Good afternoon and welcome to the Ultragenyx Third 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. It is 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 Kakkis, Chief Executive Officer and President, Howard Horn, Chief Financial Officer, Erik Harris, Chief Commercial Officer, and Eric Crombez, Chief Medical Officer. I would 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 will now turn the call over to Emil.
Thanks, Josh, and good afternoon, everyone. The third quarter was a significant one for Ultragenyx in many ways. In August and September, the FDA approved GENGLYCOS for glycogen storage disease type Ia and FAYUVI for Sanfilippo syndrome type A. These approvals are the result of years of work by our teams and the original scientists, as well as the families, patients, and investigators who took part in the studies. We also saw the disappointing data from the GTX-102 phase III that surprised us, despite compelling phase II data, which now has necessitated significant reductions across the company. These actions will bring our cost structure in line with our revenue. This enables us to be well-positioned to continue commercializing our six products for patients with rare diseases and thoughtfully invest in our development programs, all while becoming a profitable company next year.
While the clinical study miss on an important program that could have created great value has challenged us, we should recognize all that the company has successfully accomplished in its 12 years as a public company. We now have six product approvals for the first-ever treatment indications across multiple treatment modalities and are driving revenue growth globally of about 20% per year for multiple years, heading to a $1 billion+ in revenue and profitability. While today we acknowledge a setback, when I started the company with $2 million and a secretary, I would have been surprised and inspired to know that we had become a highly respected and admired team of a thousand professionals treating thousands of patients with rare and ultra-rare diseases worldwide.
There is more work to do, and we will today outline the steps we are taking to move the company to its next stage as a profitable company driving commercialization and development of first-ever treatments for rare diseases. To begin with, I'll focus on the launch of our two new gene therapy products. Both these products provide meaningful and transformative options for these rare disease patients and their families. For people living with glycogen storage disease type Ia, managing the disease means taking cornstarch every few hours, day and night, because a missed dose can lead to potentially life-threatening hypoglycemia. GENGLYCOS is the first FDA-approved treatment option for these patients and has the potential to reduce their dependence on cornstarch, easing the constant burden of care that defines their lives.
The second approval we received in the quarter was for Sanfilippo syndrome type A, which is a fatal neurologic disease that begins in early childhood. At birth, these children appear normal, achieving development milestones just like their peers. This continues for the first months, but then stops, and over the next few years, as the children progressively lose cognition, language, and motor function until they become unresponsive and bedridden for years before death. Until now, families affected by Sanfilippo syndrome type A have had no approved therapy. FAYUVI is now available to these families as a single IV infusion done as an outpatient, giving them an option to meaningfully change their children's future. This is the hope that gene therapy was supposed to provide. These approvals come at a time that our clinical study failed to prove efficacy with GTX-102 for Angelman syndrome.
Despite having some cases with transformative changes in phase II, which creates such a strong bond between us and the community, this result required us to discontinue the clinical program. It also necessitated a comprehensive review of all our expenses and priorities, with the goal of reducing our operating costs to be in line with our revenue to achieve meaningful profitability now and in the future, while still growing our business. Reduction expenses and ending a program necessarily includes actions to substantially reduce our workforce, and we are deeply grateful for the contribution of those who are impacted and are committed to providing support and resources to them during this transition. While this process was ongoing, we evaluated our UX701 gene therapy for Wilson disease and found it did not meet our criteria to advance to phase III.
Given the need to further reduce expenses, we've also made the decision to terminate the UX701 program for Wilson disease rather than try to pursue improvements. The dose finding data, including data from cohort four, showed clinical activity in some patients, but we did not observe a majority of patients achieve a sufficient biochemical response and eliminate standard of care therapy. UX701 demonstrated a favorable safety profile across all cohorts dosed. I do believe there are patients who had meaningful benefits, including some coming off their chelators and zinc therapy after receiving UX701. I also believe that gene therapy is a rational approach to treating Wilson disease better than it is treated today. Unfortunately, we are not able to continue investing to optimize the product for Wilson disease.
We are working with clinical sites and patient advocacy groups to support study participants and the broader Wilson community through this transition. We expect to present the data from the completed study at an upcoming medical or scientific congress to ensure our learnings are available to the broader community. We thank all the patients and investigators for their contributions to the program. These were not easy decisions, but they position us to focus on launching GENGLYCOS and FAYUVI well, continuing to grow our base of commercial products, and achieving profitability in 2027 and going forward. Becoming a self-sustaining company will support our ambition to lead the future of rare disease medicine. I will now turn the call over to Chief Financial Officer Howard Horn, who will provide the detail on our expense reductions and our profitability.
Thank you, Emil, and good afternoon, everyone. The details of our third quarter financials are available in our press release, and I am happy to address any questions on them during Q&A. Today, my comments will focus on guidance for 2026 and 2027, including more details and rationale on the expense reductions Emil just mentioned and our expectations for profitability. Starting with 2026 guidance, we are reaffirming our 2026 revenue guidance, specifically that we expect total 2026 revenue of $730 million-$760 million, which, as a reminder, excludes revenue from the launches of FAYUVI and GENGLYCOS, CRYSVITA 2026 revenue of $500 million-$520 million, and DOJOLVI 2026 revenue of $100 million-$110 million. We are also reaffirming our expectation that 2026 combined R&D and SG&A expenses will be flat to down low single digits versus 2025.
This includes the impact of all of our expense reductions, as well as $30 million in severance and other non-recurring restructuring charges from the first half of the year, and approximately $25 million in severance and other non-recurring restructuring charges expected to impact the fourth quarter of the year. Shifting now to 2027 guidance. Consistent with our prior practice, we expect to provide full-year 2027 revenue guidance early in the new year. For 2027 expenses, we expect R&D expenses will be less than $350 million, representing a reduction of more than 50% from 2025 levels, and we expect the majority of our 2027 R&D will be in support of our commercial products. We expect 2027 SG&A expenses will be less than $375 million, representing an increase of up to 7% from 2025 levels. These R&D and SG&A expense expectations reflect meaningful spend reductions from our previous guidance.
To achieve these targets, we have initiated substantial headcount and expense reductions. Actions we are implementing include reducing our headcount by approximately 20%, resulting in a revised workforce of approximately 1,000 employees, promptly completing the wind-down of all ongoing studies and related spend for GTX-102 for Angelman syndrome, terminating UX701 for Wilson disease, and reducing expenses across the company, including reducing our real estate footprint and right-sizing G&A expenses to fit our new profile. Spending in 2027 will be focused on our commercial efforts and our smaller targeted R&D footprint, including completing the phase III study for DTX301 for OTC deficiency, determining the path forward for UX143 for osteogenesis imperfecta, and measured spending to progress early-stage programs for future INDs. Today, we are also reaffirming our expectation to achieve full-year GAAP net income profitability in 2027 and expect to generate positive cash flow from operating activities for the year.
The factors underlying our ability to achieve 2027 profitability are the same as I outlined on our call in August: continued revenue growth from our four existing products, plus contributions from our new gene therapy launches, and disciplined expense management and capital allocation, as we just discussed. Additionally, in October, we strengthened our balance sheet with non-dilutive capital through the sale of our two PRVs. The first transaction closed last week, and we expect the second to close before the end of the month. Net proceeds total approximately $350 million after shared payments to licensors and fees, and will be reflected as other income in our 2026 financial statements. Our projected profitability in 2027 is driven by our underlying business and does not include income from PRVs. Importantly, we now have the cash needed to reach profitability without the need for additional fundraising.
Achieving and sustaining profitability has been a central goal of the company, and we're grateful to be in a position to deliver it. Finally, in closing, reductions in force are one of the most challenging parts of operating a business, and I want to echo Emil's earlier comments of gratitude to our departing colleagues for their contributions to Ultragenyx. With that, I'll turn the call to our Chief Commercial Officer, Erik Harris, to provide more detail on the performance of our current products and our two launches.
Thank you, and good afternoon, everyone. It has been an exciting few months for our commercial team, with the approvals of GENGLYCOS in August and FAYUVI in September, bringing our fifth and sixth approved medicines to patients and our first two gene therapies. Our teams have spent years preparing for this moment, and I'm pleased by how seamlessly they moved from approval to launch, initiating the process to reach the patients and families who have been waiting for these treatments. I'll begin with an update on the gene therapy launches and then turn to the performance of our established products. In the U.S., the field team leading the launch of GENGLYCOS and FAYUVI is the same team which has been in place for years supporting DOJOLVI and MEPSEVII. Their strong relationships and experience calling on medical geneticists at the centers is a significant advantage as these launches ramp up.
As with other gene therapies, GENGLYCOS and FAYUVI will be administered at qualified treatment centers, or QTCs. Most of the QTCs will administer both gene therapies. As of the end of October, we have 35 QTCs active, and we are on track to exceed our target of 40 QTCs by year-end. This network is critical to meeting the demand we expect for both products. In a few short weeks since these approvals, our team has already seen meaningful demand for both GENGLYCOS and FAYUVI, with a significant number of enrollment forms in hand, confirming the high unmet need Emil mentioned. Early feedback from KOLs has been very positive, with genuine enthusiasm from physicians who have been awaiting an approved treatment option for their patients.
As is typical with newly approved FDA treatments, coverage decisions during the initial launch period will generally be made on an individual patient basis, with timing and requirements varying by payer. We anticipate broad payer coverage, although individual approvals may take additional time early in the launch. Our UltraCare Gene Therapy Guide team has helped the first patients and families navigate coverage, with a number currently scheduled for infusions with approved reimbursed therapy. We look forward to providing more updates on QTC activation, payer coverage, and most importantly, patients treated on future calls. Outside the U.S., the unmet need is equally high, and we are seeing strong interest in access to FAYUVI parallel to the U.S. launch, and we are pursuing formal approvals, starting with the EMA and MHRA. For GENGLYCOS, we are also seeing growing interest and are pursuing formal approvals ex-U.S.
I'll turn now to the established products and start with CRYSVITA, which over the first three quarters of the year is continuing to deliver steady growth compared to the same time period in 2025. As a reminder, our partner, Kyowa Kirin, commercializes this important product in the U.S., Canada, and Europe, while our teams commercialize in Latin America and Türkiye. Combined, there are thousands of pediatric and adult patients who have benefited from CRYSVITA. In Latin America, the underlying demand for CRYSVITA remains strong, driven by Brazil, Mexico, Argentina, and Colombia. Approximately 60 new patients began commercial therapy in the quarter, with more than 1,050 patients on commercial therapy in the region. As we have stated on prior calls, we expect that ordering patterns will create some quarter-to-quarter variability, but the underlying demand remains strong and continues to grow steadily.
In Türkiye, named patient demand continues to be strong, with patients gaining access to CRYSVITA each month. As we have seen with case-by-case reimbursements in other countries, uptake can be more gradual, but demand continues to build as HCPs and patients see the benefits this transformative therapy offers. Shifting now to DOJOLVI, the trend of steady growth continues. In North America, we have nearly 700 patients on reimbursed therapy. In EMEA, approximately 315 patients are being treated through named patient or early access programs across 14 countries. In the U.K., just last week, DOJOLVI received conditional marketing authorization for the full LC-FAOD indication, and my team is eager to begin engaging with physicians and patients in that country. In Japan, the DOJOLVI launch has been going well, exceeding our expectations.
We expect global demand for DOJOLVI will continue to grow steadily as patients and physicians gain personal experience with this important therapy and more regulatory filings are completed. Year to date, EVKEEZA has grown approximately 50% versus the same time period in 2025 and was the biggest growth story in the third quarter. In our territories outside the United States, where we are responsible for commercialization, there are more than 500 patients across more than 20 countries receiving EVKEEZA, as our teams continue to successfully progress through country-by-country reimbursement, support early access, and convert appropriate patients to reimbursed therapy. In many markets, we have market share advantage over the alternatives, and our teams continue to identify and treat more of the prevalent patient pools across the regions. We expect strong growth to continue as we unlock more demand.
In closing, we have been one of the most productive commercial organizations in rare disease. With a focused, experienced team and the right partners, we bring our medicines to patients in many countries, leveraging our existing infrastructure to launch each new product and bring important therapies to rare disease patients globally. With the addition of GENGLYCOS and FAYUVI, we now have six products and are on a growth trajectory to deliver over $1 billion of revenue as these launches build on our established portfolio. My team is energized by the opportunity to help drive profitability and future growth for Ultragenyx, and more importantly, continue to bring life-saving therapies to patients with rare diseases. With that, I'll turn the call back to Emil for some closing remarks.
Thank you, Erik. This last quarter was filled with a wide range of emotions and the hope and promise that came with the approval of two first-ever treatments, gene therapies, in fact, and the disappointment we felt for families of patients with Angelman syndrome and Wilson disease. We went through the difficult exercise to right-size all aspects of our company to ensure we can be a self-sustaining company going forward. For those employees that contributed to our success who are leaving us, we wish you all the very best, taking our culture and our spirit of compassion and drive to fight for rare disease families wherever you work in the world. Your talent and skills will still contribute to what we set out to do here at Ultragenyx. The change we're implementing now will set us up for our next stage as a profitable company in control of our future.
The freedom that comes from these financial changes will allow us to continue to lead the future of rare disease, bringing novel and transformative therapies to rare disease patients who are desperately waiting. With that, let's move on to your questions. Operator, please provide the Q&A instructions.
Thank you. We will now be conducting a question-and-answer session. Thank you. One moment while we poll for questions. Your first question comes from Maury Raycroft with Jefferies. Please proceed with your question.
Hi. Thanks for taking my question. I will ask about expenses for next year, just with the guidance for R&D being less than $350 million. You mentioned the majority of the R&D expense there would be in support of commercial products. Can you provide more granularity on what those expenses or obligations are, and are there additional levers you can pull to reduce R&D more potentially? I am wondering if there is any allocation in there for setrusumab development.
Sure. I will touch on a few things, and I will let maybe Howard go deeper into it. Within that is the setrusumab spends already included within that. Most of the expenses are coming from disease monitoring program, regulatory filings, and other things to support filing approvals. I will let Howard talk a little bit about what is in the $350 million to the extent we can at this point.
Yeah. Maury, thanks for the question. Yeah, so our guidance is to be less than $350 million, and again, that is a greater than 50% reduction versus our 2025 R&D levels, and more than the 38% guidance that I think we had given the last time we quoted it. The strategy that we articulated today is that we are focused on commercial execution and on a smaller, tighter R&D footprint. So, I think you would expect that the majority of R&D spend would be going towards that commercial footprint, and that is what we quoted today, and how we plan to address it next year.
Understood. Okay. Thanks for taking my questions.
Your next question comes from Kristen Kluska with Cantor. Please proceed with your question.
Hi, everyone. Thanks for taking the question tonight. I also had one on setrusumab. Understand that you're not in a position yet to tell us what next steps are, but maybe just based on the recent data you saw, it's clear that there's activity. Should we be thinking now that there's a greater likelihood of another trial? Is there still a potential to file on the table here? If you are to run another trial, can you walk us through some of the ways you're thinking about how to mitigate any risk for the trial, again, given that we know that there's activity? Thank you.
Thanks, Kristen. The data presented at ASBMR, I think the most salient piece of that was that in patients with greater than three fractures at baseline, that we showed a clinically meaningful reduction in fractures in that population, both in ORBIT and COSMIC. That indicates that within patients who have a higher instance of risk of fractures, there is an important benefit of the increase in bone mineral density that you see. We're not really able to describe whether we have to do another trial or not. We are looking at the pathway with the FDA right now and are making those discussions what we would do. What I think we can say is that there is clear activity in this drug, and there's great demand from the patients to stay on drug.
Our feeling is, with the biomarker data on BMD being profound and large, as well as the supportive data in things like pain, physical functioning, combined with the reduction in fractures in those with high fractures, there's, we believe, a product in there, a valuable product that we are trying to pursue. We can't really describe it because we're in the process of negotiating with FDA what that might mean, so I don't want to set any expectations at this point in time. But we do think there's a product in there. How long it will take will be one of the questions we'll have to resolve, and how much data was required. But I think we're encouraged that it is a real product for OI, and we need to figure out what's the best way to move it forward.
Thank you.
Your next question comes from Joon Lee with UBS. Please proceed with your question.
Hi. Thanks for taking our question. Your OI post-hoc analysis is really interesting. Would appreciate it if you can elaborate on why the fracture data looks better against an IV bisphosphonate than placebo. Just to follow up the prior question, in your prospective study, could that possibly be a confirmatory trial with the expectation that you could get approval based on existing data? Thank you.
Yes. What you are referring to is we did a study in the two to seven-year-old younger patients study, which were more severe that had, in fact, a higher fracture rate. So in that population, we had higher fractures than we had, and even a higher fracture in the control group, and we were able to show a bigger reduction that was statistically significant in post-hoc. So I think that is primarily driven that they are younger patients, they respond more consistently, and they had a higher fracture frequency to begin with. So there is just more to detect. I do think the fracture benefit was seen in both groups, and it is just a higher fracture subgroup in the COSMIC younger patients just was able to show that more readily, even though the number of patients, by the way, were smaller in the COSMIC subset.
So that said, I think there is potential for crossover data, but I wouldn't want to, at this point, tell you how that's going to be worked out. We have to work things through the FDA. They are working with us, and we appreciate their efforts in thinking through this, but we don't have an answer exactly yet on how to use the combination data and to get this product approved at this point.
Thank you.
Your next question comes from Yaron Werber with TD Cowen. Please proceed with your question.
Hi. This is Jane on for Yaron. I do want to kind of drill down a little bit further on setrusumab. So I know that you don't have any concrete plans or a path for whether you need to choose a new study, but theoretically speaking, if you were to pursue a kind of second confirmatory study for potential approval, do you think that this could be smaller and shorter by enriching for frequent fractures? And as you prospectively think about potential plans, what kind of a cost and timeline would be acceptable within your reduced R&D budget? And then maybe when might we expect some more clarity on kind of your go-forward decisions? Thanks so much.
Right. Well, let me start with the first part, which is any investments, as you imagine, is within the context of being profitable. It is in our project for next year and so forth. We would be operating within those constraints. We believe that is very doable at this point. If a trial is required, certainly, we would want to enrich for the higher fracture patients. It would just give us more signal to be able to see a change in fractures, and I think that would be a natural thing. We would also think about what age range you would want to include, because the younger patients have more fractures and a higher response rate. But we think the drug is probably effective in all age ranges, but we would want to figure out a path that is the smartest, highest unmet need, and so forth, that would get us to an approval.
We will provide more information when we get closer to it, but there are some things we can think about if a trial is to be conducted, what it would take, and how to enrich for the right, best population that would demonstrate the benefit. But whatever we do, those costs are built in to an assumption that we are profitable, and we will work that within those constraints.
Great. Thanks so much.
Your next question comes from Yigal Nochomovitz with Citigroup. Please proceed with your question.
Hi, this is Joohwan Kim on for Yigal. Thanks for taking our questions. For FAYUVI, just wondering, are physicians and payers interpreting preserved neurodevelopmental function similarly, or are you seeing any variation in eligibility decisions across centers or specifically across plans?
We haven't seen any issue at this point. We're still developing plans. Maybe Erik can provide a little bit more detail. Our interpretation of what preserved neurodevelopmental function meant is that the patients are not non-responsive, bedridden patients. That's a patient that has lost all neuro function. It doesn't mean that their function is normal, right? That is what the discussion was with the agency, which we think is a relatively broad label. Erik, is there any details from the policies that have been published or that you can provide at this point regarding how much is there an issue with neurocognitive function?
Yeah, the discussions have been positive and encouraging, and as expected, and the initial policies have been in line with the label.
We have not seen restrictions in terms of-.
No restrictions.
Yeah. Very good. So that's your answer at this point.
Got you. Very helpful. Just one quick one on setrusumab. Just wondering, should we think of the upcoming decision as a primarily go or no-go decision on another prospective study, or are you also evaluating intermediate steps or studies that could help improve confidence before committing to a full trial?
Well, I would rather not call it go, no-go. I think there's a lot of complexities to it. I think it's more a question of what's the best way forward to take a drug that we think has demonstrated a meaningful effect on the bones of these OI patients and how do we get to clinic? So, I wouldn't look at it as go, no-go exactly. It's a little bit more of what's the best and fastest way to get the product through to patients.
Understood. Thank you very much.
Your next question comes from Ellie Merle with Barclays. Please proceed with your question.
Ellie, we can't hear you. You might be on mute. Give you a second to respond.
Hi. Can you hear me now?
Loud and clear. Go ahead.
Okay, wonderful. Thank you. This is Jasmine on for Ellie. Thanks for taking our question. I just wanted to ask, can you comment on the expected cadence of the launches for both GENGLYCOS and FAYUVI? Should we think about a potential bolus for either from pent-up demand, and how does this pace look like for both in the first few quarters? To date, have you treated any patients yet with either? Thank you.
Yeah. I think, let's talk about or start with FAYUVI. For FAYUVI, where kids are losing their brain every month, and there's families that have been waiting and waiting for this treatment, there's definitely a larger urgent drive to get on drug immediately. We'd expect some level of a surge initially, but we think what will happen is we'll start adding additional territories with the product, which will continue that. While you're thinking of just the U.S., you should really think of this as global. We already have a lot of international requests for treatment as well. I think that that will end up probably spreading out the overall utilization of the drug, even though I think there will be some degree of a bolus. For GENGLYCOS, we expect it to develop a little more methodically, not as urgently.
The patients do have a treatment, it's just a question of crossing over to something that would make their lives better and perhaps provide less risk that they can have a crash and burn event. I forgot what the last-.
GENGLYCOS launch curve?
That's the one I just did.
Treated patients?
Oh, yeah, treated patients. Well, we've begun the process of treating patients. We have multiple set up and so forth. We're not going to provide any great detail exactly, but we're encouraged that things are getting lined up and going, so we're pretty happy about how it started.
Okay. Helpful. Thank you.
Your next question comes from Tazeen Ahmad with Bank of America. Please proceed with your question.
Hi. Thanks for taking my question. One more on Sanfilippo. How do you see the competitive landscape evolving? There could be another company launching their own product, maybe as early as the end of next year. Based on your analysis of market opportunity, how many patients do you think you'd be able to convert onto your therapy, let's say, over the next 12 months? Just a general sense of it. If there is another entrant, what would you say the advantages of your product are relative to what they're saying? Thanks.
Yeah, thanks. I think there's at least a couple competitor projects. One is the enzyme replacement, the Denali product, and then there's another, which is a lentivirus gene therapy. I think our product has the distinct advantage of being a single IV infusion, and if you ever had a little kid and you have to go get lots of infusions in them or put them through a bone marrow transplant type thing, going to the hospital and getting a single infusion and then going home, it's just a much lower bar, much lower risk, in our view. We see the kind of long-term data that none of the other programs have. That is, we have eight years of durable data, and we think an excellent safety profile. So, right now, we feel like we're in the best position that a single infusion is going to be the best.
We're always look at the degree of efficacy, other things that people may raise questions about, and are continuously looking at how to continue to improve our product. But right now, we feel that what we're offering is probably the best choice for most families, and particularly if you have little kids that are very small. I haven't really talked through what we think how many patients we're going to treat. It's really not the right moment for that. We'll provide update on how we're going early in January in terms of how many start forms and so forth. But we're in position, we think, to do extremely well with Vyondys. I think that the simplicity of the treatment, the reduction in medical interventions required, I think will be kinds of things that will be appreciated from families. Thank you, Tazeen.
Your next question comes from Anupam Rama with JPMorgan. Please proceed with your question.
Hi. This is Duke Tells for Anupam Rama at JPMorgan. Thank you for taking our question. You talked a bit about what you are seeing in the Wilson disease program, but could you walk us through your decision to discontinue it, please?
Yes. We had set the standard that in order to invest for a phase III program, we wanted to see the majority of patients achieve the biochemical impact and standard care withdrawal that gave us confidence that their body is sufficiently changed with regard to copper metabolism to justify a gene therapy. While we saw some patients that were able to do that, it wasn't the majority. At this point, given our need to manage expenses, it didn't feel that spending a large amount of money chasing this down was going to be the best moment for it. I believe the gene therapy is a good strategy for Wilson. There may be some time where we come back to it, but at this moment, we need to get ourselves into a more financially controlled place, manage our expenses, and put us in position to control our future better.
While I think Wilson is a good indication, I think right now there is still more work to be done before a gene therapy would be ready to do what we want to see, which is a real complete change in copper metabolism that would give these patients a real future that is a healthier future than what they have today.
Great. Thank you so much.
Your next question comes from Maxwell Skor with Morgan Stanley. Please proceed with your question.
Great. Thank you very much for taking my question. Longer term, could you help us understand directionally where we can expect R&D spend to go? Then just one quick follow-up if I could. On Angelman, can you provide any additional information on what drove the miss? Thank you.
Yeah. Directionally, R&D, look, we had a very full pipeline. We had four or five phase III programs simultaneously, which is a very big set. Right now, we have a program that has two phase III programs and some early-stage program, and we have some other potential INDs we would file, things that we've been holding back on. Our plan is to operate in a more narrowed, focused footprint within the confines of profitability and to maintain something like five programs a year, which is where I think we can do sustainably within a profitable company. We'll be able to add new things to the clinic. We'll be looking up, but we'll be operating within the context of controlling spend and not breaking through on our profitability commitment.
Now, with regard to Angelman, we will be presenting data soon to talk about it, but basically, there was too much variation within the control group to be able to tell or distinguish their change, and it was across multiple endpoints, not any particular endpoint. We think there's a number of things to consider. We think that if you look at our phase II patients, that over a three-to-five-year period, some of these patients do have transformative benefit, but when you look at the breadth of patients in a randomized trial, it's only one year in length, we're not seeing a distinctive separation on multiple endpoints. So, we think there's more to do. We believe Angelman is a good target, and we think the strategy is a good strategy. What we did was just not enough to get us where we need to go.
At this point, there are a lot of options being developed for Angelman and strategies out there, and we think the community will continue to work through this. But at this point, there's just too much variability in the various endpoints to be able to distinctly prove an effect. Given the cost of the program and our need to get our costs in line, we felt the better strategy right now is to shrink R&D footprint and get us focused on the ones that we have that are working and put ourselves in position to control our future more accurately.
Thank you very much.
Your next question comes from Salveen Richter with Goldman Sachs. Please proceed with your question.
Hi, good evening. This is Lydia on for Salveen. Thanks so much for taking our question. Maybe just on the two gene therapy launches, could you just share what metrics you plan to share with the Street and how large of a role these launches are expected to play in the path to profitability next year? Thanks so much.
I'll start with just the kind of things we normally would provide. We're not going to provide guidance until we get a number of quarters, so we won't provide revenue guidance. We'll provide what we call the early metrics, which will be, we'll give you revenue that we get from this year, certainly, when we talk about early January. Our goal will be to talk about QTCs operating and start forms, and those would be the primary cause. As time goes on, we'll certainly start including revenue when we have the revenue. Of course, we'll also be talking about payer coverage, which gets published, and so you'll see a lot of that yourselves. Those would be the things. Payer coverage in terms of the character of it will be certainly part of what we do.
That would be, I guess, the main things that we're going to put forth. Oh, yeah. Howard, sure. Go ahead.
The second part of your question, I think, was around contribution to profitability.
Right.
The comment I had made earlier is, we have a strong base business that is growing, and that plus the contribution from these two launches will drive the top line that will get us to profitability next year. More specifics on that, we plan to share early in 2027, so stay tuned for that.
Thanks so much.
Your next question comes from Jack Allen with Baird. Please proceed with your question.
Great. Thanks for taking the questions. I guess mine is centered on CRYSVITA. You have shown a lot of impressive ability to continue to grow the product year after year, and I wanted to ask what your current expectations are as it relates to the LOE timing for this product. I think the composition of matter in the U.S. is 2032, and there is an additional padding around the dosing paradigm. I am just trying to think about when we could see biosimilars potentially intrude on the CRYSVITA franchise.
Sure. Thank you. We are obviously very aware, and our partner, Kyowa Kirin, and I have been talking about it, and they have been doing some work, as we have as well, on next-gen versions of CRYSVITA. So those are in process, and we would expect to have an improved version. What I would say to you is that CRYSVITA itself is like a next-gen product to begin with. It is fully bioavailable subcutaneously. It does not have any anti-drug antibody or hypersensitivity problems, and so it has been used chronically and very effectively. So it is a particularly good product. Developing the next-gen version that needs to improve on those characteristics, which could include dosing less frequently or potential improvements in potency. We are conscious of that, and we are doing the work to prepare for it.
I would point out to you that in many of the areas where we are, there really are not. Rarely, let us say, follow-on biologics come out. The main issue would be what happens in the U.S. I think in the biologic areas, I would not look at LOE as like a precipitous drop-off, at least in our view. But we are expecting to have next-gen versions that we put into play when the time comes. Given the improvement in the regulatory environment, we think it is actually reasonably. You can be reasonably prompt in putting together a development program that can verify, because now there is a phosphate control, in fact, is a reasonable surrogate based on the FDA's interpretation. So that puts us in a better position of setting up for the next stage. So, important product.
We continue to support it globally, and we will manage LOE effectively, I think.
Awesome. Thanks for the color.
Operator, let's move on to the next question. Operator, we can't hear you, but Luca, if you can hear us, I see you're queued up. Please go ahead.
Thanks for taking the question. Maybe I'll pivot to OTC deficiency. I know the phase III enrolled late-onset patients age 12 and older, but would an approval in that patient population be commercially meaningful on a standalone basis, or are you thinking about the commercial opportunity being contingent on eventually expanding into the severe neonatal forms, so patients under 12? Do you have any plans for a separate pediatric study, or is that kind of dependent on the outcome of the data in 2027? Thanks.
Yeah. Thank you. The OTC program showed, I think, really excellent data in terms of normalizing ammonia. If you had higher ammonia, by the way, it also normalized. So it normalized both the patients who were in better control and those who were not in good control, and resulted in strong global impression scale scores, 89% or a +2 , +3 . That is much better or very much better. 75% were +3 , very much better, compared to 0% placebo. In addition, there were five hyperammonemic crises and one death in the control group, and only one crisis, no death in the treated group. So when you look at the profile of the data, it's actually pretty strong. This is on top of current therapy, by the way.
Our view looking at that, the late-onset franchise is a valuable franchise, and with the good characteristics and the very simple infusion and good safety profile we're looking at, I think would be very sustainable. The question then of whether peds should be added, we've debated that before, and we would at some point plan to do a pediatric study, because I do think if you have a child who's in hyperammonemic crisis, that doing dialysis and trying to do a liver transplant urgently would be better managed by doing an IV infusion and giving them the ability to make their own OTC. That could hold them over until a couple years or something, let's say, until a transplant's done or something else happens.
But certainly pediatrics and severe type is an interest, but I do think we can make a reasonable product out of the late-onset versions of the program, particularly with the strong data we've already presented.
Thanks. Operator, let's move on to the next question, please.
Your next question comes from Ben Burnett with Wells Fargo. Please proceed with your question.
Okay, great. Thank you. I also wanted to ask a DTX301 OTC question. Can you talk about the design of the open-label portion of the phase III, and what is the complete responder rate that's needed for statistical success here?
Yeah. The way the trial is designed, it was reconfigured too in the middle of it, there's a randomized placebo control period of 36 weeks, which will compare ammonia control without any change in the background therapy. What we found is patients did not want to remove background therapy or diet control, not knowing if they received the gene therapy. What we do is we have them cross over onto open label. They get treated, they're all in open label, and when they're on open label, then the doctor will determine can they come off their treatments. I don't know if Eric would like to comment on the criterion for success for the second endpoint.
Yeah, so we haven't disclosed exactly how we powered that study, but we are looking for complete responders, those patients who are able to come completely off of alternate pathway medication and diet. Responders, those who are able to come at least 50% down from there, and looking at the combination of those in a responder rate.
Both those— Go ahead.
Oh, thank you. Just to clarify, are physicians here instructed to attempt to wean patients off of standard of care, or is this kind of just up to their own decision-making based on what they're seeing with plasma ammonia levels?
Yeah, we-.
Well-.
We have guidelines in place, and that is per protocol. We also have very close contact with the treating sites, and that is one of the luxuries of rare disease with relatively small number of patients in trial sites. We are able to closely follow those patients and have an active conversation on really trying to move towards tapering and give the gene therapy a real chance of working.
I put one thing forward too is-.
Thank you for the color.
Yeah, the responder definition was just something added, but controlling ammonia is by itself a validated surrogate for rare, and that should be an approvable product just as it is. The truth is, it doesn't really matter if they're on their other treatment or not. The question is, do they get better control of ammonia, and do they feel, does it help improve their function? The data show in the blinded part of the study that their ammonia control is much better, and they feel much better, and I think that's what's important.
We think the drug is working, and the rest of it is more of an operational question of how much they can push their titration and whether they feel comfortable doing it, by the way, since these patients are very fearful all their life about getting hyperammonemia, because those crises are serious and potentially life-threatening. Right now, we're real happy with what we've seen with DTX301. I think it showed up very well in the trial.
That's great color. Thank you so much.
Your next question comes from Raghuram Selvaraju with H.C. Wainwright. Please proceed with your question.
Hi, this is Yanzhe sitting in for Ram Selvaraju. Thanks for taking my question. It concerns GENGLYCOS. Could you elaborate on the post-marketing confirmatory requirements that are associated with accelerated approval, and what clinical evidence and timeline have you agreed upon with the FDA to support conversion to traditional approval? Do you know how much that development activity is incorporated into your reduced 2027 R&D spending guidance?
Yeah, so that post-marketing program is in our guidance for operating spend, for sure. That's part of what we call the R&D spend for commercial products. That would be one of them. We got agreement with FDA to use our disease monitoring program strategy, which will take 50 patients who are on commercial drug and, in other words, on paid commercial drug, and we'll monitor them, their outcomes, and we'll compare it to 20 patients who tried to get treated but had antibodies present to AAV8, which caused them to not be eligible for treatment, and those would become the 20 control patients. So that's the basic design of the trial. It basically is we're going to replicate what we did before, but in this case, it's all open label.
The problem was when we were made to do a placebo-controlled trial, that caused a lot of difficulties in managing starch in the context of not knowing what's going on with your glucose, and we think that did impair the results. We think they could be better, as we found in the crossover. I don't know if, Eric, you want to comment at all on the phase III in a second, but the endpoints that we talked about with FDA are actually endpoints we have already evaluated. In fact, those endpoints were successful, reducing number of doses and the basic time to hypoglycemia things. Those are things we already shown improvements on, so we're just going to replicate that result with an open-label form. I don't know if there's anything else, Eric, to straighten out there.
No, I think you're right. I mean, I think it really is a focus on replicating those results in the phase III and looking at glucose control in multiple ways, including in a controlled fasting challenge.
Of course, all this could have been prevented had we got an agreement not to have placebo control in the first place, which we were required to do, and so now we are in this point. But because the patients are commercial, actually, it managed the cost structure in a very dramatic way for us, and it's far less expensive, which allowed us to do a bigger study, and which was our understanding with them. But we think the data will be valuable to the product in the long run because we'll be able to show what happens when patients really know their starch and glucose quantities, and they know exactly what's going on as you're adjusting. And we think it'll be a better data set to help support the product as it continues to grow globally.
Got it. Thank you so much.
Your next question comes from Lachlan Hanbury-Brown with William Blair. Please proceed with your question.
Yes. Thanks for the question. I wanted to follow up on the point about the urgency to treat with FAYUVI and wondering how you're seeing that play out so far. I mean, are doctors calling patients, having them schedule a special appointment to come and get treated, or I guess patients and their families doing that themselves, or are they just waiting for their next scheduled appointment before they bring it up?
Yeah. No, this is not a next scheduled appointment type thing. This is patients calling the doctors, who is now calling us and saying, "We got to get something going." It's been Patient have waited for this forever, and they know every month delay is lost brain for their kid. So, it's very patient-driven. The doctors are doing everything they can to put things together and to deal with the QTC issues and get everything set. So, it's also been international. Quite a lot of patients from outside the U.S. as well. We're negotiating all of it. But I think in this is a disease state that I think is closer to SMA in terms of demand and desire, that SMA had the same kind of urgency that every month loss meant an impact on what would happen to them.
The difference is that FAYUVI will have patients that could be five, seven, eight, even 10 years old, in that range, not just one or two years as was happening with SMA. So there actually is a potentially larger age range of patients that will be driving. We've gotten inquiries and support start from a wide range of ages already. So, it's definitely patient-driven, and we're getting all the pieces put together to meet that demand.
Awesome. Thanks.
Your next question comes from Laura Chico with Wedbush Securities. Please proceed with your question.
Good evening. Thank you. I wanted to follow up on strategy. Emil, your earlier comments on five programs per year was helpful. What's the most effective way to replenish the pipeline at this point? I guess I'm asking more about how you're sourcing opportunities going forward, and where in the orphan disease landscape would make the most sense given your existing commercial footprint? Thank you.
Yeah. So, our history has always been the combination of insourcing things that we've created our own R&D and outsourcing from BD deals. We've done both types. We actually have a couple IND-ready programs for creatine transporter deficiency and CDKL5 that are in the IND stage. But those are a couple in hand. Those are both of substantial opportunities in terms of number of patients. And so those would be a couple that are already in hand that we've already developed that are actually, we've already invested in the IND enabling work. So, those are a couple, those would be a couple that could come forward. But right now, we're trying to finish what we're doing with OTCs, setrusumab, and we also have the UX016 program for GNE myopathy, which is funded by 100% by venture philanthropy.
So, we would mainly, right now, I think we have a couple internal opportunities. For external opportunities, we are getting pitched things all the time, but we're going to be very selective and smart about choices, and we're going to operate within our confines of being profitable. So, I wouldn't expect us to be doing large, costly deals, right? These are going to be smart, intent, intelligent choices of products that have high value, particularly where our expertise can unlock value that others might not be able to unlock. Hopefully that's helpful, Laura. Thank you for the question.
This now concludes our question and answer session. I would like to turn the floor back over to Joshua for closing comments.
Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at ir@ultragenyx.com. Thank you for joining us.
Ladies and gentlemen, thank you for your participation. This does conclude today's teleconference. Please disconnect your lines, and have a wonderful day.