a slight miss in the quarter, but you reaffirmed your guidance for the year. Maybe you can talk to us a little bit about 1Q dynamics and kind of what gives you confidence in the revenue guidance you provided earlier this year?

Yes. We've been asked about this a little bit today. So I think we and the Street are pretty well in lockstep for the full year. I think it's a question of how people were thinking about the quarters. I can tell you from my perspective, we actually beat our plan for the quarter. We may have been slightly under what the Street had, but the typical pattern for us is one of the sawtooth, right, a lower first quarter, higher second, lower third, higher fourth. We've seen that play out over the years. That is what is playing out again.

We did go to pains at the end of the fourth quarter to talk about in our projections for this year, how Latin America might be an impactor to our Crysvita revenue. It's not an impactor from a demand perspective, but it is an impactor in terms of sales that can be lumpy because these are larger contracts. So those are things that are playing out. But overall, for our business, we feel like start forms and other underlying signals of demand are doing really well.

Great. How do you think about growth of Crysvita at this point? And I guess, how important is that to your goal of reaching profitability in 2027?

Yes. I think this year's Crysvita numbers of $500 million to $520 million top line imply single to double-digit growth, right, where in years past, it's been very healthy double-digit growth north of 20%. So I think we are seeing some leveling there. But again, it's with dynamics described for the year that I think will sort of reset again in '27. So I see it continuing to grow. The macro question about profitability and how we think about some assumptions there from the revenue point of view, what we see is that our 4 current programs will continue to grow double digits, and that top line will be augmented in some way by new launches. We have 3, as I was mentioning, that might be in the near term. Not all 3 of them need to hit for us to get to profitability, but that's how we think about the top line.

Okay. Great. So maybe we can move on to Angelman. Like you mentioned, I think this is highly expected readout later this year. You recently provided some long-term data at the earnings call. Can you maybe remind us what that was and kind of the relevance of that and how you think that has read through to the readout in later this year?

Yes. So last week on our earnings call, we talked about some sort of longer-term Phase I/II data. By the way, just stepping back, the philosophy of why we chose to put that out was that we wanted to help people understand the magnitude of the impact and the duration of the impact and to let people know that what we had used from the Phase I/II to power our Phase III, all those assumptions were still intact, right? So that was the main thinking. Now the details that we shared were 66 patients worth of data in our long-term extension, average of 3 years, some approaching 5. And these are patients 4 to 17 years old with full deletion of the UBE3A gene. And that we shared 2 things. We shared some efficacy points that I'll come back to, and we also shared on the safety side that we had no new cases of lower extremity weakness.

And the 3 points that we shared on the efficacy side were, first, on Bayley-4 cognition, we talked about at 12 months approaching 10 points of improvement across the baseline against sort of a minimal threshold that you'd want to see at 6. We also said that in future time periods or later time periods, you saw that continuing to improve. So that's one of our endpoints that we're allocating alpha to it. The second endpoint we're allocating alpha to is what we call the MDRI. It's a mixture of 5 different endpoints, each of which have their own thresholds. But what we described there is that 1-year, 2-year and 3-year time points, the p-value was less than 0.0001, so compelling there. And then the last part was around expressive communication, which is another endpoint that we look at, and it followed a similar pattern to what I just mentioned for Bayley.

Okay. Great. How comparable are these data? Or I guess, how comparable are the patient populations that you're enrolled in the Phase I/II compared to the Phase III that would give us confidence that these results will translate to the Phase III data?

Yes. The Aspire trial and the Phase I/II are completely overlapping in who we enrolled, right? These are full deletion patients who are 4 to 17 years of age. So yes, it's a complete overlap.

Okay. And so you mentioned the split in the alpha for the readout for the Phase III. So you have the Bayley-4, you have the MDRI. Can you maybe talk or remind us the decision on using the Bayley-4 as the primary endpoint for the trial. I think the company has said in the future, they see the MDRI being kind of like the primary clinical outcome for Angelman. So why did you decide to make that decision and split the alpha between the 2 endpoints?

Yes. So stepping back, 0.04 of alpha is allocated to Bayley 4 and 0.01 is allocated to MDRI. I think, look, MDRI, this is not the first time it's been used. It's actually part of our Mepsevii label, but it is relatively new. And I think the agency has comfort with single endpoints. And so that is Bayley-4 was the one we put forward there. But at the MDRI, as you mentioned, I think that's the way people observe and experience and think about the disease, less so in a single endpoint, but more of what's the totality of impact for a patient. And so if you're a patient, if you're a caregiver or if you're a doc, I think that's the way you think about it. So that's why we thought MDRI is an important complement. And bluntly, it's also a hedge, right? It's a hedge. So we're not just putting all apples in one basket.

Okay. I guess from a clinical perspective and from a patient perspective, too, like what do you think families would see as more clinically relevant? Do you think they focus on benefit on the Bayley-4 or is the MDRI kind of more important for physicians and patients?

I guess in our discussions with patients and their families, well, families and caregivers, they don't just talk about one endpoint. They talk about many. And what you see when you look at our MDRI, not everything turns green, right? It's a heat map of the page. It's because not everybody has every issue, right? But what we're counting there is how many issues can improve for each patient. And again, I think that's how they view it.

And can you maybe discuss the kind of different scenarios where you hit on the Bayley-4, you miss on the MDRI or the other way around, what do you think would happen in those instances? And I guess, what's needed for commercial success?

Yes. Look, we -- because we have 2 endpoints, we could hit on one and not on the other and vice versa. We could hit on both or not on either, right? All the scenarios are possible. But from an agency perspective, right, they've allowed us to allocate out each. I think that means that each one is seen as valid to them. And my hope is -- well, my strong belief is we have a statistically significant trial and it gets labeled and we get it on market. I don't think there's a lot of time spent talking about what was that one number that you had in the trial. It's more about how the patients done, how are doctors observing their population.

Okay. Makes sense.

I think Howard's point is right. In order to have a statistically significant Phase III, we only need to hit on one. Both of them will be evaluated in parallel. But really -- and this is the case for every study. It's the totality of data that will be assessed, and that will be the case for us, too.

You mentioned something important. They are evaluated in parallel, not sequentially. So both are seen as having wait then.

What should we expect to see of the top line results? I guess how much data do you think you'll share? And are you planning to state some for later medical conferences or something like that?

I don't know that we've said that. I think we would share enough about our endpoints to make sure people understood that we'd had a success. But certainly, there would be more detail there. I mean this is an incredibly detailed data set where you're taking lots of measures even beyond the 5 that are in the MDRI. So there'll be a lot of rich data to plumb. But I think we would want to satisfy people's curiosity of did it really succeed, we would give enough on that.

That's right. Striking the right balance between giving people enough data to feel confident, but also wanting to do it in a timely fashion.

Yes.

Based on what we know from the natural history of the disease, what are your expectations for the Sham-Control in the trial? And what is the risk that, that might outperform and show more benefit than you would expect?

Yes. So natural history for full deletion patients is quite flat. You might get a percentage point on the Bayley for over the course of the year, right? And what I mentioned to you a minute ago is that we were seeing 10 percent -- 10 points on the Bayley-4 scale at a year. So I think the Sham arm, we believe it will follow that. There's other things we've done to try to make sort of the arms of the trial be comparable. Of course, we stratified by Bayley-4 cognition. We've also stratified by age. I think the other thing that we know is that folks who are in the 4 to 17 range who haven't been treated, they don't know that they're in the trial, right?

So I don't think there's a bias that would be introduced by the patient themselves. So those are some of the things that we think about. Also, a hot topic recently has been that the Bayley-4 has caregiver input in the Phase II, not the case in Phase III. In our case, whether it's in or out of the Phase II data, doesn't change what we had shared with the community. But I do think that's an opportunity to potentially control for any bias in the Phase III, and this is a smart decision by the agency and one we expected.

Okay. Great. You mentioned safety and how the recent update highlighted there haven't been any new instances of lower extremity weakness. Do you think that's well managed at this point? I know you implemented a few different strategies to kind of deal with that during the dosing of patients. And if you do see some, what do you think would be like an acceptable rate for these patients given the high unmet need?

I think we have a well-understood safety profile at this point. What we're using to mitigate the things that we saw before is a Trendelenburg position where you put the patient head down at a certain degree of angle. Also you do a spinal fluid flush. Those things appear to be working. I think what's also very meaningful to me is that the agency at the end of Phase II and in our subsequent discussions doesn't spend a lot of time on this, right? So I think they probably also share our view.

So yes, we -- I don't know that I have a comment on your last one. I think people understand it, which is important. I think everyone has resolved, which is also quite important. All those patients have remained in our trial. So were it to occur in the setting of a commercial situation, I don't think physicians would get frustrated by it, and I don't think it would affect adoption provided that it's in the realm of what we've seen in terms of a percentage basis of recurrence.

Okay. Great. And at the recent update, you also mentioned most patients are getting to the 14-milligram dose. How does that compare to your expectations? And can you remind us how the titration like process works?

Yes. Josh, maybe I'll ask you for help on this one. The 14-milligram dose, though, is what we have in Phase III, and that's what we would assume would be the commercial dose. But do you want to answer the other part?

And I think maybe one of the nuances between Phase II and Phase III is Phase II, there certainly was an element of dose finding. So we were working people up that titration ladder and trying to do it in a thoughtful manner. But once we figured out and established the safety profile that Howard mentioned, in Phase III, we have a very -- it's a much more sort of regimented titration pattern that all these patients will be on. And we would expect that the Phase III patients are all getting up to 14.

Okay. Great. And so I guess, assuming you have positive data later this year, what would be the next steps? And how do you view the opportunity in Angelman for your product?

Yes. I guess the next step is getting moving on BLA and get moving to be prepared to launch. We don't currently participate in a lot of competitive markets. This would be one. And so therefore, time is of the essence. I think to your second part of the question, it's quite a large market, right? We think about 60,000 patients globally in addressable markets that we could reach, maybe 20% to 25% of them in the United States. We haven't commented much on pricing, but I think given the unmet need and given the number of patients, this is quite a large market one that certainly is big enough for more than one player. And we're -- bluntly, we're just -- we're happy that we enrolled quickly, and we're happy that we're getting towards our Phase III data in the second half of the year.

How easy is it to find these patients? And I guess, how concentrated are they? Are they found around centers of excellence? Or I don't know how much of this is treated in the community setting?

Yes. So the patients -- I'd say it this way. They have extremely well-organized societies and groups. And so it's a very active community and one that we've been able to engage with throughout our clinical trials. So I think there are patients waiting for this for sure. We haven't said too much more about how we plan to do the launch and how many patients are identified. That will all come in the coming months once we put out the data. But it's a great market.

Okay. How big of a sales force do you think you would need for this launch? And is there any overlap with your existing commercial infrastructure?

So no overlap to our current infrastructure. But in a rare disease like this, you're not talking about hundreds of people for sure. You're talking about tens of people.

Okay. Got it. And maybe lastly, you're also running the Aurora study, which is expected to expand the addressable patient population. When do you expect to have data for that? And how meaningful would that expansion be?

Yes. So this is a trial that expands on our current Aspire trial, which is, again, in 4- to 17-year-olds that have full deletion. So this Aurora trial is the other age groups, older and younger that have full deletion as well as other deletion types or genomic types. That trial is going to finish enrolling at the end of this year. And I'd say 70% of the population is full deletion and roughly 30% is the remainder. So it's an important part of the overall pie and one that we wouldn't be blind.

Is there a reason to think that GTX-102 wouldn't work in these patients or you would see any difference in efficacy?

No.

Great. All right. So maybe we can move on to some of your gene therapy products. You mentioned you have 2 PDUFAs also coming up in the second half. Maybe we can start with GSDIa. What do you think is the unmet need in this indication? I think a lot of the pushback we get is like you can treat patients with cornstarch, which is pretty cheap. What is the need for a gene therapy product in this indication?

Yes. So this is our DTX401 program with the PDUFA date on August 23. Unmet need here is quite high. Let me describe, I think, what a patient today is like. They're taking cornstarch slurries every 2 to 4 hours around the clock. It's a nonstop, can't stop it. And if you do miss a dose of it, you could find yourself in a coma, seizures, death. So it's quite stressful day-to-day. And while people are using this as a mitigator of disease, it is not an impactor of disease and you still have the underlying metabolic issues in liver and kidney and other issues. So our hope with 401 is to actually address the underlying concern and get the liver functioning the way it should. So you don't find yourself in glycogen fallout as it were. So it's quite an urgent disease.

It is maybe 6,000 patients globally. We have talked about price points in the $1 million to $2 million range. And given that our PDUFA date is coming up so soon, we are in sort of launch planning, right? And so what that means for us is we manufacture this one entirely at our gene therapy plant in Massachusetts, and we have been building up inventory. It will use the sales force we currently have for Mepsevii and Dojolvi today in the United States. So that's great leverage to have. We've been talking to payers and getting their opinions, and we're excited for that launch. 111 is shortly on its heels, and I know we'll talk about that. But our commercial team thought they were going to have these programs maybe a year ago. And so they're anxious to get them.

How do you use that additional time since you were expecting this last year, how have been using the additional time you had to prepare for the launch ahead of the PDUFA?

Yes. What I left unsaid is the reason we had the additional time is there was a CRL related to our 111 filing. So this is our Sanfilippo gene therapy filing. And so it had some observations at our plant in Bedford. So we've used the time in 2 ways, importantly, to address all those issues, right? We want to make sure all of that is great. And what I'd say is it also maybe opportunistically allowed the data to ripen. And so you have even longer time in this case for 301 and for 401 to show the improvements that people are getting as time goes on, right? So I think one of the worries with gene therapy is that things will abate. And that's not what we're seeing. In fact, it's quite the opposite.

Okay. What has been the feedback from the physician community to the data you've generated so far?

Strong. Yes, quite compelling. I don't know if we're still on 401 or 105. But in both cases, 111, maybe I'll pivot to that. While 401 is a potentially lethal disease, 111 is just surely so. And that's a place where there is really no solution. And I know the patient community is extremely well organized and waiting for this, and the physician community is really excited about the data.

Okay. Maybe going back to 401, given that that's the first PDUFA you have coming up, how confident are you in the filing now given kind of the roadblocks you face with 111? Do you feel like you've like fully fleshed out all the problems you had in terms of manufacturing?

Yes. So as I was mentioning, we spent the time since last spring working through the issues at our plant in Bedford. And so I'd say we feel good about that. And I described the interactions with the agency right now is just normal, right? There's back and forth questions being asked and answered. So I have comfort that we're on a normal path.

Okay. Got it. How easy is it to find these patents? You mentioned 6,000 globally, which is not a lot. But are these kind of well identified? Is there a potential to expand the patient population once you have a therapy approved?

Yes. So in the 401 population, they're identifiable because they're taking these slurries of cornstarch around the clock. And they wouldn't survive if they didn't. So possibility to expand like in rare diseases, there's almost always a way to expand. As we state like a 6,000 number, that's in the geographies that we know we can access. That is not an entirety of the globe type number. It's meant to be a pragmatic number people can use in a modeling.

Okay. You mentioned for the initial launch, you'll use the existing commercial sales force. Do you think there will be a need to expand that over time? Or do you think that will be enough?

So certainly, onesie, twosies, right, incremental expansion to make sure that and they have now 4 products in their bag that they can cover what they need to, but no more than that.

Yes. And I think maybe to add, certainly with a multimillion dollar single-dose gene therapy, you want to make sure that you have the right sort of support structure around that dosing to ensure that it goes well. So we will invest in just a small handful of individuals to make sure that each one of those individual doses goes exactly to protocol. But to Howard's point, it is meaningfully leveraging the existing field team, but we'll make small adds just to ensure for this particular type of therapy that it's done well.

Okay. Got it. And I just saw your price range of $1 million to $2 million. Is that based on your conversation with payers? How far have you got in that in order to get confident in guiding to that type of price for this product?

Yes. We're triangulating as we always do, to find a price point. I think it is emblematic of the need, and we have gotten feedback from payers. And so that's the range we're contemplating for launch.

Got it. Got it. And how do you see the kind of the ramp of this launch going just given the small number of patients?

Yes. I think in all of these diseases, there's a bit of a bolus that you'll work your way through. But importantly, once you're through that bolus, there is an incidence that occurs every year, right? It may be in the U.S., for example, 40, 50 patients for 111 and maybe slightly higher for 401. But when you add that in other geographies, this is still a franchise that's hundreds of millions of dollars. So I think it's an important part of the P&L of the future for us. I'd also note that because of these diseases and the way we've -- we're working to get approval that there are PRVs attached to both. And so monetizing those PRVs is an important way for us to keep our balance sheet strong.

Okay. Great. Maybe we can pivot then to 111 in Sanfilippo. What is the unmet need there? I think this is even a more rare indication than the GSDIa. So how big is that opportunity in your opinion?

Yes. So comparing to 6,000, this is maybe 3,000 to 5,000 and some of the variability in that window, as you described about diagnosis. Basically, these patients, you'll diagnose them young, right, in the first few years of life and life expectancy isn't much more than the teens. So this is -- I mean, this is as bad as it gets. It's a tough disease. So we're thinking the patient numbers that I mentioned from a price point perspective, maybe a bit higher than 401, so in the 2 million to 4 million range. And that our commercial preparedness is right on the heels of the 401 preparedness. As Josh mentioned, we'll leverage the sales force we have, talking with payers already. This is a program that does come through our plant in Boston or in Bedford, but that's still finishing off. The drug substance comes from elsewhere.

Okay. What do you think is the willingness of families to dose the kids with Sanfilippo at this point? And do you think there's been a change in the perception of like gene therapies among these like rare disease, given like recent setbacks that other gene therapies have faced in terms of unexpected safety events that have happened?

Yes. So I think the willingness is high, but I think it's supported by data, in fact. So we, in this trial, have patients who are out to 8 years, right? And they're still on the curve that we would hope they'd be on and showing improvements. So I completely acknowledge that there are other things going on in the gene therapy space that you have to be mindful of. I think the facts as they relate to our gene therapy programs are encouraging. And I think adoption will be strong.

How do you view this competitive landscape? I think there are other therapies in development. I think you're ahead, you're probably going to be first approved but there might be other approvals coming up, not for gene therapies, but enzyme replacement therapy. How do you see that playing out in this market?

Yes. I think you got to be mindful of it, right? We do have a lead in this case, and it will require us understanding what the data is from the other companies. Josh, I don't know if you have any other points to add.

No, I think you hit it well.

Great. And with these 2 gene therapy launches coming up, how are you preparing for both at the same time, given the PDUFA are so close to each other? How are you preparing for like having enough product to launch and then getting like all the commercial infrastructure ready?

Yes. So the commercial part, maybe we've hit on a bit already. So that team will have the augmentation of a few heads, but we'll be ready to roll with both programs. I did mention sort of how they're being manufactured, but I think I forgot to mention that we've been building inventory for quite a while now, right? We were already thinking about this because the launch could have been last summer for 111 and maybe later last year for 401. So I think we're ready from a manufacturing point of view, and I know we're certainly ready from a commercialization point of view.

And probably worth highlighting all of that inventory that's been building has been already expensed as part of R&D. And in those first quarters of launch when we're selling the previously expensed inventory, the margin benefit is meaningful. And you kind of get to steady state once you work through that. But it's one of those interesting P&L dynamics for everyone to be aware of.

Yes. Okay. Great. How are you thinking about the regulatory environment? We just learned today that Commissioner Makary signed. How have your interactions with FDA been over the past few months? And do you think there's any potential risk given uncertainty at the agency right now?

So yes, I did -- we were in a meeting earlier today when we heard about the resignation. We -- our interactions have been basically around the 3 programs we've been spending time talking about. So I think we characterized that those have been positive and reasonably normal. I think maybe the macro thought is that it would be nice for some continuity and consistency at the agency. We've seen a lot of change in the last year and a lot of uncertainty. And so I don't know the person who will be the interim lead. I hear he's a long-time FDA person from the food side, but just some level of stability, I think, would be welcomed.

Yes. And I do think we have had a historical precedent and would expect to continue to work well with whoever is at the agency for sure.

Great. And maybe on setrusumab, when should we expect to see any updates? Where are you on analyzing the data? And do you see a path forward for that?

Yes. Good question. I don't know that I have a great update for you. I think what we'd say is we've been analyzing the data from the 2 trials that -- 2 Phase IIIs that failed to try to determine if there's a path forward and if it warrants talking with agencies. I think our conclusion is it does warrant it. But to determine what that path forward would be and if we would file remains to be seen.

I expect that we would -- when we have come to a decision about what -- where we stand with that program, we'd give the Street a full update on that.

Makes sense. And then my last question, you touched on this earlier, but what do you think is needed to reach profitability in 2027? There's a lot of moving parts in second half things could go different ways. What is kind of your base case assumption to reach that point next year?

Yes. So what we've shared is the revenue assumptions that I noted earlier. We also, in the start of this year, began a cost program, cost savings program and had a reduction in force of roughly 10% of our workforce. And those will have impacts this year and next vis-a-vis the way we described it is R&D plus SG&A percentage declines versus where we were in '25. So if you take the growth on the top line and you take those set of assumptions, you can find your way to profitability. Relatedly, I also mentioned the PRVs, which on a GAAP P&L will hit the P&L, but also, I think they're more important from a cash flow perspective or from a balance sheet perspective.

So that's the set of assumptions we start with. I will completely acknowledge that we don't have certainty about how the top line will grow. But I can say that under pretty much any set of scenarios, we have enough levers to control on the expense side to be able to get ourselves on our path to profitability. And our goal is, of course, not to just hang out at the razor's edge of profitability in '27, but to grow faster. And I think what will define the slope of our EPS line in those years will be how those launches do and how many of them and which ones.

Okay. Great. All right. I think with that, we're out of time. So thanks again for joining us.

Thanks. That was fun.

Good afternoon, and welcome to Ultragenyx First Quarter 2026 Financial Results Conference Call. [Operator Instructions]

It is now my pleasure to introduce your host, 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. We are now in our 16th year since our founding, and this year is expected to be transformative with growing revenue and multiple new drug approvals. We're on track to well exceed $700 million in revenue from our global commercial business with a consistent track record of double-digit annual revenue growth.

We have a PDUFA date for two gene therapies that would bring first-floor [ treatments ] to patients and families with no other disease-modifying options. Also, we will unwind our Phase III ASPIRE study, evaluating GTX-102 in patients with Angelman syndrome in the second half of this year. We're continuing to execute global clinical trials across the largest late-stage pipeline in rare diseases. We're also manufacturing our gene therapy products in our new facility in [ deferred ], Massachusetts.

I'll start with GTX-102 Angelman syndromes. The first patients enrolled in the Phase III ASPIRE study have reached their day 338 visit and have transitioned to open-label extension study. The rest of the patients will be completing the blinded portion of the study in the next few months at [ crossing ] our open label extension. With the AURORA study, we are expanding GTX-102 treatment to other [ ag ] and [ ggenictyabanes ] and syndrome and enrollment of study continues to go well.

We prefer to evolve the first-ever treatments for diseases that have not had significant breakthroughs in the past. And so do not simply work in disease areas where there are other competitor programs at similar stages of development. In the case of Angelman syndrome, we made an exception given the size indication and the excellent work genetics had done with the scientist [ Scott Dindot ] to develop a [ HodenASO ] that worked in a large animal model rather than just might, which often do not predict human biology.

The precode research, Scott conduct in his lab at Texas A&M is a tour to [ formable ] Cogenex. He is able to identify and target a separate and distinct region of the Andersons message those led to more efficient transcript knockdown and greater potency in the clinic. This was a superior science that led us to study Angelman syndrome.

Later in the call, Dr. Crombez will walk through the longer-term [ fac ] durability and safety data from the Phase II study in his section. But I want to highlight now that we have 66 patients on therapy for an average of 3 years and was the longest approaching 5 years. with continuing and improving benefits across multiple domains and with a favorable safety profile.

Based on this longer-term data, we believe GTX-102 can deliver clinically meaningful treatment effects and can be safely administering product dosing. What we see in the Phase II data we believe GTX-102 is making an important difference in a [ lot ] of these patients and their families.

Shifting now to our global commercial efforts. Our commercial business continues to deliver. We're now getting revenue in more than 35 countries a result of strategically investing in high-quality teams who can efficiently navigate complex approval and reimbursement process around the world. This reflects a disciplined country-by-country execution, our teams deliver every quarter. This base business is not only generating meaningful and growing revenue, it is the engine that will power our next phase of growth.

Our team is currently commercializing Globe and MEPSEVI are poised to add DTX401 and UX111 to their responsibilities as we look forward to approvals for these two products later this year. Our established global commercial business is bringing first-ever treatment to patients who need them, paving the path to profitability in 2027.

I'll now turn the call over to our Chief Commercial Officer, Erik Harris, who will provide details on his team's efforts in the first quarter.

Thank you, and good afternoon, everyone. As Emil mentioned, the underlying business remains strong, and we are well positioned to capitalize on the potential upcoming launches. Howard will share details, but we remain fully confident in our 2026 revenue guidance.

Throughout the first quarter, the commercial and field teams have continued to meet the growing demand for our products across the globe. I'll start with Crysvita and want to put the first court revenue in the right context. The revenue in North America, Latin America was consistent with our expectations and the ordering patterns we have seen in prior years. This is a business we know well. We see continued strength in the underlying demand across all of our regions, including in markets like Brazil, where bulk orders by the mystery of health can result in quarter-to-quarter variability.

In Latin America, approximately 30 patients began commercial therapy in the first quarter, bringing the total number of patients on Crysvita to more than 950 in the region. We remain fully confident in the fundamentals and strength of the business and along with our partner, KKC in North America. Our ability to continue to find and treat patients with XLH and [ TIO ].

Shifting now to DOJOLVI with the trend of our steady growth years post approval. In the first quarter, our North American team generated more than 30 start forms, far exceeding their target for the quarter. In North America, we now have more than 675 patients on reimbursed therapy. And in Europe, there are approximately 300 being treated through named patient or early access programs. The next stage of growth is likely to come from Japan where DOJOLVI was granted conditional approval last year, and we look forward to the full approval and launch of the product this quarter.

I'll close with EVKEEZA, which is another example of our experienced team's ability to successfully commercialize rare disease products. In our region outside of the United States, we are seeing exceptional growth from this program as our international commercial teams navigate the country-by-country reimbursement process and respond to requests for early access from patients and their physicians.

In total, there are approximately 370 patients across 18 countries who are receiving EVKEEZA. We expect this will continue to be an important and growing contributor to our revenue base. Beyond the individual product performance, I want to step back and highlight what I believe is the true strength of this business, the scale and reach of our global commercial infrastructure. That depth of market presence across rare disease markets that require significant expertise, patient-finding capability and reimbursement navigation is a genuine advantage.

It is what enables us to efficiently bring first-ever treatment to our disease patients. And critically, this infrastructure and experienced team on what gives me confidence as we look toward the rest of the year. My team is preparing for two new product launches, DTX401 with a PDUFA date of August 23, 2026, and UX111 with a PDUFA date of September 19, 2026. The launch readiness work is well underway across both programs and we are building on the infrastructure and expertise we have already established.

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

Thank you, Erik, and good afternoon, everyone. I'll focus on our first quarter financial results and guidance for the year. Starting with revenue. Total revenue for the first quarter of 2026 was $136 million. Crysvita contributed $93 million, including $39 million from North America, $46 million from Latin America and Turkey and $8 million from Europe, which were consistent with the anticipated quarterly timing and trends Erik just mentioned.

DOJOLVI contributed $18 million, consistent with our expectation for steady demand growth. EVKEEZA also contributed $18 million, representing 64% growth over the first quarter of 2025 and as demand continues to build following launches in our territories outside of the United States. Lastly, MEPSEVI contributed $7 million as we continue to treat patients in this ultrarare indication. Total operating expenses for the quarter were $305 million, which included cost of sales of $30 million and combined R&D and SG&A expenses of $275 million. Total operating expenses included $30 million of noncash stock-based compensation and $30 million of expenses related to the restructuring announced last quarter.

For the quarter, net loss was $185 million or $1.84 per share. As of March 31, we had $534 million in cash, cash equivalents and marketable securities. Net cash used in operations for the quarter was $197 million. Recall, in the first quarter of the year, we typically use more operating cash than in each of the subsequent 3 quarters because it includes items like the payment of annual bonuses.

In addition, the first quarter 2026 included $38 million in payments related to UX143 manufacturing activities as well as $5 million related to severance and other payments from our recent reduction in force. Net cash used in operations are expected to decrease in the remaining quarters of this year as we continue on our pathway to profitability in 2027.

Shifting now to guidance for 2026, we are reaffirming the revenue guidance we provided in February. Total revenue in 2026 is expected to be between $730 million and $760 million, which represents 8% to 13% growth over 2025 and excludes potential revenue from new product launches. Crysvita revenue is expected to be between $500 million and $520 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx.

This range reflects growing underlying global demand, partially offset by expected timing of [ organ ] patterns in Brazil that we anticipate will normalize in 2027. DOJOLVI revenue is expected to be between $100 million and $110 million. We are also reaffirming the R&D and SG&A guidance we provided on our last call. Specifically, we expect 2026 combined R&D and SG&A expenses to be flat to down low single digits versus 2025. We also continue to expect 2027 combined R&D and SG&A expenses to decrease at least 15% in 2027 versus 2025.

With that, I'll turn the call to our Chief Medical Officer, Eric Crombez.

Thank you, Howard, and good afternoon, everyone. As Emil mentioned in the opening, I'll focus on the clinically meaningful Phase I/II data that we have generated with GTX-102, our antisense oligonucleotide for the treatment of Angelman syndrome. This data is from our Phase I/II open-label single arm studies, which informed the design of the Phase III double-blind sham-controlled ASPIRE study. Given the differences in study design, these Phase I/II results are not necessarily predictive of Phase III outcomes.

In our press release earlier today, we highlighted that a total of 74 patients have been treated with GTX-102 as part of our Phase I/II program. This is one of our largest Phase I/II studies we have conducted and was designed to inform the dose, dose regimen and endpoints for our Phase III studies. There are now 66 patients in long-term extension studies with patients generally receiving the 14-milligram quarterly intrathecal maintenance dose. These patients have now been on continuous therapy for an average of 3 years and some patients are now in their fifth year of treatment.

These patients continue to demonstrate improvement across multiple developmental demands with no new cases of transient lower extremity weakness. We took a cut of the data in March of this year to be able to highlight the long-term safety and efficacy of GTX-102 in a forthcoming manuscript, and I wanted to share a high-level summary today. Starting with the Bayley-4 Cognitive Raw Score, there are 53 patients in the Phase I/II study with a Bayley-4 Cognitive Raw Score among 12. At this time point, they were approaching a mean change from baseline of 10 points, exceeding the meaningful score difference of 6 points and with longer-term follow-up, we see continuing and improving benefits in cognition.

Turning to the Multi-Domain Responder Index, or MDRI, that uses clinically meaningful score differences consistent with FDA guidance as opposed to statistically driven changes to determine a positive or negative response across 5 different developmental domains and the Phase I/II data set, we now have MDRI data at month 12, 24 and 36 that evaluates response across cognition, communication, behavior, sleep and gross motor.

When comparing response to baseline, the p value across all 3 time points is less than 0.0001. Not only is this a very powerful statistical assessment of five different measures, it is consistent with doctors and family's broader view of neurologic diseases like Angelman. It is the intersection of all these development changes that reflects how individual patients truly respond to a treatment in a holistic way. In the 48-week ASPIRE Phase III study we had primary statistical alpha split between the Bayley-4 Cognitive Raw Score and the MDRI. This is not a hierarch evaluation, meaning that both of these endpoints will be tested in parallel.

If the Bayley cognition hits less than 0.04 or if MDI hits less than 0.01, we will have a statistically successful Phase III study. We also took a look at expressive communication in our Phase I/II study assessed by the Bayley-4. Similar to cognition, we saw meaningful improvements in expressive communication that continued and improved in longer-term follow-up.

Based on the totality of data generated in our Phase I/II program, I remain confident that the developmental progress and continued learning of new skills in these patients support the meaningful benefit of using this ASO to provide UBE3A from [indiscernible]. I'm looking forward to seeing the results from our Phase III studies and the potential to replicate these results in larger controlled studies.

I'll now turn the call back to Emil to provide a reminder of our catalysts for 2026 and some closing remarks.

Thank you, Eric. I'll close with a few of the catalysts we have later this year. A full list can be seen in the corporate deck posted to our website. Starting with DTX401 for the treatment of glycogen storage disease type 1a. We continue to work well with the FDA and look forward to our PDUFA action date of August 23. The FDA has also informed us that an [ AdCom ] is not planned.

Next, for UX111 for the treatment of [ Sanfilippo ] syndrome, the BLA that was resubmitted earlier this year is being reviewed with a PDUFA action date of September 19. Lastly, GTX-102 for the treatment of Angelman syndrome is on track to read out top line Phase III data from the ASPIRE study in the second half of the year. Ultragenyx has been one of the most productive companies in rare disease companies in the industry and taking programs from early research to approved therapies for patients who have no other options.

We've done it across multiple modalities, multiple therapeutic areas, and we look forward to bringing the next set of first-ever treatments to the patients who need them. The surge in late-stage programs in the last few years has challenged us like it would anyone. But the benefit is once we turn the corner of these programs into approved products, we have the potential for a significant acceleration in our growth that will be a special moment in the history of Ultragenyx.

With that, let's move on to your questions. Operator, please provide the Q&A instructions.

[Operator Instructions] Our first question comes from Tazeen Ahmad with Bank of America.

This is Daniel on for Tazeen. I was just wondering if you could comment on the new update for Angelman, like what level of consistency are you seeing for patients improving on the Bayley and the MDRI -- and kind of how we should think about variability between the 2 endpoints for the Phase III...

I'll touch on it and maybe Eric can add some more. I think the Bayley that we're conducting is being done with -- primarily with an outside firm that's coming and doing the test at the site. So this is -- we're running a very high-quality operation in terms of how we will measure the test to help reduce variability. I think the consistency is something we can't comment on at this point in a Phase III study, but we can talk about what -- how it looked in Phase II. I think it should -- we expect it to be similar to what we've seen before. And I think the MRI has been a very robust and consistent measure just in its nature because it's multiple domains that we've seen strong results, and I think Eric just talked about them. So Eric, what do you think about the Bayley-4 consistency?

Yes. So I think looking at the results from Phase I, II and very multiplied to how we designed Phase III. The most important thing we did was include patients with full dilation. This means they're expressing no UBE3A and gives you a very consistent patient population driving those consistent results we saw in Phase II and what we think will be replicated there. And then again, as a reminder, bringing patients with other mutations that add variability into our second Phase III study at AURORA.

It's a very good point, Eric. Consistent [ jet ] type will definitely help us get consistency, particularly considering what the placebo or the untreated the sham will do because without treatment, patients with them do not gain on the Bayley-4 significantly.

Our next question comes from Joseph Schwartz with Laurence Partners.

Great. So a couple of questions on GTX-102. In ASPIRE, are you stratifying randomization or prespecifying subgroups by any baseline factors -- it seems like in rare pediatric trials, even modest imbalances in baseline severity could be important, and there's some literature in Angelman that this could influence variability I'm just wondering how confident you are that ASPIRE is protected against any potential baseline imbalances?

Look, thanks, John. I'll let Eric action specific. In general, for all of our programs, we are very aware of the all [ skewing ] issue on the randomization. So we will always -- for primary endpoints will stratify our primary end point. I view our best we can, or nothing is perfect. So what are we doing for Angelman.

Yes. So specifically for ASPIRE, both by age and cognitive as or that being our primary end point, we want to make sure we have consistent balance there.

Okay. And then we noticed that you haven't narrowed the timing for ASPIRE top line data yet. Do you have any sense when during second half of '26, you might report the data is late third quarter a good assumption since you finished enrollment in late July last year?

It's fun, isn't it? Keeping you in the dark about exactly when that's happening. Yes. I think you probably can guess based on the timing of things. The question is that when you close out an international study, a lot of end points, you do want to do it carefully. And so we're not being precise not only because we want to give resolves time to get everything straight before we do unblinding.

We've said in the second half, but you can tell by when last patient in was roughly when the trial should have the last patient out, but the timing it takes to finish up a study with sham, there's EEG, -- there's a lot of things in there that it will take a little time. So we give a Phase I program, we want to take the time to make sure we're being a little nonspecific now but it's all on track.

Our next question comes from Maury Raycroft with Jefferies.

Congrats on the progress. The Phase I/II longer-term commentary is helpful. Just clarifying could we see the details as data ahead of the Phase [ III ] top line -- and it seems like you're seeing a clear static signal on MRI in the Phase I/II and based on the point improvement you mentioned for cognition, I'm wondering if you're seeing a [ SATIP ] value for cognition versus your -- versus the natural history study data set.

Well, we -- I believe commented on the primary endpoint natural history comparison before is our powering analysis. I think we've said that, that we would we would be well powered. So I think that, that's already sort of analysis henry is just extremely powerful method. I think it's the way forward for live diseases.

You question, will you see the detailed data -- probably not. I think we haven't set which science meeting the day will come out yet. I would assume, be later in the year. we have often presented things at the FAST conference, but we haven't set at this point, a plan for the Phase II data, but it's not necessarily ahead of Phase III at this point.

But we wanted to put out a little bit of data and a use deep confidence about what's going on and just give you a sense of the magnitude and outcome and the fact that we're confident about how the drug looks and that continues to show good safety and the kind of cognitive benefit and our benefit that gives us confidence in the design and what we're conducting in Phase III.

Got it. That's helpful. And maybe one other question. Just wondering if prior to the database lock in stats plan, do you have to have any decisions with FDA on magnitude improvement on the primary endpoint? Or is it just showing a static benefit? Is that sufficient?

Yes. There's no regulatory step between us and unblinding at this point. We're all agreed. And there is no defined required minimal change for the Bayley. I think that is something that we don't need in the design is a continuous variable.

However, we will always have what is known as a clinically important change of 5 points. We'll always look at data that way, but the powering of the primary endpoint for a [ onions ] based on a continuous analysis, which is really the appropriate thing to do. But if you look at the numbers we just told you 10 that is almost twice the minimally important difference already. So I think we're at a pretty good place.

Our next question comes from Anupam Rama with JPMorgan.

This is Joyce on for Anupam. Maybe just one on the two upcoming gene therapy launches, DTX401 and UX111 in the back half of the year. Can you just discuss where you are in terms of commercial manufacturing and product scale-up and just your overall readiness from a launch -- from a CMC launch perspective.

Yes. No, good question. I think we've been manufacturing actually since last year. And for DTX401, the drug subs and drug [ pare ] both made at the plant and in Bedford. And then for UX011, we have a contract manufacturer that's making drug substance in Ohio, and we're making -- or finishing the fill finish in our Bedford plant -- we've been running around last year and this year. I think that's part of our expenses that we're spending money on is actually building inventory, and that's been going well, and we're building inventory and feel like we should be in a reasonable position at the time of launch.

At this point. So I think we're ready. I think the launch teams have been working on their work. I think the two PDUFA dates are quite close to each other, but the doctors were going to are actually the same doctors and there's certain synergies that will happen by having the same quality. Most of the centers will be doing both products, somebody [ do ] 1 or the other.

But the quality treatment centers are getting set up contracts in place. And I think the synergies of having 2 of them will be real, and we're excited about the possibility. Of course, we still need to get approval. But at this point, from both manufacturing and commercial standpoint, we're set up and moving forward, excited about the prospects of launching 2 gene therapy products.

Next question is from Eliana Merle with Barclays Bank.

Just can you give us any more color on how we should think about the time lines for getting data from the AURORA study? And if the data are positive in the Phase III ASPIRE trial, how are you thinking about what your base case will be for the agents and from a potential insulin label? And if this will include adults.

So AURORA is how we're going to expand the label to other indications, gene types and ages. So the main ASPIRE studies, 4 to 17, all deletion and so we have a younger group, the older group and the other gene types involved in AURORA. The study is still continuing to enroll and enrolling well, but it's also an international study, and we'll continue to collect data -- so we'll have update at that time. We haven't really said through anything about how we'd approach our filing launch at this point in time. We're going to wait and see what the data look like and our make put together our plans. The study with or [ though ] is still more enrollment to do.

Our next question comes from Yaron Werber with TD Securities.

Really appreciate the color on Angelman. You mentioned the 14 mg was generally the maintenance dose being used. Can you give us some color on whether there might be more than 1 dose being used, why that might be happening and whether there could be more than one maintenance dose in the label. And secondly, in terms of profitability projections, given that PRVs are selling for substantially over $100 million at this point. Any color on what you're modeling in terms of PRB monetization and whether we can expect that full year 2017 profitability to be sustainable.

Okay. Well, I'll touch on the dose at a high level. I don't know if Eric has anything more to add, but then I'll let Howard deal with the RB is a profitability question. So the vast majority of patients are 14. And from the main trial, the protocol actually ASPIRE brings them to 14 in terms of how it's done. There are some patients that have certainly been on drug for a longer period of time in various regimens. So I don't know if there's anything else to add it. I think it's a very high fraction on 14.

Yes. And that is what we expect to label on. So we expect a maintenance dose of 14 milligrams every 3 months. Once we get into commercialized setting, we have our DMP, we can explore potentially a different dosing. Maybe some patients would benefit from every 2 months, some could benefit from a higher dose there, too. But our plan is to prior -- after discussions with the FDA with a 14-milligram maintenance dose.

That's really the main source of what you're going to see. So Howard...

So with regard to the PRV, we watch this with interest to see how they've been selling. As part of our plans, we have 2 PRVs we plan to monetize, for 111 and one for 401. We -- I think we've stated in the past that we've baked it into our model at a little over $100 million each. So anything above that would be upside. Of course, there's also an opportunity for a PRV with 102, which would also be upside to our model. So that's how we're thinking about monetization.

And I think you'd also asked the question about sustainability of profitability post '27. Our plan is to not just hang out at the Raiser's Edge, but to continue to grow profitability. And depending on the launches we have and their success, we'll figure out how much we can reinvest back into the pipeline versus drop to the bottom line. But that will be a fun conversation to have in due course.

Our next question comes from Salveen Richter with Goldman Sachs.

Ahead of the Phase III Angelman's data in the second half, can you speak to the path forward in the event that MDRI hits that Bayley-4 doesn't?

I think as Eric noted today in the script is that we still consider that a positive study that is we have essentially two ways to succeed. The Bayley Cog can succeed and the MDRI provides maybe a more robust option. We negotiated this position with the FDA. I think while their tendency is to stick with single primary endpoints as their approach, we think the MDRI is actually a smarter and better way to go for neurologic disease. This is an opportunity to move in that direction.

Our expectation is, as Eric had said, that a missed Bayley-4, but a positive MDRI is still a demonstration of efficacy in the program. Obviously, that would assume that, let's say, Bayley Cognition just missed and then MDRI hit. That would be one potential scenario. We would not expect, for example, Bayley Cognition to go negative and then have an MDRI positive, have that work out. So the question really be, could Bayley miss for some reason and MDRI provides an insurance policy and support for efficacy in the product that's broader than just cognition. So we feel like there's ways -- it's 2 ways to win for the program, and we're actually expecting both to hit. But as you know, we can always miss in our best intentions in a randomized controlled trial, but I think the combination of both gives us a higher chance of being positive regardless of what happens in the patients.

Our next question is from Kristen Kluska with Cantor Fitzgerald.

For this latest Angelman cut that you looked at for the Phase I/II data -- can you tell us how the 1-year plus data is stacking for cohorts A and B relative to what you saw across different measures for Cohorts 4 and -- and whether that's further strengthened your position of the dosing regimen and techniques you took forward in Phase III?

Okay. Yes. So -- we've shown the cohort A and B before, and I think the cohort A and B is continuing to behave. And I would say -- remember, that's the most of the patients. CMD is relatively few patients. It's really mostly A and B. So I think what we're talking about is cohort A and B extending now through the full year, and that's the data that we're talking about.

So it's really driven off of A and B. That A and B is, we think, is pretty comparable to what you're seeing in the Phase III because the A and B was in all the international sites. So that included the 7 or 8 countries that we're also doing studies, including a high overlap with the sites that we're actually using.

So I think that the A and B cohort, which is the primary driver of the data you heard about today, is very replicable with regard to what we're doing in Phase III, both from a sites, countries and patient type. So I think it is a good model. I think the data should be in line with what we expect in Phase III.

Our next question comes from Maxwell Skor with Morgan Stanley.

This is Selena on for Max. On Angelman, could you describe the contribution of caregiver input to Bayley-4 cognition in the Phase I/II and how that changes over time with the longer follow-up data?

Well, thank you for that very technical detailed question. I'm not sure everyone knew about caregiver input. But just to be clear, in the ROS scores that we're using for the Bayley-4, the FDA does not want us to include caregiver input, all right? So all the analysis has to be done by the psychologist tester -- and so we are not including any caregiver input in the Bayley-4 primary endpoint per FDA request.

Now out of the -- I'm getting the number, is it 20 or 30 items or something? There's like a couple of items where caregiver input -- 2 or 3 that can have an effect. So when we look at [indiscernible] with or without caregiver, we don't think for Bayley-4 cognition, there's significant issue. If you're doing the expressive Bayley, there's actually a lot more caregiver input potential. And so it might have more effect on the receptor -- I'm sorry, expressive communication than on cognition. So it's only a couple of 2 or 3 things we haven't seen it have an impact, but we are doing it without caregiver input in the Phase III trial.

Emil and Eric, I think the question was maybe more around the Phase I/II data that we've talked about if we were able to look at that without the caregiver input, and I don't think that's how the Phase I/II was run. Yes, that's correct. For Phase I/II, we did use caregiver input, and it was part of the conversation designing Phase III that the FDA made that require. we actually performed the test both ways in Phase III, but the primary endpoint does not use caregiver. And that's important to eliminate bias, and that's true for both your actively treated in your control group. So it's a reasonable request.

So we can analyze without those items, they will not have a meaningful impact. That's what I said that if we drop them out, they're not impacted because there's only a couple of items out of a very large number where it might impact them, right, okay? So the situation is those 2 or 3 items that the caregiver says that they think they're developing, but the doctor to see it, they see it, they could score a point or 2. But we're saying if you drop those out, it's still -- it's fine in cognition. So our point would be that we see in Phase I/II is -- would be consistent with or without caregiver input, right? Does that answer the question, Josh, we did.

Our next question is from Jack Allen with Baird.

Congrats on the progress. So I wanted to ask about what your expectations are as it relates to the sham performance in the ASPIRE study. I know there was a limited data set from Angelman, but are there any other surrogate neurodevelopmental indications that you've looked at as it relates to sham performance? And then my other follow-up was on the profitability. And any comments you can make as it relates to what you need as it relates to success from the gene therapy programs in Angelman that's baked in for assumptions for profitability. Do you account for those in the profitability guidance? Or is it just the current base business?

Well, I'll let Howard deal with the profitability question, but let me deal with the sham performance. Well, obviously, we would not expect sham to have an effect. And we haven't looked at all possible studies, but certainly in our own -- in Angelman and the controlled studies we've seen, we haven't seen much change.

I would say to you that when you're talking about the performance of development, these kids are not going to have a placebo effect exactly, right? Because they're not thinking, "Hey, I'm getting a treatment, I should be better. They're not going to think this way. They're not -- development and changing by not having caregiver input, which is maybe why the FDA doesn't want it, it allows there to be a more objective assessment of what's happening.

So we're really saying could they get better on their own without anything happening. What we're saying is that the deletion patients just don't. So we're pretty comfortable that sham forms will not be important. I don't know that there's other developmental disorders that are comparable, maybe Rett syndrome or other types like that. But at this point, we don't feel that the sham should be any different from a natural history and the deletion patients are pretty stable in terms of their Bayley cognition scoring.

They do not change much, and we're talking about less than 1 point a year. So whether it's a randomized trial or even a natural history. So at this point, we're comfortable with it. But I understand your point right now, we seem comfortable with it. And we have adequate power even if there was a higher background signal, we should have power to overcome that with the treatment effect we expect.

And [ Jack ], regarding profitability and launch success assumptions, right now, what we've said for top line is that we assume continued double-digit growth from our current products plus contribution from upcoming launches, which could include 111, 401, -- we haven't said much more than that, but maybe what I can say is that it certainly doesn't require all of them to be successful for us to get to profitability. And we have different levers we can pull to make sure we can live up to our promise of 2027 path to profitability.

Our next question comes from Ben Burnett with Wells Fargo.

I wanted to ask about the GTX-102 program and great to hear about the long-term data. I think you mentioned there were 66 patients in the long-term extension. Could you comment on sort of the reasons for discontinuations? And then I have a follow-up.

Yes, we can do that. It's actually been a little here a little there, but it's mostly often in the beginning. Maybe you can comment on that, Eric.

Yes. So very consistently, it was all due to burden of study participation. I mean we do need to remember that some of these patients live very far away from treatment sites, and it does become a burden for these families. So that was across the board, the reason for dose discontinuation study burden.

It sometimes happened kind of early, too, because some people realize they just couldn't do it. But yes, so it wasn't safety related.

Okay. Okay. And then the other question I just want to ask is just around Crysvita. So I appreciate kind of the commentary you gave on the call just around some of the variability around sort of ordering patterns. But I guess the question is, is to what visibility do you have kind of going forward through the next couple of months? And sort of what gives you sort of the confidence in kind of the yearly guidance number for Crysvita?

Yes. I'll let Erik comment a little bit because Erik is very close to the team at Karen on what's going on. But I think one other element of this is that every year, we're going to have one other factor, which is the way the royalty is in the first part of the year, it's a little bit lower than it crosses the threshold and it goes up. So whatever revenue is coming, our percentage goes up as the year goes on, and that's why the quarterly revenue goes up as well. So it's an ordering pattern thing, and there's going to be this continuous ramp-up of our percent in the royalty stream. So it's just going to reset, every year and crawl back up. Erik what gives you confidence in Crysvita going forward in the North American territory?

Yes. No, it's quite simple. We're very confident in the underlying demand that we continue to see with finding patients and patients wanting to be treated across our regions, which is why we reaffirmed our guidance. And consistent with prior years, we expect the same sawtooth pattern that we've seen previously with lower Q1 and a rebound in Q2 and softer Q3 and a strong Q4. So we expect, as we have in previous years to continue to deliver on our commitment to the street.

Yes. I think the thing that we would see in Q1 though is like the start forms. What's the start? That's the demand you talked about. And so -- and continuations and so forth. So demand is strong in Crysvita. It's a great product. People stay on it when they get on it. And they continue to grow it, and we're here to support them and do our own work where we're commercializing. But we -- Crysvita continues to grow and do well. And we just have to understand there's always this quarterly plan. It's going to happen almost the same every year. So we feel comfortable how the year will go.

Our next question comes from Yigal Nochomovitz with Citi Group.

I was curious about the long-term extension data, and you mentioned that you've seen the positive improvements in multiple domains and patients are continuing to improve developmentally. I'm just wondering how you assess those metrics with respect to sufficient powering on the endpoint for the ASPIRE trial for the Bayley-4 cognition. Do those observations in the long-term extension study development improvement, give you confidence that the powering on the Bayley-4 is sufficient for the ASPIRE trial. And what would be the clinically meaningful delta that you'd want to see on Bayley-4?

Yes, Yigal, thanks for the question. I think, look, we -- I think Eric just talked about hitting around 10 points, let's say, in the 1-year time frame. So that's the part of the AMD cohort and the others together that have gotten to the 1-year mark. Some people are at the 3- to 5-year mark. What we're saying is that 1 year, they're hitting a number, which is pretty close to what we've been expecting the whole time, and that size gives us shows that we were adequately powered and it's well above the MID at 1 year.

So we're feeling comfortable about that size. And by the way, most people that know that just that test are shocked at how much change there is because it usually doesn't move at all for most people or expert, including Kim Goodsky, who's our physician who was a abdominal specialist. He says, you just don't see this thing move. So 10 points is a big number.

What we are saying and what Eric put forth is that when you continue to follow these kids over the longer haul, they continue to go up in dayly cognition. And so that kind of tells us that the patients are having a sustained benefit of the ASO on their function in their brain and they continue to gain ground. That to me is really important. And that's what the long term is telling you. I think Phase III, of course, is very important for getting filed an approval.

But what is the commercial potential of a product I think the long-term safety and product treatment and continuing ground tells you this treatment that has the ability to help kids over a long period of time in the post-market setting. And so with Phase III in hand, being able to get to commercial setting, I think this gives us more confidence that the potential of the drug to be a long-term benefit for patients with Angelman syndrome.

Okay. And then one on UX111. Since the resubmission, have you had any other requests for information since the acceptance in April? Or any other inspection requirements post acceptance of the BLA?

Yes. We're having what I would call routine discussion with the agency. We normally don't discuss the details of those. We've had what I would call routine discussions on the BLA, and those continue. And at this point, we feel that business is normal moving forward. And we won't really comment in detail about it until something a decision gets made. We're excited about the potential of that program and are planning for a launch, assuming we get approval.

Next question comes from Gavin Clarke with Evercore.

This is [indiscernible] for Gavin. So two from us. One is for Angelman MRI end point. So just a full clarification of the debt analysis, but what is the delta versus sham control is actually defined? Is there a difference in the medium net response between the 2 arms or the difference in the proportion of the of the patients that are treating a net response in a list on domain.

And secondly, we have a question about 106 in maps, which we saw recently got IND clearance -- so wondering what is the key difference between this new molecule versus previous 1 that looks like also run through the same indication but failed in the Phase III. What are some key takeaways we can learn from that history study to inform the current time design?

Sure. Thanks. So for the MDI, what we're looking at is net domain improvement. So each patient will have a number of domains that they hit, right? And we look at net domain improvement comparing the distribution curve of the treated patients to the distribution curve of the placebo controlled patients, right?

So it's a net domain improvement, how many positive wins per patient do you see? And we've shown before that we had often 2 domains or more on average per patient around that in that range. But those domain can be variable. There can be various combinations. There are some patients that had as many as 4 or 5 domains of improvement. So we'll look at those distribution curves for the net domains per patient, right? That's the statistical comparison.

For genyopathy, I've been involved with that program from the very beginning. horrible muscle disease, we think maybe around 10,000 patients out there, and we think it's very chronic and terrible disease. The original molecule, sale acid replacement didn't work as well because the sal acid just didn't penetrate. What the new drug is a prodrug, one that we designed that has an enhanced hydrovicity that helps target uptake into muscle and gets released and transported by a sal acid transporter.

So it allows it to get taken up into the lysosome and cleared across the lysomal membrane into the muscle. And that improved hydrovicity mechanism will allow us to, in the animals or in dogs to deliver large amounts of sic acid to the cells substantially better than the other molecules, like many, many fold better. So we think the potency is just dramatically better, and that puts us in a better position to actually achieve the replacement therapy that's required.

And we know from the prior work and particularly the biopsy work that these patients have an 85% depletion of s acid in their muscle. This drug should take us back to complete replacement, if not above replacement levels of s acid. So we have greater hope this can be an effective drug for geneopathy.

It's a program I should point out, is funded through a venture [ philanthy ] agreement with the patient group and who are very interested in the product moving forward. And we were able to do that even under our financial constraints with the fact that they were funding it. So they're funding us through the Phase II proof of concept, which is allowing this program to move forward at this point in time.

Our next question comes from Luca Issi with RBC Capital Markets.

Maybe Emily and Eric, circling back on a couple of prior questions. What is your relative level of conviction on Bayley for cognition versus MDRI? It feels to me that during the call, it came across as incrementally more positive on MDRI versus Bayley for cognition. One, would that be fair? And two, if so, can you still amend the protocol to potentially reallocate more alpha to the MDRI versus the Bayley for cognition? Again, any color there, much appreciated. And then maybe super quickly on OI, I did not see anything in the press release or in the prepared remarks. So should we assume that you have discontinued that program?

Discontinued OI.

I missed it. So the MDRI is a more powerful measure. It has 5 endpoints in it. The gain power from all those endpoints. It is a very powerful way. We've been promoting it. We used it in our MEPSEVI program. It's just new for regulators. And so at this point, in our agreement with regulators, we put 80% of the power into the Bayley-4, which is actually where you need the power because it's -- there's a sort of a smaller magnitude effect.

The MDRI hits very strong statistical significance. So you don't really need more alpha upside MDRI even if you have higher confidence in it because it's a tremendous amount of power in it. so I think what we've done is the appropriate proportionate and we don't really need to shift it more. The OI, we continue to do evaluations and discussion. We put a little bit in the release on this. We'll -- we'll inform the Street when we have a decision what we're doing, but we did not discontinue the program. It continues at the moment and until we complete and get answers to key questions and make a determination.

Our last question comes from Raghuram Selvaraju with H.C. Wainwright.

This is Amit for Ram. I just have a question about the PDUFA dates coming up in the second half 2026. Can you frame the cadence of the commercial rollout and what to expect a meaningful revenue from both UX111 and DTX401. And then the second question is on the GTX-102 in Angelman. You mentioned discontinuation rates due to non-safety burden. Are you preparing any way to reduce discontinuation rates in the commercial setting? Or do you not foresee that being an issue?

Sure. So obviously, launch of gene therapy is complicated, the reimbursement part of it and so forth. We're not guiding on any revenue, what the revenue would be for this year, but we're certainly planning to move forward on getting the launch together. I'm sure Eric could go through this in great detail. I'll just summarize for you, Eric, that there'll be obviously various policies at launch we'll have to manage.

But eventually, we are talking to payers and appropriate meetings now to help lay sort of the planning process for that. But the reimbursement will be some of the process, and then we'll have to work through and get patients treated. So our expectation is that there will be some time from PDUFA date to be able to get things going. We're trying to work as hard to get it going within a few weeks and to see how we can get it going.

We expect to have product available, and it's more a question of getting the commercial process going. But I think the team has been working aggressively on getting all the pieces in place that would take. And I've been participating with them on some of the payer meetings that look at what the plan is, what the policies were and how to navigate the process to get the best outcome for patients. For discontinuation rates, we actually find the dis case rate very limited.

Actually, it's really small handful. And usually, the treatment effect that patients start seeing is so meaningful that that's something that patients have been looking for the whole -- patient families are looking for their whole life. So we don't expect a big discontinuation rate. But as we move forward in it, we will clearly need to manage the accessibility and convenience. And this may involve bringing in a device to help make lower punctures easier. But we're going to do our best to make sure this is as [ burnless ] as possible.

And I would say to you that a randomized trial or any kind of clinical trial has way more burden than getting something clinically in terms of what you have to do. So I think the amount of tests and stuff is a lot. And I think for an [ Asgeman ] family, that was probably more of a factor. So at this point, based on what we've seen, we're not expecting discontinuation to be a big deal. But we are also going to do our best to take care of patients before there's an issue and give them the best patient experience we can in terms of a convenience for a treatment that involves an intrathecal delivery of an ASO.

We have reached the end of the question-and-answer session. I would now like to turn the call back to Joshua Higa for closing remarks.

Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at [email protected]. Thank you for joining us.

This concludes today's conference. You may disconnect your lines at this time. And we thank you for your participation.

Good morning, everyone. I'm Joe Schwartz from the biopharma equity research team at Leerink Partners. It's my pleasure to host our chat with Ultragenyx. We have Eric Crombez , CMO of the company with us today. Thanks so much for joining us.

Great, and thanks for having me.

So maybe you can start us off with a brief overview of the company's recent events and your priorities for this year.

Sure thing. I'll start with our commercial success we've had led by Crysvita. So certainly, a lot of continued growth there. Great to see double-digit growth year-over-year, along with Crysvita seeing really great growth with Dojolvi and Evkeeza specifically and also having Mepsevii there in the background. So great background of commercial revenue there supporting everything we're doing on the pipeline.

And then turning to the pipeline, obviously, a big focus on Angelman with the data readout in the second half of this year, but also really nice to see progress with our gene therapy pipeline. We've been working on this for quite a long time. And with our PDUFA date now in hand for GSDIa, getting Sanfilippo closely done behind that, and then obviously, not forgetting about OTC and Wilson there, a lot of depth in that clinical pipeline. And then again, with that maturity and getting these things across the finish line, launching into the commercial space, looking forward to the potential of bringing new things into the pipeline.

Great. Okay. Well, let's dive in. And I guess we'll start with Angelman. In the Phase III study, we noticed that the primary endpoint will be measured without caregiver input, which seems a bit different from the Phase I/II. Could you contextualize how caregiver input can influence Phase I/II study data? Is there any way that this might have inflated any of the responses that we're seeing? Or how do you think this nuance when going from Phase I/II to Phase III could influence results?

Yes. The change was really driven by the concern around placebo effect. So with Phase I/II, obviously, it's open label, everyone's on drug. They know they're being treated. Using caregiver input is how the Bayley design is, how it's standardly administered in all children. But going into a blinded study, obviously, the parents don't know if their children are being randomized to active treatment or sham control.

Certainly, everyone wants their child randomized to active treatment. They want their children to be doing better and in a blinded setting, you really do have to think about placebo control. And the best way to control for that and it really does for me, control that is taking out that caregiver input.

So that means when you're administering the Bayley in clinic with the standard Bayley with neurotropical children, if they will not do something in front of the assessor and the parent says, they reliably, consistently do this at home you can give them credit for this. Taking caregiver input out of it means they need to perform these test in front of the assessment in order to get credit for that. So really just trying to control that placebo effect to the best of our ability.

Okay. Interesting. And then in the Phase I/II, we saw an improvement in the Bayley cognition score of more than 10. Is this what you're hoping to see in the pivotal? I think the minimally clinical different value is around 5. So can you give us your thoughts on like how you're thinking about the magnitude of potential benefit that you need?

Yes. And I think, first, thinking about this statistically and what we need to hit statistical significance, I think it is best to go back to the slide. We presented at the FAST meeting a couple of meetings ago. Where we show change in cognition by Bayley-4, both by GSV and raw scores. We thought it was important to do this because GSV is the standard scoring for Bayley. That's what people are used to seeing and that allows for development to continue over time in an individual child and just really tracking that over time.

The FDA, they don't like any type of modeling, any type of adjustments to score. So they always prefer raw scores. And that's the conversation we had really all along heading into Phase III. So it wasn't a surprise to us. We understood that, but we wanted to show that data side by side to show that whether you're doing it by GSV or by raw scores, the results are similar. They are comparable. We still achieve greater than 90% power.

And then shifting to raw scores because that's what our primary endpoint is based on for Phase III we did see in treated patients a 10.9 difference change from baseline in those treated patients.

And then when we're thinking about performance of our placebo group, we obviously go back to natural history. Naturally, history tells us that developmentally, it's a very flat curve. It's not 0, but it's very flat. So when we looked at the change in raw score from natural history, we actually gave that room to increase threefold when we were looking at how this could perform in a clinical trial, not because I expect it to be any different, but you have to allow for unexpected things to happen.

So when we were powering our studies and originally coming up with 120 patients for the Aspire study, we were looking at that delta of 10.9 in actively controlled patients versus that 1.2 that 3x natural history in the placebo group. That's what drove that.

Then shifting to clinical significance, and I think the best thing to look at is how we build cognition into the MDRI, the Multi-Domain Responder Index. And it really is the same as clinical significance, but the FDA has shifted in the field is kind of shifting to MSD's Meaningful Score Difference. It is the same thing as clinical significance. You have to set and agree to that, Meaningful Score Difference. So for cognition by Bayley-4 to say you have achieved clinical significance in the MDRI. It is a change of plus 5 that you mentioned earlier.

Okay. Super helpful. Thank you. So based on natural history data, it seems as though the standard deviation is greater for the raw scores versus the GSVs, so have you taken all of that into account in the power of the study?

Yes. No, I mean, absolutely. Again, there's kind of like what you expect if everything behaves in an ideal way, but then you have to give yourself a plus minus accepting that things don't always go in an ideal way and you just have to give yourself room there. So that's -- when we talk about -- and it was actually a question from one of the agencies in Europe is why are you overpowering the study? And our answer was it's neurology and if you ever want to overpower something you want to do it in neurology.

So originally designed to enroll 120 patients. We over-enrolled 229 because there was such demand and we had a lot of patients in screening and for me, once they've committed to the study, they've signed consent, we want to get them through dosing. So that even helps from a powering perspective.

Very interesting. And I think MDRI could be considered more impactful as an endpoint because it captures more about the child's development. Has the FDA actually agreed that a win on the MDRI could support approval of Bayley-4 primary cognition is not met?

Yes. So it was great to see the progress with the FDA, with MDRI. We came to end of Phase II expecting to have another good conversation negotiation around that. And to be honest, they came to the table really kind of bought into the MDRI, what we were doing using at a second primary endpoint applying alpha to it.

So you're right, it is a powerful tool because you're looking at scoring across all of the key domains, how you're really looking at thinking about development and allowing for variability in these children because again, it is neurology.

And the FDA said, it is a straightforward tool. We're not doing sophisticated statistics where you can manipulate anything. It's a straightforward scoring system that you can always take a part put back together again, and they verbalized that back to us.

We received a breakthrough designation. We had a breakthrough meeting. They confirmed because we wanted to clarify again that they understood, we're bringing forward the MDRI, we're bringing forward as a primary endpoint. We are applying alpha for this and making it a secondary endpoint and they confirm that they're on board with that.

Okay. Great. And how much was the dose that you selected for the pivotal trial based on the relationship you've seen in terms of knockdown and protein restoration and how much was potentially limited by the lower extremity safety signal? I think previously the company was dosing much higher than you are in the pivotal. So I'm just trying to understand that dynamic.

Yes. And I think to me and that's a little bit standard drug development, very true in this case. You're using your animal model data, and we did have data in nonhuman primates, and that's obviously a good model to inform your dosing strategy for your Phase I/II. The original dosing was done by genetics when they were running this program. And I think really does stress that you do want to start low and build up with dosing with your dose finding because if you get ahead of yourself, it can really set you back there.

So once we brought that program in-house and restarted dose finding at a lower level, we did that experiment, and we enrolled 74 patients in that Phase I/II to make sure we understood dosing and what was the right dose to bring into Phase III. So I would say that the animal model data really informed our Phase I/II design, and then it was the clinical data coming out of the Phase I/II that drove the selection for Phase III.

Okay. Helpful. And I think the company has stated several times that GTX-102 is the most potent ASO and development for Angelman. Can you help us understand how this claim is informed. Is it based on preclinical data for ATS knockdown, mRNA or protein increases or all of the above?

Yes. So Emil, our CEO and I are both, we're both genetics. So we're used to thinking about it at the molecular level, and we're also at our core clinical development people. So yes, we are informed by what's going on in the research space. And again, it is important to understand that and inform everything. But we're really driven by decision-making on the clinical data. And again, with 74 patients worth of dating in the Phase II, we have a lot of clinical data. So that claim is really based on what we're seeing from that Phase I/II data set and then the doses we're using and seeing a really good effect from across all domains there.

Okay. I think there was a recent peer-reviewed paper, which outlined that for Locked Nucleic Acid ASOs, there might be a translation gap where almost 90% knockdown of the transcript was required to achieve only 50% protein restoration. And since GTX-102 leverages LNA chemistry, I'm wondering if you can remind us what level of knockdown and protein restoration you're achieving? And do you have a reason to believe that specific aspects to GTX-102 design could allow it to avoid any such translation issue?

Yes. So with a lot of these recent conversations and understand we're in a competitive space. There has been a lot of talk and conversation around this. And obviously, there's a third party coming into the mix here. So I actually went back to Scott Dindot, he was the scientist who started all of this work. He's been leading this work and he continues on and had another conversation around this. And really understanding the work we've done in nonhuman primates understanding the relatively newer work that's been done in some mouse models.

We're in agreement. He isn't an agreement that you probably do want to have greater than 80% knockdown of that antisense molecule in order to achieve at least 50% expression from the paternal alleles. So we do agree with that kind of threshold, if you will, in our data that we did in-house show that we can achieve that.

Okay. And then do you have an idea of what amount of protein restoration is required to drive a clinical benefit in Angelman, how do you think about that? .

Yes. So again, I'm a clinician, I'm happy to go back to the experts and get their sense on this because this is what they've done, and they're much closer to it and know a lot more than what's published beyond in literature. And in talking to Scott that his thinking, our best thinking it's probably around 35% expression from that paternal allele or the maternal allele depending on what you're doing to have a really good effect there.

Okay. And then how does Aurora fit into the picture for GTX-102? And how has that study been enrolling? Can you walk us through the filing plan here and what your expectations are around the label?

Yes. So Aurora is our second Phase III study. It's important because it does round out that label there. And yes, that's important. But to me, in all sincerity, I think what can be very hard in rare disease is when you're studying subsets, and then you potentially have a label that excludes a group of patients there. So our Aspire study, our main Phase III study is still looking at patients with full deletions.

That is the great majority of patients. But again, there are patients out there with missense mutations, uniparental disomy and imprinting, and we don't want to leave them behind. Everyone understands they can really benefit from this drug as well.

So Aurora is a true basket study. So we're looking at younger, older patients and patients with those different mutations there. It is open label. It is going well. And the strategy there is really to do a straightforward extrapolation to Aspire. So establish comparable safety, get efficacy data that we can then bridge back to Aspire and ultimately have a full label for this drug.

Okay. Great. Maybe we can switch gears to DTX401. We really like this program. We sometimes call it a sleeper to investors. It was great to see the BLA accepted last month. How is that review going?

Yes. No, it is great, and it's great. And Sanfilippo and GSDIa want to have kind of been jocking to be our first gene therapy approval. With now having our PDUFA date in August in hand for GSDIa. I think it's there. It's going well. So we cleared our 2-month validation period. We received our PDUFA date. We're in that review period, where we're receiving our IRs, or Information Requests. So we're at it, and I'm looking forward to August.

Okay. Fingers crossed. The agencies been a bit of a stickler when it comes to CMC, especially when it comes to gene therapy. Can you talk about how you feel about where you are in your manufacturing and ability to address questions during the review? Given I think it's going to be your first gene therapy product and your first one manufactured in-house?

Yes. And I think that definitely brings the Sanfilippo gene therapy into the conversation as well because we are doing manufacturing for both of those products at our facility outside of the Boston, Cambridge area, and that's our manufacturing facility that we built from the ground up.

So with manufacturing with the challenges everyone has had for a very long time, we thought it was important to bring that in-house, take control over that. And that has been a success on all levels from manufacturing to cost of goods to everything there. And we really like having control there. And ultimately, we want to bring all gene therapy manufacturing into that plant.

So that's been helpful, but then also with doing manufacturing for Sanfilippo and GSDIa, they at the same facility that initial CRL, complete response letter did have pullover into GSD1a because any findings that was specific to the facility, not to the product itself would have applied equally.

So that's why we took extra time with GSDIa. We made sure we had everything right, finished and complete for that initial filing for GSDIa. We really didn't take any risk there. We didn't way to perform anything or finish anything and try to negotiate doing that during the review period. And again, it was great to get through that 2-month validation period and be underway now.

Very helpful. So when we throw around the world, curative, people often get hung up on the durability of a treatment. I think here with GSDIa, we saw the efficacy of cornstarch reduction actually get better over time. How are you thinking about DTX401 duration? And does that give you confidence in the FDA review?

It does. And I think what's nice is, and I started with our gene therapy programs as part of Dimension Therapeutics. So I've been with these gene therapy programs from the beginning and anything with DTX in front of it means that you started that at dimension. So we've been doing this for a long time, and we can always go back to these Phase I/II patients who have been in trial for a very long time and showing really strong durability. And I think that was the question with liver-directed gene therapy is how often do your hepatocytes turnover? What is it going to be? And I think everyone had their thoughts there.

I think we're seeing strong durability. We're seeing that the turnover hepatocytes maybe is not as fast as we thought, and we really are holding on to those transgenes. So I think with the total package there, including those Phase I/II patients and the durability we're seeing there makes a very strong case to the FDA.

Okay. Well, let's talk about the primary endpoint a little bit. On the one hand, cornstarch reduction is a great endpoint since we can easily conceptualize how impactful changes in it are to patients. But on the other hand, some people just wonder are you just swapping one thing for another, and how meaningful is it? Can you talk about some of the other end points such as glycemic control or any others that come to mind that can help us envision what DTX401 could mean for patients and caregivers?

Yes. And we almost kind of shorthand the way we talk about GSD1a and reduction in cornstarch because it's always been this concept that it's been the reduction of cornstarch in the context of maintaining good glucose control. So that was always fundamental what we're doing here.

And yes, early on, and we've had this conversation, and I think we've made a lot of progress with the agencies, also with payers and reimbursers about understanding that, and it's not just a food product or something like that. And bringing in the patient groups to speak to the FDA was very compelling.

We also did that in Europe, and that really showed the importance of this. And prior to really understanding that you could use raw cornstarch to be solely digested in your GI tract to give you 2 to 4 hours of glucose control took this from a universally fatal disease, and that's how we really thought about GSD1a in children is they didn't make it out of the pediatric age group to something that could be managed with the use of cornstarch.

But again, that's cornstarch every 2 to 4 hours, including overnight, and they still were not doing well. They still had problems with their livers, problem with their kidneys, high cholesterol, high triglycerides. They were still having a lot of metabolic problems there. So they weren't thriving. They weren't doing as well as they could do.

And obviously, with gene therapy, you're getting to the heart of this disease, and you're letting them for the first time, break down glycogen in the liver to produce glucose during times of fasting. And we've seen that as part of interviews that our formal part of the studies. We've seen that anecdotally where people feel like they can go back to work, they can travel, they can go away from home. Because they had this dependent on cornstarch and this fear if they were separated from it, that this would be life-threatening for them.

So Yes, it's easy to think in a simplistic way about cornstarch, but it really was lifesaving for them. And the hypoglycemic episodes, particularly in pediatric patients can remain life threatening.

I get it, interesting. So can you remind us what the standard immunosuppression regimen was in the studies and how you expect this to be implemented in the real world, if it's approved? And what liver signal did you see?

Yes. So again, we started our gene therapy pipeline really focused on liver-directed gene therapy, and that was really when we started with these inborn errors of metabolism programs really looking to what was done with in the hemophilia space for gene therapy, and that was the use of steroids.

Using for adult 60 per kilogram and then doing weight-based loading for pediatric patients. So for us in our Phase III, it's an 8-week bolus and then titration of cornstarch. If you have a rebound in LFTs, if you have prolonged LFTs, those steroids would be continued until your LFTs were in the normal range.

And I think with the patients, we've dosed across our pipeline and what we've seen broadly with liver directed gene therapy in the E13 range. We saw that typical rise in LFTs that were always clinically silent, resolved with use of steroids and resolved without sequelae.

And I think we understand this gene therapy, even administration needs expertise. These patients are complicated. They do need to be followed by people who understand this disease. And that means they're by and large in tertiary medical center. So we've started identifying those centers where we're going to be launching and doing this, and it's something they can steroid to something they can very easily handle.

Okay. So how do you view the commercial opportunity then for DTX401. And are there obvious early adopters and later adopters? Or is there another better way of thinking about that?

Yes. And I'm probably not always the best person to ask about uptake and penetration because being a clinician and being a geneticist and treating a lot of these patients, if you really have to take cornstarch every 2 to 4 hours, and GSD1a is one of the diseases where you have a very consistent phenotype. You don't see this broad spectrum with these mild patients who are roughly fine. These are really people who need cornstarch every 2 to 4 hours. So to me, if that's your lifelong regimen and having to deal with everything else that comes with that, then you will benefit from this gene therapy. So we talk about roughly 6,000 patients in the territory we cover 20%, 25% in the U.S. And for me, I think they will be very high penetrants there.

Okay. Interesting. So switching gears again to UX 111. This program has had a bit of a rocky path, but it seems like things are getting back on track. Can you give us your current sentiment and how optimistic you are that you can get it over the goal line?

Yes. So received our Complete Response Letter, our CRL for Sanfilippo. That was obviously a surprise to us. work closely with the FDA to understand and the FDA was very open to speaking with us to make sure we were able to satisfy that response.

Unfortunately, we did receive that Incomplete Response Letter or our IRL there. And what that means is during the 2-week review period, validation period, in contrast to your 2-month validation period for an initial submission, they came to the determination that we had not completely answered all of their questions in the CRL. What was required to satisfy the IRL was more of things like SOPs, paperwork, things we could just satisfy in writing. I didn't have to run additional assays, didn't have to do assay work. didn't have to do any new work there. So that means we can easily satisfy it. If we were clear, they wanted this as part of the CRL, we could have provided that. So that means it's a very quick response timeline.

Again, luckily, it's a 2-week validation period, not a 2-month validation. So I'm expecting to get through this and receive a PDUFA date and really have those approvals for GSDIa and in Sanfilippo very close to each other in the second half of this year.

And can you help us understand how well suited heparan sulfate as a biomarker that's reasonably likely to predict clinical benefit in MPS? Are there different ways in measuring it that are important or other nuances? Any reason to question, HS is an [ RLSE ]?

So I don't think there's any reason to question heparan sulfate here. And I think the academic community, treating community us and the industry. We all understand we'd like this and find the correlation to be very strong there.

Obviously, we brought that along as originally as a basis for approval, I think what it comes down to is really what is your view on accelerated approval in the use of biomarkers generally not specific to heparan sulfate. So we think heparan sulfate is a great biomarker here. We think it could have been used for the basis of approval. Unfortunately, but a little bit fortunately, with the duration of time we've had working through this filing, we are coming up to achieving the original FDA request to have all patients reach their fifth birthday. And that was going to be their clinical outcome there. And that's with the idea that by natural history, these children by 5 years of age, are very neurodevelopmentally damage. And if these children are still doing well, you've shown that your drug is effective.

Where we stand today and with our resubmission, the majority of patients in this trial have reached their fifth birthday. So we are really shifting away. And the FDA said this during our last review period that with the strength of our clinical data, we're really moving away from a biomarker accelerated approval to really looking at this as a clinical approval.

Okay. Great. So shifting to Wilson disease. We've seen a few interesting cuts of data from this program of yours? Now for the upcoming data with the new immunosuppressant regimen, what should we be looking for?

Yes. So we're taking the time to make sure we get Wilson right, and we really want to see the efficacy there to really differentiate to chelators. I think when you have a fairly effective treatment there that people will argue patients are somewhat happy with that you're really showing positive differentiation. You're doing something beyond that. And that's different than something with GSD1A. I guess there's cornstarch, but the highest unmet medical need emphasized with Sanfilippo there. So we've set a very clear bar for success. We want to see the majority of patients off a chelators doing well there.

And then with going up in dose and using stronger immunomodulation, I think that's at least additive, if not synergistic there, with making sure in this additional cohort and then looking at the data in totality that we have the right dose to bring in to Phase III to have a successful commercialized product.

Okay. And what have you seen so far? And what do you hope -- or how do you hope that the next look compares?

Yes. So with our last data readout, we were very close to that bar of 50% of patients coming off of chelators. So we want to obviously see if we can do better than that. What's nice about Wilson in being a copper transporting disorder is you can look at copper in a lot of different ways. So you really can be confident in what you're seeing. And if you're really establishing the normal trafficking of copper, yes, we are measuring clinical endpoints. We're looking at neurologic outcomes, and that's important. But having those types of biomarkers separate as a basis of approval really helps with decision-making in Phase I/II.

Awesome. Thanks for all the insights, Eric. Really appreciate it.

Thank you.

Hi, everyone. Good afternoon. Welcome to Miami. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very happy to have Ultragenyx here with us for a fireside chat. And joining us from Ultragenyx is Dr. Eric Crombez, the Chief Medical Officer and EVP.

Eric, thank you so much for joining us.

Well, it's an exciting year for the company heading into the Angelman Phase III. But before we dive into that, maybe just to start off with as a commercial stage rare disease biotech, could you provide a high-level overview of the story?

Yes. Great. And thanks for having me. Great to be here. So just very briefly, founded in 2010, public in 2014. Founded by our current CEO, Emil Kakkis, with a real focus on rare disease and focusing on patients and diseases where there still remains a high level of unmet medical need.

And really with that focus on rare disease, trying to bring along enough platforms, whether it be enzyme replacement therapy, small molecule gene therapy, other modalities where we really have the diversity of platforms where we can focus on that unmet medical need and then figure out the best way to tackle these diseases.

Great. And before we dive into the pipeline, maybe just to touch on the global commercial footprint, which is less common for a biotech of your size. What led you to pursue the strategy rather than partnering ex-U.S.

Yes. So we do have and have built over the years a broad commercial footprint, it speaks to the strength of our commercialized products that is led by Crysvita and that is in partnership, but then also bringing along Dojolvi, Mepsevii and Evkeeza. And for us, really having control, direct control broadly across the various regions, certainly starting with North America, Europe, now with an office in Japan kind of as a jumping off basis for Asia and then also a deep and rather large team for South America.

And I think what that allows us to do, in addition to maintaining control is really leveraging the expertise we have. It may be unusual, but also what we do is unusual and not relying on what some people may consider a very traditional large commercial footprint, but also relying very heavily on our medical affairs expertise and the team to really lead all of that work.

Great. And you're also approaching profitability in 2027, which is, again, less common for a biotech of your size. Could you highlight the factors getting you there? And maybe what profitability would mean for the company long term?

Yes. And I think that has kind of been our north star, if you will, for a while now and really focus on profitability in '27. Certainly, that has relied heavily on the base business, again, that is led by Crysvita but also really growing and growing in meaningful ways with Dojolvi, Mepsevii has been with us since the beginning, and then Evkeeza doing very well most recently.

There is some dependence on approval and commercialization, launch of our late-stage programs. We do have a large and robust pipeline that has grown and progressed to late stage. And then looking also at PRVs. Our modeling currently has 2 PRVs originally focused on GSDIa and MPS III, but with its recent reauthorization also puts into play one for Angelman.

And then again, with the advancement of our pipeline that I spoke about, the transition from late-stage rather large, rather expensive Phase III trials into approval into commercialization and launch and the cost reductions that's realized there even if there is some investment early on in the pipeline, those are much smaller scale Phase I/II, which are much less expensive than what we're investing in these Phase III programs.

Great. And before I jump into Angelman's, which I'm sure most people in this room and on the webcast are curious about, could you provide us a high-level overview of the pipeline and the programs in development?

Yes. So I guess, looking at kind of at our near-term approvals, so now being led by GSDIa recently received our PDUFA date in August that will be followed closely behind for our Sanfilippo program. So those 2 lead gene therapy programs kind of have traded spaces for which it was going to get approved first and be our first gene therapy approval.

Importantly, followed behind that is the Angelman program and the Phase III data readout later this year. We have talked about the OI data readout at end of the year and our continued analysis of that data before making final decisions with that program. And then importantly, we do have our OTC program and Wilson also gene therapy. And then, again, a lot going on within our research group and a lot of potential to bring new things into the pipeline when appropriate.

Great. Yes, a lot going on. So maybe starting with Angelman, can you provide an overview of the program, the data we've seen so far and sort of expectations as we head into the Phase III?

Yes. So a big value driver for the organization this year, very important to us. We have been talking about the prioritization of this program for a long time. So it's really great to see that program heading into data readout this year. We did a relatively large Phase I/II study, and that was important to us because we always recognize the complexity and variability within neurology.

We took the time to dose a total of 74 patients in that Phase I/II study that really allowed us to understand dosing, understand this, AO, understand the end points before we design and then launch that Phase III there. So two Phase III study Aspire and Aurora. Aspire leads that is our sham-controlled Phase III trial. We enrolled 129 patients between 4 and 17 years of age with full deletion.

We like that approach and really continuing on with the same patient population we studied in Phase I to best understand how this drug will work in those patients. But importantly, in this case, focusing on patients with full deletions, meaning these patients are not making any UBE3A. That makes them a very consistent phenotype. And to me, that's the best way to have clear signal detection when you're reading out these Phase III studies.

This does make patients also at the severe end of the spectrum. It is the majority of patients, but it is not the totality of the patients affected with disease. And that makes the importance of bringing along Aurora, our second Phase III study that is open label. It is a true basket study where we're looking at younger and older patients and then patients with other genotypes missense mutations, uniparental disomy and [ printing deuvex ], understanding that we really do need to bring this drug forward for all patients who could potentially benefit from it.

And in terms of the Phase III design, that's helpful context. But can you elaborate a bit more on sort of why the Bayley-4 cognitive score was chosen as the primary endpoint?

Yes. So cognition assessed by Bayley-4 is our primary endpoint. [ From -- 4 ] patients total in the Phase I/II, we had data to look at. And we're looking at across all of the key domains, cognition, gross motor behavior, speech and sleep, all of them are important. It really was what we were bringing forward as our primary endpoint in the basis of powering for that.

So we did see a great response in cognition. Importantly, though, we like cognition because it is foundational to speech, walking, improving sleep, it's foundational to the gaining of all those additional skills, which we will look at as secondary endpoints. So really looking at a totality of really how these patients are affected.

And what would you need to see, I guess, to be statistically significant in Phase III as well as to be clinically meaningful on this cognition core?

Yes. So I think when we're talking about statistical significance, I think it's still most helpful to look at the data we presented at the fast meeting a couple of meetings ago. And that's where we looked at evaluation of cognition for Phase I/II that's changed from baseline, both by GSV scores, that's how you would traditionally assess this in a Bayley assessment but also by raw scores.

And looking at raw scores is important because that is the FDA preference. They don't like modeling. They don't like adjustments to score. So the raw score is their preference, and I don't disagree with that. Looking at raw scores for cognition, we saw a 10.9 point difference improvement from baseline. That compares to natural history. And the way we were looking at natural history for powering is allowing for at least a time improvement over natural history, just accepting some things can happen in a Phase III trial that showed a change of 1.2.

So looking at the difference between those two scores is how we power this, how we end up with originally needing 120 patients for statistical success there. We did over enroll to 129 patients because there was such demand and we had so many patients entering screening. We didn't want to leave them behind once they committed to the study, we wanted to allow them to dose there.

So that's our basis for statistical significance. I think the best way to think about clinical significance is going back to what the FDA now is talking a lot about meaningful score differences that is the equivalent of clinical significance there, but the way we're talking about it now. And for the work we're doing on the MDRI, our second primary endpoint for Aspire and an important kind of hedge to cognition as a primary endpoint setting a MSD, a meaningful score difference, of plus 5.

Great. And what would you expect from the comparator arm? I know we have the natural history data, but sometimes you see patients perform differently under the guys of a clinical study. So how should we think about that?

Yes. And then the natural history for rare disease for Angelman, it is pretty robust. And I think we can rely on and we have dependent on it quite a bit as we are analyzing our data powering in the study. The truth is, is that developmental line, it really is very flat. These children by natural history aren't really growing, developing and learning new skills in a meaningful way as you would expect. It's not 0. And that's how we got to [ 1.2, 3x ] natural history to allow for things to happen.

And that, to me, is being very generous when you're thinking about things that could happen in a Phase III trial. Importantly, what we've done is really think about the potential for placebo effect with Angelman. I think these parents are very motivated. These parents obviously understand there is no treatment available currently for this disease. And if they want to give their children a chance to develop and learn new skills, these ASOs are the best way to do this.

So you could understand enrolling in a trial, you want to be randomized to the active treated. You want them to be doing better, when there's a potential for placebo effect there. And you could have seen that in the Bayley assessment because as you do a Bayley and neurotypical children as it was designed, you allow for caregiver input.

So that means if a child is in front of you having an assessment on and they can't do something, but the parent says, they reliably and consistently do this at home, you can score that. We don't allow for a parental input. So it's really what can the child do in front of the evaluator, what are they demonstrating as new skills and then that controls for that placebo effect. So we do expect to see that control group run very consistent to what we've seen in natural history.

Great. That's helpful. So just going back to what you saw in Phase II, could you remind us in more detail of what was seen there on this Bayley-4 cognitive score? And in particular, just what the GSV is versus the raw score and what those 2 are meant to illustrate?

Yes. And GSV score was our original focus for the Phase I/II. It's how this was designed and validated and then that's your -- the score after adjustment. So you have -- so you can consistently follow neurotypical children as they develop, and it's a good way to do that there.

Again, the FDA doesn't like any modeling or adjustments to those scores. So they just like the score as it is, as you purely add that off as you're doing there. And again, it was important for us to show that yes, the numbers do change marginally. But as we designed a results showed in those -- in that comparison from ways to, they are very comparable. And whether you're looking at GSV or raw scores, we still have greater than 90% power.

Okay. Great. And then maybe just to highlight a bit the Aspire trial and sort of the strategy there and the time line for that?

Sorry, just Aspire or Aurora?

Maybe let's just go over both, yes.

Okay. Yes. So again, Aspire leads that trial enrolled very, very quickly, yes, that speaks to the strength of the team, and it also speaks to the prioritization, we really did bring our best and brightest over to lead that study. I think it also importantly speaks to when you can enroll Phase III trial like this, that is intrathecal injection under anesthesia in roughly 7 months, the unmet medical need there and how these parents are really willing to move heaven and earth to get these children treated, and even just thinking about this as an intrathecal drug, there is a burden to participating in the clinical trial and all of those assessments.

So again, I think they see this as their best chance for their children to develop, learn and grow and having a much more meaningful interaction with the parents and with the rest of the family there. So again, data readout, second half of the year, that study leads. Again, Aurora is important. It is open label that does help us with enrollment and burden for these children to participate. And really as a basket study, establishing comparable safety to Aspire. And then really a straightforward data extrapolation over to Aspire to show that this drug has the same benefit risk profile in all patients affected with Angelman.

And so the base case is, if successful, in the Phase III [ ARISE ] study that you'd potentially be filing for a broad label?

Yes. We -- again, to me, what can be very hard with rare disease where you often have subtypes is focusing on one subtype and then leaving a group of patients behind who are suffering from the same disease and really could clearly benefit. So we recognize the importance of having a full label and really bringing this drug forward for all patients with Angelman.

And when should we expect the next update from this open-label study?

So we talked a lot about whether we should do another broad analysis of that Phase I/II study. we really came to the conclusion that we did not need that data to help us as Phase IIIs were underway. And then really recognizing the amount of work it takes and it really is the same team working in Angelman, we need that understanding and expertise and not wanting to distract from the Phase III.

We understand this is a competitive environment. We understand the importance of going fast but also with a high level of quality and integrity of that data set there. So we asked the team to focus there. We do not have plans for another update and just honestly really focus on that data readout in the second half of this year.

So you have another company in the space, Ionis developing a drug for Angelman's. What's your perspective on how your efficacy and safety compare relative to the Ionis program?

Yes. And I think from talking to investors, talking to treaters, both who are participating in either trial or both or physicians who are experts in Angelman, but not participating in the trials. I think a lot of them are waiting for the Phase III data where we can make a head-to-head comparison, both for efficacy and safety. But on the whole, seeing some level of equivalents there and, I think, also supported by both of us being granted breakthrough designation by the FDA, which is a very high bar.

So to me, that's great. I think it's great validations for ASOs as the right way to approach this disease. It is large, where there are a lot of patients there. So I guess if the sentiment is roughly equality out there, then I guess all things being equal, I'm glad to be in the lead.

Great. Can you elaborate on the safety that you've seen?

Yes. So with the safety profile, and I think probably the focus there is on the lower extremity weakness that we've talked about. And a subset of those 74 patients, what we described as the dose expansion patients was we're really doing additional patients to make sure we truly understand dosing to go into Phase III because to me, if you can, you want to bring a single dose into Phase III, bringing multiple doses and just really drives up your patient numbers and just makes everything so much harder there.

So with those dose expansion patients, we saw 2 events of lower extremity weakness. One was in retrospect. The PI saw elevated protein and a CSF sample went back to the family and asked if there was any possible challenges with walking and they said maybe, yes. So that's about as mild as I get.

The second case was also mild and resolved on its own. So I think at this point, we're very confident in understanding. We understand the cause of this lower extremity weakness. We put in place a mitigation plan that did its job. And ultimately, I think we'll find with the phase -- full Phase III data readout. So this is the benefit risk profile for ASOs I don't think this is going to be something unique to all our ASO.

Okay. Interesting. Can you elaborate on the mitigation plan that you put in place?

Yes. So really, this is looking at the chemistry of any ASO, potential for irritation at site of injection. So really, that mitigation was not allowing that drug to pool at the site of injection. So that's really involved around a flush, and that's just moving it through into the CSF.

And then Trendelenburg, while these children are not in anesthesia, in young children, when you're doing intrathecal, you do want to use anesthesia, so they don't develop this fear of going to the doctor fear of entering in the hospital there. So while the patients are recovering from anesthesia, we put them in a slight incline that's just using gravity again to get it away from the site of injection. So just really straightforward trying to avoid that concentrated localization.

Okay. That makes sense. Turning to like osteogenesis imperfecta. Maybe just -- can you give us an update, an overview of that program where it stands today and sort of next steps from here?

Yes. So we spoke about that Phase III data across the two studies at JPMorgan in January. And that's kind of where we are with conclusions we've drawn from those studies, and that was really based on how the studies were designed with the primary endpoint.

Where we are today and truly trying to understand the totality of the Phase III data coming out of those two studies. And that's not just doing additional analysis, looking at subtypes, which includes types of osteogenesis imperfecta but different age groups.

But also going back to the sites, talking to the PIs, asking the PIs to really talk to the patients and truly understand the effect this drug has had on the patients in these trials. And yes, we have measurements to do that in a controlled way as part of our end point but it still doesn't really truly capture the full picture of what's happening, how are they really feeling? How has this changed their life on a day-to-day basis, what type of activities they are doing? What type of risk they're doing and truly what is the full picture around any fractures they may be having.

And that's really what takes time here, is going back really on a patient-by-patient level in addition to all the additional analysis we're doing. So we can really understand is this driving towards a no-go decision with this program? Or is there something there in a subset of patients that we think is clearly showing benefit risk. And if we come to that conclusion, if we get to that point, then obviously, the next step would be go back to the FDA or back to regulators have that conversation and make sure there is a path forward. But today, we are still really truly trying to interrogate data set and really understanding it to the fullest success.

That makes sense. And what are the time lines in terms of this data analysis?

Yes. So we haven't really given time lines, so you don't want to rush this process. We understand that we need to go fast. We are not going to take forever, if you will. But again, when we failed to meet our two primary endpoints. We need to make sure we thoroughly analyze this, make sure we truly understand this. So we wanted to give ourselves that time before we put an external time line on that. So more to come.

Makes sense. And then for your gene therapy program, kind of remind us of the time lines there and the submissions.

Yes. So GSDIa, I guess, now is our lead gene therapy program with PDUFA in August is great. Sanfilippo, we had that IRL that is all really just requiring additional paperwork and written response. So we'll do that quickly. that's a 2-week validation period, not the normal 2-month validation period.

So do you expect to get a PDUFA date for Sanfilippo not too far behind GSDIa, both within this year. So more to come on that. And then OTC in Phase III, that study has always remained a little bit in the background for the prioritization of how we've been talking about it, but OTC remains on track for that Phase III data readout.

And then also for our Wilson program, still with that additional cohort, making sure we understand that we are able to get the majority of patients off of standard of care doing well before we make that final dose selection to invest in Phase III.

So a lot of programs, maybe if you could just high level kind of the size of each indication and how you think about kind of the unmet need in those?

Yes. So Angelman leads both by size, we're talking 60,000 patients in the territories we cover. A lot of people have talked larger numbers than I think 60,000 is probably modest, but still very big, rare. That also has arguably very high unmet need, but nothing available for these patients. .

Sanfilippo very similar situation. These patients have absolutely nothing available to them, and they once they become symptomatic between their first and second birthday really deteriorate to the point by 5 years of age. They have a lot of accumulated neurodevelopmental damage and don't live beyond their teens traditionally.

GSDIa, these episodes of hypoglycemia can be life-threatening, particularly in pediatric patients. So again, that is our focus where there is true high, high unmet medical needs in these patient populations.

Makes sense. Maybe just in terms of the submissions, given broadly some of the changes at the FDA, how are you thinking about the approvability here of your gene therapy programs?

Yes. So I think if there's any benefit from going through the CRL and now with the IRL is we are clear what the FDA inspections are. And the findings with the CRL were really based on things with our manufacturing facility, things that we are absolutely able to do and to fix and respond to.

The FDA has always been complementary of the data coming out of that Sanfilippo program. And they have remained complementary. We recently did a data update at the World meeting and showing really the strength that's held up over time. So a lot of confidence there. And then also with GSDIa, we learned a lot from that Sanfilippo experience. Again, very strong Phase III data that's held up over time, hitting statistical significance for a primary endpoint.

So again, with our PDUFA date in August, a lot of confidence there. And then obviously, working again with the importance place on that Angelman readout in the second half of the year.

Great. Welcome. Well, Eric, thank you so much for joining us, and thank you, everyone, in the room and talk to you all soon.

Thank you.

Okay. Well, good afternoon, everybody, and welcome once again to the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the biotech team, and it's a great pleasure to introduce and have with us today, Eric Crombez, who's Chief Medical Officer and EVP at Ultragenyx.

Eric, good to see you. Thanks for coming.

Thank you.

So lots going on in -- maybe we'll start with Angelman syndrome. That's going to be the next, I think, one of the big catalysts in the second half, maybe even Q3, the way we're kind of calculating and trying to back into a more fine-tuned timing. The Aspire study is about 130 patients, 4- to 17-year-old with a deletion. That's about 70% of patients fall into that, Randomized 1:1 versus sham. The primary endpoint is cognition based on the Bayley IV. You obviously also have a Tandem study, the Aurora study, which we'll get into that in a second. When you're kind of thinking about powering for a benefit, what's considered clinically meaningful for cognition?

Yes. So I think, obviously, interconnected, but a little bit different. So I think the best way to think about clinically significant and for Angelman with our conversation with the FDA, we've shifted to MSD, Meaningful Score Difference. So when we're setting that threshold, and we specifically needed to do that as part of our MDRI, which is a second primary endpoint for us and set that MSD, your clinical significance at plus 5. That is a little bit different than how we're powering our Phase III study. And I think the best way to look at that is to go back to that slide of Phase I/II data that we showed at FAST. And the purpose of that slide where we're looking at Bayley cognition, both by GSV and Raw score. Our intention there wasn't just to give an update on the Phase I/II patients, how they're doing, but really show how we powered our Phase III study.

We looked at GSV scores. That's fine. The FDA prefers to look at raw scores that is just what they always prefer. They don't like any kind of modifications to what you're doing there. So in that context, we saw a mean difference of 10.9 in our actively treated patients. And then the natural history data we are looking at, and I think really confirmed by any treater or anyone who understands the disease, really looking at natural history, extrapolating that into our control group and seeing a max change of one over time. With our modeling for statistical powering, we looked at 3x natural history, so a mean change of 3. So 10.9 change in actively treated up to 3 in your control group, that's how we get to our statement of greater than 90% power for success for our Phase III ASPIRE study.

So that would be almost a difference of 7 points. And what's clinically meaningful? Is it about a 3-point change or a 5-point change?

5.

5-point change. And that's from a baseline of that varies in cognition between 420 and 460, 480 depending on the patient. And that's a 1 year. How do you prevent variability or placebo effect?

Yes. So to me, the best way to prevent variability is to enroll the most homogeneous patient population you can. That is why we made the decision similar to Phase I/II to enroll only patients with full deletions in the Aspire Phase III study. So those patients full deletion, not making any UB3A. So that gives you your most homogeneous patient population. It also gives you your most severe patient population there. That's the best way to have clear signal detection and that does contrast to what Ionis is doing with putting all patients into a single Phase III with the potential there for patients with uniparental disomy, imprinting defects, missense mutations to express some UB3A and get to some language a few words just by my natural history.

And then for placebo effect, the most important thing we did was to remove caregiver input. Normally, for Bayley, if you have a child here and say they refuse to walk for whatever reason, the parent says they walk consistently at home every day, it's fine. You can give them credit for that if you're doing the Bayley clinically. For our clinical trial, we do not allow caregiver input. You need to perform those tasks in front of the rater.

Each visit essentially?

Yes.

When you're looking -- so then you have the Aurora Tandem study, right? And that's a Phase II/III supporting the kind of the broader study with 4 different cohorts across all genetics and all treatment groups. What do you need to show in that study?

Yes. So we're taking a basket study approach. And again, we stayed very tight with our enrollment criteria for Phase III. So patients with other genotypes, younger and older patients in Aurora. So we took a basket study approach there. It does become a bigger trial because of that, certainly more complex, but I think the best way to round out the label for our Angelman product. And really, we're taking an extrapolation approach. So we will establish safety and efficacy in the Aspire study. We will importantly establish safety in the Aurora study, get as much efficacy data as we can and then extrapolate back to Aspire.

That study is 60 patients, right, Aurora?

Correct.

So it's about half the size of Aspire. So Aspire really is -- and together, can they drive a broad label or you file first for Aspire and then supplement?

No, yes. So 60 patients and open label. So it really does -- the basis of our approval package will be based on Aspire. And again, though, we do want to take an extrapolation approach there because obviously, all of these patients being affected by Angelman syndrome, need access to these drugs, and we do want to launch with as full label as we can.

Yes. So Oak Hill is kind of giving a regenesis to rugonersen from Roche. And they just recently published their data. They had a nice EEG delta effect, and they had some effects on the Bayley and the Vineland very similar, I believe, to what you saw and what Ionis saw. Ben Philpot did an experiment looking at data in preclinical models. And in their hands, they feel that the Roche compounds got the best mRNA expression, protein expression and reduction of the anti ATS strand. Any thoughts on that as a corollary to what we could expect in the clinic?

I think in a broad sense, yes. And it certainly is the same type of experiment, same type of data we did for our own proof of concept to enable us moving into the clinic there. And we have talked a lot about the potency of our ASO, and we started the molecular basis of that and where you're binding and continuing through expression of mRNA levels. So I think all of this data is supportive. To me, it's supportive of an ASO approach as being the right way to target something like Angelman. And certainly, I think it's great when people are looking at other modalities like gene therapy. But to me, you want to get it to as many neurons as possible. UBE3A is involved in how synapses are communicating with each other. I've been doing gene therapy for a long time. We have a lot of gene therapy. I think ASOs is the better way to do this and a better way to really hit as many neurons as possible.

Maybe just to go back to Aspire. The primary endpoint is cognition. That's got 90% of the alpha, the MDRI, the Multiple Disease Responder Index has 10% of the alpha. Is that the primary -- as you mentioned, I think you mentioned is the primary secondary endpoint. So that's hierarchically the next one after the primary?

So it's not hierarchical. And if you read our protocol, it is primary endpoint key secondary. Statistically, in our SAP that we've submitted to the FDA and discussed with them several times, because we're applying alpha to MDRI, the Multi-domain Responder Index, statistically, it becomes part of your primary endpoint family. So we will test those in parallel, not sequentially. You do not have to win on cognition to test MDRI. And traditionally, why the FDA does not like splitting alpha is because they say you're getting 2 bites at the same apple, which, in this case, it's really what we're trying to do here. We're really trying to support cognition with the idea that if we win on MDRI or cognition, we have hit a primary endpoint, we have a positive Phase III study.

So -- but they're not co-primary.

They're essentially -- so essentially, the distinction becomes important because of that hierarchy, they're both primary endpoints.

Can you hit either or? You can hit either or?

Yes. So I mean, I don't -- there's not a scenario. I mean, it just doesn't work where you wildly miss cognition and hit on MDRI. If you hit on MDRI and miss on cognition, it really means you're barely missing cognition. So positive MDRI barely missing on cognition, we would say we have hit a primary endpoint. We have a positive Phase III. Certainly, that doesn't obligate the FDA, never obligates the FDA to give you approval. They're always going to say it's based on the totality of the evidence, but we would be having a conversation with a positive Phase III study.

So on the MDRI, the MCID is 5 points as well?

So MDRI and why we've been working so long with the FDA to bring that forward is because you're bringing your key domains, behavior, gross motor, speech, sleep, language into a single tool to evaluate those individually, you have an MSD, a Meaningful Score Different for each. You negotiate with those FDA -- with the FDA ahead of time. Cognition is 5, something like receptive communication is 6. So we set an MSD for each of them individually.

And what's clinically meaningful for each subtype, for each subdomain?

Yes. So I mean, you set a separate MSD for behavior, gross motor, cognition, receptive language behavior.

Okay. So it's about -- you have to show a 1 point or 2-point change from baseline for each one and that rolls into the broader MDRI.

Yes. So like if you're just looking at cognition across the thing, if you hit 5 or greater, you get a plus 1 in that domain. If you don't, then you get a 0. If you do worse, you can get a negative 1. And then as you look across those 5 domains for an individual patient, if you hit on every domain, you're a plus 5 for the MDRI. So that's why it's a nice tool because it allows you to accept the variability that any neurologic indication happens. You're not doing sophisticated statistics where you can do funny things. And the FDA even acknowledged we can take this tool apart if we want to. So starting at end of Phase II, they really got on board with the MDRI. We had the conversation about alpha. We reinforced at our breakthrough designation meeting. So they're fully aware of our plans.

Because you're essentially validating the MDRI for the first time in this study.

Yes.

Any questions from the audience by any chance? Okay. Well, let's move to -- several programs to really discuss. Maybe just setrusumab because we do get a lot of questions on it. As you think from here on, there was a benefit and the one area that you did see more of a benefit is vertebral fractures and then obviously, in bone mineral density. Historically, vertebral fractures is not -- was less of a priority for FDA. And the bone mineral density, obviously, is a profound effect. The question is how it translates into function. The FDA is getting more comfortable with that in osteoporosis, but there's also 50 years' worth of data that doesn't exactly exist here. So as you think about a pathway forward, kind of how are you thinking about it strategically, how to approach the agency?

Yes. So strategically, we're really thinking about it in exactly the same way that we talked about it at JPMorgan. We have been talking about the changes in bone mineral density. They did hit statistical significant -- and to your point, with osteoporosis, they have 50 years of data. We're never going to have that in this case, and you're probably never going to have that in any rare disease. The mechanism of actions for these drugs are very similar. So it is very, very helpful. Yes, you need to validate any given biomarker for a specific disease, but it is very, very helpful that, that came out in December. So we are looking at that. That would obviously give you a pathway towards accelerated approval like we talked at JPM there.

And then you need to support it for accelerated approval, you need a reason to believe clinically. The vertebral data was very compelling and also validated from the treating community and then really reinforcing once we've gone back to them talking about that drives a lot of disability, that drives a lot of pain. Oftentimes, that is honestly how they're treating, whether it's bisphosphonates or them thinking about the use of setrusumab there. So it's a good clinical endpoint. Obviously, we would need to talk about a confirmatory study. But then also PGIC, pain, there is supportive data that if you -- if we went down accelerated approval with bone mineral density, you would use that as the reason to support that and then you would need to do your confirmatory study in the long term.

And the confirmatory study would look at can it be a 24-week endpoint in fractures and pain? It would be a pain endpoint first or a fracture endpoint first?

I think if you gave me a complete do over and guarantee the results would be the same, I'd be fine as pain for a primary endpoint. Pain is a tough endpoint in any study. What's nice about the confirmatory study is you're on the market, you have a commercial drug, you're generating revenue that you can then reinvest into a confirmatory study. I think you're going to want to do something longer term and something we would not be able to do as an additional Phase III, but it's a very different setting there. And then crossover patient extension, I think, will be very, very helpful. I don't necessarily expect though they're going to give us a different answer than what we've already seen. I think you would -- in a confirmatory study, you'd want to do something bigger.

Okay. Got it. So maybe bigger and longer on fractures. When you say -- right, you say you're not expecting anything different from what you heard originally for the Phase III program?

Right.

And that would be presumably, I imagine with a younger patient population, the accelerated approval?

Yes. I think that's our job now, and that's where we are. And in a sense, maybe it sounds like we're taking a long time, but this is not just us doing additional analyses on everything. We need to talk to each treater. We need to understand what's happening with these patients on a patient level, like how are they feeling? What are they doing? Is this a case where people are feeling better, they're taking more risk, and that's why they're fracturing. The other side of that is there's always the possibility that your studies are telling you your drug is not as effective as you thought. So we really need to interrogate this on a patient-by-patient basis, and it takes time.

With respect to even pricing in that sense, with an accelerated approval, is the label different than you would have been otherwise and that carries some connotation to price? How are you thinking about that?

No. I mean, I think for rare disease, accelerated approval has worked very well. I don't think it's really impacted overall pricing and value of the program. I think for us, that can -- that would very much be a win. I think it's true for most diseases. It's certainly true for most rare diseases. Children do respond better. I think it's an obvious subgroup of patients to look at.

So I guess the label will be supported more on BMD and vertebral fracture. And I guess that's what I was thinking about, like the differentiation over placebo. So vertebral fractures would be sufficient.

Yes. Yes. I don't know if I should say this publicly or on record and stuff, but who looks at -- I'm not sure how many treaters actually look at labels, but that's fine. Certainly, we care about them, certainly, the regulators do and as do payers.

Okay. Maybe we'll move to -- we're all trying to read the tea leaves every morning of what's going on with FDA and then what's going on with FDA and gene therapy and it depends on the programs. For you in Sanfilippo, I think the feedback from FDA was that the data you've shown is sufficient clinically and it would not be approved, it would not be eligible. They're not going to be evaluating it for approval based on biomarkers. So that was a huge telltale sign. But in the meantime, there's obviously been kind of more challenges in terms of the manufacturing side and the IRL. What do you think is really going on behind the scenes here with FDA?

Yes. I mean, I think it hasn't been as consistent as it has been previously. And I think we're all trying to navigate around that and through that. I think it is good even with the IRL, the working team, the people working on these programs day-to-day, they have engaged with us. It's been clear with the IRL, we have said this is really a case of additional paperwork, additional written responses in contrast to the CRL, we don't need to do new work. We don't need to generate new data. So it will be a relatively quick response.

I think if we understood that they wanted this as part of the CRL conversation, we could have easily have provided it. Luckily, once we resubmit, it's only a 2-week validation period compared to like your first initial with this 2 months. So it's a relatively small delay, but it's a delay, and we do understand these patients are out there, and they are continuing to accumulate damage and there's potential not to have as much benefit as they could. So we are eager to respond to that IRL and get back under review.

So it's really about SOP and protocols that they're looking for changes.

Correct. Yes. Everything is essentially paperwork or written response. We're not doing any new work.

You don't have to change -- it's a question of writing standard operating procedures of the way manufacturing just aligning the process with that, the written work. And the top point will be a 6-month review again? Or is that a 2-month review?

No. So you're kind of starting over again. So 2-week validation period up to a 6-month review.

And do you need to submit updated clinical information, clinical data each time?

No. So we did that for the CRL, and that's the big contrast here is that was a meaningful delta. And the FDA is always going to ask in that context for updated clinical data because they do not want to approve a drug and have you come back and say, I have 6 months more new data that may be changed something. So in that context, they're going to want new data. We presented that at world. It is very compelling. This is a very small delay, so no need for additional clinical data.

And the same manufacturing, the next product that is actually being made at Bedford is 301. 401, which is GSDIa, I believe, is being manufactured through a contract manufacturer.

No. So that's why we had -- that's why the CRL and Sanfilippo did result in a delay to our filing for GSDIa. We do make GSDIa at our facility here in Bedford. And that's why it was important for us to clear our validation period for GSDIa. We just press released on that. So again, that was reassuring that the FDA, it's still working, and we cleared that validation period. We got our PDUFA date for GSDIa. And to your point, anything specific to the facility in Bedford that was affecting Sanfilippo would absolutely apply to GSDIa, and that shows that we're moving through the process to answer their questions and correct anything that needs to be corrected.

So do you need to update or can you update those SOPs in parallel for 401?

Yes.

You can?

Yes. And the truth is we started our conversations with the filing for Sanfilippo when Peter Marks was in charge. So we had a conversation, and there was a much more flexibility on what could be done during a review period versus what had to be done with submission. You can call that an element of risk, but it was well discussed. When Peter left, we understood the changes coming through. So we took much less risk with GSDIa. So that package was at a different point than what we originally submitted for Sanfilippo.

In terms of the SOPs, is 301 made in the contract manufacturer?

So not yet.

Not yet. Okay.

Yes. Eventually, we will move everything into Bedford, but we need to do it. We accelerated the movement of GSDIa into Bedford just to have better control, but we're doing it one by one.

So 301 is external and then you could bring it back in. What's the timing? Just remind us seeing the data from the Enh3ance study and then when you potentially can file?

So for OTC. Yes. So OTC definitely has been quiet. I mean I think we talked about quite a while ago, and I think it probably was around really bringing Sanfilippo into the pipeline, and that really was a mature Phase III data set. So we made the prioritization with Sanfilippo and GSDIa. Honestly, good that we did given lift that's been involved there. But the Phase III for OTC has progressed. We've talked about doing an ammonia data readout at 36 weeks. That's important. Ammonia actually is a validated biomarker because of the work done with RAVICTI. So that is clinical in nature. And then full study readout is to week 64, and that's looking at responders as far as those patients who can discontinue alternate pathway medication and then liberalize their protein-restricted diet.

And enrollment has concluded or not yet?

Yes. No, enrollment was concluded quite some time ago. Again, I think, again, things were very dominated by OI and Angelman and that went back and forth. We were bringing forward Sanfilippo and GSDIa. That's been the spot like OTC has been working through. We did not stop investing or stop that Phase III trial. That trial has been ongoing in the background. And luckily, hopefully, we'll be getting both of those 2 gene therapies across the finish line and into commercial, and we'll obviously be pulling everything else up through the clinical pipeline.

Okay. So at this point for 301, you're waiting for the clinical, the 64-week data or there's other things that are going on in parallel?

Yes. No, I mean, obviously, we'll have the ammonia data internally, and we'll have that discussion. But then, yes, for full study readout to support a filing, that would be a full study readout and all patients getting to week 64.

Which presumably is this year, I imagine.

So we haven't updated guidance on that, and I'll just blame Josh.

Josh, we have another microphone. It's easy to give it to you. Okay. And then some of the questions we get a lot is for both of them. For 111, the data is compelling, huge unmet need, not a big market. For 401, how important is reducing corn starch intake? The data obviously is a lot more clinically meaningful when you look at your long-term extension, but still can it really support a price of $2 million, $3 million per patient per year commercially. Any thoughts about the level of unmet need here?

Yes. And I think to me, when you're talking about what is a successful gene therapy, what is not a successful gene therapy and look at what's happened in the commercial space today, I do think Sanfilippo is absolutely at the extreme end of unmet medical need. There's nothing you can do for these children. And by their fifth birthday, they are very damaged children and don't live past their teenage years typically. So highest unmet need, I agree, relatively smaller numbers between 3,000 and 5,000 patients in the territories we cover, but we think it will be a very successful launch and products because of that. I think GSDIa is a step down from that, but still with very high unmet medical need. And we've done a lot of educating externally with payers, regulators. The patient groups have gone and talked to the FDA, they've talked to other people because it's not corn starch. It's the fact that without that corn starch every 2 to 4 hours, they can get into a situation where they're so hypoglycemic, they can start to have seizures and it can be life-threatening, especially in pediatric age group. So it really is that honestly, daily threat that gets worse with any intercurrent illness where they can really get into serious medical trouble with that hypoglycemia.

And at that point, can you launch fairly quickly thereafter? Or is it takes time to build inventory? How does that work?

Yes. So I mean -- and that is part of the reason why we did make the prioritization around Sanfilippo and GSDIa because obviously, if you're going to be launched, you need to have that material on hand to launch. And for gene therapy, that is a big investment. So doing 3 in parallel would be a tremendous lift. We're prepared to launch and launch right away with Sanfilippo and GSDIa. Again, that allowed us with that prioritization to bring OTC and that level of investment in manufacturing up behind that.

Okay. And what can we expect this year, just minus in 701 as you continue to dose escalate?

Yes. So that -- and so I think Wilson is another example of talking about unmet medical need and being really in a situation where there are chelators and zinc available, they do a decent job of treating that disease. So yes, we clearly believe there is still high unmet medical need, but we've set the clear bar that we need the majority of patients off of chelators in order to declare success. So as we've moved through these dosing cohorts and with Cohort 4 at 4013, which is a very good dose for liver-directed gene therapies, we want to see the majority of patients off the chelators in order to declare success to move into Phase III. And doing that prematurely, I think, could you set yourself up where you maybe would not have as successful as a product as you could if you do not optimize that efficacy.

And so do you think we'll see some data this year? Yes. In the second half, most likely from the highest cohort?

Yes. So most recently, our guidance was this year in 2026, we want to give ourselves the ability because it's not -- it doesn't really help you to set an endpoint for patients coming off a chelator. So it takes -- if some are moving in the direction and they're close, fine. We'll wait for those patients to progress and then declare success. So we don't have a firm, firm, firm data on that.

Great. Maybe any final question from the audience? Maybe just to go back to Angelman, how far Aurora is still enrolling. So it sounds like Aurora is about 9 to 12 months sort of behind Aspire, 6 to 12 months behind.

Yes. I mean I think that's fair. We really did try not to overlap with our sites. We have a little bit of overlapping, but Aspire leads the way here. It is the most important of the 2 Phase III studies. So we wanted that enrolled and operationally under control before we launched the second Phase III.

Well, terrific. Eric, good to see you. Thanks for coming. We appreciate it.

Thank you.

Thank you.

Good afternoon, and welcome to the Ultragenyx Fourth Quarter and Full Year 2025 Financial Results Conference Call. [Operator Instructions]

It is now my pleasure to 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; Howard Horn, Chief Financial Officer; Erik Harris, Chief Commercial 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.

2026 is poised to be a significant year for the company as we reach key inflection points across multiple programs. This includes 2 potential approvals in MPS IIIA or Sanfilippo Type A syndrome and Glycogen Storage Disease Type Ia and the pivotal data readout in Angelman syndrome. These programs are excellent examples of our mission to bring important first-ever treatments of patients and families while also delivering meaningful long-term value to shareholders.

Just last week, we presented updated data at the WORLDSymposium from the UX111 for MPS IIIA program. The new data reflects an additional year of follow-up and continue to demonstrate sustained and significant further separation of early treated patients in multiple neurologic end points including the Bayley, cognitive and communication scores when compared to the decline observed in MPS IIIA natural history.

The data also show a significant and durable reduction in the toxic substrate heparan sulfate [ in ] other disease cause biomarkers that show a restoration of lysosomal function regardless of age or stage of disease. This reduction in CSF HS can be effectively measured by any of a number of different assay methods available, and all HS measures correlate significantly to stabilization or improvement in clinical function. These results in human and animal models were thoroughly discussed substantiate and ratified by highly trained and qualified academic clinician and industry leaders that are the internationally recognized expert in this field at a Reagan-Udall convened workshop in 2023.

For the entire UX111 study program, we now have more than 8 years of follow-up. And overall, these data continue to support a clinically meaningful and durable clinical effect of UX111 regardless of age or stage disease all supported by consistent improvement in multiple relevant direct measures of disease activity, including CSF HS.

We resubmitted the UX111 BLA to FDA late last month, and earlier today, we received [ a ] complete response letter. We had provided complete responses to each CRL item, but now the FDA is requiring additional details within supportive documentation on the CMC CRL responses made and their impact. This information is typically provided during the inspection, and we were prepared to do so, but we'll not provide the supportive documentation as a part of our BLA resubmission.

Our efforts to bring these transformational therapies to patients are supported by our established and still growing commercial business, which again delivered significant 20% year-over-year growth in 2025. We're now bringing treatments to patients in more than 35 countries, each of which contributed revenue in 2025. This commercial infrastructure will power our growth into 2026 and beyond as we leverage the investments expertise and relationships we have established around the world to commercialize 3 additional treatments over the next 2 years. Eric Harris will outline for you our results across [ programs ] last year and discuss our vision to expand and deepen our global commercial footprint in the coming years.

As noted in our press release earlier today and following the UX111 CRL last year, and the data from the UX143 trials, we made the necessary decision to implement a strategic [ construction ] plan to reduce our operating expenses and ensure our resources are squarely aligned with our highest impact opportunities going forward.

Howard will now go through some of the details, but these actions were necessary to keep us on path to profitability in 2027, while still advancing a meaningful pipeline of new products.

Thank you, Emil, and good afternoon, everyone.

Before I go through our financials and our guidance, I want to expand on the objectives of our strategic restructuring plan. The plan refocuses our head count and expenses on our near-term value drivers, while reducing internal and external spend from areas across the business, including manufacturing, clinical, early stage research and G&A. It is an important part of our broader strategy to become profitable in 2027, together with continuing to grow our base business of 4 commercial products and investing in 3 successful launches for UX111, DTX401 and GTX-102.

Today, in connection with the restructuring, we announced a 10% workforce reduction impacting approximately 130 full-time employees. Reductions in force are a challenging part of operating a business, and we are grateful to these colleagues for their contributions to Ultragenyx.

Now turning to the financials. I'll focus on the full year 2025. Please refer to our press release for details on the fourth quarter. For 2025, we reported total revenue of $673 million, representing 20% growth over 2024 and exceeding the upper end of our guidance range. Crysvita contributed $481 million, including $275 million from North America, $177 million from Latin America and Turkey and $29 million from Europe. In total for Crysvita, this represents 17% growth over 2024 and also exceeded the upper end of our guidance range. Dojolvi contributed $96 million, which represents 9% growth over 2024. Evkeeza contributed $59 million, representing 84% growth over 2024 as demand continues to build following launches in our territories outside of the United States. Lastly, MEPSEVII contributed $37 million as we continue to treat patients in this ultrarare indication.

Total operating expenses for 2025 included cost of sales of $109 million and combined R&D and SG&A expenses of $1.1 billion. For the year, net loss was $575 million or $5.83 per share. As of December 31, we had $738 million in cash, cash and equivalents and marketable securities.

Shifting now to guidance. I'll start with revenue. Total revenue in 2026 is expected to be between $730 million and $760 million, which represents 8% to 13% growth over 2025 and excludes potential revenue from new product launches. Crysvita revenue is expected to be between $500 million and $520 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. This range reflects growing underlying global demand offset partially by expected timing of ordering patterns in Brazil that we anticipate will normalize in 2027. Dojolvi revenue is expected to be between $100 million and $110 million.

Turning now to R&D and SG&A expenses. With the implementation of the strategic restructuring plan I discussed earlier, we expect 2026 combined R&D and SG&A expenses to be flat to down low single digits versus 2025. This guidance nets the restructuring reductions from the restructuring with severance and other onetime nonrecurring restructuring costs and targeted launch investments in UX111 and DTX401. We expect 2027 R&D expenses to decrease from 2025 levels by 38% or approximately $280 million, driven by the completion of clinical and manufacturing spend on multiple Phase III studies and the reduction of early-stage research efforts. 2027 SG&A expenses are expected to increase in support of new product launches and our existing approved products. On a combined basis, R&D and SG&A expenses are expected to decrease at least 15% in 2027 versus 2025.

With that, I'll turn the call to our Chief Commercial Officer, Erik Harris, who will provide detail on his team's efforts in 2025.

Thank you, Howard, and good afternoon, everyone. I want to begin by expanding a bit on Emil's earlier comments about the strength and durability of our existing commercial business, which continues to deliver strong performance across markets and products.

Since 2017, we have built a portfolio of 4 marketed products across multiple therapeutic areas, all of which continue to deliver strong growth and meet or exceed guidance year after year. That consistency comes from careful planning, disciplined investment and repeated strong execution in some of the most complex rare disease markets globally. Crysvita remains an important part of our base business. Our partnership with Kyowa Kirin in the U.S. remained strong, and we continue to find and treat commercial patients across Latin America and Turkey. In Latin America, the Crysvita business is anchored in Brazil and Argentina with solid reimbursement growth in Mexico and Colombia over the past year, translating into meaningful revenue contribution from those countries.

Additionally, we continue to respond to MPS request in other LatAm markets, a testament to the growing underlying demand for this product. This steady progress is due to the thoughtful investments we have made, paired with strong local execution. As I have mentioned in previous earnings calls, we continue to expect some variability in revenue driven by uneven ordering patterns. This is particularly evident in Latin America, where Brazil's Ministry of Health places the largest orders in the region. This pattern is reflected in the 2026 Crysvita guidance range, Howard mentioned earlier and includes growing global demand growth partially offset by the expected timing of ordering patterns that we expect will normalize in 2027.

Moving on to Dojolvi. 5 years post launch, the product continues its steady growth with more than 100 start forms in the U.S. for the third straight year. In EMEA, we have seen continuous NPS growth across the region, while also achieving 2 regulatory wins last year, namely early marketing authorization in Kuwait in September 2025, and approval of the early access pathway in the U.K. in April 2025. In Japan, last year, we announced Dojolvi was granted conditional approval, and we look forward to the full approval and launch of the product in Japan in the second half of 2026.

Finally, with Evkeeza, which is another powerful case study of Ultragenyx' ability to drive growth in a relatively small market through relentless patient identification and effective commercialization pathways. We began commercializing in our territories outside of the U.S. with formal reimbursement approvals in just the last couple of years. In the EMEA region, we now have patients on reimbursed therapy across nearly all major markets with approximately 350 patients across 20 countries who are receiving Evkeeza today.

In December, we achieved a significant milestone with the registration of Evkeeza in the Kingdom of Saudi Arabia, reinforcing our commitment to bringing life-changing therapies to patients globally. We also commercialized Evkeeza in Japan, where we've seen sustained steady progress since the initial launch in January 2024, positioning us not only to launch additional new products in Japan, but also to serve as a foundation for broader APAC commercialization opportunities.

Over time, we expect Evkeeza will continue to grow meaningfully and add to our expanding revenue base. In summary, we entered 2026 with a proven commercial infrastructure and an experienced team that consistently executes with discipline and precision as we launch and scale complex rare disease therapies globally. With 2 potential gene therapy launches and pivotal Angelman data ahead, we are well prepared and confident in our ability to deliver the next phase of growth required to reach profitability.

With that, I'll turn the call to Dr. Crombez to share the clinical and regulatory milestones for the coming year.

Thank you, Erik, and good afternoon, everyone. I'll spend a couple of minutes to highlight the upcoming clinical and regulatory catalysts for 2026.

I'll start with DTX401 for the treatment of glycogen storage disease type Ia. We completed the submission of our rolling BLA at the end of December, and we expect to have a PDUFA action date in the third quarter of this year. Next, UX111 for the treatment of Sanfilippo syndrome type A. We recently presented the encouraging long-term data at the WORLDSymposium that Emil mentioned earlier in the call. In response to the [ IRR ] we received earlier today, our manufacturing and regulatory teams are urgently working to provide the detailed support of documentation that will allow us to resubmit our BLA as quickly as possible given the critical need for this life-changing therapy.

For UX701 for the treatment of Wilson disease, we completed enrollment of the 5 patients in the fourth dosing cohort last year and we expect to share data from all 4 cohorts later this year. Lastly, GTX-102 for the treatment of Angelman syndrome. We are continuing to treat patients in the 48-week Aspire study and continuing to enroll patients in the support of Aurora study. We expect to share Aspire Phase III data in the second half of 2026.

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

Thank you, Eric. By implementing the strategic restructuring plan we announced today, we are focusing our resources and energy on the highest value opportunities in our commercial and development portfolio. The development team will support patients and investigators who are participating in our clinical studies around the globe, work through the 2 BLA submissions and prepared to read out Phase III data from the Angelman study.

At the same time, the commercial team will continue expanding the geographic reach of our 4 commercial products and prepare to launch 3 more programs. All of these efforts continue our mission of leading the future of rare diseases with first-ever treatments.

With that, let's move on to your questions. Operator, please provide the Q&A instructions.

[Operator Instruction] Our first question comes from Joon Lee with Truist.

The primary end point for your Phase III Angelman study is Bayley-4 cognition, while that of Ionis is the expressive communications domain. Was your decision to use cognition over expression -- expressive communication based on the greater probability of success or because that's higher on the list of parents desirability or priority list? And are you able to share what percentage of the patients coming out of Phase III have opted to roll over into the long-term extension portion of the study?

Right. So the Bayley cognition is a fundamental activity. And by the way, you can't have communication without cognition as well. It's all intertwined. We think the Bayley cognition is a core, an important function of these patients. And we are demonstrating substantial rise in that function. Expressive communication is clearly important, but takes more time. It has to develop and evolve, and we feel while we are evaluating expressive communication in our program, and we'll have data on it, we didn't think it made sense as a primary endpoint given its heterogeneity and the complexities of this development.

Now our own trial though will not only depend on Bayley cognition, we also have allocated some of the power of the study to the multi-domain responder index, which will give us a combination of cognition, receptive communication, sleep, behavior and motor function, which will give a broader assessment, which is very important to parents as well. So we think the combination of what we have will provide the important insight in how their patients are doing that will be [ important ] in both the patients and doctors and will include all information, including things on expressive communication.

Regard to -- your second question, which was rolling over, we had very few -- I don't even know how many dropouts in our program. Everyone has continued on treatment. I don't know, Eric, if you want to comment on the extension or rollover of patients?

Yes. Similar to what we saw in Phase I and II. The Phase III studies do have a very high retention rate, including patients electing to continue in a long-term extension study. I think parents really do understand this is the opportunity for their children to grow, develop and gain and learn new skills, which isn't something you see by natural history.

The next question comes from the line of Maury Raycroft with Jefferies.

I'll also ask one on Angelman. Wondering if you could just talk more about the patient baseline profile, now that you have the study fully enrolled relative to your Phase I/II enrolled patients. And what specific parameters in the baseline data do you expect to influence control arm performance on cognition? And what are your latest expectations for what you can show on cognition in the treatment and control arm?

Yes. Well, if you remember, Maury, in our Phase III trial, we did an expansion trial. That trial was intended to look at 8 countries where we're going to run the Phase III. So the point of that was 50 extra patients and potentially evaluate Phase III patients type patients from all the different countries. The baseline data that we saw and presented on cohorts A and B, which is the ex U.S., is pretty reflective of what we're seeing in our Phase III program. So we're comfortable with that. That what we're seeing in Phase III is comparable to what we saw in the expansion program, which is what the expansion was about, again, at least giving us a sense for what the broader population would be in multiple countries, not just U.S.

With regard to the cognition and control, we assume both -- [ there's ] the natural history in randomized control [ phase ] is only 1 point or less cognitive change in the Bayley. It's a very rigorous measure. It's very hard to move. It's not something [ prone to ] placebo effect. We are taking great care in the conduct of this and where possible, we actually have a central firm that's providing the testers on the patients with Angelman in our study, that helps assure quality and of the assessments, so they're done in a very consistent way.

So we feel pretty comfortable with the amount of change we'll see in the control group. It's small. We don't think there was a placebo effect. But of course, there's always variation, this is neurology. And we have a study we think of an appropriate size to help manage variation. But what we also have done is built in the multi-domain responder index, which gives us another opportunity to look at these patients in a broader way with more power.

The next question comes from the line of Anupam Rama with JPMorgan.

This is Priyanka on for Anupam. Can we get more color on how Ultragenyx is planning to achieve profitability in 2027 when burn in 2025 was around $466 million. And can you remind us how many drug launches will contribute to the 2027 top line?

Sure. I think Howard went through some things about major cost reductions that are occurring based on the progress of programs. And I'll let him tell you the details in one second. The combination that the base business of growth is going to be a real important part of where we get to. Certainly, there's some contribution potentially from the others. And Howard, maybe you can provide a little more reiterate some of the clarity of how we're making that move in [ pathway ] toward profitability.

Yes, happy to. I'll go through it now. Also, I'll note there's some -- there's a page or two on this in our corporate deck if you want to refer to that later as well. But our pathway to profitability assumes a few things. Emil mentioned that on the revenue side, continued growth from our current products in the double-digit range, plus contribution from some of the upcoming launches. On the expense side, we -- or I mentioned a little bit ago, 2026, we should expect combined R&D and SG&A to be flat to down low single digits versus '25. And in '27 for combined to be down 15% or more.

We have as part of our sort of cash plan, we have the $735 million that we noted today, we are also considering 2 PRVs as part of our plan to get to profitability. Maybe I'll also note that while we're in launch mode, some of the dynamics of the P&L that are also important to consider would be things like R&D trends or rather tends to be reduced due to capitalization of manufacturing costs post approval. Also gross margins tend to be elevated given prior expensing of pre-approval inventory that's being sold during the launch. So those are some dynamics to think about as you go through your modeling. So I think I'll stop there.

And I think it's important that part of the expense in '26 are building that inventory that's launched. And so what's really happening, some of the expenses you're talking about now are actually building inventory that will be launched. So those combinations hopefully give you a magnitude of effect that will push us there. We do need to get 2 approvals. We do have the PRVs and our 2 PRVs and our financial plan. But we think with the cuts we put in place today and additional things we're working on will put us in a good position to be -- keep 2027 profitable.

The next question comes from the line of Joseph Schwartz with Leerink Partners.

This is Will Soghikian on for Joseph Schwartz. I have one on Angelman and then a quick follow-up. So for GTX-102, the company has consistently stated that it is the most potent ASO in development. We're just wondering, is this claim based on the ATS knockdown or perhaps it's mRNA or protein increases preclinically? And can you just remind us what type of relationship you've seen between knockdown and protein expression? And then I have a quick follow-up.

Well, obviously, knockdown and expression can really only be monitored in an animal model, right, because we're not doing brain biopsies in our patients, right? So to be clear, those estimates have to come from nonhuman primates. Now because our ASO is identical to the nonhuman primate sequence, we conduct an experiment in the nonhuman primate for example, that Ionis can't conduct because they do not have homology in nonhuman primate.

So our experiments in nonhuman primate have shown that we are knocking down the antisense transcript substantially across the brain and or inducing UBE3A expression. And we do it at levels of around 1 to 2-milligram dosing over a few doses. So a relatively low dose that would be in the range of let's say, 10 to 14 milligrams translated into humans. We know now also that based on our ASF presentation last year that we showed an effect on Bayley cognition [ in ] other end points. And that Ionis showed a similar effect in Bayley cognition in a 6-month time frame, though they didn't show our higher level of benefit over time. And that is happening at doses in our study that are in the 5 to 14 range, while they are using 40 to 80 milligrams and Roche used even higher doses.

So we're achieving daily cognition comparable in substantially different doses. So that substantiates what we found in nonhuman primates before that what we predicted was true and that our effect we're seeing in on nonhuman primate translates to humans with a potent effect at a lower dose level.

Great. And then just one quick follow-up, if I may. I think the DTX301 program completed enrollment about a year ago now. So just wondering if you could give us a quick update on what's going on there.

Yes. So the DTX301 program, which is a gene therapy for ornithine transcript amyloids, or OTC, is the Phase III is continuing and we expect to roll out data from the ammonia endpoint sometime this year.

The next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

This is Rick Miller on for Kristen. For the IRL received for 111, would you characterize the issues raised there as expected? Is there any insight you can give us there? And then looking more broadly at the gene therapy pipeline, how should we be thinking about how the strategic restructuring impacts your priorities there, if at all?

Yes. So on the IRL, the list of issues on the [indiscernible] are known to both parts to [ FD ] and us, obviously, we had the same list. But the question is, what do you put in the package? And we put in with answer to how we're handling each thing, SOP changes, [ cap ] agreements, things that we're doing, put them all in there. So they understood all of it. They actually want all the supportive documentation like the SOPs and the follow-ups on effectiveness, et cetera, which we normally wouldn't think be part of a BLA, but the FDA has requested that we provide these.

We believe we have the answers to what they've requested. I think these are important issues, certainly, and we have addressed them before, but we'll provide them the full documentation, which is a substantial amount, but we'll provide full documentation as properly as we can in a resubmission for the BLA.

With regard to the restructuring and gene therapy pipeline, we obviously have a big footprint in gene therapy with 2 gene therapies, right, at the BLA stage at this point. We have a third gene therapy OTC that's in Phase III and a fourth the Wilson disease that's in Phase II currently. We have another IND stage program for CDKL5 that is on the sidelines. With the restructuring, we were hoping to be able to move forward one more gene therapy into the clinic. But right now, the main purpose is to get what we have in play, they are late stage out and approved that open the door to us and doing more.

We don't plan on decreasing our future in gene therapy, but we don't plan on our future being only in gene therapy. So while we have another gene therapy program, we also have 2 other INDs, for example, they're teed up there, not gene therapy. Because we do want to be a diversified company and don't want to be all in one place. So the restructuring will actually enable us to put more of our early stage programs into play as we finish up our Phase III program. We'll continue some work in gene therapy, but it won't be [ an exclusive ] place for our pipeline going forward.

The next question comes from the line of Allison Bratzel with Piper Sandler.

Maybe just a quick one, going back to setrusumab. I think you previously discussed a hypothesis that Orbit missed. You guys treated patients felt better, became more active and that's more likely to fracture. As you dig into the data, I guess, are you seeing a clear correlation between increased physical activity levels and fracture rates in the treated arm that could support that narrative? Or is there any way to validate that hypothesis? Any more insights on that would be appreciated.

Well, as we said, we are continuing to evalute the data deeply. What we presented before showed that the treated setrusumab arm in orbit had improved activity in function reported and decreased bone pain, so they clearly did feel better and we're doing more. Establishing how that directly results in refractures is something we're looking at. We don't have any information to provide. We're continuing to do the evaluation. And at this point in time. But certainly, data suggests that patients were reporting they had better physical functional less bone pain. So it's consistent with that. We continue to evaluate data on the program, and we'll provide more information with a definitive answer for the program is determined.

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

This is Lizzy on for Salveen. Maybe just another on Angelman following up to the question before. Given you are using a different endpoint than Ionis, I guess what is the regulatory bar and how confident are you that's kind of established going into [ that ]?

Well, I realize as many people making a point about the differences, I actually think both programs have a lot of the same end points. In the end of the day, whatever is primary, whatever is secondary. You talk about the commercial, it's going to look at everything. It's not going to just decide the commercial future will be decided on what endpoint or not.

The regulatory bar is defined by the pharmaceutical design here, which is basically a randomized [ sham-controlled ] trial that will have a continued variable analysis of daily cognition. The FDA appreciates that we believe the magnitude of clinical benefit is around 5 to 6 points, but we don't have that built into the primary endpoint. We're essentially looking for a continuous variable change. And what we know is we can see changes single-digit size changes. We had some patients that get in the double-digit range for improvements. So there is [ a variation arrange ]. We presented on this before of [ whoever they ] respond.

Our expectation is we can demonstrate a statistically significant, clinically meaningful change in cognition, which is what we observed in the A and B cohorts and presented before, that, that will be sufficient to be able to get approved. Now in addition to that, we believe, though, that other endpoints will be successful and the multi-domain responder index is our way to take a broader view of the disease and capture more of the benefit.

For the FDA, it's a new type of endpoint analysis. However, they've allowed us to put it in there and include an alpha allocation. We do think it's a way forward for neurology with heterogeneous diseases. And that bar is something we're setting for each endpoint based on what the clinical [ meaningful ] changes, what are the minimum change for what's considered an important change for disease. Those things we have discussions on with the agency are setting those in understanding with them will provide validation data that comes from the Phase III to help substantiate the regulatory bar of a responder for the MDRI. So the combination of both of those things, the continuous variable analysis of Bayley cognition and then the minimally important difference driven changes in the MDRI will put forth what we think is clinically important in regulatory sufficient data to achieve a filing for this disease, assuming the trial is successful.

Our next question comes from the line of Yaron Werber with TD Cowen.

This is Stephen [indiscernible] on for Yaron. Couple of questions here. We've got the opportunity for 2 PRVs coming in 2026. Any sense of how soon you'll be able to monetize assuming it kind of all goes well? And are you planning to engage potential buyers beforehand, maybe an update on time line? And then separately, on the UX701 program, I think you previously mentioned a first half of this year update on the cohort with the highest dose as well as on the prior cohorts as well. Is that being pushed out to later given the full year '26 time line? Or are we misreading that?

Right. On the 2 PRVs, well, first step is you have to get both products approved so you get the PRV issued. I don't know if -- Howard, do you want to comment on our timeline for dealing with PRVs and sale?

Yes. I think I'd say we would monetize them promptly. And whether we would pre-monetize them with an option agreement or we'd monetize them the normal way after they were in our hands remains to be seen.

Right. So on the Wilson program, the timeline for data is highly dependent on how the patients are progressing. We believe that we needed at least 6 months of time. And what we showed before is like [ 6 to 8 ] months of time in their first cohorts to show the effect on copper efficiently. So we're just providing less precision on the timeline there to give ourselves the opportunity to continue to see what goes on with those patients. But it's not meant to be an important change. It's just being less specific as we want to watch how these patients do with the higher dose that were provided.

We also want to make sure they have enough time to have their standard of care withdrawn if they achieve the proper [ copper ] context. So [ it's ] just being a little less precise but not a fundamental change.

Our next question comes from Tara Ahmad with Bank of America.

Okay. I think that might be. I wanted to ask a couple of questions. First, can you just clarify, and I'm sorry if I missed this earlier. But with an IRL, when you resubmit, can you just define what timelines are possible on review the final decision from the time that you now resubmit the responses that the agency is looking for? And then a question on 401 for GSDIa. Do you have any updated thoughts on what pricing could look like there? And do you have a sense on what kind of potential launch trajectory would you expect? Would it be kind of slow and steady? Or could it be steep from the outset?

Great. So on the IRL timeline, so what we just submitted was a resubmitted BLA to the complete response letter that we received. So what's happening here is that we have to resubmit that resubmission essentially. So the timeline is similar to what we had before, we would resubmit with the additional information not built into the BLA, and we'd expect a couple of weeks for them to determine if this has all the pieces of documents in it that they want at that point, then a PDUFA date would get set approximately 6 months after the original submission. So the question how long it takes to get there, we're -- we haven't determined yet how long it takes us to get the documents together and put it in, but we're working diligently and putting that together.

Now the other question with regard to GSDIa launch, is that correct?

Yes, and pricing.

Yes, that's right.

Yes. GSDIa is a very urgent disease in the sense that patients are drinking starch every few hours all day long, all at night, right? So there's a lot of urgency. [ We expect ] there to be a lot of interest early on. But I would say that, that market is probably going to develop in a little more steady fashion than, for example, MPS IIIA, where the patients have an urgent, absolutely must get treated immediately to try to stave off loss of brain, right? So MPS IIIA will happen probably more urgently [ than ] GSDIa. But we do expect there'll be a strong steady demand, but I wouldn't expect to be like all at [ once ] at the beginning. Now with GSDIa, we haven't set pricing at all, but we have talked about a $1 million to $2 million range of pricing, whereas with MPS IIIA, we've talked about a $2 million to $4 million range.

Our next question comes from the line of Maxwell Skor with Morgan Stanley.

So regarding the Aspire study, can you just describe what site training looks like for uniform conduct of Bayley-4? And are there any practical considerations or added complexity when administering the assessment in, let's say, older pediatric patients versus younger ones?

Very detailed technical question but an important one, because conduct of the Bayley is very important. First off, as a company, we've always put more emphasis on endpoint design valuation training than most any companies. We have an entire department that does this activity that you're talking about, which is our endpoint development strategy group or EDS group. That group is run by a senior PhD and there's a group of who are basically experts in trial design, endpoint design and as well as training and evaluation. So we developed a comprehensive training for all the sites.

In addition to that, for the Bayley cognition, Bayley score specifically, as many sites as we could, we have installed a centralized company to provide the Bayley scoring with experts who are knowledge about Angelman and how to conduct the Bayley in an Angelman patient. And we're providing those testers where as many sites as we possibly can to help assure the quality and consistency of the evaluation of the Bayley. We think that will have a substantial amount of consistency to what we're doing in addition to our own training program.

But you're right, this is a very important area, and we've done a lot to do that. And I would say, I don't think there's any other company that has a department of people that actually do this very activity. So I want to thank Dr. [ Shreiner ], who runs our group. All the work she've done in putting this together on our Angelman program, it took her and her team a lot of work to get it done.

Our next question comes from Yigal Nochomovitz with Citi.

I just had a follow-up on OTC. Can you just describe a little bit more about that study. It's not one that you speak about much. Is it sort of a lower prominence in your expectation set around success or not? And what would you need to see for the study to hit? And then with regard to the IRL, Emil, you mentioned that some of these requests were -- would have otherwise occurred during inspection. So does that mean that the inspection would be limited or not occur or be different?

Yes. So the OTC program with Phase III, we try to prioritize what we discussed just all the time, and we have so many different programs. It's definitely a burden for everyone to put everything on everything that's going on. But it's there and it's continuing. And I think OTC is a real important disease, [ and there's ] a really serious need for better treatments.

What we have -- the Phase III trial which enrolled around 37, I believe, the randomized controlled trial and the data we'd be looking at was on the change in ammonia between the treated and control groups. That ammonia [ member ] in the trial people [ would have ] variable ammonia. Some are normal at the beginning, some are high. We're looking at do we control ammonia better as the primary endpoint for the blinded portion of the study. Then the second portion of the study, we'll look at whether a patient can get off standard of care or not or how well they get off standard of care. It is an important program, but it's not our top priority program. So we are pursuing it. We'll get the data. It gives us another opportunity for us as a company, another valuable available asset going forward, and we'll read out data this year on it.

With regard to the IRL, I have no doubt the FDA will come and inspect as well as they should. I think providing the documentation is to provide them greater confidence upfront that we have actually done everything they want. We've described the answers and what we've done, but they actually want to see the materials of the things we've done, right? Not just describe changes and SOPs, but actually show me the SOPs, et cetera, and all the parts of that go along with that.

They were requests that are important in developing a quality manufacturing program. We have done the work. So now we'll provide them a more comprehensive complete set of supporting documentation, which is a very large volume of information, by the way, and a lot of documents, but we'll provide it to them upfront so they can see that we have done everything they've asked.

Our next question comes from Luca Issi with RBC Capital.

Great Maybe, Emil, kind of going back to the FDA, maybe a little bit bigger picture. I guess, what was your reaction to the REGENXBIO CRL the other day? It sounds like the FDA has some reservations around using serum biomarker compared to natural history for ultrarare disease. Is that just a one-off related to their program specifically? Or is the conclusion at this point that this FDA has essentially raised the bar for all the companies developing drugs for rare ultra diseases? Again, any thoughts there, much appreciated. And then maybe, Howard, a quick one. When you guide $730 million to $760 million top line for 2026, what is the simple kind of back of the envelope math or what proportion of that is cash versus noncash?

Very good. So with regard to the REGENXBIO decision, look, we put in our script today that heparan sulfate data presented at the Reagan-Udall meeting are definitive in demonstrating a relationship and that how you measure spinal fluid heparan sulfate can be done by multiple different methods that give very similar patterns of response and are, I believe, equally predictive.

The FDA's ruling there would appear to show more pushback toward the biomarker. We received also in our review, more emphasis on our clinical end points than the biomarkers. But we believe that the biomarkers are disease cause measurements and are an accurate way of measuring disease and efficacy, and we continue to support them with the FDA and publicly.

Are the FDA pushing back? They appear to be more resistant to the biomarkers than had been agreed upon at the Reagan-Udall meeting. They have said publicly, though that they are supportive [ of its IRL ] approval in rare disease products. And it would be important to see that those statements turned into action for all the patients that deserve these treatments for diseases like Hunter that [indiscernible] worked on as well as Sanfilippo and other neurologic diseases that are waiting for their first ever treatment.

The biomarker is an extremely important way to really tell what you're doing and how effectively. So while there may be pushback and the bar may be raised there, we do need to make sure that the FDA cares what the needs of patients are and can appreciate the science behind biomarkers we have chosen and why there are meaningful ways to measure disease and predict appropriate clinical outcomes.

Our next question comes from Sami Corwin with William Blair.

I guess I was curious what you're modeling for the potential sale of the priority review vouchers internally. And if the recent renewal of the rare PDS disease PVR legislation change those assumptions at all? And then just how much a change in price could impact your path to profitability in 2027?

Okay. So you got that PRV and path to profitability, Howard. We just didn't answer that other question. I just noticed on the...

We'll follow up and [ look you up ] offline on that one. But as it relates to PRVs, we were not modeling what had recently been seen, meaning not modeling the $200 million range. We were modeling something a little bit north of $100 million. We were very excited to see that the legislation was reapproved. I think that gives us an opportunity to not only get the 2 PRVs that we've mentioned for the gene therapies, but for 102 and for other programs in the future. And right now, we continue to have that just north of $100 million is our base modeling assumption. So anything that would exceed that would add to our balance sheet.

This now concludes our question-and-answer session. I would like to turn the floor back over to Joshua Higa for closing comments.

Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at [email protected]. Thank you for joining.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Rati Pinge, Joyce Zhou and Priyanka Grover. Our next presenting company is Ultragenyx. And presenting on behalf of the company, we have CEO, Emil Kakkis. Emil?

Thank you, Anupam. I'm certainly happy to be here at the JPMorgan conference again to give you an update on Ultragenyx. This is our forward-looking statement. We're a company that's leading the future of rare disease medicine. That means the company works on first-ever treatments and diseases have never seen a treatment before, developing new ways of measuring, studying and developing drugs for these treatments.

And we try to help not only ourselves, but other companies as well as patient foundations, and it seems like everyone is doing rare disease drug development these days. We want them all to succeed, and we continue to drive forward in a number of different programs. Our differentiated strategy is really looking at potent biology in a bad disease and really picking well for those situations and picking the best mode for each disease.

And then we try to be very creative in how we do development, looking at adaptive trial designs, endpoint choices and so forth. And it's often necessary to invent things and adapt to new diseases that have never been studied before. And finally, we commercialize. We believe in a very lean commercial model focused on patient find and patient support. We also have a very, I think, powerful method in post-marketing which allows to reduce R&D spend and allows us to turn over our programs and our teams over to the next pipeline opportunities.

Now since going public in 2014, we have 4 commercial products approved, commercializing in more than 30 countries around the world and generating revenue that continues to grow, and we'll talk about it a little more. But we've also been able to turn over our team to 5 Phase II/III programs at the same time with 2 approvals coming this year. And that process is a part of how we're optimizing the rare disease drug development model in terms of trial design as well as in how we manage the post-marketing commercial launch.

Now we've had some data on setrusumab recently, which was very disappointing. We missed in the trials, and I'm going to show you a little more about that data to get to explain what happened and what we know about our setrusumab program. So we had 2 randomized studies, and I'll go through these studies in detail, neither hit their primary endpoint, but both studies demonstrated substantial improvements in bone mineral density as expected from the Phase II studies.

Additionally, we found improvements in vertebral fractures and the consequential effect of that, which is improvement in patient-reported pain and functional outcomes, which is what we also saw in Phase II, kids getting up, running around and doing better. So we saw data here, which we'll show you now about functional outcomes that I think are a real important part of what we see.

And we'll try to understand a little more about the fractures, what we see, how it's working. And I'll hopefully give you a little bit of better understanding what went on in these studies because they are -- were so important to us in our evaluation. So I'm going to go into a little bit more, let's say, trial detail than a normal presentation because this is the moment when we need to do it.

So there were 2 randomized Phase III studies. The Orbit Phase III was a placebo-controlled trial in patients 5 to 25 years old. This is the trial on the left, a traditional randomized trial, placebo-controlled. On the right is Cosmic, which is a different trial in 2- to 7-year-olds that is active controlled.

Cosmic was intended to look at younger patients with more severe disease. and they need to be controlled with active. They could not be put in placebo for that reason. So this is the 2 designs. If you look at the patients that we enrolled in the 2 designs, in Orbit, they were generally balanced, but there were more type 3s, which are severe in the setrusumab arm and more type 4s in the placebo arm. And if you look at Cosmic, they're relatively well balanced. So there were 64% of the more severe type versus 54.

So a little bit enriched in more severe type within the active controlled study. If you look at the pediatric subset, there are 67 patients in Orbit that were pediatric and similarly to the 69 in the other studies. So there's a significant overlap in the what I would call the prepubertal population of pediatric patients, and peds and teens together about 85%. So the majority of the study is less than 18-year-old pediatric.

And this will become important as we go through the data. So who did we enroll in the studies? So when you look at the fractures in Orbit, the mean was about 3.2 in both groups and placebo and setrusumab had about a median of 2. So we enrolled the population we expected with a minimum threshold of 1. In the Cosmic study, we expected more severe disease, and we saw patients with higher mean fractures.

And setrusumab had a higher median of around 4 fractures. So a more severe population in Cosmic, which is what we expect. And if you look at the stratification with fracture number, it was clearly shifted more severe in the Cosmic study than in Orbit. And this probably becomes important when we start looking at fracture reduction.

Now in Orbit, because it was placebo controlled, we had to include a rescue arm because patients did not want to enroll in a trial that could go as long as 2 years, be off their bisphosphonate treatments. So if they hit a certain number of fractures, they could exit the study; 19%, 19.5% did exit the study. The placebo, though exited with type 3, type 4 patients, essentially, as you would expect, at nearly twice the rate of what the treated patients. So there's clearly a differential between which patients came out.

Now their AFR would be calculated from their first 12 months in for those patients that exited. So you could still calculate AFR, though it might affect other endpoints that would happen at other points. Cosmic, there were no rescue criteria because both arms had treatment. So it's important staging of what we see. Now when you get into the trial itself, what we saw is substantial improvement in bone mineral density in the Orbit study, essentially 1 Z-score change, exactly what we saw in Phase II.

So the drug is working, and you can see very tight error bars working as you would expect. On the Cosmic side, a substantially better improvement of bone mineral density over bisphosphonates, clearly working better. And we believe the type of bone mineral density you make with setrusumab will be a better quality of bone because you're making bone, not just preventing resorption. So the bone mineral density data replicated exactly what we expected.

Now if we dive in the Orbit fracture story, this is where things started to change. If you look on the right, you can see the cumulative fracture distribution curves, and you can see the groups are not really separating whichever way you look at it without the primary endpoint, without vertebral fractures and fingers and skull and the others where you look at total fractures, very similar.

And because the story comes really -- if you look at the placebo group, based on the negative binomial model, it was only a 0.55 fracture rate estimated. But the median, if you look above is 0, which means of 52 patients, 26 patients had no fractures in the study. So this gives you very little power now to tell the difference. The fracture frequency in the UX143 group was actually fine, 0.71. It was not very high, considering what the pretreatment fractures were at.

So both study arms were lower. The placebo is slightly favored, but that's only with the primary endpoint, looking at all fractures are about the same. So the question is what's going on here in the study with fractures. This was the part that was a surprise. Now we know from the Phase II study patients felt better and got more active. So one of the question is did they get more active and cause more fractures, that we won't know for sure, but we did look at how they did, and Orbit is a placebo-controlled trial.

And the POSNA-PODCI is a pediatric orthopedic assessment. If you look at the POSNA-PODCI graph, you can see the setrusumab-treated patients had a statistically significant improvement in pain comfort versus placebo. And in sports activity, also a strong trend for improvement. The other scale, the Patient Global Impression Scale also showed in the same peds plus teen subset that statistics have an improvement in bone OI pain and a statistically significant improvement in daily activities. So both in pain and functional activity in both -- 2 different measures in a placebo-controlled trial are showing the drug is working.

So you might wonder, well, if the fractures aren't better, why are they doing better? I think it could be because they're doing better and they're running around. And we did see that in Phase II that some kids had fractures, but we still should have seen some differentiation, we didn't. But this is the Orbit story, we think this shows an activity, but we didn't show the fracture differential.

So now let's talk about Cosmic. In Cosmic, the story is a little different. The fracture rate was higher. If you look at the mean or median, you could see there was 2.6 was the mean for the bisphosphonate group. So several fold more fractures going on in the study. If you look at the cumulative distribution graphs on the right, you can see that they're separating quickly, right, after initiation of trial. There's a little turn up in the graph that happens to be when we do a 12-month skeletal survey.

That's why a bunch of fractures are added because we see the fractures on a survey that weren't seen before and they're added. But you can see the separation of the 2 lines gets even greater. So this is separating in the way we would have thought, right? This is what we were expecting. When you do the negative binomial model, it shows a 21% difference, but still not significant, but it's -- the pattern looks more like what we would have expected to see.

Now when we look a little deeper at these fractures, what we saw is this. You can see on the left of the table here, it's just the total number of fractures seen. And you can see there's less fractures in the 143 group. But if you look at the vertebral factor, there's a very substantial difference, about a 59% reduction in vertebral fractures. And beyond vertebral, if you look at all of the trabecular bone including the scapula and also some of the fingers and feet that have more trabecular bone, all of those had the 59% reduction.

So clearly, the bones that have created the most bone mineral density are having the best effect. The long bone difference then there wasn't as much. The long bones may take longer, perhaps. But we see a very substantial effect. This is still a trend P-value 0.08 at this point. If you look at the fracture, they are non-morphometric in the spine, you could see a 94% reduction.

These are true fractures of the vertebrae, are essentially getting eliminated. So we think those are quite important. But this is what we see, did see an activity of the drug that bone mineral density improvement is resulting in improvement in trabecular bone, particularly vertebral fractures. So when you look at safety in the program, the safety was good. There were only a couple of patients in each arm that came out from safety in Orbit.

So relatively no problems in safety. Safety was fine for -- in both studies. So what do we see going on here. Overall, we think the data suggested the drug is active. It's clearly improving bone mineral density in a profound way, in a way we think is the best. How is that translating? Well, the bones that are trabecular are clearly having a reduction in fractures. The long bone is less so. And this is the pattern we're seeing. But those changes are resulting in kids that have less bone pain or more active.

And we've clearly seen a number of cases of kids that don't walk well. They are walking much better and getting about. So we think the drug is clearly active in this disease. But the question is -- the real question is why the AFR missed, and that's the challenge we have to deal with. We continue to do more work looking at the data, but this gives you an idea of what we've seen. I think it replicates a lot of what we saw in Phase II, but again, the AFR did not hit what it need to hit, and we'll have to continue looking at all the data to understand it better, but hopefully that gives you a sense of where we're at with setrusumab at this point in time.

So let's talk about what else is happening. It's a company in the pipeline. Sanfilippo syndrome, a very horrible disease, one of the worst progressive CNS debilitating disease. And we've been developing a gene therapy that was given to us by Abeona. And the data we've seen on it shows a biomarker restoration of lysomal function in the brain combined with a substantial and persuasive statistically significant improvement over natural history for these patients in multiple neurologic endpoints.

The data were strong. We received the CRL last year for CMC issues, which were very resolvable. We are resolving them. We expect to file early this year, and we would expect to be able to get approval based on the data we have and what we've shown in this program. Now one of the questions in gene therapy is are these going to exceed because I think people think gene therapies have failed. Some have done well. The entire success of gene therapy is highly predicted by one key factor.

What is the level of patient urgency. If you know patient urgency, is there another treatment? Is there no other treatment? Are these kids going to die or have risk of dying or have substantial impact? Sanfilippo, these kids are going to die and the parents know it. This is a situation of a high urgency. We believe this will be one where patients will want to get treated, and our goal will be to make it accessible to as many of these patients as possible. We'll work through that filing and look for an approval, hopefully, around the middle of the year.

The review in a refile is about 6 months. Second program, we already have completed a BLA filing in December is for DTX401 for glycogen storage disease. This is also an urgent see. These kids are every few hours eating starch to keep their glucoses up from falling. If they miss starch at night, they can die. It is running on a treadmill, an emotional and stressful treadmill all their life. When we enrolled these studies, we had great demand to enroll in the studies. We have -- when we had to cut off the enrollment, we had people very upset. There's a lot of demand in this one as well, urgent.

We've shown a randomized controlled data, which were excellent with reduction in cornstarch need and that continues to improve with time. But it's also associated with excellent impression scale scores in these patients and particularly 95% of the crossover patients showed that they had improved. We think this treatment will do well. We think the urgency is high. And it's really the first time they've had a treatment that truly corrects the underlying problem of their liver disease.

That filing is in, and we'd expect assuming we move through validation, we'll get through to a PDUFA date would be about 8 months' time from filing. GTX-102 is the other major event of the year. Angelman syndrome, we have a very potent antisense oligonucleotide that turns on UBE3A expression. We've had data on over 60 patients in Phase II showing profound developmental improvements, improvements in cognition, receptive communication, sleep, motor, fine motor, and the Phase III trial enrolled very quickly and finished enrollment in July last year. It's a 48-week study. So we'd expect in the second half of this year to be the Phase III data come out.

Now we're doing 2 studies. The first study on the left is a placebo -- I'm sorry, a sham controlled but blind -- double-blind study, 129 patients, ages 4 to 18, the same age range that we used in Phase II. So we feel we understand that population. The primary endpoint is the Bayley score, which is a validated neurologic score. But we're also supporting that with applying about 20% of the power toward a Multi-domain Responder Index, which is what we believe should be the future of neurologic disease evaluation.

Neuro is often harder because it's complex, it's variable. The multi-domain allows us to capture 5 domains of effect and look for major changes in 5 domains and accumulate that efficacy. And therefore, heterogeneity is managed, and you're able to find the improvements where they exist in patients. And we've shown in the Phase II study data that the MDRI is quite powerful and important. So those are the major parts of that development program. We've added now another study called Aurora, and this is to expand exposure to other genotypes and ages, a number of different ones I won't go through today, but the idea is to help expand who can be treated safely and what does their efficacy look like.

The randomized trial is obviously the important driver for a pivotal file for a filing. So the second half of this year is what we'd expect. Finally, I'll touch on Wilson disease, the gene therapy. We've shown some very interesting early results. We wanted to increase the dose to get to a dose level where we could essentially eliminate the need for other treatments in Wilson disease with this gene therapy.

And while there's always a question about how many patients would need a gene therapy versus their chelators. We're now looking at some of the data from the biopsies. What I've been shocked to see is how many of the well-controlled Wilson patients have tremendous liver injury going on, which make me believe that maybe the chelators are not as good as people think. That maybe a larger fraction of patients should be on it. And we presented at a liver disease meeting last year -- late last year that some of the patients with liver inflammation did have a decline in liver inflammation with the proper canalicular expression of the transporter that we are delivering by the gene therapy.

That was encouraging, where Cohort 4, which is at a higher dose with improved immune modulation as will be coming out later this year. So Wilson, I think, is a great prospect for changing the future of a disease with a truly specific treatment. Now with all the commercial -- with all the clinical activities and catalysts, we've also been building a global commercial business. We just announced our -- preannounced our numbers, which are we beat our consensus with expected $62 million (sic) [ $ 672 million ] to $674 million, which is a 20% growth rate. And you can see we've been steadily growing our commercial business in these 4 products globally, adding countries and growing each country.

I think this is a strong base business for the company and a base value point. But we'll also be able to leverage our commercial global experience as these new products come forward and be able to launch through this existing commercial franchise, which is part of our original vision, that in rare, to really truly succeed, you need to be able to capture revenue across the world, not just in one territory or another. You need to capture rare across all territories, if possible.

We're going well, and I feel good about the growth of this base business going forward. Now with the setrusumab challenge, we are planning expense of -- significant expense and headcount reductions. With that in the Sanfilippo CRL that we received, both of them provide a challenge to our financials, but with the strong revenue, double-digit growth we're having, combined with some expense and head count reduction we'll have to make, we will invest, of course, in the launches that we're planning.

But with these expense reductions, will put us in line to continue our goal, which is heading to our profitability in 2027. And we expect -- we have $735 million in cash, plus we expect 2 PRVs will occur before the sunset clause in September, which allow us to be able to bolster our cash position. Now the PRV should get reauthorized, but if it's not, we still have a chance to get these 2 PRVs in time.

Together with our expense reduction, we put us on path to get to profitability. That strong base business then is giving us the engine to get where we need to go, 2 gene therapy potential launches, the Angelman program also coming up, Wilson and whatever we end up doing with setrusumab going forward. So we're excited about what we've been able to do as a company.

We'll get through the certain current challenges, but these are the catalysts for the year. Two gene therapies, which would come on around the middle of the year, Wilson data later in the first half and Angelman data in the second half of this year. So it should be a rich year of both regulatory and clinical milestones. So we've had a history of consistent and strong revenue growth with our base business. We have a number of catalysts in our programs.

And I think with the revenue growth, the new launches planned, we are heading to profitability in 2027, which is, of course, a rare place to get in any biotech company. So I'm proud of the work that the team has done to get us there and whatever challenges we have, we will overcome them and move forward. And I'm excited about the prospects of how much we have going on. I mean, 2 BLAs in 1 year, plus other programs plus growing commercial revenue. It's a strong story for Ultragenyx. Thank you.

So now Anupam, questions.

I'll start out with the first couple of questions. But if there are questions in the audience, feel free to raise your hand and ask, happy to call on you.

Emil, I was wondering if you could put the data that you just presented on setrusumab into context of what's kind of most important to patients, right? You hit stat sig on pain in both studies. Some of our diligence suggests that pain is one of the most important thing to these patients. Like how do we put all the new data into context?

Well, the pain data come from the measures from the same Orbit placebo-controlled study because the other study was open label, so you can't really do pain in an open label, but in a placebo-controlled trial with 2 different pain and with both hit. And I would say having studied it here and there, it's very hard to hit pain. So that's impressive to us. But when you ask patients, they have recently created a list, the OIF -- OI Foundation. Top on the list is bone pain. The fourth in the list is fractures.

So that -- their view is that the pain, the functional activities and other things are actually more important than fractures. But the truth is, from a regulatory standpoint, the fractures are what was stated. So we have to now adjudicate between those 2 realities. We have an effect on bone pain and functional, which is important to patients. We had an agreement or understanding with AFR. So now we have to navigate in that world.

How do you think about next regulatory steps now that you have the totality of this data? Like is there a path forward, you believe, even if it's in a subset of patients such as pediatrics?

I think right now, our most important thing is to really understand more about the data and why it is the way it is. Long bone did not appear better. Is that because kids were more active and they fractured? Or is there something else going on there? So we need to understand all of that to understand it better. And then we need to do that before we end up going. If we go to the agency, we'll want to do that with a firm understanding of what we have in front of us. And I think there's a little more work to do before we make that move.

Questions from the audience? We've got an e-mail portal question here. It's more broad in nature, but would you consider divesting your viral vector manufacturing to improve your profitability?

Well, the truth is if you're going to be in the gene therapy area, it's better to retain that from a cost structure standpoint. And we're one of the usual companies because we don't have just one product. We actually have 2 products that were approved. We have others in development. So I actually think we're someone that can leverage a plant better than most. And I think at this point, it doesn't make sense.

The cost markup and the reliability of contract manufacturing or gene therapy has been, I would say, problematic. And I think right now, we're better off not doing that. We've made the investment. It's behind us. We're now ready to turn the plant forward. I think it's much smarter to keep to the plan and manage our other expenses rather than the plant.

Maybe just going back to setrusumab now. You've presented us with these additional assessment since the top line. What are the additional assessments that you're hoping to conduct here in the next few months that could give you a better understanding of what happened, but also what is the potential of this product?

Well, we need to understand the various components of the fractures, why they happen, are they associated with trauma or not with trauma in the different subsets and different ages. So we kind of need to really understand that relationship well. The vertebral fractures improvement we're seeing is fundamental, and it's something that certainly was important to me, and I had talked about before, I think, Anupam, is that the vertebral fractures in type 3s and 4s are what caused them to become disabled and wheelchair-bound.

And if you could prevent that from happening, it's an important thing, right? There's no question that's important. And I've talked about that specifically before, it's why we ran Cosmic. We ran Cosmic because I wanted to treat those little kids with type 3 and 4 to see if we could change that future. So there is something there to deal with, but we just have to figure out what does that mean from a regulatory standpoint. But we want to go in with the full knowledge of what we have right now, and that's what we're going to work on, understanding it fully, to appreciate why the vertebral fractures and trabecular are better. It makes sense.

It's probably because bone mineral density improvement is faster in the trabecular bone. But what happens in the long bones, what happens in the cortical bones, is it -- will it take more time? Is there some way to look through the data and understand it? I think that will be important in trying to put forth a proposal once we understand all of that. So that's what we have to figure out. I think the symptom stuff is clearly showing that patients are feeling better on treatment. So I think that's a strong positive and important to patients. Certainly, the patients want to stay treated that we know.

Questions from the audience? Yes. I can repeat the questions.

Just a question on bone and cartilage genetic diseases in general as a therapeutic area? Are you still excited about that?

I think there are some many genetic bone and cartilage disease that don't have treatment. So we think it's a very strong area for development. And while most people shied away from bone and cartilage because getting drugs into the bone and cartilage is hard. What we're seeing is a lot of ways for us to manage bone and cartilage without necessarily have to get into the bone exactly like with XLH in controlling phosphate or in this case, controlling bone regulation with setrusumab rather than fixing the defect in collagen, we're actually just fixing the dysregulation that occurs that leads to not enough bone being made. So I think these are good areas for further work, and we are committed to working in the bone space for that reason.

I think we have a question over here.

Will we expect more data from setrusumab, like a long-term data -- long-term follow-up data?

Well, I would expect -- we have not a plan yet, but I would expect as we learn more about the data, just as we presented today, we'll provide an update on that data both longer term but also further deeper understanding of what we've done so far. So we're not done yet. We're going to be working that. But despite doing that, we are going to manage expenses and manage the burn, too. So we're not going to wait for that. We're going to be doing that because we need to. But we'll continue to work through and figure out what is the path for setrusumab, and we'll put out more data when we have more information on it.

There is a question over here.

Just curious, did you report the BMD gains for more cortical rich sites like femoral, neck or total hip?

We didn't report them out. We haven't studied them. In the original ASTEROID study, they did study all the bones. So from the ASTEROID study, and these are in adults, the lumbar spine measurements was about 10.9% in a year. But when you look at the cortical bone, it was about 2% to 3% range. Now the problem with cortical bone is that 2% to 3% means a lot because it's just a small tube of bone more will strengthen the bone. So you can't quite equate those numbers.

With trabecular bone though, there is more surface area. So there's more places for bone cells to lay down more bone and maybe make more bone more rapidly, whereas in the tube of a cortical bone, you're dealing with one surface area of the tube and laying down bone. So it's possible it takes more time in the cartilage bone, but we don't have that true answer yet, but there is bone production in both types of bone, as you would expect. But trabecular bone is clearly more responsive and what we're seeing now is, let's say, a bigger effect in the trabecular bone.

A question in the audience.

Did you check the biomarker of formation and resorption, like P1NP and CTx on both trials?

We did look at the P1NP. I don't know about Cosmic, but in Orbit, we did P1NP, and of course, it increases as expected. You couldn't get the BMD improvement without P1NP being laying down. So it correlated the way you would think. So there is more P1NP and that makes more bone mineral density. But bone mineral density is the real end game. Think of it as the accumulation. P1NP is a transient measure of how much bone is being made today, but the BMD is accumulation of the net total bone. It's a better marker ultimately in showing what you're doing, but we did look at P1NP, and it gets -- it improves, increases.

Additional questions? I'm going to just switch gears now a little bit to GTX-102 in Angelman. Emil, you've had a wealth of data presented over the last several years, I think, maybe 4 or 5 updates, and it's kind of matured over time. If you had to highlight what are the couple of data points we should be thinking about in the totality of that data give you confidence going into Phase III with the Bayley-4 endpoint. What would they be and why?

Well, I think at ASF, we put forth the biggest summary of all the data on the Bayley there, and we showed a meaningful change in Bayley that you don't see in control patients, whether it's from the natural history or from the levodopa controlled study. There's less than 1 point change in the Bayley, and these kids really don't change in natural history. They're just flat. So to see 5 points improvement in the Bayley, which is a clinical meaningful threshold is, I think, something that's quite important and very difficult to do.

And even less than 5 points is probably meaningful, but it's a continuous variable analysis for the Bayley. So we think that the control should be relatively flat. And it is though an international study. So we always have to consider when you run international studies, there's more complexity to that. So the Bayley, I think, is important. The cognition, by the way, is supported by the fact that patients have better attention span and better receptive communication, which makes it easier for them to deal with the Bayley cognitive testing.

I'd still go back to the Multi-domain Responder though, because the data we've shown there has been p-value less than 0.001, even with just 13 patients earlier or later with the larger group of patients, it's very powerful. And with the heat map, you can kind of see how patients are getting better and majority of patients have 2 to 5 domains of improvement and in multiple endpoints. And I think it tells you the breadth of the treatment effect in a way that's more relevant to what patients want.

The Bayley is a somewhat arcane tool that has regulatory standing, but truthfully, if I told you 5 points, most of you would know what 5 points mean, right? It's arcane. But if you tell someone that they are having clean improvement in their sleep or in their gross motor function, right? If we tell them -- those kind of things you see in the multi-domain, I think are a little more understandable. Now to support that further Anupam, we do have a development checklist that's closer to maybe what Taysha is doing with Rett, which is we're asking the question, have you hit these developmental milestones? Can you do these things?

That development checklist we presented at one of the original Analyst Days where we showed data and you should go look at that because that tells you the meaning of things for patients. And look and see that the majority of patients who could not understand 1 or 2-step oral commands before are now able to understand the parent tells them a command and they can understand it orally. Normally, what parents do with Angelman syndrome is that they will demonstrate sitting to tell the kids to sit because it's like the kid doesn't speak your language, speaks no language. How do you tell someone what to do when you don't have language to share?

So imagine now you can tell them sit down or stop, and they actually understand what that means. It's quite transformative for a family life to be able to do that and have the kid actually paying attention to you, first off, right? They actually are listening to you and responding to you. When you look at all the development checklist items that we put forth, you could see these are fundamental things that are quite important.

So this is why our -- we have high hopes for this. Now we just have to navigate the regulatory waters of daily MDRI and the rest of it. But we're confident and we have a lot of patients continuing to get intrathecal injections every 3 months on a pump. You know that parents are not doing that for nothing, right? They're not going to keep doing that for nothing. So we have a lot of patients continue to get treated and doing well. So I think we're excited about the potential for Angelman syndrome treatment.

Any final questions from the audience? All right. Thank you so much, Emil.

Thank you all.

All right. We're going to go ahead and get started here. So next up, we have Chief Medical Officer from Ultragenyx, Eric Crombez. Eric, I'm just going to turn it over to you for a brief introduction of where the company stands today, and then we'll get into it.

Yes. So Ultragenyx founded very dedicated to developing and commercializing drugs for patients with rare disease that has been core to our mission from the beginning, and we are very much [indiscernible] to that core there. Certainly, a lot of success in the commercial setting led by Crysvita and very much supported by Mepsevii, Evkeeza and Dojolvi. But I think what a lot of people are looking forward to is really with the progression of our development pipeline and a lot of Phase III data readouts and filing in the near term. I think as far as value drivers in the near term led by osteogenesis perfecta.

Perfect. All right. So I think we have to start off on the setrusumab side. Maybe before we dive into that, what was the rationale to do the royalty financing at this point in time?

Yes. So I think really what drove us to, I guess, start thinking about doing something was with the complete response letter for our Sanfilippo program that pushed off the potential revenue from the sale of a PRV. So with pushing that off into the d, it made sense for us to think about topping off the balance sheet. We started a competitive process. It truly was competitive and comprehensive. Obviously, we know Omar, they know us. And I think we think, and I think I've heard consistently that it was a good deal. It's nondiluted, was not tied to the stock price on any given day. So really just the right deal at the right time and just a good opportunity to top off the balance sheet.

Makes sense. All right. So going into Orbit and Cosmic, are you still planning to show both of those readouts together at the same time?

Yes. And we've thought about doing them separately, staggering them by a little bit of time. But we think we've heard and very much understand that it makes sense to talk about both studies at the same time.

Yes. All right. So one piece that I've always found interesting is you've noted you think Orbit probably has a higher probability of success, I think, largely due to the sample size there. I think Emil thinks maybe Cosmic may have a higher POS just given the event rate. How do we square both of those?

Yes. So I mean, I think -- I guess what's underneath that message is between the 2 of us, we are very supportive and very confident in the success of both programs. And the truth is both studies were powered for success. And importantly, Cosmic is powered to show superiority. Just from a pure numerical stats-driven probability of success, it is very marginally higher if you look at just straightforward statistics. But if you believe with the younger, much younger patient population enrolling in Cosmic and the really great results we saw there, there is potential for a very power effect there. And I think that's what Emil is being anchored on.

Yes. That makes sense. I'm going to summarize a question I've got from investors in a lot of different ways, and we can ask different scenarios a lot, but I'll just phrase it one way, which is, let's say, Orbit is statistically significant. The effect size is on the lower side with the low to mid-30% and Cosmic misses on statistics, but numerically is still beating our bisphosphonates. Maybe it's in the 10% to 15% effect size ballpark. Is that a commercially viable profile?

So I think the easy top line answer is yes, that's commercially viable. I mean we've seen the use of bisphosphonates. And it's important to remember that when you're making this type of diagnosis with a disease that's severe being able to offer nothing is just a terrible position to be in. And I think that's why bisphosphonates has been used to the extent they have. That type of profile does show you are consistently beating bisphosphonates to be fair and honest, that is probably a floor of where my expectations are. I mean we powered Orbit to detect at least a 50% treatment effect with that 159 patients. And with the 67% response rate we saw consistently in Phase II, that gives you room for something unexpected to have happened there. We've heard treaters really consistently say a treatment effect size down to 40% is clinically meaningful to them. I know some will get down to 30%, but I think it's fair to say that's kind of a floor for any of our expectations.

Just from a statistical perspective, have you said what the minimum effect size is you think that would be detectable in the trial? Like where are you 50% powered roughly?

Yes. So with the 159 patients enrolled, that gives us greater than 80% power to detect that 50% treatment effect.

Okay. What's your current thinking on how long the bisphosphonate effects last?

Yes. So very confident that it is months plural. I think in my mind, and I think most people would agree that once you get to that 12-month mark, you're probably seeing meaningful washout of bisphosphonates. I think if you're thinking about a total complete washout of bisphosphonate, you're maybe talking about multiple years. But I think with all patients going to at least 18 months with final data readout, I think it is fair you are seeing real washout of bisphosphonates at that point.

Okay. I think in the Orbit study, I'm not sure if this is true for Cosmic also, but there is the ability to go on to receive rescue treatment. What are the criteria to do that? And how many people have gone on to do that?

Yes. So I mean, I think there definitely is -- originally, there is the ethical argument. There's also a very practical argument that if you have patients who either you know are assuming were randomized to placebo and having a lot of fractures. We're talking patients with 10, 15 fractures in the first year of enrollment in the study. Is it fair to continue following them in a way and letting them continue to fracture at that rate? So yes, there's an ethical debate there, concern there. There's also the practical debate that you're going to start to see patients drop out if they're having that type of fracture rate.

So the protocol has guidelines for when a PI can approach the medical monitor for a discussion on rescue. The medical monitor needs to approve every single rescue. So there was nothing automatic. There was nothing that just triggered them being transferred to this. So we did keep tight control of it. We haven't said exactly how many patients have been rescued, but I can say when designing the study and when powering the study, we account for dropouts, we account for patients being rescued in what we have seen is absolutely within our expectations for our original planning.

Okay. That makes sense. Makes sense. And that's true both for discontinuation, dropouts and the rescues, both of those pieces are within expectations?

Yes. And I think fair to say dropouts has been a nonissue for this trial.

Yes. All right. That's helpful. Just a few on the commercial side then. What's the latest thoughts on pricing?

So pricing for us, and I think the usual answer, it's too early, wait and see what will happen here. But I think we're in a very ideal situation where we have the experience from Crysvita. We have that play book. It was a very successful launch. So when we think about pricing for osteogenesis imperfecta, I think it is very fair to say that Crysvita is a very good model and where we're currently thinking about pricing.

What about duration of treatment, too? Like I mean, there is a paradigm that exists today where bisphosphonates are not treat forever type of paradigm. So how do you think that will evolve?

Yes. So I mean, to me, there is 0 debate here in my mind. I mean, understanding the biology, understanding how setrusumab works, this is a lifelong treatment. This antibody takes out sclerostin and that allows the osteoblast to continue to generate, make more osteoblasts, lay down more collagen, lay down stronger bone and stopping fractures. If you take that away, sclerostin will shift that balance back to it was prior to treatment and patients will lose ground. We saw that in ASTEROID, the original adult study done, and that study was originally designed for 12 months only. Patients did improve and then after stopping treatment, did lose ground again.

Yes. Okay. What about the type 1 versus type 3, 4 patients? Have you said the mix in the trial again?

Yes. So for Orbit Phase III, closer to 50% type 3s and 4 combined versus type 1. That's a little bit in contrast to the Phase II part of Orbit, which was 1/3 of patients, type 3s and 4s.

And what's the split of patients commercially? Like not just the prevalent population, but the actual patients that are diagnosed in the system managed today?

Types 1 versus [indiscernible]?

Yes.

I'm a phone a friend.

[Technical Difficulty].

That makes sense. Perfect. All right. I guess last question just on setrusumab, big picture since we're kind of right before the readout. I don't know if you're at any other conferences this week, but this might be the last one. Like any kind of closing thoughts on level of confidence, et cetera, you want to make as we're heading into that data?

Yes. No, and I think it is important, having not achieved success with IA2 that our confidence remains unchanged and higher. Probably success for full data readout remains the same, and this is how the study was designed and powered and originally designed to work there. I think, again, I fall back on the biology, the mechanism of action for this drug and the really consistent results we saw in Phase I/II across all patient types. We saw the increase in biomarkers supporting the increase in bone mineral density, supporting the reduction in fracture rate. And all patients are responding. They're all doing well and supported by a very, very clean safety profile.

Awesome. All right. Look forward to seeing that data soon. Let's switch gears. Let's go over to Angelman side. Are you going to share anything over the next, I guess, 9 months before we get data? Like can you make any directional comments on like blinded data variability baselines, anything like that?

Yes. We've started those conversations. I think the truth is for us internally, we understand how this drug works based on the 74 patients that were enrolled in the Phase I/II. For rare disease for us, that is a big Phase II study. So we feel like we do not have unanswered questions there. The truth is with Aspire fully enrolled earlier this year, now initiating enrollment in Aurora, the second Phase III study, it's 2 big global Phase III study that still does have relatively complicated dosing.

We want to make sure the patients are hitting their visits. We're doing cleaning, everything is in the database and everything is as high quality as possible. So we certainly can. We've had that discussion. The question is, would that be beneficial to release that type of data? Or is it better to keep the team really focused on executing? Because once we get to midyear in the second half of the year with data release with positive results, we are then head down heading towards filing and that is a priority for us.

Yes, that makes sense. Just on the safety side, on the lower extremity weakness point. I mean, I'm sure this is something that you guys in the DSMB are monitoring very closely. Like what's the level of -- or I guess, the threshold for disclosure for anything that would be ongoing there?

Yes. I think generally, the disclosure, I think if we're just really talking safety for disclosure would be anything that's new or change, a meaningful change to what you've seen before. And I think with the time we took to enroll the additional 53 patients in what we call the dose expansion, and that included the trend Trendelenburg that included the flush with the understanding that ASOs from a chemical perspective can be irritating at the site of injection. So that's just flushing the drug away from site of injection.

Trendelenburg is using gravity to help you do that. We saw in those 53 patients only a couple of episodes of new lower extremity weakness. They were both very mild. One was only picked up in retrospect, both resolved very quickly without sequelae. So we felt that we understand the safety event. We understand and we're able to mitigate it to a great degree. So I think it's something that is part of the benefit risk profile. We're looking at that in totality, but very much something understood and with our end of Phase II meeting, not even a topic of conversation with the FDA.

Awesome. What about the dropout discontinuation rate for the study? I guess like when you were setting it up initially for powering, what did you expect?

Yes. I mean, I think as a general rule, we always -- typically, and this is probably true for most people, you're going to at least start without accounting for at least like a 5% dropout rate. With these types of studies, there are very, very low dropout rates. We saw it in the Phase II because this is a chance for these kids to develop, learn and gain new skills. The parents understand this Phase II data, and it really is the first chance they've had to see their children grow and develop and gain new skills. So it's essentially no dropout rate, and I expect it to stay very low over the course of these studies.

All right. Great. Are there any prespecified subgroup analyses in Aspire?

So prespecified, I mean, as far as the primary endpoint as part of top line, we're really looking at the patients in total and really just as a reminder because for Aspire, our main Phase III study, we're sticking with patients with full deletions as we evaluated in the Phase I/II. That is the great majority of patients, probably between 70% and 80% of patients with Angelman syndrome. More importantly, with full deletions, that means these patients are not making any UBE3A, which means they are severe, but also very homogeneous in their phenotype, making signal detection easier there. So if we were doing an all-in approach, all mutations into a single study, you would want to do the sub-analysis. We're taking care of those patient populations in Aurora. So from a primary analysis, it is that total patient population. Certainly, we'll look at pediatrics -- younger pediatrics from older, but it is really looking at them as a single group.

What were your expectations when you were setting up the control arm like powering versus the control arm?

Yes. So I mean, at its core, and I think natural history supports this, we all understand this treating community understands, particularly when you're talking about patients with full deletion, they have a very flat developmental curve. When we talk about neurotypical children, you're always looking for them to continue on their developmental curve, grow, develop, gain new skills. Their developmental curve is very, very flat. Certainly, we allow for some change there, some noise within that plus or minus as we're designing the study, but we expect that to remain fairly flat.

How often do you measure Bayley in the study?

So the Bayley is something you're putting them through. You always have to worry about learning skills and practice skills like this. So it's done with the 48-week primary efficacy analysis period. It's done 3 times.

Okay. That makes sense. I guess what's the evidence that you can kind of improve cognition communication, reverse the disease as opposed to prevent any type of progression?

Yes. No, and that's what's really unique and really such a unique opportunity here and why there's so much hope and potential with this drug because often with neurology, that's exactly what you're doing. You're hoping to stop deterioration or even just slow it down. And with Angelman syndrome, UBE3A affects the way synapses communicate with each other. So your neurons remain intact. You're not losing these neurons over time. So with the knocking down of imprinting from the paternal allele, you're expressing UBE3A. The synapses start communicating. These neurons are intact. So that gives you the potential to really have true development there.

Great. How many patients are coming on to the study with seizures? Like how -- what's the average frequency of seizures?

Yes. So I would say seizures is an important part of this disease. I can't tell you 100% of patients have seizures and what that frequency is. It hasn't been a big focus for us because we're not using a seizure approach. We're really looking to directly affect this disease and affect development there. So we will look at that. Most patients do have seizures. I think it could be a potential biomarker there to help with treatment decisions. But again, we're obviously very focused on the attainment of new developmental skills.

I guess, all the secondary endpoints also, how does the hierarchical testing work out there?

Yes. So hierarchical testing is just kind of a nice way to really try to control for false positives. So you're basically just ranking your endpoints in order. You're trying to do that kind of with a lens of importance, but with the development, you could argue that all of them are important there. So you're just putting them in a rank order, testing them one at a time. And as long as you're still hitting statistical significance as you move through your list, you keep moving through. As soon as you have an endpoint that does not achieve statistical significance, you stop testing further endpoints.

What's the order of the endpoints, do you know?

Yes. So for us, obviously, we're looking at cognition as a primary endpoint. That's important. And then we're looking then at communication, very focused on receptive communication, gross -- gross motor behavior and then sleep.

Okay. Really helpful. All right. Maybe in the last 30 seconds, we can just kind of wrap up and not really going to do a justice today, but I'm just going to flag 401, 111, 701.

Yes. So in addition to important programs, important value drivers for the organization with OI and quickly followed by Angelman, as a group, the gene therapy programs remain very important to us. And honestly, with the refiling, the response to the CRL with Sanfilippo and a 6-month review clock for that versus the standard review for GSDIa, which we said will finish submission this month, that puts them very close up to new PDUFA dates in the middle part of this year, and we're looking forward to and expect them to be very successful launches.

Awesome. We're out of time. Thanks so much for joining, Eric.

Thanks.

We can get started. Welcome, everyone. I'm Yigal Nochomovitz, one of the biotech analysts at Citi, and welcome to our Global Healthcare Conference in Miami.

So our next session is with Ultragenyx. We have the Chief Medical Officer, Eric Crombez. Eric, welcome. Thank you for making the trip. We've been covering you for many years and have been a lot of progress.

So maybe we could start out just at a high level. You obviously have a very important catalyst coming up essentially imminently with setrusumab. So before we get into the details of that, just kind of set the stage as far as what is the opportunity there? You had and are continuing to have a lot of success with Crysvita, another genetic disease. So talk about what the opportunity is in osteogenesis imperfecta and how you're setting up for a market launch there?

Yes. Great. And thanks for having me. So osteogenesis imperfecta, it is our near-term value driver. We've been talking about final data readout around the end of the year, and we've defined that as December or January. So we're certainly within that period now and is about as near term as it gets. So osteogenesis imperfecta, also known as brittle bone disease, and I think really illustrates the disease and the opportunity. The only currently available treatment to really stopping these patients from fracturing with very little to no trauma is bisphosphonates. Those are used off-label in the U.S. and most parts of the world.

The truth is it's better than nothing, I think, as a treating physician making a diagnosis like this. with children and adults really fracturing on a very regular basis, multiple times a year, sometimes the no trauma, it helps. We certainly think we can do better with this antibody. This antibody takes out sclerostin, which really affects the balance between osteoblasts and osteoclast to build and break down bone as children grow and remodel and as adults remodel. So we really think shifting the balance towards osteoblasts, having the ability to lay down more collagen, increase bone mineral density and then the resulting reductions in fractures really will not only improve the fracture rate for these children but quality of life. It keeps them from leading a very protected sedentary lifestyle, allows them to become more active and not fracture.

For us, for rare, it's a big indication. We think at least 60,000 patients in the geographies we cover. And really, for us, and really for anyone, a very unique opportunity to really repeat what we were able to do with the launch of Crysvita. Similar type of bone disease, similar type of effort we would need to launch and support that program. And certainly, while Crysvita was a very, very successful launch, we do think with those lessons learned and the opportunity here with the osteogenesis imperfecta, we could potentially do even do better.

Okay. So you've generated obviously, a lot of data. You had data from MREYO and now you have your own data. So maybe you can just kind of walk us through -- summarize what that data is telling us and how that helps as far as looking at probabilities of success for what we'll get into the 2 studies, COSMIC and Orbit?