Ultragenyx Pharmaceutical Inc (RARE) 2024 Q4 法說會逐字稿

Good afternoon, and welcome to the Ultragenyx fourth-quarter and full-year 2024 financial results conference call. (Operator Instructions)

下午好，歡迎參加 Ultragenyx 2024 年第四季和全年財務業績電話會議。（操作員指令）

It is now my pleasure to turn over the call to Joshua Higa, Vice President of Investor Relations. Please go ahead.

現在我很高興將電話轉給投資者關係副總裁 Joshua Higa。請繼續。

Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, Chief Medical Officer.

謝謝。我們發布了一份新聞稿，詳細介紹了我們的財務結果，您可以在我們的網站 ultragenyx.com 上找到。參加本次電話會議的還有執行長兼總裁 Emil Kakkis；艾瑞克‧哈里斯（Erik Harris），商務長；霍華德‧霍恩 (Howard Horn)，財務長；以及首席醫療官 Eric Crombez。

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.

我想提醒大家，在今天的電話會議中，我們將做出前瞻性陳述。這些聲明受某些風險和不確定性的影響，我們的實際結果可能存在重大差異。請參閱我們最新的 SEC 文件中討論的風險因素。

I'll now turn the call over to Emil.

現在我將電話轉給艾米爾。

Thanks, Josh, and good afternoon, everyone. 2024 was a pivotal year for the company as we advance six late-stage programs in serious genetic conditions, most without any approved therapies while also expanding access and growing revenue from our four commercial products worldwide.

謝謝，喬希，大家下午好。 2024 年對公司來說是關鍵的一年，因為我們推進了六個針對嚴重遺傳疾病的後期項目，其中大多數項目均未獲得任何批准的療法，同時我們還在全球範圍內擴大了四種商業產品的使用範圍並增加了收入。

In the middle of the year, we increased our guidance for total revenue and now confirmed that we exceeded the upper end of that range for 2024. After filing our first BLA for Sanfilippo gene therapy earlier than planned, we now expect to have a second BLA for GSD1a gene therapy submitted the FDA in mid-2025. And if both are approved, we would have six commercial products on the market. Combine that progress with the expected Phase 3 data on UX143 on osteogenesis imperfecta and expect a full enrollment of our Phase 3 for GTX-102 for Angelman syndrome, we are set for a strong year of value creation greater than any year in our company's history.

今年年中，我們提高了總收入預期，現在確認 2024 年的總收入已經超過了該範圍的上限。在比計劃提前提交第一份 Sanfilippo 基因療法的 BLA 後，我們目前預計將在 2025 年中期向 FDA 提交第二份 GSD1a 基因療法的 BLA。如果兩項產品都獲得批准，我們將有六種商業產品推出市場。結合這項進展以及 UX143 治療成骨不全症的預期第 3 階段數據，並預期 GTX-102 治療 Angelman 綜合徵的第 3 階段將全面招募患者，我們將迎來比公司歷史上任何一年都更具價值創造能力的強勁一年。

Our international growth in 2024 was particularly impressive. We successfully launched Evkeeza in Europe, Canada, and Japan, while broadening access to our other commercial therapies in Latin America, Canada, and Turkey. We've also been working within these regions to establish clinical trial sites to prepare drug submissions with regulatory authorities and bring our therapies into more geographies through named patient programs. We're looking forward to another year of strong global revenue growth in 2025, supported by multiple products in launch mode globally. This progress sets us firmly on a path toward full-year GAAP profitability in 2027.

我們在 2024 年的國際成長尤其令人印象深刻。我們成功地在歐洲、加拿大和日本推出了 Evkeeza，同時擴大了我們在拉丁美洲、加拿大和土耳其其他商業療法的覆蓋範圍。我們也一直在這些地區合作建立臨床試驗地點，準備向監管機構提交藥物申請，並透過指定患者計劃將我們的治療方法推廣到更多地區。我們期待 2025 年全球營收能再次強勁成長，這得益於全球多種產品的推出。這一進展使我們堅定地走上了 2027 年全年 GAAP 盈利的道路。

In January, I discussed in depth our priorities for this coming year, so I will use our time today to focus on our UX111 program for Sanfilippo syndrome, which has the potential to be our next approved product and our first commercial gene therapy program.

今年 1 月，我深入討論了我們今年的重點工作，因此今天我將重點關注針對 Sanfilippo 綜合徵的 UX111 項目，該項目有可能成為我們下一個獲批的產品和第一個商業化基因治療項目。

Last week, we presented important new clinical data at the World Symposium in San Diego that were also included in our BLA submission last December. We filed for accelerated approval based on the substantial and sustained decrease in levels of heparan sulfate cerebral spinal fluid, or CSF HS, following treatment with UX111.

上週，我們在聖地牙哥世界研討會上展示了重要的新臨床數據，這些數據也包含在我們去年 12 月的 BLA 提交中。我們申請加速批准，因為使用 UX111 治療後，硫酸肝素腦脊髓液（CSF HS）水平大幅持續下降。

CSF HS is what I call a disease-caused biomarker because it's directly responsible for disease pathology and progression. It's not just a random measure associated with the disease; it is the disease. These new data show that a sustained reduction in CSF HS exposure is statistically associated with significant continued growth in the Bayley III cognitive raw score for the sub domains of cognition, receptive communication, and expressive communication compared to natural history data, which show a climb during this age period.

我稱 CSF HS 為疾病引起的生物標記，因為它直接導致疾病的病理和進展。這不僅僅是與疾病相關的隨機測量；它是疾病。這些新數據表明，與自然史數據顯示的在這一年齡層上升相比，CSF HS 暴露的持續減少與認知、接受性交流和表達性交流子領域的 Bayley III 認知原始分數的持續顯著增長具有統計學相關性。

Importantly, we also saw that older children with more advanced disease at the time of treatment were able to retain clinically meaningful functional abilities, including communication, ambulation, self-feeding following treatment with UX111 when the Bayley score is not an effective measure. As we stated in the release, we know from caregivers, clinicians, and others that stabilizing the disease so that a child can retain or even slow down the loss of key skills like walking independently, communicating, and self-feeding has profound impact on their quality of life. The earlier we treat, the better is the long-term outcome. And in the long run, newborn screening will identify patients at birth and potentially enable an optimal treatment outcome.

重要的是，我們還發現，當貝利評分不再是有效衡量標準時，接受 UX111 治療時病情更為嚴重的大齡兒童仍然能夠保留具有臨床意義的功能能力，包括溝通、行走、自行進食。正如我們在新聞稿中所述，我們從護理人員、臨床醫生和其他人那裡了解到，穩定病情，使孩子能夠保留甚至減緩獨立行走、交流和自我進食等關鍵技能的喪失，對他們的生活品質有著深遠的影響。越早治療，長期效果越好。從長遠來看，新生兒篩檢將在出生時識別患者，並可能達到最佳治療結果。

Whether treatment from birth or later in life, these gains or retention of function with UX111 treatment are remarkable compared with the progressive loss of function expected in these patients, these results give us -- give me confidence that UX111 will be a successful product once approved with the potential to make a meaningful difference for patients with Sanfilippo syndrome Type A and their families.

無論是從出生開始治療還是在以後的生活中接受治療，與這些患者預期的逐漸喪失功能相比，UX111 治療所帶來的功能的提高或保留都是非常顯著的，這些結果給了我們——讓我相信，一旦獲得批准，UX111 將是一款成功的產品，並有可能為 A 型 Sanfilippo 綜合徵患者及其家人帶來有意義的改變患者及其家人。

Our UX111 program also serves a strong example of how we are leading and driving changes for the field. Our progress in Sanfilippo and the progress of other companies in the MPS field is made possible by FDA's willingness to accept CSF HS as a primary biomarker endpoint.

我們的 UX111 計畫也是我們如何引領和推動該領域變革的有力例證。我們在 Sanfilippo 方面的進展以及其他公司在 MPS 領域的進展得益於 FDA 願意接受 CSF HS 作為主要生物標記終點。

Last February, we joined patient advocates, regulators, academics, and industry representatives in a workshop hosted by the Reagan-Udall Foundation to discuss qualifying biomarkers in support of rare disease regulatory pathways. This was an opportunity to take decades of work by academic researchers and clinicians in neuronopathic MPS diseases and put together a body information to provide support for leveraging accelerated approval to change the paradigm for drug development in these diseases.

去年二月，我們與患者權益倡導者、監管者、學者和行業代表一起參加了由雷根 - 烏達爾基金會主辦的研討會，討論支持罕見疾病監管途徑的合格生物標誌物。這是一個機會，可以將數十年來神經性 MPS 疾病領域的學術研究人員和臨床醫生的研究成果匯總在一起，形成一個資訊整體，為利用加速審批來改變這些疾病的藥物開發模式提供支持。

Given my long history working on treatments for MPS diseases, including four of the five currently approved enzyme therapies in the US, this was an incredible achievement and opens up the possibility of accelerated development for the broader rare disease community, especially those impacted by metabolic diseases of the brain. We're pleased and thankful to see the FDA's folks on the rare disease over the past year with the advancement of first-ever treatments, some of which were at risk of being shelved entirely. We will continue our advocacy and engagement efforts to advance rare disease regulatory policy.

鑑於我長期致力於 MPS 疾病的治療，包括美國目前批准的五種酶療法中的四種，這是一項令人難以置信的成就，並為更廣泛的罕見疾病群體，特別是那些受腦代謝疾病影響的群體，加速發展開闢了可能性。我們非常高興和感激地看到 FDA 的研究人員在過去一年中在這種罕見疾病領域取得了前所未有的進展，其中一些治療方法之前面臨著被徹底擱置的風險。我們將繼續我們的宣傳和參與努力，以推動罕見疾病監管政策。

With that, I'll turn the call over to our Chief Commercial Officer, Erik Harris, to provide a more detailed update on the progress across our commercial portfolio.

接下來，我將把電話轉給我們的首席商務官埃里克哈里斯 (Erik Harris)，以提供有關我們商業組合進展的更詳細資訊。

Thank you, Emil, and good afternoon, everyone. 2024 was a strong year for the Crysvita franchise. Both the Kyowa Kirin team in the US, Canada, and Europe, and our team in Latin America and Turkey delivered outstanding results and led to the revenue beat, raised, and beat that Emil mentioned earlier.

謝謝你，艾米爾，大家下午好。 2024 年對於 Crysvita 系列來說是強勁的一年。美國、加拿大和歐洲的 Kyowa Kirin 團隊以及我們在拉丁美洲和土耳其的團隊都取得了出色的成績，並實現了 Emil 之前提到的收入、收益和利潤的超越。

I'll start with Crysvita in Latin America, where we lead the commercial operations. In 2024, our team generated approximately 290 start forms that led to approximately 250 patients on reimbursed therapy. We now have approximately 750 patients on commercial products in the region as the team continues to exceed our expectations.

我先從拉丁美洲的 Crysvita 開始，我們在那裡領導商業運營。2024 年，我們的團隊產生了大約 290 份開始表格，使大約 250 名患者獲得了報銷治療。目前，我們在該地區約有 750 名患者使用商業產品，團隊的表現不斷超出我們的預期。

Similar to what we saw in the United States, once doctors in Latin America see how well that patients are doing on therapy, they frequently write prescriptions for their other patients. Growth in the region has accelerated following successfully negotiating reimbursement from the Brazilian and Mexican authorities, the two largest payers in the region and continued expansion in other South American countries.

與我們在美國看到的情況類似，一旦拉丁美洲的醫生看到患者的治療效果很好，他們就會經常為其他患者開處方。在成功與該地區最大的兩個付款方巴西和墨西哥當局談判報銷事宜並繼續向其他南美國家擴張後，該地區的增長得以加速。

In the US, our partner, Kyowa Kirin, is leading commercialization and had a strong fourth quarter driven by growing underlying demand. Over the course of the year, the number of start forms generated exceeded our expectations as did the number of patients on reimbursed therapy. We believe this confirms there are still a large number of patients who could benefit from this therapy and gives confidence there are still meaningful opportunities to grow this product.

在美國，我們的合作夥伴協和麒麟 (Kyowa Kirin) 正在引領商業化，並在不斷增長的潛在需求的推動下在第四季度表現強勁。在這一年中，產生的開始表格的數量超出了我們的預期，接受報銷治療的患者數量也超出了我們的預期。我們相信，這證實了仍有大量患者可以從這種療法中受益，並且讓我們有信心仍有有意義的機會來發展該產品。

Moving on to Dojolvi. Growth of new start forms in the fourth quarter continued to steadily increase. In 2024, our team generated approximately 120 start forms that led to approximately 105 new patients on reimbursed therapy across the US. This brings the total since launch in 2020 to almost 575 patients on reimbursed therapy. The split between pediatric and adult patients continues to be approximately 65% PEs and 35% adults. The number of new prescribers continue to grow in the fourth quarter with approximately half writing more than one prescription.

繼續前往 Dojorvi。第四季新開工數成長率持續穩定提升。2024 年，我們的團隊產生了大約 120 份開始表格，為全美約 105 名新患者帶來了報銷治療。這使得自 2020 年啟動以來接受報銷治療的患者總數達到近 575 名。兒童和成人患者的比例仍約為 65% 為 PE，成人為 35%。第四季度新開處方人員的數量持續增長，其中約有一半開出了一張以上的處方。

For Dojolvi, across the EMEA region, revenue is a result of named patient sales requests. There are over 250 patients treated under MPS across 14 countries in the region. The majority of demand is in France, but we are receiving an increasing number of requests from other countries in the EMEA region, including the Middle East. The demand for this product is quite strong in this region, especially given where we are not actively marketing the therapy and simply responding to name patient requests.

對於 Dojorvi 而言，在整個 EMEA 地區，收入來自指定患者的銷售請求。該地區 14 個國家的超過 250 名患者接受了 MPS 治療。大部分的需求來自法國，但我們收到來自 EMEA 地區其他國家（包括中東）越來越多的請求。該產品在該地區的需求相當強勁，尤其是考慮到我們並未積極推銷該療法，而只是響應指定患者的要求。

I'll close with a few comments on Evkeeza, which we have been launching outside of the US over the past year or so. In the EMEA region, we have patients from all of the major countries, including France, Italy, Germany, Austria and the Middle East. We now have treated approximately 190 patients across 14 countries. This is a result of our commercial commercialization efforts or responding to named patient requests as we continue to successfully navigate the country-by-country pricing negotiations.

最後，我想談談對 Evkeeza 的一些評論，過去一年左右，我們一直在美國以外推出這款產品。在 EMEA 地區，我們的患者來自所有主要國家，包括法國、義大利、德國、奧地利和中東。目前我們已經為14個國家的約190名患者進行了治療。這是我們商業化努力或回應指定患者請求的結果，因為我們繼續成功進行逐國定價談判。

In Japan, the team continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. We expect Japan to contribute more meaningfully to their total revenue as we launch Evkeeza and our future programs in this country.

在日本，繼去年獲得定價和報銷批准後，團隊繼續保持發布勢頭。我們預計，當我們在日本推出 Evkeeza 和我們未來的項目時，日本將為他們的總收入做出更有意義的貢獻。

As I have mentioned on previous earnings calls, we continue to expect quarter-to-quarter variability in revenue primarily due to uneven ordering patterns for Crysvita in Latin America, but we remain confident in the growing underlying demand for all of our products around the world. Our teams were excited to deliver strong results in 2024, and we are looking forward to potentially commercializing two or three new products in the coming year or so.

正如我在先前的財報電話會議上提到的，我們仍然預計收入將出現季度波動，這主要是由於 Crysvita 在拉丁美洲的訂購模式不均衡，但我們對全球對我們所有產品的潛在需求不斷增長仍然充滿信心。我們的團隊很高興能夠在 2024 年取得強勁業績，並期待在未來一年左右實現兩三種新產品的商業化。

In the US, our inborn errors of metabolism team that is currently commercializing Dojolvi and Mepsevii, look forward to being able to promote UX111 and DTX401 as transformational gene therapies once approved. For UX143, we will need to build out the US team in preparation for a potential launch, and we will be able to use our deep institutional knowledge from our successful Crysvita launch, where there is a 90% overlap in call points.

在美國，我們目前正在商業化 Dojorvi 和 Mepsevii 的先天性代謝錯誤團隊期待能夠在獲得批准後將 UX111 和 DTX401 推廣為轉化基因療法。對於 UX143，我們需要組建美國團隊，為潛在的發布做準備，並且我們將能夠利用我們在成功發布 Crysvita 時所獲得的深厚機構知識，其中呼叫點有 90％ 的重疊。

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

接下來，我將請霍華德分享有關我們的財務表現和指引的更多細節。

Thanks, Erik, and good afternoon, everyone. I'll focus on full-year 2024 corporate results and our 2025 guidance, starting with total revenue. For 2024, we reported $560 million, representing 29% growth over 2023. Crysvita contributed $410 million, including $249 million from North America, $135 million from Latin America and Turkey, and $26 million from Europe. In total, this represents 25% growth over 2023. If you focus on Latin America and Turkey, where we are responsible for generating sales, this represents 78% growth over 2023.

謝謝，埃里克，大家下午好。我將重點放在 2024 年全年公司業績和 2025 年指引，首先是總收入。我們報告稱，2024 年的營收為 5.6 億美元，比 2023 年成長 29%。Crysvita 貢獻了 4.1 億美元，其中來自北美的 2.49 億美元，來自拉丁美洲和土耳其的 1.35 億美元，以及來自歐洲的 2,600 萬美元。總體而言，這意味著 2023 年的成長率為 25%。如果您專注於我們負責創造銷售的拉丁美洲和土耳其，那麼這意味著 2023 年的成長率將達到 78%。

Turning now to Dojolvi. It contributed $88 million, which represents 25% growth over 2023. Evkeeza contributed $32 million as demand continues to build following launches in our territories outside of the United States. And Mepsevii contributed $30 million as we continue to treat patients in this ultrarare indication.

現在轉向 Dojorvi。它貢獻了 8800 萬美元，比 2023 年增長 25%。隨著我們在美國以外地區推出產品後需求不斷增加，Evkeeza 貢獻了 3,200 萬美元。梅普塞維 (Mepsevii) 捐贈了 3000 萬美元，繼續為這種極為罕見的疾病患者提供治療。

Total operating expenses for the year were $1.1 billion, which included R&D expenses of $698 million, SG&A expenses of $322 million, and cost of sales of $77 million. Operating expenses included noncash stock-based compensation of $158 million. For the year, net loss was $569 million or $6.29 per share. As of December 31, we had $745 million in cash equivalents and marketable securities.

全年總營運費用為 11 億美元，其中包括研發費用 6.98 億美元、銷售、一般及行政費用 3.22 億美元以及銷售成本 7,700 萬美元。營業費用包括 1.58 億美元的非現金股票薪酬。全年淨虧損 5.69 億美元，即每股 6.29 美元。截至 12 月 31 日，我們擁有 7.45 億美元的現金等價物和有價證券。

In 2024, net cash used in operations was $414 million. Importantly, in 2025, we expect reduced net cash used in operations compared to 2024. As you remember from prior years, we typically use more operating cash in the first quarter than in the other three quarters because it includes items like the payment of annual bonuses. This year, the first quarter will also include $45 million in payments for two milestones that were achieved in the fourth quarter of 2024. One for the initiation of our Angelman Phase 3 study and one for a sales milestone for Evkeeza. We will continue to prioritize expense management and focus our investments on the execution of our upcoming commercial launches and advancing our Phase 3 programs.

2024 年，經營活動所用淨現金為 4.14 億美元。重要的是，我們預計 2025 年營運淨現金使用量將與 2024 年相比減少。正如您從前幾年所記得的，我們通常在第一季使用的營運現金比其他三個季度多，因為其中包括支付年度獎金等項目。今年第一季還將包括 2024 年第四季實現的兩個里程碑的 4,500 萬美元付款。一個是啟動我們的 Angelman 第三階段研究，一個是 Evkeeza 的銷售里程碑。我們將繼續優先考慮費用管理，並將投資重點放在即將進行的商業發布和推進我們的第三階段計劃上。

Shifting to revenue guidance for 2025. Total revenue is expected to be between $640 million and $670 million, which represents 14% to 20% growth over 2024. Drivers include increasing demand for our products in Latin America, continued penetration of the pediatric and adult XLH markets in the US, and growth from Evkeeza in Europe and Japan.

轉向2025年的收入指引。預計總收入在 6.4 億美元至 6.7 億美元之間，比 2024 年增長 14% 至 20%。驅動因素包括拉丁美洲對我們產品的需求不斷增加、美國兒科和成人 XLH 市場的持續滲透以及 Evkeeza 在歐洲和日本的成長。

Crysvita revenue is expected to be between $460 million and $480 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. This range represents 12% to 17% growth over 2024. As a reminder, in the first quarter of the year, we restart at the lowest tier of our royalty structure in North America.

Crysvita 的收入預計在 4.6 億美元至 4.8 億美元之間，其中包括所有地區和 Ultragenyx 的所有形式的 Crysvita 收入。這一範圍代表 2024 年的成長率為 12% 至 17%。提醒一下，今年第一季度，我們將以北美特許權使用費結構的最低級別重新啟動。

Dojolvi revenue is expected to be between $90 million and $100 million, which represents 2% to 14% growth over 2024. As in prior years, our Dojolvi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to name patient requests.

Dojorvi 的營收預計在 9,000 萬美元至 1 億美元之間，比 2024 年成長 2% 至 14%。與前幾年一樣，我們的 Dojorvi 預測表明，在我們實現商業化的國家，成長速度較快；在我們回應指定患者請求的國家，成長速度較慢。

With that, I'll turn the call to our CMO, Eric Crombez, who will provide an update on our key clinical data readouts expected this year.

說完這些，我將把電話轉給我們的行銷長 Eric Crombez，他將提供我們今年預計的關鍵臨床數據讀數的最新資訊。

Thank you, Howard, and good afternoon, everyone. I'll provide some brief operational updates on our late-stage programs and review our upcoming clinical milestones. Starting with UX143 for the treatment of osteogenesis imperfecta. The Phase 3 Orbit study is progressing well, and the safety profile is similar to what was observed in Phase 2. Based on the Phase 2 data we previously shared, we are confident that this study will show a clinically and statistically significant reduction in annualized fracture rate at either the second interim analysis or the final analysis. The Orbit and Cosmic studies will both have an interim analysis midyear after all patients have been on therapy for at least 12 months and the alpha spend for each study will be 0.01. If IA2 for Orbit is not achieved, the study will proceed to full study analysis in the fourth quarter.

謝謝你，霍華德，大家下午好。我將簡要介紹我們的後期專案的營運更新，並回顧我們即將實現的臨床里程碑。從UX143開始治療成骨不全症。第 3 階段 Orbit 研究進展順利，其安全性與第 2 階段的觀察結果相似。根據我們先前分享的第 2 階段數據，我們相信這項研究將在第二次中期分析或最終分析中顯示出年骨折率在臨床和統計學上顯著降低。Orbit 和 Cosmic 研究都將在所有患者接受至少 12 個月的治療後於年中進行中期分析，每項研究的 alpha 支出為 0.01。如果 Orbit 未能達到 IA2，則該研究將在第四季進行全面研究分析。

Moving to GTX102 for the treatment of Angelman syndrome. Enrollment in the Phase 3 Aspire study is going well, and we are on track to complete enrollment in the second half of this year. Based on the strong interest from physicians and patient families for this transformative therapy and with our team's commitment, I have confidence that we will be able to enroll the planned 122 patients in less than one year. In parallel, we are also working to initiate our Phase 2/3 study Aurora, that will study younger and older patients and those with other mutations. Once this protocol is through the regulatory process, we will share additional design details.

轉向 GTX102 治療 Angelman 症候群。第三階段 Aspire 研究的招募工作進展順利，我們預計在今年下半年完成招募。基於醫生和患者家屬對這種變革性療法的濃厚興趣以及我們團隊的承諾，我相信我們將能夠在不到一年的時間內招募計劃中的 122 名患者。同時，我們也正在努力啟動 2/3 期研究 Aurora，該研究將研究年輕患者、老年患者以及其他有其他突變的患者。一旦該協議通過監管程序，我們將分享更多設計細節。

Shifting now to our gene therapy programs and starting with UX111 for the treatment of MPS IIIA. Emil already shared the latest data we presented last week, and we expect to receive confirmation of our BLA acceptance shortly. This will also confirm our PDUFA date, which we expect to be in the second half of the year. The biomarker data and the newly presented clinical improvements in multiple domains show the impact of therapy can have for families and patients who otherwise face a legal disease. I look forward to completing this work and to the launch of our first gene therapy product.

現在轉向我們的基因治療項目，並從 UX111 開始治療 MPS IIIA。Emil 已經分享了我們上週展示的最新數據，我們預計很快就會收到 BLA 接受的確認。這也將確認我們的 PDUFA 日期，我們預計將在今年下半年。生物標記數據和多個領域新呈現的臨床改善表明，治療可以對原本面臨法律疾病的家庭和患者產生影響。我期待完成這項工作並推出我們的第一個基因治療產品。

Next, DTX401 for the treatment of glycogen storage disease type 1a. Work on the BLA filing is going well, and we are on track for FDA submission midyear. We have talked about the decision to move manufacturing for this program to our facility in Bedford, Massachusetts. And while this requires some additional work in time, it enables far greater control over the manufacturing process, improved quality, and reduced costs.

接下來，DTX401用於治療1a型肝醣累積病。BLA 備案工作進展順利，我們將按計畫於年中向 FDA 提交申請。我們已經討論過將該項目的生產轉移到馬薩諸塞州貝德福德工廠的決定。雖然這需要花費一些額外的時間，但它能夠更好地控制製造過程，提高品質並降低成本。

Finally, I'll touch on DTX301 for the treatment of ornithine transcarbamylase deficiency. As noted in our press release today, we have completed enrollment in the Phase 3 study with a total of 37 patients randomized 1:1 to placebo or DTX301. We did amend the Phase 3 protocol to allow a blinded comparison of the ammonia production primary endpoint through week 36 and will now evaluate the reduction in removal of standard of care after unblinding given the reluctance of patients and doctors to stop alternate pathway medications a blinded study. This reluctance stresses the severity of this disease with the irreversible damage caused by high ammonia levels and the need for a one-time treatment option that establishes the normal ability of the urea cycle to metabolize ammonia.

最後，我將談談用於治療鳥氨酸轉氨甲醯酶缺乏症的 DTX301。正如我們今天的新聞稿中所述，我們已經完成了第 3 階段研究的招募，共有 37 名患者以 1:1 的比例隨機分配接受安慰劑或 DTX301 治療。我們確實修改了第 3 階段方案，以允許對第 36 週的氨生成主要終點進行盲法比較，並且現在將評估揭盲後標準治療的移除減少情況，因為患者和醫生不願意停止盲法研究的替代途徑藥物。這種不情願強調了這種疾病的嚴重性，高氨水平會造成不可逆轉的損害，並且需要一次性治療來建立尿素循環代謝氨的正常能力。

The primary endpoints are unchanged and are: one, response as measured by change in 24-hour ammonia levels during the first 36-week blinded period compared to placebo patients; and two, percent of responders who were able to remove alternate pathway medications and protein-restricted diet. This responder endpoint will now be assessed across a whole group of patients including placebo crossover patients for up to 64 weeks. The new design increases the power of the study by assessing ammonia early where reductions occur rapidly and then assessing the diet and drug removal by evaluating all patients compared to the baseline in the long follow-up period.

主要終點沒有變化，並且是：一、與接受安慰劑治療的患者相比，透過前 36 週盲期內 24 小時氨水平的變化來衡量反應；二是能夠去除替代途徑藥物和限制蛋白質飲食的響應者的百分比。現將對包括安慰劑交叉患者在內的一整組患者進行長達 64 週的此反應終點評估。新設計透過早期評估氨的含量（氨的含量快速降低），然後透過評估所有患者在長期追蹤期間與基線相比的飲食和藥物去除情況，增強了研究的能力。

These changes will allow us to reduce cost and to shorten the overall timeline by ending enrollment at 37 patients and making the study more patient-centric. The protocol amendment reflects the real-time feedback we heard from patients and physicians about the fear of removing lifesaving treatments in a blinded placebo-controlled study. As a patient engaged company, we need to hear their concerns during trial of conduct and now have made a better trial design with their feedback.

這些變化將使我們能夠在 37 名患者時結束招募並使研究更加以患者為中心，從而降低成本並縮短整體時間表。該協議修正案反映了我們從患者和醫生那裡聽到的關於在盲法安慰劑對照研究中取消救命治療的恐懼的即時回饋。作為一家以患者為中心的公司，我們需要在試驗過程中聽取他們的擔憂，並根據他們的回饋制定更好的試驗設計。

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

現在我將把電話轉回給艾米爾，讓他做一些結束語。

Thank you, Eric. In 2025, we'll continue building on the outstanding clinical and commercial execution that put us in place to transform into a leading rare disease company with a commercial financial engine that supports its clinical pipeline. We have a number of near-term catalysts, which Eric has already covered, and I expect to have three potential approvals in the next year or so. As a company, Ultragenyx has arrived. We are creating the paradigm for the next generation of rare disease companies changing the future for rare disease patients.

謝謝你，埃里克。2025年，我們將繼續以出色的臨床和商業執行力為基礎，轉型成為一家領先的罕見疾病公司，並擁有支援其臨床管線的商業金融引擎。我們有許多近期催化劑，Eric 已經介紹過了，我預計明年左右將有三項潛在批准。作為一家公司，Ultragenyx 已經到來。我們正在為下一代罕見疾病公司創造典範，改變罕見疾病患者的未來。

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

下面，我們來回答您的問題。接線員，請提供問答說明。

(Operator Instructions) Tazeen Ahmad, Bank of America.

（操作員指令）美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

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

嗨，大家好。感謝您回答我的問題。因此，我將討論 OI 以及我們應該如何思考——我想您已經多次談論過這個問題，但是 Emil，您是否可以說明一下您對第二次中期讀數是否足以停止研究的信心，而不是需要進行第三次中期？我知道您對試驗設計和成功的可能性表現出了整體信心。但我們想聽聽您對於第二次中期停止研究的重要性的看法。謝謝。

Great. Well, we believe the second interim certainly has a much greater chance of hitting than the first one because it's a 0.01 threshold and because the patients will have had at least 12 months of treatment to allow the group to separate. So there's certainly greater comps in the second interim. But we feel confident one way or another, the trial is going to end and we'll be successful this year. But just -- we've been watching the Phase 2 patients, they are doing great, and we feel very good about how Phase 3 conduct is going.

偉大的。嗯，我們相信第二個中期肯定比第一個中期有更大的機會達到目標，因為它的閾值是 0.01，而且患者至少要接受 12 個月的治療才能分開組別。因此，第二階段的業績肯定更為強勁。但不管怎樣，我們都充滿信心，試驗將會結束，我們今年將會成功。但只是——我們一直在觀察第二階段的患者，他們表現得很好，我們對第三階段的進展感到非常滿意。

So we have confident in the second interim than we did in the first but it's either a second interim or in the study, but we have a product that's going to work and we're excited about that product and bring it to OI patients.

因此，我們對第二個中期比第一個中期更有信心，但這要么是第二個中期，要么是在研究中，但我們有一個可以起作用的產品，我們對該產品感到很興奮，並將把它帶給 OI 患者。

Thanks, operator, let's move to the next question.

謝謝接線員，我們進入下一個問題。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Good afternoon. Thanks for taking my question. Just a follow-up to the first one here. Maybe help us understand if it doesn't hit on the second interim? What would those reasons be or what are the risks to that? And then how long would we have to wait for the final analysis? Thank you.

午安.感謝您回答我的問題。這只是這裡第一個的後續。如果它沒有在第二個中期達到，也許可以幫助我們理解？這些原因是什麼或有哪些風險？那我們還要等多久才能得到最終的分析結果呢？謝謝。

Well, we said the second interim will be midyear. For it not to hit at 12 months. It's usually in rare disease that have to do with the amount of variation and the number of fractures. If there's a lot of variation, there's a wide range of patient baseline fracture rates because we have some type 3, 4 and then type 1 patients. A large variation could create some challenge. But I think that so far, we feel like the trial is proceeding as expected. So if it doesn't hit in the second interim, we'd expect to release data by the end of the year on the final assessment for the trial.

嗯，我們說過第二次中期將在年中。以免它在 12 個月時就發作。這通常是一種罕見疾病，與變異量和骨折次數有關。如果存在很大的變異，那麼患者的基線骨折率範圍就會很廣，因為我們有一些 3 型、4 型和 1 型患者。較大的變化可能會帶來一些挑戰。但我認為到目前為止，我們感覺審判正在按預期進行。因此，如果第二次中期試驗沒有達到預期，我們預計在今年年底前發布試驗最終評估的數據。

Anupam Rama, JPMorgan.

摩根大通的 Anupam Rama。

Hi, guys. This is Priyanka on for Anupam. Thanks for taking our question. One Orbit hits, will you immediately prepare to file or wait for the Cosmic analysis to finish and add it to the application? Thanks.

嗨，大家好。這是 Priyanka 為 Anupam 表演的。感謝您回答我們的問題。一旦 Orbit 命中，您會立即準備提交還是等待 Cosmic 分析完成並將其添加到應用程式中？謝謝。

If Orbit hits, first of all, we will have the data clean and locked and there won't be a need to follow any -- for any longer. So it will be more quickly to reach final analysis and to file. And so compared to interim, one is probably just a one quarter delay in filing off the quarter, too. So it should come more quickly at that result.

如果軌道器成功撞擊，首先，我們將清理並鎖定數據，並且不再需要追蹤任何數據。這樣可以更快地進行最終分析和歸檔。因此，與中期相比，本季的申報可能也只是延遲了一個季度。因此，這個結果應該會更快到來。

Thanks, operator. Let's move to the next question.

謝謝，接線生。我們來討論下一個問題。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you. Sorry, I will ask another question. Given the study complete enrollment on May 1, 2024, is it fair to assume June/July timeframe, you should share the second interim update? And then how would you communicate with the investor in the case this study didn't hit a step? And in the case, the study hits steps would you need to take extra time to analyze the data and therefore share the update a little later?

謝謝。抱歉，我將問另一個問題。鑑於研究將於 2024 年 5 月 1 日完成招募，是否可以假設 6 月/7 月的時間範圍，您應該分享第二次中期更新？那麼，如果這項研究沒有任何進展，您將如何與投資者溝通？在這種情況下，研究是否需要花費額外的時間來分析數據，然後稍後再分享更新？

Yeah. So we will be managing the second interim like the first, a DMC will meet and looks at the data and if they don't inform us that hit, then we know it didn't hit, and we will expect to communicate the Street where we're at, at that point in time. You asked whether it's fair to consider June, July, I guess that's possible, but we haven't set the time, we said midyear, which is in that range, but we're not committing to an exact time. We're trying to keep you guessing a little bit, Gena. So did I miss -- did I get your question?

是的。因此，我們將像管理第一個中期事件一樣管理第二個中期事件，DMC 將開會並查看數據，如果他們沒有通知我們發生撞擊，那麼我們就知道沒有撞擊，並且我們希望在那個時間點與我們所在的街道進行溝通。您問考慮六月、七月是否公平，我想這是可能的，但我們還沒有確定時間，我們說是年中，在那個範圍內，但我們沒有承諾具體的時間。我們想讓你稍微猜一下，吉娜。所以我錯過了嗎——我是否理解了您的問題？

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

是的。所以如果您達到這個目標就意味著稍後再與我們分享，因為您需要花幾週時間來分析數據？

Yeah. But because the database is locked, we would the DMC would see the data, we would find out it hit. We would then get to unwind and look at the data ourselves and relatively sooner after that, we would expect to put out results. It won't be like the first time where we had it to go two months more room, remember when we had to take two more months? So we should be relatively quicker to come out with the actual top-line results anyways.

是的。但是由於資料庫被鎖定，DMC 看不到數據，就會發現它命中了。然後，我們就可以放鬆下來，自己查看數據，相對較快就能得到結果。這不會像第一次那樣，我們不得不多花兩個月的時間，還記得我們不得不多花兩個月的時間嗎？因此，無論如何，我們應該能夠相對快速地公佈實際的營收結果。

Okay, great. Thank you.

好的，太好了。謝謝。

Yaron Werber, TD Cowen.

亞倫·韋伯（Yaron Werber），TD Cowen。

Hi, thank you. Right. So I also, shockingly, we have a 143 question. In the Orbit study, are you stratifying just remind us type 1, 3, and 4 between the two arms?

你好，謝謝。正確的。因此，令我震驚的是，我們有 143 個問題。在 Orbit 研究中，您是否進行分層，只是提醒我們兩組之間的類型 1、3 和 4？

And then secondly, when you look at the primary fracture rates, do you have a secondary looking fracture rates by type underlying type? Thank you.

其次，當您查看主要骨折率時，是否有按類型劃分的次要骨折率？謝謝。

Yeah. So in general, we do stratify but it's mainly for its overall fractures and its age. I'll let Eric talk about the way we're approaching.

是的。因此，一般來說，我們確實會進行分層，但主要是為了了解其整體斷裂和年齡。我會讓埃里克談談我們的方法。

Yeah. So because the primary endpoint is annualized fracture rate, you want to stratify by fracture rate so while that definitely will kind of encompass the different types there, the strict stratification is based on fracture rate coming into the study.

是的。因此，由於主要終點是年骨折率，您需要按骨折率進行分層，儘管這肯定會涵蓋不同類型，但嚴格的分層是基於研究中的骨折率。

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

因此，3 型和 4 型可能有更高的斷裂，但我們關注的是這一點 — — 按照三型、四型和一型來進行，這看起來不是正確的方法，斷裂是一種更好的方法。因此我們也考慮年齡，以確保各組之間的年齡平衡。至於其他終點，我們關注的是總骨折數，而不僅僅是手指、腳趾、頭骨以外的骨折數，這些總骨折數就是終點。對於亞型之間的子集，我相信我們會在其中進行敏感性分析，但這不是正式的次要終點。

Yigal Nochomovitz, Citi.

花旗的 Yigal Nochomovitz。

Hi. This is [Rena] on for Yigal. Thanks for taking my question. I just wanted to ask one on OI. I was just wondering if at the point of hits, whether it be the second interim or the final if we would learn maybe retrospectively, like any kind of retrospective analysis you'd share on how close the studies were to hitting at either the first interim or the second interim, respectively?

你好。這是 Yigal 的 [Rena]。感謝您回答我的問題。我只是想問一個關於 OI 的問題。我只是想知道，在達到預期時，無論是第二次中期還是最後一次中期，我們是否可以回顧性地學習，就像您可以分享的任何回顧性分析一樣，研究分別在第一次中期或第二次中期接近實現預期有多大？

Do you want us to tell you what didn't -- what happened at IA1 or IA2 later? Do you have like personal bet with other investors about that to try to settle? I don't know if we would show what the other -- and we haven't decided that. I think what matters if the study hits, the study work and the drug works. And I'm -- right now, I'm not committing with it, but to show all little bits and pieces of what happened.

您想讓我們告訴您 IA1 或 IA2 之後發生了什麼嗎？您是否曾與其他投資者就此事進行過個人打賭並試圖解決？我不知道我們是否會展示其他內容——我們還沒有決定。我認為，研究是否成功、研究是否有效、藥物是否有效才是最重要的。而我 — — 現在，我還不想對此做出承諾，只是想展示發生的事情的點點滴滴。

We're pretty comfortable that, look, we -- if you look back, we presented Phase 2 data, remember, at six months and showed you a 67% reduction with a P-value 0.04. And then we did the same group of patients, but now at 14 months, and they have 67% reduction in fractures. But now that a P-value was 0.0014.

我們非常放心，看，我們——如果你回顧一下，我們展示了第 2 階段的數據，記住，在六個月時，顯示減少了 67%，P 值為 0.04。然後我們對同一組患者進行了研究，但現在已經 14 個月了，他們的骨折減少了 67%。但現在 P 值為 0.0014。

That is a reasonable model for what would be going on here that the groups are separating, you just need to go a little further to get the P-value where it needs to be and hit the threshold set.

對於群體分離的情況，這是一個合理的模型，您只需進一步即可獲得所需的 P 值並達到設定的閾值。

So I look at that Phase 2 data we've already shown you is kind of a model for what's going on. But right now, we put out the data we have and I don't know if we'll put out the rest to settle scores. But thank you.

因此，我認為我們已經向您展示的第二階段資料可以作為正在發生的事情的模型。但是現在，我們公佈了我們擁有的數據，我不知道我們是否會公佈其餘的數據來算舊帳。但謝謝你。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特（Maury Raycroft），傑富瑞（Jefferies）。

Hi. This is Farzin on for Maury. Just to clarify an earlier point, you mentioned that if the second interim hit, you do the final analysis quickly. So just wondering if you need to supplement the final data page with the 18-month data or not?

你好。這是 Farzin 代替 Maury 上場。只是為了澄清先前的觀點，您提到，如果第二次中期打擊，您會很快進行最終分析。所以只是想知道是否需要用 18 個月的數據來補充最終的數據頁面？

So if we hit at the second interim, that package will include all those patients with at least 12 months of data. The range though would be like from 12, there are some patients at that point would have 20 months -- is 12 to 20 months of exposure time. So it's a pretty long period of time, actually, it's almost two years in all patients. So that will be, I think, plenty for that.

因此，如果我們達到第二個中期目標，該計劃將包括所有擁有至少 12 個月數據的患者。不過，範圍可能是從 12 個月開始，有些患者的暴露時間長達 20 個月——即 12 至 20 個月。所以這是一個相當長的時間，實際上，對於所有患者來說，這幾乎是兩年的時間。所以，我想，這就夠了。

I didn't mention someone asked about Cosmic earlier, Cosmic will be evaluated in parallel. And but we won't close out Cosmic if Orbit doesn't hit. If Orbit hits, then we'll look at Cosmic but the data will be ready to be looked at. But we wouldn't stop Cosmic if Orbit doesn't hit because we need Orbit in order to file. But we wouldn't hold out filing to get 18-month data. We'd file with the data we had and we had that discussion with the FDA.

我之前沒有提到有人問過 Cosmic，Cosmic 將會並行評估。但如果 Orbit 沒有命中，我們也不會關閉 Cosmic。如果 Orbit 成功擊中，那麼我們就會觀察 Cosmic，但資料已經準備好要查看了。但如果 Orbit 沒有成功，我們不會停止 Cosmic，因為我們需要 Orbit 來提交文件。但我們不會拖延提交申請以獲取 18 個月的數據。我們將根據所掌握的數據進行歸檔，並與 FDA 進行討論。

Got it.

知道了。

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

Thanks for taking our questions. If the OI study goes to completion in 4Q, does that implies that the magnitude of the set may not be as great as expected? And in that case, how competitive would setrusumab being compared to bisphosphonate?

感謝您回答我們的問題。如果 OI 研究在第四季度完成，是否意味著 OI 的幅度可能不如預期？那麼，setrusumab 與雙磷酸鹽相比有多具競爭力呢？

Actually, it would not mean it's not as great. If you remember, earlier when we had six-month data and 14 months in Phase 2, they both had 68% reduction in fractures. What it has to do with this is the two lines have to separate. So the biggest creation that there's too much variation, and those variations might cause a delay. But the actual rate separation could very well be 67%. It's just you have a lot of patients that may have 10 fractures a year or one fracture a year in the same study and some of the ones may not fracture, for example, and then during -- for whatever reason. And so it's really more about separating the two groups. But I don't think it necessarily tells you what the percent reduction is.

事實上，這並不意味著它不那麼棒。如果你還記得的話，早些時候，當我們有第 2 階段的六個月數據和 14 個月數據時，骨折率都減少了 68%。與此相關的是，兩條線必須分開。因此，最大的問題是變化太多，而這些變化可能會導致延遲。但實質利率差距很可能達到 67%。只是，在同一項研究中，許多患者每年可能會發生 10 次骨折或每年發生 1 次骨折，而有些患者可能不會骨折，例如，無論出於何種原因。因此這實際上更多的是為了區分兩組人。但我認為它不一定會告訴您減少的百分比是多少。

We think if you listen to some of the KOLs that 50% or greater reduction in fracture is considered really important. And frankly, when we look at patients after a year, 15, 16 months of therapy, we've had some or longer, many of them are not fracturing at all at some point. So we feel very comfortable that the long-term outcome here is greatly reduced fractures, whatever the number is. But I think the biggest issue is the variation in how much fractures are occurring in each group and that wide range that probably exists that will impact how the study reads out.

我們認為，如果你聽一些 KOL 的意見，你會發現減少 50% 或更多的骨折是非常重要的。坦白說，當我們觀察經過一年、十五、十六個月或更長時間的治療的患者時，我們發現其中許多患者在某個時候根本沒有骨折。因此，我們非常放心，無論骨折次數有多少，長期結果都會大幅減少。但我認為最大的問題是各組發生骨折的程度有差異，而且可能存在的較大範圍差異將影響研究結果。

We are using co variables to manage that variation, but that would be the number one reason. So I don't think you can conclude the drug is not working well if we go to the end. Remember, the original plan here was to do a two-year study, so the only reason we felt we could go sooner is because the percent reduction was higher than we thought and at the speed of response was faster. Those are the things that give us confidence that we can go earlier. But we've been moving this up from 18 months to two-year study, right, down to what we're talking about now to the 12- to 18-month timeframe. So 18 months is still a win, and I feel confident whichever one happens that we have a drug that will be far better than bisphosphonate and certainly the best treatment for OI that's available.

我們正在使用共同變數來管理這種變化，但這可能是首要原因。因此，我認為，如果我們堅持到最後，你仍然不能斷定該藥物效果不佳。請記住，這裡最初的計劃是進行一項為期兩年的研究，因此我們覺得可以更早進行的唯一原因是，減少的百分比比我們想像的要高，而且響應速度也更快。這些都給了我們信心，讓我們能夠更早行動。但是，我們已經將這個研究週期從 18 個月提前到 2 年，再縮短到我們現在討論的 12 到 18 個月的時間範圍。因此，18 個月仍是一個勝利，而且我相信，無論發生哪種情況，我們都將擁有比雙磷酸鹽更好的藥物，並且無疑是目前治療 OI 的最佳藥物。

Jeff Hung, Morgan Stanley.

摩根士丹利的 Jeff Hung。

Thanks for taking my question. I just wanted to clarify, make sure I understood correctly. You talked about how the Phase 2 data and the 0.014. But just firstly, for situation with the Orbit Phase 2 portion have hit with the second interim analysis criteria, and if not, how were the baseline fracture rates different from the Phase 2 portion? Thanks.

感謝您回答我的問題。我只是想澄清一下，確保我理解正確。您談到了第二階段的數據和 0.014。但首先，對於 Orbit 第 2 階段部分的情況，是否符合第二個中期分析標準，如果沒有，那麼基線斷裂率與第 2 階段部分有何不同？謝謝。

Yeah. So what I said was the Phase 2 data at six months last patient in we had 0.04 and then with the 14-month data, we had 0.0014, right? So that was the difference. You're asking how close does that reflect what's going on? Well, the Phase 2 patients are fairly similar in terms of the entry criteria for fractures are the same. They're made up of type 1, 3, 4. Their Phase 3 has somewhat more 3s and 4s, but not a dramatic difference. So it's a very comparable population, age range types included and baseline fracture requirements. So I think that those are reasonable ways to look at what Phase 3 should be happening.

是的。所以我說的是，上一位患者在第 2 階段的六個月數據中，我們有 0.04，而第 14 個月的數據中，我們有 0.0014，對嗎？這就是差別所在。你問的是這與正在發生的事情有多接近？嗯，第二階段的患者在骨折的入選標準方面相當相似。它們由類型 1、3、4 組成。他們的第 3 階段有更多的 3 和 4，但差異並不大。因此，這是一個非常可比較的人口，包括年齡範圍類型和基線骨折要求。所以我認為這些是觀察第三階段應該發生什麼的合理方法。

And so the only question has to do with how the variation in the population, how big is it? And how much it moves in the timeframe. But I think the data from Phase 2 are a reasonable model for what's happening. Is that helpful?

所以唯一的問題是人口的差異有多大？以及它在時間範圍內移動了多少。但我認為第二階段的數據可以合理地反映當前的情況。這樣有幫助嗎？

Yes.

是的。

Joseph Schwartz, Leerink Partners.

Leerink Partners 的 Joseph Schwartz。

Hi. This is Will on for Joe. Thanks for taking our questions today, and congrats on the progress this quarter. I have one on OI and then a follow-up on UX111. So just first for OI, wondering if you could sort of paint a color on characteristics of the patients in the Phase 2 that had fractures while they were on treatment, do we know the subtype of these patients, and how does that impact your thinking about the Phase 3, which has, as you said, a few more severe patients? Thank you.

你好。這是威爾代替喬上場。感謝您今天回答我們的問題，並祝賀本季的進展。我有一個關於 OI 的，然後有一個關於 UX111 的後續內容。首先對於 OI，我想知道您是否可以對第 2 階段中接受治療時出現骨折的患者的特徵進行概括，我們是否知道這些患者的亞型，以及這對您對第 3 階段的看法有何影響？如您所說，第 3 階段的患者病情較為嚴重？謝謝。

Okay. So the phase -- the patient that fracture is surprisingly that were not necessarily type 3s and 4s only. There were 17 type 1s, and they were some of the ones that had fractured were type 1. So it's not like having type 3s and 4s made more fractures necessarily. The 3s and 4s tend to have higher fracture rates. But the ones that did have fractures were not necessarily like only types 3s and 4s, for example, it was -- I think they're mostly type 1s, if I recall. So there's no, I would say, a pattern there that would tell you something about how Phase 3, I think. Actually, there's no pattern. It was probably more impressive is how much all three types respond very comparably in bone density improvement. I think that was the most interesting thing that we saw.

好的。因此，令人驚訝的是，骨折的患者不一定只是第 3 型和第 4 型。共有 17 個 1 型，其中一些發生骨折的就是第 1 型。因此，3 型和 4 型並不一定會導致更多的骨折。3 和 4 型糖尿病患者的骨折發生率往往較高。但確實有骨折的不一定只有 3 型和 4 型，例如——如果我沒記錯的話，我認為它們大多是 1 型。所以我想說，這裡沒有可以告訴你有關第三階段情況的模式。事實上，沒有任何模式。可能更令人印象深刻的是這三種類型在骨密度改善方面的反應非常相似。我認為這是我們見過的最有趣的事情。

And you had a follow-up with 111?

您對 111 有後續跟進嗎？

Great. Yeah, thank you. Yeah. Just on 111, since it's going to be the first gene therapy launch for you, guys. How are you thinking about pulling learning from other programs or experiences that had test or maybe not -- were that successful in the commercial rollout? And how does this kind of set you up for other gene therapy launches down the line including 401? Thank you.

偉大的。是的，謝謝。是的。就在 111，因為這將是你們第一次基因治療啟動。您如何考慮從其他已經過測試或可能沒有測試過的計劃或經驗中吸取教訓——這些計劃或經驗在商業推廣中是否成功？這對您未來推出的其他基因療法（包括 401）有何幫助？謝謝。

Yeah. Well we are a very dynamic commercial organization, and we're used to launching new things in disease that has never been treated before us, what we've essentially done everything on time. I'll let Eric say a few words if you'd like.

是的。我們是一個非常有活力的商業組織，我們習慣在從未治療過的疾病領域推出新事物，我們基本上按時完成了所有工作。如果你願意的話，我會讓艾瑞克說幾句話。

But the -- we are going to be looking at what everyone is doing for sure. Our goal would be to get our work with payers so upfront get to understand the value proposition, the data we have in hand and allow them and hopefully, to create as rapid and prompt a pattern of review and approval because urgency and time really matters to these kids that a six-month delay is not allowable. This is a very severe disease. So I would look at UX111 as being more like against [one SMA] in terms of life or death alternative treatment. I do think there's an urgency, I think the payers will respect that. We just need to make them aware of it. And I don't know, Eric, if there's anything -- simple thing you can touch or how we're going about the launch?

但是——我們肯定會關注每個人在做什麼。我們的目標是與付款人一起開展工作，以便提前了解價值主張、我們手頭上的數據並允許他們並希望創建盡可能快速和及時的審查和批准模式，因為緊迫性和時間對這些孩子來說確實很重要，所以不允許六個月的延遲。這是一種非常嚴重的疾病。因此，從生死替代療法的角度來看，UX111 更像是針對 [一種 SMA] 的治療。我確實認為情況緊迫，我認為付款人會尊重這一點。我們只需要讓他們意識到這一點。艾瑞克，我不知道您是否能談談任何簡單的事情，或者我們如何進行發布？

Yeah. We've been in close contact with the potential treatment centers because remember, we're in with those customers now with both Dojolvi and Mepsevii. And so we're learning a lot about the coordination that will be required between the patients and the physicians for delivery of the gene therapy. We're ready -- we'll be ready to go.

是的。我們一直與潛在的治療中心保持密切聯繫，因為請記住，我們現在與 Dojorvi 和 Mepsevii 都有合作。因此，我們正在學習大量有關患者和醫生之間進行基因治療所需的協調的知識。我們已經準備好——我們隨時可以出發。

And we'll certainly want to learn for successful launches of (inaudible), and there's a lot of people out there that have that knowledge. And I think there's an advantage now coming out now with several products out there and knowing what works, what hasn't.

我們當然希望學習成功發射（聽不清楚），而且有很多人擁有這方面的知識。我認為現在推出多種產品是優勢，因為我們知道哪些有效，哪些無效。

And I think the truth about rare disease about gene therapy launches, it's all about urgency. Disease, they don't have a treatment; that's lethal. The [option] is going to be much faster, and we think UX111 fits [that mold cyclical]. So we're looking forward to a good launch, and we're excited about the opportunity of treating this disease. They've been (inaudible) waiting forever for something, and this is the first time it's actually happening. And I know they're grateful and excited about finally something be done for their kids.

我認為關於罕見疾病基因療法推出的真相是，一切都迫在眉睫。疾病，他們沒有治療方法；這是致命的。[選項] 將會更快，我們認為 UX111 很合適[該模具具有週期性]。因此，我們期待著一個良好的開端，我們對治療這種疾病的機會感到興奮。他們（聽不清楚）一直在等待某件事，而這卻是第一次真正發生。我知道他們很感激並且很興奮，因為他們終於能為他們的孩子做點什麼了。

Kristen Kluska, Cantor Fitzgerald.

克里斯汀·克魯斯卡，坎托·費茲傑拉。

Hey, everyone. This is [Ric Miller] on for Kristen. Thanks for taking our question. We're going to mix it up a little bit and ask about OTC deficiency. So just to better understand the amended protocol you talked about today. When the patients in the Phase 3 are in the initial 36-week blinded period, are they still eligible for titrating down on ammonia damages and diet control or would that just be an option in the following unblinded period?

嘿，大家好。這是 [Ric Miller] 為 Kristen 表演的。感謝您回答我們的問題。我們將稍微混合一下並詢問 OTC 缺陷的情況。所以只是為了更好地理解您今天談到的修訂協議。當第 3 階段的患者處於最初的 36 週盲期時，他們是否仍然有資格減少氨損傷和飲食控制，或者這只是接下來的非盲期的一個選擇？

And then based on the natural history for the disease, is there any good understanding that you have based on what a meaningful reduction in ammonia looks like and how this correlates with normalizing some of the clinical effects you see? Thanks.

然後，根據該疾病的自然病史，您是否對氨的有意義減少有很好的理解，以及這與您所看到的一些臨床效果的正常化有何關聯？謝謝。

Sure. Well, we already have treated a lot of patients and know that none of them wanted to reduce. So we kind of know during the line of period, none of them would reduce. So we're -- if we have the option or not, it doesn't matter. The truth is it's a little cleaner if no one would, but since they have it, it doesn't matter. So we're going to look at ammonia baseline relative to later.

當然。嗯，我們已經治療了很多病人，並且知道他們中沒有人願意減少。所以我們知道，在整個期間，它們都不會減少。所以，我們是否有選擇權並不重要。事實是，如果沒有人願意的話，情況會更乾淨一些，但既然他們有它，那就無所謂了。因此，我們將稍後觀察氨的基線。

What we know is we allowed up to 200 micromole in the study, so there will be a number of patients that have significantly elevated ammonias which on a chronic basis are not good. And these ammonias we're talking about our 24-hour curves, right? So they're monitoring during a 24-hour cycle that go up and down.

我們知道的是，我們在研究中允許的濃度高達 200 微摩爾，因此會有許多患者的氨水平顯著升高，這對於慢性病患者來說並不好。我們討論的這些氨是 24 小時曲線，對嗎？所以他們以 24 小時為週期監控上升和下降的情況。

So we -- back from our Phase 2 data, that should drop within six weeks and very rapidly drop to normal range. So we expect that the patients that have high ammonias are clearly abnormal range, that are clearly impair cognitive function, right, above 80 or so should normalize. And that's why we think we'll have a lot of power.

因此，從第二階段的數據來看，該數字應該在六週內下降，並迅速下降到正常範圍。因此，我們預計，血氨水平高的患者明顯處於異常範圍，認知功能明顯受損，80 以上左右就應該恢復正常。這就是我們認為我們將擁有巨大權力的原因。

So I think that the degree of ammonia change in those that are elevated will be clearly from abnormal cognitive impairing type range and into a normal range where you expect greater clarity of thought and function. We'll be monitoring those things as well.

因此，我認為，氨水平升高的人體內氨的變化程度將明顯從異常認知障礙類型範圍進入正常範圍，在正常範圍內，人的思維和功能將更加清晰。我們也會監視這些事情。

The problem, of course, is removing their drugs is they're so afraid of crashing and because it can't happen suddenly that we're just reserving that after to after they get them blinded. And so we'll actually have the same endpoints and really the same trial. It's just that we'll unwind people after 36 weeks and then they can start titrating, but we'll get lined controlled blinded data for that period, which we think will be clinically meaningful ammonia reductions.

當然，問題在於，他們因為太害怕崩潰而停止服用他們的藥物，因為這不能突然發生，所以我們只是在他們失明之後才保留這種藥物。因此我們實際上會有相同的終點和相同的試驗。只是我們會在 36 週後讓患者放鬆，然後他們就可以開始滴定，但我們會獲得該期間的對照盲法數據，我們認為這將是具有臨床意義的氨減少量。

I don't know if there's anything else I missed, Eric, that you'd add?

艾瑞克，我不知道我是否還遺漏了什麼，可以補充嗎？

Well, I would just want to draw the parallels to GSD1a. I mean, we had a lot of reluctance there in the blinded period to be aggressive with reduction of [corn stars], but once all patients rolled over to a long-term follow-up in an unblinded setting, we saw a further reduction in all patients and very closely mimicking what we saw in the Phase 2. So I think we're confident we'll see something similar here in this Phase 3 and get much closer to a duplication of what we saw in the Phase 2, which was done in an unblinded manner.

好吧，我只是想將其與 GSD1a 進行比較。我的意思是，在盲法期間，我們非常不願意積極減少 [玉米星]，但一旦所有患者都進入非盲法環境下的長期隨訪，我們發現所有患者的玉米星都進一步減少，並且非常接近我們在第 2 階段看到的情況。因此，我認為我們有信心在第 3 階段看到類似的結果，並且更接近第 2 階段所見結果的重複，而第 2 階段是以非盲方式完成的。

And the percent of responders is a complete response, so they have to get off their drug and diet control to be considered a complete responder, which what the FDA heard. So I think having all patients be assessed that way, I think, is -- will help the power of the study because of a two few more patients and doing it within patient comparison is a lot more powerful than doing a two group comparison. So thanks for the question on OTC and breaking up the OI nomination. Next.

有反應者的百分比是完全反應，因此他們必須停止藥物和飲食控制才能被視為完全反應者，這也是 FDA 所聽到的。因此，我認為對所有患者都進行這樣的評估將有助於增強研究的效果，因為多對兩個患者進行評估並且在患者間進行比較比進行兩組比較要有力得多。感謝您提出有關 OTC 和分解 OI 提名的問題。下一個。

Luca Issi, RBC Capital.

加拿大皇家銀行資本 (RBC Capital) 的 Luca Issi。

Great. Thanks so much for taking our questions. I guess we'll revert back to the mean here and maybe ask a question on OI. What's the latest thinking on duration of therapy assuming that the trial is successful. We think that the FDA will cap the duration of therapy to 12 months as they have done for romosozumab in osteoporosis? Or do you think this will be a chronic dosing with no cap. So that's one.

偉大的。非常感謝您回答我們的問題。我想我們會回到這裡的平均值，也許會問一個關於 OI 的問題。假設試驗成功，對治療持續時間的最新想法是什麼。我們認為 FDA 將會把治療時間限制在 12 個月，就像他們對骨質疏鬆症藥物 romosozumab 所做的那樣？或者您認為這將是沒有上限的慢性給藥。這就是其中之一。

And then second, very quickly, can you just remind us why for Angelman running a sham-controlled trial is the better way to go versus a placebo-controlled trial? Thanks so much.

第二，您能否很快提醒我們一下，為什麼對 Angelman 來說，進行假對照試驗比進行安慰劑對照試驗更好？非常感謝。

Sure. So on the duration, it's one of the first things we did in taking over the program is does not make the assumption that 12 months makes any sense for these patients. And what we are learning already is that the assumption that 12 months that the treatment stops working, essentially you don't need to go longer, you then lock it in with the [phosphate]. That model is true, maybe 80-year-old women with osteoporosis.

當然。因此，就治療期限而言，我們接手該計畫時做的第一件事就是不假設 12 個月的治療期限對這些患者來說有任何意義。我們已經了解到，假設 12 個月後治療不再有效，基本上你不需要再繼續治療，然後你就可以鎖定它[磷酸鹽]。那個模型是真的，也許是80歲的女性患有骨質疏鬆症。

But when you're talking about these kids, their bones want to resorb, the kids that stop -- the adult have stopped treatment before that were OI patients in the Asteroid study started losing ground, and it's pretty clear to us that OI it's just different. And when we look at patients long-term treated, they continue to gain ground in BMD for quite a bit of time. And our view is that we should be treating until optimal clinical effect and our expectation is that will become a chronic treatment.

但當你談論這些孩子時，他們的骨頭想要被吸收，那些停止治療的孩子——那些在 Asteroid 研究中被診斷為 OI 的成年人已經停止了治療，而 OI 患者的情況開始惡化，我們很清楚，OI 就是與眾不同的。當我們觀察長期治療的患者時，我們會發現他們的 BMD 在相當長的時間內持續成長。我們的觀點是，我們應該一直治療直到達到最佳臨床效果，並且我們期望這將成為長期治療。

And it's possible down the road they could go to maintenance therapy where they get less frequent dosing. But it's pretty clear that one year is you're not done after one year and that most of these kids probably need at least two years, continuous therapy, if not and chronic therapies our expectations.

而他們以後可能會選擇維持治療，以減少服藥頻率。但很明顯，一年的治療並不意味著結束，大多數孩子可能需要至少兩年的持續治療，如果不是，那麼我們期望的是慢性治療。

So we'll -- the FDA is aware of that concept that change, and we'll have to help them understand why it's the right way. I think the data we have is already telling us that that's right, that the patients are continuing to benefit when you have a bone raw density, for example, it's minus 2% to minus 4% of these four, while to gain a lot of ground in one year, they're continuing to gain ground in the second year, clearly, linearly. So we're very comfortable that we're making the right call here.

因此，FDA 意識到了這個概念的改變，我們必須幫助他們理解為什麼這是正確的方法。我認為我們擁有的數據已經告訴我們這是正確的，當骨原始密度為這四個的負 2% 到負 4% 時，患者將繼續受益，而在一年內獲得很大的進步，他們會在第二年繼續進步，顯然，是線性的。所以我們非常放心我們的決定是正確的。

And this one thing's important as a company is that we don't just follow what everyone says, we're looking at what's really going on and look at the science and the science says these kids need to get treated longer, and we're going to continue to do that. And we'll work with the HD in the long term, would there be a maintenance later? Perhaps. But I think at this point, we're talking about chronic therapy for this disease, and that's the best way to probably maintain the right balance of bone production versus bone resorption, which they need that constant stimulation to make that set point right.

作為一家公司，重要的是我們不能只聽從別人的說法，我們要關注實際情況，研究科學，科學表明這些孩子需要接受更長時間的治療，我們將繼續這樣做。而且我們會長期和HD合作，後期會有維護嗎？也許。但我認為，目前我們正在討論這種疾病的慢性治療，這可能是維持骨骼生成與骨吸收之間適當平衡的最佳方法，他們需要不斷的刺激才能使該設定點達到正確水平。

Now, like an osteoporosis patient, which they are officially trying to up their bone production, but they don't have an intrinsic problem like these kids do, right? So you have an underlying genetic cause. I think it's just a different biologic situation then we think chronic treatment is the right answer.

現在，就像骨質疏鬆症患者一樣，他們正在正式嘗試提高骨骼的生成，但他們沒有像這些孩子那樣的內在問題，對嗎？因此，您有潛在的遺傳原因。我認為這只是一種不同的生物學情況，因此我們認為慢性治療是正確的答案。

That second question on Angelman.

關於 Angelman 的第二個問題。

The Angelman sham versus placebo, we actually proposed placebo originally, the FDA, at the time, said there -- has considered it was potentially unethical to have do sham treatment or placebo treatment. We opted not -- and we had heard something similar from EMA. So we opted to go with the sham just because we thought there was an ethical or a regulatory burden there that we have to go through, not them, just them, but IRBs. But I think you could do the study either way, I don't think it's in a matter. Sham has more work, right?

Angelman 假治療與安慰劑的比較，我們最初實際上提出了安慰劑治療，但 FDA 當時表示，認為進行假治療或安慰劑治療可能是不道德的。我們選擇不這樣做——而且我們從 EMA 也聽到了類似的消息。所以我們選擇了虛假的嘗試，因為我們認為我們必須承擔道德或監管負擔，不是他們，只是他們，而是 IRB。但我認為無論用哪種方式你都可以進行這項研究，我認為這並不重要。Sham 還有很多工作要做，對嗎？

Yeah. I mean, the real difference between Angelman and placebo is we -- in the placebo-controlled patients, we will not be injecting artificial CSF. So that really is the practical difference in the sham design. So it's really not a big significant difference between the two designs, but you don't need to administer artificial CSF.

是的。我的意思是，Angelman 和安慰劑之間的真正區別在於，在接受安慰劑對照的患者中，我們不會注射人工 CSF。所以這確實是假設計上存在的實際差異。因此，這兩種設計之間實際上並沒有很大的顯著差異，但您不需要管理人工腦脊髓液。

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

因此，我們已經管理了所有先前的綁定和執行方面。進行虛假試驗的工作量要大一些，但我們覺得——我不想與 IRB 或 EMA 或其他監管機構在註射安慰劑或讓這些孩子每次注射都成為注射的問題上進行艱苦的鬥爭。但我不認為這有什麼關係，也不會對治療的意義產生影響。我們確信設計能夠帶我們到達我們需要去的地方。

Super helpful. Thanks so much.

超有幫助。非常感謝。

Liisa Bayko, Evercore ISI.

Liisa Bayko，Evercore ISI。

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

你好。感謝您回答這個問題。關於 OI 變化性的問題。在您準備試驗和假設的工作中，您能談談您對可變性的任何類型的註冊表或資料庫視圖嗎？有沒有什麼方法可以描述這一點？我想，是否存在一種趨勢，例如如果一個病人骨折了，他們在某段時間是否更容易或更不容易發生骨折？我只是喜歡周圍有一些色彩。太感謝了。

Well, we know from our Phase 2 baseline data that there was a pretty wide range. There were patients who had 0.7 or one fracture or a year and some I think they're up at five or six or seven fractures a year, is that right, Eric?

嗯，我們從第二階段基線數據知道，範圍相當廣泛。有些病人每年骨折的次數為 0.7 次，或者說只有一次，而有些病人每年骨折的次數高達五次、六次或七次，對嗎，艾瑞克？

Yes.

是的。

So that's a pretty wide range of baseline fractures. We know in the young patients, they tend to have more fractures. So if you talk about the really young ones, the younger you go, the more fracture you have. So those are the factors to age, particularly and with that wide array, then you have to imagine that you have to power the study to increase the reduce fractures across a wider array of change. So we think that we're well powered to do that in the design.

因此，基線骨折的範圍相當廣泛。我們知道年輕患者更容易發生骨折。因此，如果你談論真正年輕的人，那麼年齡越小，骨折就越多。因此，這些都是與年齡相關的因素，特別是由於因素範圍如此廣泛，那麼您必須想像您必須加強研究力度，以在更廣泛的變化範圍內增加和減少骨折。因此我們認為我們有能力在設計中做到這一點。

And if you look at what happened in Phase 2 over after a period of time, really the majority of the patients have not had any more fracture stop having fractures completely. And certainly, we put in our deck, there've been -- one of the docs said they've not seen a single [fragility] fracture since starting setrusumab. So we're comfortable that we're going to be able to show the delta. I was just saying if you ask me why would interim two not work Well, it's a question of variation is usually to think in these studies, but we feel comfortable that with enough time, they will separate and you'll get an important result for this disease.

如果觀察一段時間後第二階段發生的情況，實際上大多數患者都不再出現骨折，完全不再出現骨折。當然，我們已經證明，其中一位醫生說，自從開始使用 setrusumab 以來，他們就沒有見過一處 [脆性] 骨折。因此我們很高興能夠顯示這一差異。我只是說，如果你問我為什麼中間兩個方法不起作用，嗯，這是一個變異的問題，通常是在這些研究中思考的，但我們感到放心，隨著時間的流逝，它們會分開，你會得到關於這種疾病的重要結果。

Ed Arce, H.C. Wainwright.

埃德阿爾塞，H.C.溫賴特。

Hi, good afternoon, everyone. This is Thomas (inaudible), asking a couple of questions for Ed. Thank you so much. So perhaps switching case to their 102. As you work to finalize the sign for the Phase 2 Aurora study, can you discuss some factors between the two patient populations that would differentiate the study from Aspire?

大家下午好。這是湯瑪斯（聽不清楚），向艾德問了幾個問題。太感謝了。因此或許可以將案例轉換為 102。在您努力完成第二階段 Aurora 研究的簽約時，您能否討論兩組患者之間的一些因素，這些因素會使研究與 Aspire 有所區別？

And then taking a bigger picture overall strategy of 102, do you also expect Aurora would have data to supplement BLA that we expect to be based on the Aspire data simply expected sometime in the second half of 2026?

然後從更大的角度考慮 102 的整體策略，您是否也預期 Aurora 會有補充 BLA 的數據，我們預計這些數據將基於 Aspire 數據，預計在 2026 年下半年某個時候？

Okay. So on GTX102, the main study, to remind everyone, the main study is Aspire is focused on deletion patients at aged 4 to 17, which is the same population we study in Phase 2. So the Aurora study is simply to support labeling across different age groups and different genotypes.

好的。因此，關於 GTX102 的主要研究，需要提醒大家的是，主要研究是 Aspire 專注於 4 至 17 歲的缺失患者，這與我們在第 2 階段研究的人群相同。因此，Aurora 研究只是為了支持不同年齡層和不同基因型的標記。

For under 4, we'll have some patients treated open label. We'll look at the same end points but just how does under 4-year-old patients, they respond comparable that we saw in our Phase 2 or in what's in Phase 3. And our experience in rare disease world that you can expand the label for age, simply by treating in a small number of patients in an open label format and collect data that's comparable to your blinded step. For the -- we will also do that for some older patients.

對於 4 歲以下的兒童，我們將為一些患者提供開放標籤治療。我們將觀察相同的終點，但 4 歲以下患者的反應如何，他們的反應與我們在第 2 階段或第 3 階段看到的類似。我們在罕見疾病領域的經驗是，您可以擴大年齡標籤，只需以開放標籤形式對少數患者進行治療並收集與盲法步驟相當的數據即可。對於－我們也會為一些老年患者這樣做。

For the non-deletion types, we'll look at patients in the main range and the point will be the same to look -- that's the different genotypes, collect enough patients to show it's safe to give it to them and that using comparable endpoints, we can demonstrate a magnitude effect is comparable.

對於非缺失類型，我們將關注主要範圍內的患者，重點是相同的——即不同的基因型，收集足夠多的患者以表明給予他們藥物是安全的，並且使用可比較的終點，我們可以證明量級效應是可比較的。

In our experience, that kind of data would allow us to support labeling and so our intent is to have cut of data from Aurora in time for BLA filing, but we will probably still continue to collect data in Aurora during the review process in case the agency wanted more.

根據我們的經驗，這些數據可以讓我們支援標籤，因此我們的目的是及時從 Aurora 中截取數據以進行 BLA 備案，但我們可能仍會在審查過程中繼續收集 Aurora 中的數據，以防該機構需要更多資訊。

And the other advantage of Aurora is that we can also do it in other territories around the world, giving more doctors exposure to the treatment and to gain support for regulatory filings that might occur in other parts of the world. So those are some of the factors of how Aurora will work.

Aurora 的另一個優點是，我們還可以在世界其他地區開展這項業務，讓更多的醫生接觸到這種治療方法，並獲得可能在世界其他地區進行的監管備案支援。這些就是 Aurora 運作的一些因素。

Yaron Werber, TD Cowen.

亞倫·韋伯（Yaron Werber），TD Cowen。

Yeah. Thanks for taking my follow-up. I just had a couple, Emil. I know the first one on 401. So given that you're fully enrolled now and the primary is at 36 weeks, and then you unblind, is there a chance that we'll get the data, the first sort of the primaries this year?

是的。感謝您關注我的後續問題。我剛剛有了一些，艾米爾。我知道 401 上的第一個。那麼，假設你現在已經完全入學，初選在 36 週進行，然後你就會解盲，我們是否有機會獲得今年第一批初選的數據？

And then secondly, I think I misheard, but I just want to double check. It sounds like you're saying in Cosmic, you'll do an interim analysis now midyear as well. Is that indeed -- that's going to be the first interim for that? And I think you mentioned it 12 months, but with a 0.01 alpha, but I thought that was referring to Orbit. So I just want to double check the interim analysis on Cosmic.

其次，我想我聽錯了，但我只是想再檢查一下。聽起來你在《宇宙》中說過，你現在也會在年中做一個中期分析。這確實是——這將是第一個中期計劃嗎？我覺得您提到了 12 個月，但 alpha 值為 0.01，但我認為那是指 Orbit。所以我只是想仔細檢查一下 Cosmic 的中期分析。

Sure. So I think you're speaking of 301 for OTC, yes, so the 36-week data could provide data. We're not saying when yet. It depends a little last patient in and having 36 weeks, et cetera. But it could be, we haven't provided the exact timing of that data yet to you.

當然。所以我認為你說的是 OTC 的 301，是的，所以 36 週的數據可以提供數據。我們還沒透露具體時間。這取決於最後一位病人的住院時間以及 36 週的情況等等。但有可能，我們尚未向您提供該數據的確切時間。

For IO, when we run the interim on the Orbit study, we'll run an interim on Cosmic. At the same time, we'll look at Orbit. If Orbit's positive, then we'll look at the Cosmic data, if Orbit is positive, then we'll look at Cosmic and it also is being looked at a 0.01 P-value.

對於 IO，當我們對 Orbit 研究進行中期研究時，我們也會對 Cosmic 研究進行中期研究。同時，我們將關注 Orbit。如果 Orbit 為正，那麼我們將查看 Cosmic 數據，如果 Orbit 為正，那麼我們將查看 Cosmic，它也將被視為 0.01 P 值。

If Orbit doesn't stop, then there's no reason to stop Cosmic at this point. So we'll keep them going until we final. But we want to do the more in parallel. So the idea is to have both trials in the billing, which is the FDA's preference, which would give us the full label. We also think it gives us labeling against bisphosphonates as well as versus placebo, right? So they both studies add value to the commercial launch of the program. The 0.01 for both studies.

如果 Orbit 不停止，那麼就沒有理由停止 Cosmic。所以我們會繼續努力直到最終結果。但我們希望同時做更多的事情。因此，我們的想法是將兩個試驗都納入計費，這是 FDA 的偏好，這樣我們就可以擁有完整的標籤。我們也認為它為我們提供了針對雙磷酸鹽以及安慰劑的標籤，對嗎？因此這兩項研究都為該計劃的商業化推出增加了價值。兩項研究均為 0.01。

Okay, thanks.

好的，謝謝。

Thank you. There are no further questions at this time. I'd like to pass the call back over to Joshua for any closing remarks.

謝謝。目前沒有其他問題。我想將電話轉回給約書亞，讓他做最後發言。

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.

謝謝。今天的電話會議到此結束。如果有任何其他問題，請透過電話或ir@ultragenyx.com與我們聯繫。感謝您加入我們。

This concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation.

今天的電話會議到此結束。現在您可以斷開您的線路。感謝您的參與。