Good afternoon, and welcome to the Ultragenyx Second Quarter 2025 Financial Results Conference Call. It is now my pleasure to turn the call over to Joshua Higa, Vice President of Investor Relations.

Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, Chief Medical Officer. I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

Thanks, Josh, and good afternoon, everyone. In April 2025, we marked our 15-year anniversary as a company. Over that time, we've taken 4 programs all the way through approval in multiple regions and added a fifth that we are commercializing outside of the U.S. At the same time, we've also refilled the clinical pipeline and now have 5 Phase III clinical programs fully enrolled or at the BLA submission stage. Over the last 15 years, Ultragenyx has been the most productive rare disease company in the industry across a broad range of modalities and therapeutic areas. Through the first half of 2025, we continue this momentum with meaningful progress across our larger programs. I'll begin with UX143, setrusumab for our fully human monoclonal antibody for the treatment of osteogenesis imperfecta. The Orbit and Cosmic studies are continuing to the final analysis that will occur around the end of the year. While I hope the studies might have stopped early at the interim time point last month, we remain confident in completing a successful study. We're pleased the safety profile is as expected and that after looking at the data, the DMC recommended we continue to the final analysis. The continued treatment of Phase III should further strengthen the bones of the treated patients. The additional 6 months of treatment for the treated subjects, along with the larger p-value threshold at 0.04, will help power the final assessment. We look forward to unblinding the Phase III datasets and sharing results around the end of the year. Based on all the data we've seen in Phase II, we are confident UX143 will be a transformational treatment for pediatric and adult patients with osteogenesis imperfecta. The combination mechanism of building bone and reducing excess resorption is at exactly the sites in their body where they need more bone and will increase bone strength and reduce fractures while at the same time improving overall bone health. In addition to reducing fractures, we are encouraged by the functional effect we are seeing on increasing physical activity and ability that speaks to the long-term potential for this treatment. Now shifting to GTX-102, our antisense oligonucleotide, or ASO, for the treatment of Angelman syndrome. GTX-102 received Breakthrough Therapy designation from the FDA in June. BTD aims to expedite the development and review of drugs that are intended to treat serious or life-threatening diseases, and whose preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies. Historically, there have been relatively few Breakthrough Therapy designations granted in the field of neurology because it can be challenging to demonstrate a meaningful potential clinical effect in neurologic disease symptoms. But for GTX-102, we have been able to do that. The BTD designation was obtained based on our Phase I/II study data in 74 patients with a full maternal UBE3A gene deletion that showed consistent developmental gains with rapid, sustained and continued improvements across multiple symptom domains when patients have been on therapy for up to 3 years. For GTX-102, the magnitude and durability of our Phase I/II data indicate our ASO is meaningfully improving the lives of patients who have this neurodevelopmental disorder. Last week, we also announced that GTX-102 Phase III study, Aspire, completed enrollment ahead of plan with 129 patients in 7 months. The interest from investigators and patients helped drive the rapid enrollment, but I also applaud our team for their efforts to expeditiously enroll the study. We're thankful for the support from the patient communities and investigators who helped us exceed our expectations. We're now on track to read out Phase III data from this 48-week study in the second half of 2026. Now switching to our commercial progress for the first half of 2025. Our commercial teams continue their trend of delivering double-digit revenue growth. The $306 million in total revenue across the first 2 quarters represents 20% growth versus the prior year and keeps us on track to deliver $640 million to $670 million of total revenue this year. Crysvita is continuing to grow in line with our expectations from royalty revenue in the U.S. and Canada and product revenue in Latin America and Turkey. Dojolvi, Evkeeza and Mepsevii also continue to contribute to our top line. Each of these launches are progressing well. I'll now hand it off to our Chief Commercial Officer, Erik Harris, to give us some additional details on his team's recent performance.

Thank you, Emil, and good afternoon, everyone. As Emil mentioned, my team is continuing to successfully commercialize 4 products across the globe. Starting with Crysvita in Latin America. In the second quarter, our team generated approximately 50 new start forms that led to approximately 50 patients on reimbursed therapy. We now have approximately 825 patients on commercial product in the region as the team continues to exceed our expectations for Crysvita. We continue to receive positive feedback from health care providers in the region who tell us how much better their patients feel when on Crysvita, which has led to an increasing number of doctors writing prescriptions for multiple patients. We expect growth in the region to continue following the successful negotiation of reimbursement from the Brazilian and Mexican authorities, the 2 largest payers in the region, and continued expansion in other Central and South American countries. I'll now shift to Crysvita in the United States and Canada, where our partner, Kyowa Kirin, has been leading commercialization for Crysvita since the transition in April 2023. Revenue in the second quarter 2025 was supported by increasing new start forms and new patients on reimbursed therapy. We expect 2025 U.S. and Canadian Crysvita revenue to continue growing as they work to identify new pediatric and adult patients with XLH and convert them to treatment. Moving on to Dojolvi in the United States. Growth of new start forms in the second quarter continue to steadily increase, consistent with the patterns we have seen in prior quarters. Our team generated approximately 30 new start forms and added approximately 30 new patients to reimbursed therapy. This brings the total since launch in 2020 to approximately 600 patients on reimbursed therapy. The split between pediatric and adult patients continues to be approximately 65% pediatric and 35% adults. The total number of prescribers also continues to grow with a total of approximately 270 unique prescribers at the end of the second quarter. For Dojolvi across the EMEA region, there are approximately 280 patients treated under named patient sales across the region. The majority of demand is from France, but we are seeing continuous growth across the EMEA region, including Kuwait, Saudi Arabia and Greece. The demand for this product is quite strong across this region, especially given the fact that we are not actively marketing the therapy and simply responding to named patient requests. Before I close, I'll make a few comments on Evkeeza, which we began commercializing in territories outside 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 from nearly all of the major countries, and we have added almost 100 patients since the beginning of the year with a total of approximately 285 patients across 15 countries. We continue to successfully navigate the country-by-country pricing negotiations and respond to named patient treatment requests across the whole EMEA region. Our team in Japan continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. In Canada, we are continuing pricing negotiations with government health authorities and recently added younger pediatric patients to the label. Over time, we expect Evkeeza revenue to contribute more meaningfully to the total revenue as we continue to successfully launch this transformative product for HoFH patients with its high potency due to a novel mechanism of action, regardless of background therapy. As I have mentioned on previous earnings calls, we continue to expect some quarter-to-quarter variability in revenue, primarily due to uneven ordering patterns for Crysvita in Latin America, but we remain confident in the growing underlying demand for all of our products around the world. With that, I'll turn the call to Howard to share more details on our financial results and guidance.

Thanks, Erik, and good afternoon, everyone. I'll focus on second quarter 2025 financial results and guidance for the year. Starting with total revenue. In the second quarter of 2025, we reported $166 million, representing 13% growth over the second quarter of 2024 and 20% growth for the first half of 2025 over the first half of 2024. Crysvita contributed $120 million in the second quarter, including $79 million from North America, $35 million from Latin America and Turkey, and $7 million from Europe. Dojolvi contributed $23 million, consistent with its expected steady growth trajectory. Evkeeza contributed $15 million as demand continues to build following launches in our territories outside of the United States. Mepsevii contributed $8 million as we continue to treat patients in this ultra-rare indication. Total operating expenses for the quarter were $274 million, which included R&D expenses of $165 million, SG&A expenses of $87 million and cost of sales of $23 million. Operating expenses included noncash stock-based compensation of $39 million. For the quarter, the net loss was $115 million, or $1.17 per share. As of June 30, we had $539 million in cash, cash equivalents and marketable securities, which included $80 million of net proceeds raised through our ATM facility. For the 3 months ended June 30, 2025, net cash used in operations was $108 million. In total, for the 6 months ended June 30, 2025, it was $275 million. We now expect 2025 net cash used in operations to modestly increase compared to 2024, primarily driven by timing delays associated with UX111, DTX401 and UX143. We remain on our path to GAAP profitability in 2027, and we'll continue to focus on growing revenues and rigorously prioritizing our spend, including stopping and delaying certain expenses prior to upcoming potential commercial launches. Shifting to revenue guidance for 2025, we are reaffirming the guidance we provided in February and May. Total revenue is expected to be between $640 million and $670 million, which represents 14% to 20% growth over 2024. Crysvita revenue is expected to be between $460 million and $480 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. This range represents 12% to 17% growth over 2024. Dojolvi revenue is expected to be between $90 million and $100 million, which represents 2% to 14% growth over 2024.

Thank you, Howard, and good afternoon, everyone. I'll start with GTX-102 for the treatment of Angelman syndrome. As Emil mentioned, we completed enrollment in the Phase III Aspire study ahead of initial expectations. Enrolling 129 patients across 6 countries in a randomized controlled study in 7 months is a remarkable accomplishment. This would not have been possible without the incredible dedication and support from the Angelman community, study site teams and investigators. The accelerated enrollment of the Phase III study underscores the urgent need and strong desire for an effective treatment for these patients. We will now shift our enrollment efforts to the Aurora study that will target younger and older patients and those with other genotypes. This study is open label and intended to provide supportive information on safety and efficacy in this expanded patient population. The protocol has been finalized, and we expect to begin enrollment in the second half of this year. Data from this ongoing study will be included in approval filings after successful completion of the Phase III Aspire study. Shifting to UX111 for the treatment of MPS IIIA or Sanfilippo syndrome type A. We received a complete response letter for our BLA filing last month, and we are actively working with the FDA to resolve the observations through a planned Type A meeting that should lead to an understanding of what is required for refiling of the BLA. Once resolution has been achieved, we expect to resubmit the BLA and anticipate an up to 6-month review. I think it's important to note that the clinical review has been ongoing and that the FDA acknowledged at the late-cycle review meeting that the neurodevelopmental outcome data is robust and that the biomarker data provided additional supportive evidence. The CRL did not note any review issues related to the clinical data package nor comment on the clinical inspection. There is a request for updated clinical data for specific clinical and biomarker endpoints and safety to be included in the resubmission. Next, DTX401 for the treatment of glycogen storage disease type Ia, where we are now on track to submit a BLA in the fourth quarter of this year. We have been working on the BLA over the last couple of quarters and the nonclinical and clinical sections are ready to submit. We want to proactively resolve any relevant CMC and facility questions that derive from the UX111 CRL that could possibly impact the DTX401 submission before we finalize the CMC section of the BLA. We expect to resolve the observations over the next few months and then finalize the BLA submission. Finally, UX701 for the treatment of Wilson disease. Recall, we are in the dose-finding stage of the study. In Cohort 4, we are evaluating a dose of 4.0e13. All patients in this cohort will receive immunomodulation therapy with rituximab and tacrolimus, in addition to the prophylactic oral corticosteroid regimen patients in Cohorts 1 through 3 received. Enrollment and dosing in Cohort 4 is underway, and we expect to complete enrollment in the next month or 2. I'll now turn the call back to Emil to provide some closing remarks.

Thank you, Eric. I'll quickly recap the milestones and catalysts over the second half of the year. For UX143 in osteogenesis imperfecta, we expect to have top line data from the final analyses of the Orbit and Cosmic studies around the end of the year. For GTX-102 in Angelman syndrome, we'll continue treating patients in the 48-week Aspire study and we will begin enrollment in support of the Aurora study in the second half of 2025. For UX701 in Wilson, we'll complete enrollment of the fourth cohort in the next couple of months. We expect to make a determination on the Stage 2 dose in 2026. For UX111 in Sanfilippo syndrome, we are working toward a Type A meeting with the FDA to get agreement on our plan to resolve their observations, which we believe we can address. Following this, we would work through agreements to resubmit the BLA, which will be followed by a review period that could take up to 6 months. Lastly, for DTX401 in GSDIa, the BLA submission is on track and should be submitted in the fourth quarter. These last 15 years at Ultragenyx have been incredibly fulfilling, and yet the best is still to come. While the news of last month did delay our approval for UX111 and didn't accelerate the OI program, we're confident in the strong portfolio we have to build our future. Over the next 6 months, we expect to continue growing revenue, tightly manage expenses and cash burn while we maintain our path to profitability in 2027. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Our first question comes from Joseph Schwartz with Leerink Partners.

This is Will on for Joe. Congrats on the progress this quarter. So one for us. Considering the leadership at the agency has been rather fluid lately, could you provide a glimpse into any of your recent FDA interactions, especially at CBER? Are you noticing any meaningful changes in messaging and/or the folks that you're interacting with? Just trying to get a sense for how impactful these headlines we've all been seeing are on a day-to-day interaction basis for Ultragenyx.

Well, I think our interactions since the CRL of late have been good. I think they are productive, and we're working toward getting our Type A meeting package sent in. So we're pleased with how things are going. I know they're under a lot of duress at the agency, a lot of turmoil and change, but things have been going well. We're pleased with the progress so far.

Our next question comes from the line of Joon Lee with Truist Securities.

This is Mehdi on for Joon. Given GTX-102 and rugonersen both use LNA chemistry, could you please elaborate on nontarget site-dependent factors that drive very different dosing regimens that you both have for these drugs?

The LNA chemistry we're using is selected mainly because it is significantly more potent. While it may have more toxicities, its potency is considerably better for the target, at least an order of magnitude or more compared to non-LNA chemistry. This choice is intentional, as we believe the potency allows for dosing in the 5- to 14-milligram range, which is advantageous because it results in fewer non-target side effects due to the lower chemical concentration. Comparing different molecules is challenging; for example, rugonersen and the version from Roche both utilize LNA, while the one from Ionis employs a different chemistry. Each chemistry comes with its own pros and cons. We are confident that the LNA strategy for this target provides us with much greater potency and a better therapeutic window, which we believe explains the positive outcomes we've observed in our program so far and the receipt of Breakthrough Therapy designation following the FDA's review of our data.

Our next question comes from the line of Gena Wang with Barclays.

I have a 2 stats question. The first one is regarding the Cosmic trial. Emil, maybe can you remind us what's the reason to run the Cosmic trial? And then what is your assumption for the bisphosphonate arm? And if the trial fails but Orbit is positive, how do you see the payer and the physician uptake of the drug? My second question, if I may, just also very quick stats question regarding Phase III Aspire. Your secondary endpoint, you allocate 10% of alpha. Just want to confirm, is that the 0.005? And why isn't it statistically hierarchy to have a full 0.05 alpha allocated for the secondary endpoint?

Thank you for your detailed questions. The Cosmic study aims to examine young patients with severe disease who are unable to participate in a placebo-controlled trial. These patients are currently on bisphosphonates, and we're randomizing some of them to continue on this treatment while others will switch to our drug. We did not anticipate any changes in the fracture rate for those on bisphosphonates but rather assumed they would remain stable. Our goal is to achieve a 50% improvement in outcomes. While a head-to-head trial might typically have less statistical power, the narrow population of young patients who respond quickly to our drug may actually enhance the study's outcomes. We are hopeful for success, and even if the study only shows a difference, it can still provide supporting evidence for this age group and help validate our drug against bisphosphonates. We are confident that the combination mechanism of our drug will outperform the variable response seen with bisphosphonates, and we want to provide data to demonstrate that setrusumab is superior. In the Aspire study, we have allocated 90% of the power to the Bayley score and 10% to the key secondary endpoint, the MDRI. This allocation reflects the strong statistical significance of the MDRI, which does not require as much power. Our plan allows for either endpoint to be successful independently, providing a more secure statistical approach. We believe the MDRI method, which is new for the FDA, will be a leading way to assess complex neurological developmental disorders, and we are eager to showcase its effectiveness in this study.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

Emil, for the third and final read for Orbit, there's some debate among investors regarding whether the statistical significance at 18 months will make the level of clinical benefit matter more than it did at 12 months. The argument is that if it takes this long to show separation from bisphosphonates, how much better is it compared to them? I'd like to hear your views on how you think doctors would perceive this argument. Does it matter, as long as it's statistically significant, how much separation is observed at the 18-month time point?

Yes. Thanks, Tazeen. I think if you look at the treatment effect estimate, the difference between patients, I think you could have the same difference. But because of more variation, it just might take longer to separate the groups, but the treatment effect size could very well be the same. But we have to caution people that if it's 60%, 67%, 40%, 50%, in this range, it is substantially better than what's certainly observed. I don't think that, that percent number is going to have a dramatic impact exactly on what happens. I think any number in that range is a strong benefit to patients. What we can see from Phase II though is that the effect on functional ability and other aspects of the patient's health is substantial. That is what's going to drive the benefit. To give you the parallel, Tazeen, I always talk about the XLH, the Crysvita story, we had an RSS score. It was a primary endpoint, but there's no patient looking at the RSS score change percent telling us whether they're going to put the kid on the drug or not. The truth is that proves that it does improve rickets. But the reason it was so successful is the patients feel great, are more functional, more active, just like we're seeing with OI. That's what drives prescriptions. That's what drives patient demand. The numbers we have to hit, we will hit the numbers. I think the thing in utilization will come from the overall benefit. We think what we're seeing in Phase II makes this drug at least as good as Crysvita and its effect on OI. So that's why we're confident about where it goes.

Our next question comes from the line of Anupam Rama with JPMorgan.

This is Billy on for Anupam. Just while appreciating the FDA acknowledged that the neurodevelopmental outcomes data are robust and the biomarker data are supportive evidence, what additional clinical data is likely to be included in the resubmission? Is this more kind of longer duration data we're thinking or additional biomarkers that would be asked for?

Yes, they specifically requested an update on the clinical endpoint data and the biomarker data since some time has passed. They wanted the latest information we have, which we do have. Patients continue to participate in the study, so we will gather their Bayley data and Vineland data, which are the developmental data they view as robust. We will also include any CSF biomarker data we have in that assessment as requested. This update will primarily focus on the ongoing data, and given the time that has elapsed, they would like to ensure that everything is proceeding as we expect. We believe the patients are doing well, and it will be considered a standard update of the clinical data.

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

For the Orbit study reading out later this year, I know you still have very high conviction in the trial being successful. But I wanted to talk about a hypothetical scenario where maybe the fracture data falls slightly under what you were hoping for, but you see really strong benefits on pain. Do you still think that there is a strong case to make for the FDA here? Could you argue that this will drive higher adoption for patients since they deal with this on a daily basis over the fracture aspects?

Well, I think that your point is maybe there's some variation in fractures, and you just missed that, and you have other supportive data. I think the FDA will always look at the totality of the data in our rare disease program. We've had that many times in many programs. Our sense here is that we're seeing a fundamental mechanistic effect on bone mineral density; the effect it has on fractures depends on how many fractures that patient has in their particular condition. We have a lot more Type IIIs and Type IVs in the study. They have a lot of complex problems, and I'm sure that the support of other data would help us in any situation, whatever the statistical or treatment size is. And that's just generally been the case. We feel confident what the fracture data will be, what it is. We're seeing what's going on in Phase II. We know that as time goes on, there's very few fractures among patients after they've established on the treatment. We feel good we'll be able to do that. Hypothetically, I think the data will always be more than just fractures in this disease state. The body of data we have, we think, will support its use, however we come out with on fractures.

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

I just had a clarifying question, firstly, regarding GSDIa and the filing. I think Eric, you mentioned that you were making sure that you wanted to resolve any of the outstanding CMC issues on 111 before submitting GSDIa. Could you just clarify, is there a specific question that you're trying to answer on CMC related to GSDIa by virtue of clarifying something on UX111? Or is this simply just a matter of taking extra precaution to make sure that you've got everything right before filing the GSDIa BLA?

Eric, did you want to answer that? Or would you like me to answer that?

I'll give it a shot, and certainly happy for the follow-up. But it's important to remember that the manufacturing facility up in Bedford is producing the gene therapy for MPS IIIA as well as for GSDIa. So any findings related to that manufacturing facility would potentially pull through to the GSDIa. So we just want to make sure we work through all of that and any pull-throughs to GSDIa.

So. Hello? Can you hear me?

Yes. No, I think we're good. Go ahead.

Okay. I was going to say on OI, given the first 2 interims have passed and now we're looking at the final one, I'm just curious if you have any updated thoughts as far as what you believe the expected placebo AFR would be. Obviously, we've done some work, and there are a number of epidemiologic studies out there, both in Scandinavia as well as the United States, which point to various ranges for AFR. I'm just wondering if you could comment on what you believe would be the most likely scenario at this point as well as on some of the more specific aspects of the statistics again regarding this concept of variance or overdispersion which, as we know, is a feature of this particular dataset given the way the fractures are distributed.

Yes. We are aware of the annualized fracture rate reported in the literature. Based on the available natural history data from the principal investigators, we utilized much of the pretreatment data as a baseline for both the Orbit and Cosmic studies to inform our modeling. We specifically focused on patients with a baseline annualized fracture rate between 0.72 and 1 to support our interim analysis and the primary efficacy analysis period at 18 months. Although we did not modify the entry criteria for Orbit Phase II transitioning into Orbit Phase III, the Phase II data showed a natural increase in patients with Type IIIs and IVs. These patients required strong safety and efficacy data to justify the risks associated with attending clinics to consent and begin participation in the study. Therefore, there is a higher number of patients with Type III and Type IV osteogenesis imperfecta in the Phase III Orbit study compared to Phase II.

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

This is Tommie on for Salveen. How are you thinking about the bar for the Angelman data next year, both from a regulatory and competitive standpoint? And wondering if you've received any updated feedback about the use of Bayley-4 as a primary endpoint.

Yes, Eric, would you like to take it? Please go ahead.

No, sorry, Emil. I didn't know if you guys were back online or not. But again, I guess I'll give it a start and you can certainly jump in. But the bar, I think, for Angelman, it hasn't moved for us. So certainly, we had our interactions with the FDA. We do feel like we have full buy-in with the study there. We do work through our statistical analysis plans with them as well, so have been in communication with them. Again, following back to the data we generated in Phase II, and that was quite a few number of patients there who continue to see the attainment of new developmental skills over time. We are not seeing a plateau effect; we are seeing them continue to gain new abilities, and that's very important to them and their parents. We have a lot of confidence in our primary endpoint with Bayley cognition. Again, cognition is foundational to everything else you're looking at there, whether it be expressive language, receptive language, motor or anything else there. It is foundational and we think an appropriate endpoint. Again, we talked about using MDRI and really being an ideal tool for these type of indications because you're really looking at all of these aspects on a very straightforward transparent scoring system to really look at the benefit in totality and allowing some variability between individual patients. So again, I think that rapid enrollment and really, it's not just 129 patients over 7 months, it's 129 patients in a very complex study. And that really speaks to the enthusiasm with sites, with patients and their families to really gain access to this therapy.

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

I was just wondering, can you elaborate a bit on how PRV proceeds are being factored into your path to 2027 GAAP profitability? Any insights into your relative confidence in receiving all 3 PRVs?

Yes. Well, obviously, PRVs are an important part of it, and I'll let Howard maybe talk through that, the PRVs and how we're working them into our cash plan.

Yes. We have PRVs from 3 of our programs, so 111, 401, and 143 factored in. There has been a shift in timing on those, but we still think all of them come through. So yes, I think that's where I'll stop.

Yes. If it's reauthorized, it simplifies the process for the first one. However, if it isn’t, we are confident that the other two will still be completed in time and we anticipate their value will be greater. Overall, whether we have three with reauthorization or just two without it, we believe our total cash position will remain unchanged.

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

This is Jaena on for Yaron. Congrats on the quarter. You noticed that there's going to be more of a prioritization on controlling spend, including stopping and delaying certain expenses. Can you give us some more granularity about what this entails? And are you exploring any options in the event that responding to the CRL for UX111 takes longer than expected?

Yes, thank you. We are focusing on practical aspects right now, and perhaps Howard can elaborate on this. Our goal regarding the CRL is to progress effectively. We have reviewed the entire list and received considerable feedback, and we have already implemented many changes. Therefore, we believe there is nothing on the list that cannot be accomplished; they are manageable tasks. We are actively addressing them, so we are not anticipating any issues in completing this process. We are confident it will be finalized. Thus far, we feel the FDA has been responsive during our discussions. Howard, can you share how we are managing costs?

Yes. Our goal has been and remains to be GAAP profitable, full-year GAAP profitable in 2027. How you get there, of course, is continuing to grow the top line, but also making sure that we are good stewards of our cash. With some of the delays that we've experienced this summer, we did the natural thing, which is to delay those expenses and make sure we're being prudent and using our funds well.

Yes, it involves not hiring individuals that would have been brought on for launches and managing other staffing needs. Additionally, we are thoroughly reviewing all expenditures that should be postponed rather than continuing to push forward without hesitation. We hope this approach will guide us to a point where we can secure funds and manage our current situation. It is a wise part of overseeing the company in these circumstances, and we have successfully navigated similar challenges before. Thus, we are quite adept at making the necessary adjustments.

Our next question comes from the line of Sami Corwin with William Blair.

Congrats on the progress. I had one on UX111 and then a broader question on your AAV platform. Do you think that the CBER leadership change will be helpful or hinder the CRL resolution for UX111? And then given the recent safety events with systemically administered AAV, are you thinking about modifying your immunosuppression regimens at all? Or are there any additional precautions you've implemented to decrease the risk of AAV-related serious adverse events?

So look, I think there's a lot of very good people at FDA. They're still there doing their jobs. Our sense is that they won't impact their ability to do their jobs. I think in some ways, it might be simpler for the next period because of the team that's head down in the work can do their job and work with us in solving these things. I think it'll stick to a very practical, matter-of-fact, line-by-line resolution of issues raised. I think it's very doable without having high-level leadership for these kinds of things, these kinds of resolutions, because the clinical data were felt to be robust and strong, and there's a little less uncertainty in judgment because the safety was excellent. There's no real question marks there. It's really more about getting the things, boxes checked on all the CMC pieces, which we think we can do. We're not so concerned about leadership for that particular aspect of it. With regard to the AAV platform, we're highly supportive of the AAV as a treatment strategy. We obviously have a lot of investment in it. For many of the liver-targeted ones, we're doing at relatively lower doses compared to others; we have not seen substantial safety issues like you're talking about, either death or very serious liver complications. The lower dose that we use, we think, are in a very safe range, and we feel very good on them. Now we are looking at enhancing immunomodulation, but it is more about trying to alter or support more efficacy or managing anti-transgene responses. We are looking at that in our Cohort 4 for UX111 to try to manage the immunological responses. But if the drug works with just the simple steroids, fine. That's what we can get approved on. Our goal is always to continue to look to optimize. But it's not a central thing to try to prevent a death; it's more about trying to optimize the outcome. We will look at and be more agile looking at immunomodulation where needed. So far, we don't have any programs that are of the high-dose type that have created more complexities. If you have a lethal disease as Duchenne is or others, it is not inappropriate to have a situation that would challenge a patient. I think parents should have the right to make their decisions about the risk/benefit. We think that a lot of these horrible diseases are a death sentence and a horrible death sentence for families. They should be given the opportunity to make the best healthcare decision for their child. I think they can be capable of making that decision with an approved product.

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

This is Farzin on for Maury. I wanted to clarify for setrusumab. If you can provide more granular timing on the Street disclosure, like the last patient visit should be end of October. So it sounds like there will be no DMC review and you'll be unblinded to the data. So technically, it should be faster than 2 months than it took prior to?

So you'd like what day and time for the data are coming out? I'm sure we can put that out. Well, yes, the last patient, I remember, there's this whole process of getting all the last datasets, the X-rays reviewed, finalized, clean, and no issues. We have to look at it blinded to make sure there's nothing wrong, no aberrations. It's a Phase III study, so it's not something you want to rush through. It's the final assessment, so we want to make sure we do it carefully. We've been saying it's around the end of the year. It could be before the end of the year, it could be just after the end of the year; it's somewhere in there. We don't want to nail it down because, frankly, it's not possible to. We're not trying to be cagey here; we just want to make sure we allocate the time provided to get the study closed out absolutely perfectly. Every aspect of the study is perfect. We owe it to the patients and our investors to make sure that everything is perfectly correct when we go out and release data.

Makes sense. And then for the Angelman, the demand is there clearly, and these are all deletion patients. But can you talk more about the patient baseline profile relative to your Phase I/II enrolled patients? Should we expect more durability data from the Phase I/II cohort of patients, maybe this year?

Well, the patients in the Phase II and now enrolled in the Phase III are essentially the same. They're 4-to-17-year-old deletion-only patients. So they're actually identical; the same criteria were used. They are really very comparable. Whatever we saw in Phase II is probably pretty much what you should see in these Phase III patients. With the Aurora study, we're going to look at younger patients or older patients with deletion. We'll also look at patients that have missense mutations or the ICD/UPD type. We're going to gain knowledge. The idea was to gain sufficient safety data to show that you can administer the drug and then show that their efficacy, even though in an open-label format, is comparable to the effect that we'll demonstrate and prove as a cause and effect of the drug in the randomized controlled study. That's the idea on the approach we're taking. Did that answer your question? We haven't planned out right now. The team is working on 2 Phase III programs right now, and that is our focus. The last thing I want to do is put another item on their plate of running more. Patients continue to get the drug and are doing fine, and we're encouraged with it. We hadn't planned another cut of data yet. We got to get the Phase III done and do them well.

Our next question comes from the line of Jack Allen with Baird.

Congrats on the progress. I wanted to ask a couple on the setrusumab program. As it relates to Orbit, what kind of standard deviation are you seeing in any blinded data that you've seen? How confident are you in the existing statistical analysis plan that you have outlaid? And do you think there is any need to update that SAP? And then I have a quick follow-up as well.

Yes, we haven't really discussed standard deviation yet. I know people are trying to calculate dispersion, though you didn't use that term. Many are mentioning dispersion to indicate they understand statistical concepts. We're aware that everyone is doing the math for us, but we haven't released the standard deviation, and I don't have it readily available. There is a significant amount of variation, as we've noted that about one-third of the patients had fracture rates at baseline of 3 or above, with two-thirds below that. Our age range spans from 5 to 25 years old, which adds to the variability. These factors all contribute to the standard deviation for both the actual fracture rates and bone mineral density responses. We are confident in the statistical analysis plan because the negative binomial model is indeed the best method to analyze this type of fracture data. I even conducted a brief search using AI, which you could try as well, and it confirms that the negative binomial approach is the most effective one according to research comparisons. There are various details involved, such as which covariates to include that influence variation, allowing for adjustments in the model. In any statistical plan, it's common to incorporate some flexibility regarding the covariates used to account for variations not related to the treatment effect. This ensures we obtain accurate results.

Great. Great. That's super helpful context. And then you did mention that the Phase II seems to be demonstrating a very durable effect and even a deepening of response over time, at least that's how I would characterize some of your earlier comments from setrusumab. I just wanted to ask if there are any plans to present updated data from the Phase II cohort of 24 patients and when we may see that dataset, if there are plans?

Well, we don't have plans yet. The study is ongoing. The patients are doing really well, and we can consider doing that at some point. We haven't made a specific plan yet to do it.

Our next question comes from the line of Hannah Wei with Guggenheim Partners.

This is Hannah for Debjit. We have a question regarding OI program. Could you clarify which bisphosphonate therapy for patients were on before entering the Orbit study? And roughly, how many patients were on request?

Yes. We haven't disclosed which bisphosphonate on, but we have said the vast majority; I think it's greater than 90%, have had bisphosphonates on board, like a large fraction. So it's primarily because it's enrolling patients with a higher fracture rate, the higher ones are in the study. The fraction that had been on bisphosphonates was, I think, above 90%. But we haven't said which ones. It's several different ones, so it wouldn't help you.

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

This is Dan speaking on behalf of Ram. Congratulations on exceeding expectations. Have you heard anything noteworthy from Kirin regarding the U.S. or Canadian Crysvita markets? The royalties seemed relatively flat on a year-over-year basis in Q1 but increased by over 17% in Q2 compared to the previous year. Can you explain this? How much of that increase do you anticipate will be sustainable in future year-over-year quarter comparisons?

Yes. Well, I think there's always a little bit of lumpiness in those regions because of how they're ordering and buying. I haven't any particular explanation. I don't know, Erik, if there is something of insight that you have, but I think there's just regional lumpiness when the governments are managing what goes on.

Yes. No, we think the underlying demand has been pretty consistent and pull-through. As Emil mentioned, the ordering patterns have just been a little lumpy.

Yes. We're not providing more details than that.

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

This is Shelby on for Luca. Emil, we have heard you in recent interviews noting that the FDA asked for things like more probes in your shipping validation for the Sanfilippo CRL as well as an inspector who was particularly stringent with his review. Can you expand on that? And then maybe bigger picture, can you share your opinion on whether you think the FDA is missing the forest for the trees here? Any color there much appreciated.

Well, I think one of the FDA's jobs is actually to check every tree in the forest. That's part of the rigor of the process. If there's a CRL, it has a lot of bits and pieces because there are a lot of bits and pieces. I think I'd say these are all things that need to get taken care of, and there are lots of parts and pieces to it. I think they're doing their job with regard to that detail. Should it be a CRL or could we have done it in time? Those are questions you could ask, but we're going to do the work they ask for. We're doing them, and I think we'll be able to work that out with the agency and get it done. FDA has to focus on certain details; it's part of the rigor they apply, and we appreciate that. Particularly in CMC, rigor is essential, and there are reasons for a lot of things that have happened. We're going to comply and improve what we can with everything we do.

And ladies and gentlemen, we have reached the end of the question-and-answer session. I'll now turn the call back over to Joshua Higa for closing remarks.

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