Ultragenyx (RARE) 2026年第三季度财报电话会：基因疗法上市与2027年实现盈利

Ultragenyx Pharmaceutical（NASDAQ: RARE）在2026年第三季度财报电话会议上概述了两款基因疗法的上市计划、大幅削减成本的举措，以及在2027年实现GAAP盈利的计划。该公司还确认终止GTX-102和UX701项目的研发，同时保留更为精简的罕见病研发管线。

核心要点

• Ultragenyx重申2026年总营收指引为7.3亿至7.6亿美元，其中不含来自FAYUVI和GENGLYCOS上市带来的收入。
• FDA分别于8月批准GENGLYCOS用于治疗Ia型糖原贮积症，并于9月批准FAYUVI用于治疗A型圣菲利波综合征。这两款药物是Ultragenyx获批的第五款和第六款药物，也是其首批两款基因疗法。
• 管理层预计2027年将实现全年GAAP净利润盈利和正向运营现金流，这得益于四款成熟产品的增长、两款新产品上市的贡献以及费用的降低。
• 该公司正在裁员约20%，使员工规模保持在约1000人。预计2027年研发费用将低于3.5亿美元，较2025年下降50%以上。
• 在GTX-102治疗天使综合征的3期临床研究未能证明疗效后，Ultragenyx终止了该项目。该公司还终止了用于治疗肝豆状核变性（Wilson病）的UX701项目，原因是大多数患者未能达到所需的生化反应，亦未能停用标准疗法。
• 出售两张优先审评券带来了约3.5亿美元的净收益。管理层表示，公司目前拥有充足的现金，无需额外融资即可实现盈利。

关键财务数据

业务与运营表现

FAYUVI与GENGLYCOS上市情况

截至10月底，Ultragenyx拥有35家活跃的合格治疗中心，并预计在年底前超过40家的目标。预计大多数中心将同时开展这两种基因疗法的治疗。

管理层报告称，两款产品均出现显著的早期需求并收到了大量入组申请表。数名患者已获得报销批准并排期接受输注，但公司未提供接受治疗的患者总数。

管理层预计，由于A型圣菲利波综合征会导致进行性神经功能衰退，FAYUVI在初期会出现一定程度的需求集中。美国以外地区也表现出了浓厚兴趣。预计GENGLYCOS的普及将更具条理和循序渐进，因为符合条件的患者目前已通过频繁摄入生玉米淀粉来控制病情。

关于FAYUVI与支付方的早期沟通被评价为积极正面，初期政策与产品说明书保持一致，未见额外限制。Ultragenyx还在寻求美国以外的监管批准，首先针对FAYUVI向欧洲药品管理局（EMA）和英国药品和健康产品管理局（MHRA）提交申请。

成熟产品

与2025年同期相比，CRYSVITA在2026年前九个月继续保持增长。在拉丁美洲，本季度约有60名新患者开始接受商业化治疗，使该地区患者总数超过1050人。管理层提醒，订单模式可能会导致季度间出现波动。

在北美，接受DOJOLVI报销治疗的患者接近700人。在欧洲、中东和非洲地区（EMEA）的14个国家中，约有315名患者通过指定患者用药或早期用药项目接受治疗。该产品还获得了英国针对全适应症LC-FAOD（长链脂肪酸氧化障碍）的有条件上市许可。

EVKEEZA年内迄今的营收较2025年同期增长约50%。在Ultragenyx负责的美国境外市场中，20多个国家的500多名患者正在接受该疗法治疗。

管理层业绩指引

管理层重申其预期，即2026年研发及销售与管理费用合计将较2025年持平至下降低个位数百分比。公司的重组举措包括收尾GTX-102研究、终止UX701项目、缩减办公场地面积以及精简一般与行政职能人员规模。

2027年的支出将侧重于商业化执行和更精简的研发管线。重点任务包括完成用于治疗OTC缺乏症（鸟氨酸氨甲酰基转移酶缺乏症）的DTX301的3期临床研究、明确UX143/setrusumab治疗成骨不全症的监管路径，以及推进选定的早期项目进行IND申报。

Ultragenyx计划每年维持约五个研发项目运作，同时将投资控制在其盈利目标之内。潜在处于IND阶段的项目包括针对肌酸转运蛋白缺乏症和CDKL5缺乏症的候选药物。

该公司计划在2027年初提供2027年全年营收指引。在积累更多季度的商业化经验以提供各具体产品营收指引之前，公司最初将先行报告上市运营指标，例如活跃治疗中心数量、患者起始治疗申请表数量以及支付方覆盖情况。

风险与关注事项

• 临床执行风险：GTX-102在为期一年的3期临床研究中，多个终点均未能与对照组拉开显著差距。管理层将这一失利部分归因于对照组存在极大的变异性。
• 研发管线收缩：UX701在部分肝豆状核变性患者中显示出活性且安全性良好，但大多数患者未能获得充分的生化反应，亦未能停用标准疗法。
• Setrusumab监管不确定性：管理层认为该药具有临床意义的活性，尤其是在基线骨折率较高的患者中，但尚未确定FDA是否会要求开展另一项前瞻性研究。
• 上市报销风险：FAYUVI和GENGLYCOS早期的报销决定按单个患者逐例审批，不同支付方的批准时间和具体要求可能存在差异。
• GENGLYCOS确证性试验义务：加速批准需要开展上市后研究项目。商定的方案设计包括50名接受商业化治疗的患者，以及20名因存在AAV8抗体而不符合治疗条件的对照组患者。
• 费用纪律约束：包括任何额外的setrusumab试验在内的研发投资，必须与公司2027年的盈利承诺保持一致。

分析师问答环节要点

Setrusumab：管理层表示，来自ORBIT和COSMIC试验的分析显示，在基线骨折次数超过3次的患者中，骨折发生率出现了具有临床意义的下降。如果需要进行另一项试验，Ultragenyx可能会倾向于富集招募更年轻或骨折发生频率更高的患者。公司目前正在与FDA讨论监管路径，并已将潜在支出纳入其盈利框架之内。

用于治疗OTC缺乏症的DTX301：3期临床设计包括一个为期36周的随机、安慰剂对照期，在不改变基础治疗的情况下评估血氨控制情况，随后进行开放标签治疗。该研究将评估停用替代途径药物及饮食控制的完全应答患者，以及将这些干预措施减少至少50%的患者。

GENGLYCOS确证性研究：Ultragenyx预计这项开放标签上市后研究将评估血糖控制、生玉米淀粉用量减少情况以及低血糖发生时间。管理层表示，该项目已纳入2027年研发费用指引，且由于参研患者将使用商业化产品，成本应相对较低。

CRYSVITA专营权：Ultragenyx及其合作伙伴协和麒麟（Kyowa Kirin）正在研发下一代版本，可能提供给药频次更低或效力更高的方案。管理层预计，生物制品的专营权到期不会导致销量立即断崖式下滑，但指出美国市场是关注的重点区域。

管线补充：该公司计划将自主研发的候选药物与精选的业务拓展机会相结合。管理层表示，预计不会开展大规模、高成本的交易，并将优先考虑能够发挥Ultragenyx罕见病专业优势从而提升价值的资产。

财报电话会议完整实录

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完整财报电话会议逐字稿

管理层陈述

Operator

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

It is now my pleasure to turn the call over to Joshua Higa, Chief of Staff and Vice President of Investor Relations.

Joshua Higa

Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Howard Horn, Chief Financial Officer; Erik Harris, Chief Commercial Officer; and Eric Crombez, Chief Medical Officer. I'd like to remind everyone that during today's call; we will be making forward-looking statements.

These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

Emil Kakkis

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 3 that surprised us despite compelling Phase 2 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 create great value has challenged us, we should recognize all that the company has successfully accomplished in 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, adding to $1 billion plus in revenue and profitability.

So while today, we acknowledge the setback, when I started the company with $2 million in the secretary, I would have been surprised and inspired to know that we have become a highly respected admire team of 1,000 professionals treating thousands of patients with rare and ultra-rare disease 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 1a, managing 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 month, but then stops over the next few years as the children progressively lose cognition, language and motor function until they become unresponsive and veteran 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 2, 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 in expenses and ending of programs 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 the Phase 3. So given the need to further reduce expenses, we've also made a decision to terminate the UX701 program for Wilson disease rather than try to pursue improvements. The dose-finding data, including data from Cohort 4 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 the 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. and 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 mission to lead the future of rare disease medicine. I'll now turn the call over to Chief Financial Officer, Howard Horn, who will provide the detail on our expense reductions and our profitability.

Howard Horn

Thank you, Emil, and good afternoon, everyone. The details of our third quarter financials are available in our press release. I'm 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 and 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 to $760 million, which, as a reminder, excludes revenue from the launches of FAYUVI and GENGLYCOS; CRYSVITA 2026 revenue of $500 million to $520 million and DOJOLVI 2026 revenue of $100 million to $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 nonrecurring restructuring charges from the first half of the year and approximately $25 million in severance and other nonrecurring 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 rightsizing 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 3 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 nondilutive 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 totaled 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.

Erik Harris

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 in 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 Turkey. 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 Turkiye, 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.

Emil Kakkis

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 change 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.

Operator

[Operator Instructions]

Your first question comes from Maury Raycroft with Jefferies.

分析师问答

Maurice Raycroft

I'll 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? And I'm wondering if there's any allocation in there for setrusumab development.

Emil Kakkis

Sure. I'll touch on a few things, and I'll let maybe Howard go deeper into it. We are -- within that is the setrusumab spend already included within that. And most of the expenses are coming from disease monitoring programs, regulatory filings and other things to support the filing approvals. But I'll let Howard talk a little bit about within the $350 million to the extent we can at this point.

Howard Horn

Yes, Maury, thanks for the question. Yes, so our guidance is to be less than $350 million. And again, that's 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. And so I think you'd expect that the majority of our R&D spend would be going towards that commercial footprint, and that's what we quoted today and how we plan to address it next year.

Operator

Your next question comes from Kristen Kluska with Cantor.

Kristen Kluska

I also had one on setrusumab. So I 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. So should we be thinking now that there's a greater likelihood of another trial? Is there still potential to file on the table here? And then 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?

Emil Kakkis

Thanks, Kristen. So 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. And 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 these -- 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. And 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 and those with high fractures, we believe, a product in there, a valuable product that we are trying to pursue. And we can't really describe it because we're in the process of negotiating with FDA what that might mean.

And 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.

Operator

Your next question comes from Joon Lee with UBS.

Joon Lee

Your OI post-op analysis is really interesting. I would appreciate if you can elaborate on why the fracture data looks better against an IV bisphosphonate and placebo. And just following up to the prior question, in your prospective study, could that possibly be a confirmatory trial with some expectation that you could get approval based on existing data?

Emil Kakkis

Yes. What you're referring to is we did a study in the two- to seven-year-old younger patients in the study, which were more severe 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 post hoc. So I think that's primarily driven that they're younger patients, they respond more consistently and they had a higher fracture frequency to begin with that.

So there's just more to detect. I do think the fracture benefit was seen in both groups and 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 that there's -- how that's going to work out. We have to working 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.

Operator

Your next question comes from Yaron Werber with TD Cowen.

Jaena Han

This is Jaena 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 for whether you need to do a new study. But theoretically speaking, if you were to pursue a kind of setting 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 time line 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?

Emil Kakkis

Right. Well, let me start with the first part, which is any investments within the context of being profitable, that's 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 that just give us more signal to be able to see a change in fractures. And I think that would be a natural thing. We'd also think about what age range you'd 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 want to figure out a path that's the smartest, highest unmet need and so forth that would get us to an approval. So we'll provide more information when we get closer to it. But, there are some things we can think about -- if a trial 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 into an assumption that we're profitable, and we'll work that within those constraints.

Operator

Your next question comes from Yigal Nochomovitz with Citigroup.

Unknown Analyst

This is Yuan Kim on for Yigal. For FAYUVI, just wondering, but are physicians and payers interpreting preserved neurodevelopmental function similarly? Or are you seeing any variation in eligibility decisions across centers or specifically across plans?

Emil Kakkis

We haven't seen any issue at this point. We're still developing plans. Maybe Eric can provide a little bit more detail. But our interpretation of what preserved neuro lung function meant is that the patients are not nonresponsive bedridden patients. That's a patient that has lost all neuro function. It doesn't mean that their function is normal, right? So that is what the discussion was with the agency, which we think is a relatively broad label. And 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?

Erik Harris

The discussions have been positive and encouraging and as expected and the initial policies have been in line with the label.

Emil Kakkis

So you have not seen restrictions in terms of restrictions.

Erik Harris

No restrictions.

Emil Kakkis

Yes. Very good. So that's your answer at this point.

Unknown Analyst

Got you. Very helpful. And just one quick one on setrusumab. Just wondering, but should we think of the upcoming decision as a primarily go or no-go decision on another prospective study? Or are you also evaluating kind of intermediate steps or studies that can help improve confidence before committing to a full trial?

Emil Kakkis

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 to get the 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.

Operator

Your next question comes from Ellie Merle with Barclays... We can't hear you. You might be on mute. Give you a second to respond.

Unknown Analyst

This is Jasmine on for Ellie. So I just wanted to ask, can you comment on the expected cadence of the launches for both GENGLYCOS and FAYUVI? So 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? And then to date, have you treated any patients yet with either?

Emil Kakkis

Yes. So I let's start with FAYUVI. For FAYUVI, where kids are losing the brain every month and there's families have been waiting and waiting for this treatment, there's definitely a larger urgent drive to get on drug immediately. And we'd expect some level of a surge initially. But we think what will happen is we'll start adding additional territories of the product, which will continue that.

So while you're thinking of just U.S., you should think of this as global. We already have a lot of international requests for treatment as well. So 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 make -- perhaps provide less risk that they can have a crash and burn event. I forgot the...

Joshua Higa

GEN-001 launch curve.

Emil Kakkis

That's the one I just did.

Joshua Higa

Treated patients.

Emil Kakkis

Yes, treated patients. Well, we've done the process of treating patients. We have multiple setup and so forth. So we're not going to provide any great detail exactly, but we're encouraged that the things are getting lined up and going. So we're pretty happy about how it started.

Operator

Your next question comes from Tazeen Ahmad with Bank of America.

Tazeen Ahmad

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 on to your therapy, say, over the next 12 months, just a general sense of it. And if there is another entrant, what would you say the advantages of your product are relative to what they're doing?

Emil Kakkis

Yes. Thanks. I think there's at least a couple of 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 of 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. And we see the kind of long-term data that none of the other programs have that 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 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. So 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 a position, we think, to do extremely well with Vyondys. And I think that the simplicity of the treatment, the reduction in medical interventions required, I think, will be the kinds of things that will be appreciated for families.

Operator

Your next question comes from Anupam Rama with JPMorgan.

Unknown Analyst

This is Duke Tales for Anupam Rama, JPMorgan. You talked a bit about what you were seeing in the Wilson disease program, but could you walk us through your decision to discontinue it, please?

Emil Kakkis

Yes. We had set the standard that in order to invest for a Phase 3 program, we wanted to see the majority of patients achieve the biochemical impact and standard of care withdrawal that gave us confidence that their body is sufficiently changed with regard to copper metabolism to justify a gene therapy. And while we saw some patients that were able to do that, it wasn't the majority. And 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 a position to control our future better. So while I think Wilson is a good indication, I think right now, there's 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's a healthier future than what they have today.

Operator

Your next question comes from Maxwell Skor with Morgan Stanley.

Maxwell Skor

So longer term, could you help us understand directionally where we can expect R&D spend to go? And then just one quick follow-up, if I could. On Angelman, can you provide any additional information on what drove the miss?

Emil Kakkis

Yes. So directionally, we had a very full pipeline. We have four or five Phase 3 programs simultaneously, which is a very big set. And right now, we have a program that has two Phase 3 programs, some early-stage program, and we have some other potential INDs that we would file things that we've been holding back on. Our plan is to operate in a more narrow focused footprint within the confines of profitability and put to maintain something like five programs a year, which is where I think we can do sustainably within a profitable company.

So we'll be able to add new things to the clinic. We'll be looking, but we'll be operating with 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 a particular endpoint.

We think there's a number of things to consider. We think that if you look at our Phase 2 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. And at this point, there are a lot of options being developed for Angelman and strategies out there, and we think the community will be continuing 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. And given the cost of the program and our need to get our costs in line, we felt that 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 a position to grow our future more accurately.

Operator

Your next question comes from Salveen Richter with Goldman Sachs.

Lydia Erdman

This is Lydia on for Salveen. 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?

Emil Kakkis

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. But our goal will be talk about QTCs operating and start forms. And those will be the primary cause. As time goes on, we'll certainly start including revenue when we have the revenue. And we will Yes. And of course, we'll talk about payer coverage, which gets published and so you'll see a lot of that yourselves. So those would be the things and payer coverage in terms of the character of it will be certainly part of what we do. So that would be, I guess, the main things that we're going to put forth. Howard, go ahead.

Howard Horn

And then the second part of your question, I think, was around contribution to profitability. The comment I had made earlier is we have a strong base business that's 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.

Operator

Your next question comes from Jack Allen with Baird.

Jack Allen

I guess my is centered on CRYSVITA. You've 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 loss of exclusivity timing for those products. I think the composition of matter in the U.S. is 2032, and there's an additional patent around the dosing paradigm. I'm just trying to think about when we could see biosimilars potentially intrude on the CRYSVITA franchise.

Emil Kakkis

Sure. Thank you. Well, we're 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's fully bioavailable subcutaneously. It doesn't have any antidrug antibody or hypersensitivity problems.

And so it's been used chronically and very effectively. So it's 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're 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 aren't rarely, let's say, following biologics come out. The main issue would be what happens in the U.S. I think in the biologics areas, I would not look at loss of exclusivity 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.

And given the improvement in the regulatory environment, we think it's actually reasonably you can be reasonably prompt in putting together a development program that can verify because now there is that phosphate control, in fact, is a reasonable surrogate based on 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 do manage LOE effectively, I think.

Operator, we can't hear you. But Luca, if you can hear us, I see you're queued up. Please go ahead.

Luca Issi

Maybe I'll pivot to OTC deficiency. I know the Phase 3 enrolled late onset patients aged 12 and older. But would an approval in that patient population be commercially meaningful on a stand-alone basis? Or are you thinking about the commercial opportunity being contingent on eventually expanding into the severe neonatal forms of patients under 12? And do you have any plans for a separate pediatric study? Or is that kind of dependent on the outcome of the data in '27?

Emil Kakkis

Thank you. So the OTC program showed, I think, really excellent data in terms of normalizing ammonia -- and if you had higher ammonia, by the way, it also normalized. So it normalized both the patients who were in better control and those were not in good control and resulted in strong low impression scale scores, 89% or plus 2 plus 3, that is much better or very much better. 75% were plus 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. And this is on top of current therapy, by the way. So 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 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. And that could hold them over until a few couple of years or something, let's say, until a transplant is 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.

Operator

Your next question comes from Ben Burnett with Wells Fargo.

Benjamin Burnett

Okay. Great. I also wanted to ask a DTX301 OTC question. Just can you talk about the design of the open-label portion of the Phase 3? And what is the complete responder rate that's needed for statistical success here?

Emil Kakkis

Yes. So the way the trial is designed, it was reconfigured to in the middle of it is -- there's a randomized placebo-controlled period of 36 weeks, which will compare ammonia control without any changes in background therapy. what we found is patients did not want to remove background therapy or diet control, not knowing that they receive the gene therapy. And so what we do is we have them cross over on to open label, they get treated, they're all in open label. And when they're on the open label, then the doctor will determine can they come off their treatments. And I don't know if Eric would like to comment on the criterion for success for the second endpoint.

Eric Crombez

Yes. 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 and a responder rate, ahead.

Benjamin Burnett

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 ammonium levels?

Eric Crombez

Yes. We have guidelines in place, and that is per protocol. We also have very close contacts with the treating sites, and that is one of the luxuries of rare disease with relatively small number of patients and trial sites. We are able to closely follow those patients and have an active conversation on really trying to move towards tapering and give this gene therapy a real chance of working.

Emil Kakkis

Yes, the responder definition was just something added, but controlling ammonia is by itself a validated surrogate for rare, and that should be an approval product just as it is. And 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? And the data show in the blinded part of the study that their ammonia control is much better and they feel much better. I think that's what's important. So 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. So right now, we're real happy with what we've seen with DTX301. I think it showed up very well in the trial.

Operator

Your next question comes from Raghuram Selvaraju with H.C. Wainwright.

Unknown Analyst

This is Yan Zi sitting in for Ram Selvaraju. It concerns GENGLYCOS. So could you elaborate on the post-marketing confirmatory requirements that are associated with accelerated approval? And what clinical evidence and time line 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?

Emil Kakkis

Yes. So that post-market program is in our guidance for operating spend for sure. That's part of what I would 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, unpaid 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 will be 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. And 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, and 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 3 in a second. But the endpoints that we talked about with the 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've already shown improvements on. So we're just going to replicate that result with an open-label form. And I don't know if there's anything else, Eric, to straighten out there.

Eric Crombez

No, I think you're right. I mean I think it really is the focus on replicating those results in the Phase 3 and looking at glucose control in multiple ways, including in a controlled testing challenge.

Emil Kakkis

Yes. Of course, all of this could have been prevented if had we got an agreement not to have placebo controlled 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 is our understanding with them. But we think the data will be valuable to the product in the long run because we're able to show what happens when patients really know their starch and glucose quantities and they know exactly what's going on as they're adjusting, we think it will give a better data set to help support the product as it continues to grow globally.

Operator

Your next question comes from Lachlan Hanbury-Brown with William Blair.

Lachlan Hanbury-Brown

I wanted to follow up on the point about the urgency to treat with FAYUVI and sort of 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 the patients and their families doing that themselves? Or are they just waiting for that next scheduled appointment before they?

Emil Kakkis

Yes. No, this is not a next scheduled appointment type thing. This is patients calling the doctors who are now calling us and saying, we've got to get something going. So it's been a patient have waited for this forever, and they know every month delay is lost brain for their kids. 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 all 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 this is a disease state that I think is closer to SMA in terms of demand and desire that SMA has the same kind of urgency that every month loss has an impact on what would happen to them. The difference is that FAYUVI will have patients that could be 5, 7, 8, even 10 years old in that range, not just one or two years is what's happening with SMA. So there actually is a potentially larger age range of patients that will be driving. But 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.

Operator

Your next question comes from Laura Chico with Wedbush Securities.

Laura Chico

I wanted to follow up on strategy. 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?

Emil Kakkis

Yes. So our history has always been the combination of in-sourcing things that we've created in our own R&D and outsourcing from BD deals. We've done both types. We actually have a couple of 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 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 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 of internal opportunities. For external opportunities, we are getting pitched things all the time. 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.

Operator

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

Joshua Higa

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.

Operator

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