Ultragenyx Pharmaceutical Inc (RARE) 2025 Q2 法說會逐字稿

Good afternoon, and welcome to the Ultragenyx second-quarter 2025 financial results conference call. (Operator Instructions) At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call.

下午好，歡迎參加 Ultragenyx 2025 年第二季財務業績電話會議。（操作員指示）在準備好的發言結束時，您將有機會在通話的問答部分提問。

It is now my pleasure to turn the call to Josh Higa, Vice President of Investor Relations.

現在我很高興將電話轉給投資人關係副總裁 Josh 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; Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, Chief Medical Officer.

謝謝。我們已發布了一份新聞稿，詳細介紹了我們的財務業績，您可以在我們的網站 ultragenyx.com 上查閱。與我一起參加此次電話會議的還有執行長兼總裁 Emil Kakkis、首席商務官 Erik Harris、財務長 Howard Horn 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，我們將做出前瞻性的陳述。這些聲明受一定風險和不確定性的影響，我們的實際結果可能有重大差異。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.

我現在將電話轉給艾米爾。

Thanks, Josh, and good afternoon, everyone. In April 2025, we marked our 15-year anniversary as a company. Over that time, we've taken four programs all the way through approval in multiple regions and added a fifth that we are commercializing outside of the US. At the same time, we've also refilled the clinical pipeline and now have five Phase 3 clinical programs fully enrolled or at the BLA submission stage. And over the last 15 years, Ultragenyx has been the most productive rare-disease company in the industry across a broad range of modalities and therapeutic areas.

謝謝，喬希，大家下午好。2025年4月，我們公司迎來了成立15週年。在此期間，我們已經在多個地區批准了四個項目，並增加了第五個項目，我們正在美國以外進行商業化。同時，我們也補充了臨床管線，目前已有五個 3 期臨床項目已完全入組或處於 BLA 提交階段。在過去的 15 年裡，Ultragenyx 一直是業界廣泛的治療方式和治療領域中最俱生產力的罕見疾病公司。

Through the first half of 2025 continue this momentum with meaningful progress across our larger programs. I'll begin with UX143, setrusumab, for our fully human monoclonal antibody for the treatment of osteogenesis imperfecta. The Orbit and Cosmic studies are continuing to the final analysis that will occur around the end of the year.

到 2025 年上半年，我們將繼續保持這一勢頭，並在更大的專案上取得有意義的進展。我將從 UX143（setrusumab）開始，這是我們用於治療成骨不全症的全人單株抗體。軌道和宇宙研究正在繼續進行，最終分析將於年底進行。

While I hope the studies might have stopped early at the interim time point last month, we remain confident in completing a successful study. We're pleased the safe profile is as expected and that after looking at the day of the DMC recommended we continue to the final analysis.

雖然我希望研究可能在上個月的中期時間點提前停止，但我們仍然有信心完成一項成功的研究。我們很高興安全狀況符合預期，並且在查看了 DMC 建議的當天之後，我們繼續進行最終分析。

As we head to the final analysis, the continued treatment of Phase 3 should further strengthen bones of the treated patients. The additional six months of treatment for the treated subjects along with the larger P-value threshold at Poof, will help power the final assessment. We look forward to unblinding the Phase 3 data sets and sharing results around the end of the year.

當我們進行最終分析時，第三階段的持續治療應該會進一步增強接受治療的患者的骨骼。接受治療的受試者需接受額外六個月的治療，加上 Poof 更大的 P 值閾值，將有助於最終評估。我們期待在年底左右公佈第三階段資料集並分享結果。

Now based on all the data we've seen in Phase 2, we are confident UX143 will be a transformational treatment for pediatric and adult patients with osteogenesis imperfecta. The combination mechanism of building bone and reducing excess absorption is at exactly the sites in their body where they need more bone will increase bone strength and reduce fractures, while at the same time, improving overall bone health. In addition to reducing fractures, we are encouraged by the functional effect we are seeing on increasing business activity and ability that speaks to the long-term potential for this treatment.

現在，根據我們在第 2 階段看到的所有數據，我們相信 UX143 將成為患有成骨不全症的兒童和成人患者的變革性治療方法。建構骨骼和減少過度吸收的結合機制正是在身體中需要更多骨骼的部位，這將增加骨骼強度並減少骨折，同時改善整體骨骼健康。除了減少骨折之外，我們還看到它在增加業務活動和能力方面的功能效果，這讓我們感到鼓舞，這證明了這種治療方法的長期潛力。

Now, shifting now to GTX-102, our antisense oligonucleotide, or ASO for the treatment of Angelman syndrome. GTX-102 received breakthrough therapy designation from the FDA in June. BTD aims to expedite the development and review of drugs that are intended to treat serious or life-threatening diseases. And those preliminary clinical evidence indicate that the drug may demonstrate substantial improvement over existing therapies.

現在，我們轉向使用 GTX-102（我們的反義寡核苷酸，或稱為 ASO）來治療 Angelman 症候群。GTX-102 於 6 月獲得 FDA 的突破性療法認定。BTD 旨在加快治療嚴重或危及生命的疾病的藥物的開發和審查。這些初步臨床證據顯示該藥物可能比現有療法有顯著改善。

Historically, it seems like there have been relatively few breakthrough therapy designations granted in the field of neurology because it can be challenging to demonstrate a meaningful potential clinical effect of neurologic disease symptoms. But for GTX-102, we have been able to do that. The BTD designation was obtained based on our Phase 1/2 study data in 74 patients with a full maternal UBE3A deletion that showed consistent denominal gains with rapid, sustained, and continued improvements across multiple symptom domains when patients have been on therapy for up to three years.

從歷史上看，神經病學領域授予的突破性治療稱號似乎相對較少，因為證明神經系統疾病症狀具有有意義的潛在臨床效果可能具有挑戰性。但對於 GTX-102，我們已經能夠做到這一點。BTD 頭銜是根據我們對 74 名患有母體 UBE3A 完全缺失的患者進行的 1/2 期研究數據獲得的，這些患者在接受長達三年的治療後，在多個症狀領域表現出一致的名義增益和快速、持續和持續的改善。

For GTX-102, the magnitude and durability of our Phase 1/2 data indicate our ASO is meaningfully improving the lives of patients who have this neurodevelopmental disorder. Last week, we also announced that GTX-102 Phase 3 study, Aspire, completed enrollment ahead of plan with 129 patients in seven months.

對於 GTX-102，我們第 1/2 階段數據的數量和持久性表明我們的 ASO 正在顯著改善患有這種神經發育障礙的患者的生活。上週，我們也宣布 GTX-102 第三階段研究 Aspire 提前完成招募，七個月內共招募 129 名患者。

The interest from investigators and patients to help drive the rapid enrollment, but I also applaud our team for their efforts to expeditiously enroll the study. We're thankful for the support from the patient communities and investigators who helped us exceed our expectations. We're now on track to read out Phase 3 data from this 48-week study in the second half of 2026.

研究人員和患者的興趣有助於推動快速招募，但我也讚揚我們的團隊為迅速招募研究所做的努力。我們感謝患者社區和研究人員的支持，他們幫助我們超越了我們的期望。我們現在預計在 2026 年下半年讀取這項為期 48 週的研究的第三階段數據。

Now switching to our commercial progress for the first half of 2025, our commercial teams continue their trend of delivering double-digit revenue growth. The $306 million of total revenue across the first two quarters represents 20% growth versus the prior year, and keep us on track to deliver $640 million to $670 million of total revenue this year.

現在轉向我們 2025 年上半年的商業進展，我們的商業團隊繼續實現兩位數的收入成長。前兩個季度的總收入為 3.06 億美元，比上年增長了 20%，並使我們今年預計將實現 6.4 億至 6.7 億美元的總收入。

Crysvita is continuing to grow in line with our expectations, from royalty revenue in US and Canada, and product revenue in Latin America and Turkey. Dojolvi, Evkeeza, and Mepsevii also continue to contribute to our top line. Each of these launches are progressing well.

Crysvita 繼續按照我們的預期成長，包括美國和加拿大的特許權使用費收入以及拉丁美洲和土耳其的產品收入。Dojorvi、Evkeeza 和 Mepsevii 也繼續為我們的收入做出貢獻。每次發布都進展順利。

I'll now hand it off to our Chief Commercial Officer, Eric Harris, to give us some additional details on his team's recent performance.

現在我將把話題交給我們的首席商務官埃里克·哈里斯 (Eric Harris)，請他向我們介紹一下他的團隊最近表現的更多細節。

Thank you, Emil, and good afternoon, everyone. As Emil mentioned, my team is continuing to successfully commercialize four products across the globe, starting with Crysvita in Latin America. In the second quarter, our team generated approximately 50 new start forms that led to approximately 50 patients on reimbursed therapy. We now have approximately 825 patients on commercial product in the region as the team continues to exceed our expectations for Crysvita.

謝謝你，艾米爾，大家下午好。正如艾米爾所提到的，我的團隊正在繼續在全球範圍內成功地商業化四種產品，首先是拉丁美洲的 Crysvita。在第二季度，我們的團隊產生了大約 50 份新的開始表格，使大約 50 名患者獲得了報銷治療。目前，我們在該地區約有 825 名患者使用商業產品，因為團隊對 Crysvita 的表現繼續超出我們的預期。

We continue to receive positive feedback from healthcare providers in the region, who tell us how much better their patients feel when on Crysvita, which has led to an increasing number of doctors writing prescriptions for multiple patients. We expect growth in the region to continue, following the successful negotiation of reimbursement from the Brazilian and Mexican authorities the two largest payers in the region and continued expansion in other Central and South American countries.

我們不斷收到該地區醫療保健提供者的正面回饋，他們告訴我們他們的患者使用 Crysvita 後感覺好多了，這導致越來越多的醫生為多名患者開處方。我們預計，隨著與該地區最大的兩個付款國巴西和墨西哥當局成功談判報銷，並在其他中美洲和南美洲國家繼續擴張，該地區的增長將繼續。

I'll now shift to Crysvita in the United States and Canada, where our partner, Kia Kieran, has been leading commercialization for Crysvita since the transition in April 2023. Revenue in the second quarter 2025 was supported by increasing new start forms and new patients on reimbursed therapy. We expect 2025 US and Canada Crysvita revenue to continue growing, as they work to identify new pediatric and adult patients with XLH and convert them to treatment.

我現在將轉到美國和加拿大的 Crysvita 業務，我們的合作夥伴 Kia Kieran 自 2023 年 4 月移交以來一直領導 Crysvita 的商業化。2025 年第二季的收入得益於新開始表格的增加和報銷治療的新患者的增加。我們預計 2025 年美國和加拿大 Crysvita 的收入將繼續增長，因為他們致力於發現新的 XLH 兒科和成人患者並將其轉化為治療。

Moving on to Dojolvi in the United States. Growth of new start forms in the second quarter continue to steadily increase, consistent with the patterns we have seen in prior quarters. Our team generated approximately 30 new start forms and added approximately 30 new patients to reimbursed therapy. This brings the total, since launch in 2020, to approximately 600 patients on reimbursed therapy.

繼續前往美國的 Dojorvi。第二季新開工數量持續穩定成長，與我們在前幾季看到的模式一致。我們的團隊產生了大約 30 份新的開始表格，並為報銷治療增加了約 30 名新患者。自 2020 年啟動以來，接受報銷治療的患者總數已達到約 600 名。

The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults. The total number of prescribers also continues to grow, with a total of approximately 270 unique prescribers at the end of the second quarter.

兒科患者與成人患者的比例仍約為 65% 為兒科患者，35% 為成人患者。處方人員總數也持續成長，第二季末共有約 270 名獨立處方人員。

For Dojolvi across the EMEA region, there are approximately 280 patients treated under named patient sales across the region. The majority of demand is from France, but we are continuous -- but we are seeing continuous growth across the EMEA region, including Kuwait, Saudi Arabia, and Greece. The demand for this product is quite strong across this region, especially given the fact that we are not actively marketing the therapy and simply responding to named patient requests.

對於 EMEA 地區的 Dojorvi 而言，該地區約有 280 名患者透過指定患者銷售進行治療。大部分需求來自法國，但我們看到整個 EMEA 地區（包括科威特、沙烏地阿拉伯和希臘）的需求持續成長。該產品在該地區的需求相當強勁，特別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請求。

Before I close, I'll make a few comments on Evkeeza, which we began commercializing in territories outside the US with formal reimbursement approvals in just the last couple of years.

在結束之前，我想對 Evkeeza 發表一些評論，我們在過去幾年開始在美國以外的地區進行商業化，並獲得正式的報銷批准。

In the EMEA region, we now have patients on reimbursed therapy from nearly all of the major countries, and we have added almost 100 patients since the beginning of the year with a total of approximately 285 patients across 15 countries. We continue to successfully navigate the country-by-country pricing negotiations and respond to named patient treatment requests across the whole EMEA region.

在歐洲、中東和非洲地區，我們現在幾乎擁有來自所有主要國家的報銷治療患者，自今年年初以來，我們增加了近 100 名患者，總共擁有來自 15 個國家的約 285 名患者。我們繼續成功地進行逐國定價談判，並回應整個 EMEA 地區的指定患者治療請求。

Our team in Japan continues to build on the launch momentum, following the pricing and reimbursement approval that we received last year. In Canada, we are continuing pricing negotiations with government health authorities and recently added younger pediatric patients to the label. Over time, we expect Evkeeza revenue to contribute more meaningfully to the total revenue as we continue to successfully launch this transformative product for HOFH patients, with its high potency due to a novel mechanism of action regardless of background therapy.

繼去年獲得定價和報銷批准後，我們日本的團隊將繼續鞏固這一發布勢頭。在加拿大，我們正在繼續與政府衛生部門進行價格談判，最近也將較年輕的兒科患者也納入了治療範圍。隨著時間的推移，我們預計 Evkeeza 的收入將對總收入做出更有意義的貢獻，因為我們將繼續成功地為 HOFH 患者推出這款變革性產品，無論背景治療如何，它都因新的作用機製而具有高效力。

As I have mentioned on previous earnings calls, we continue to expect some quarter-to-quarter variability in revenue, primarily due to uneven ordering patterns for Crysvita in Latin America, but we remain confident in the growing underlying demand for all of our products around the world.

正如我在之前的財報電話會議上提到的那樣，我們仍然預計收入會有一些季度變化，這主要是由於拉丁美洲對 Crysvita 的訂購模式不均衡，但我們仍然對全球對我們所有產品的潛在需求不斷增長充滿信心。

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

說完這些，我將把電話轉給霍華德，讓他分享更多關於我們的財務表現和指導的細節。

Thanks, Eric, and good afternoon, everyone. I'll focus on second quarter 2025 financial results and guidance for the year.

謝謝，埃里克，大家下午好。我將重點放在 2025 年第二季的財務表現和年度指引。

Starting with total revenue. In the second quarter of 2025, we reported $166 million, representing 13% growth over the second quarter of 2024, and 20% growth for the first half of 2025 over the first half of 2024.

從總收入開始。2025 年第二季度，我們的營收為 1.66 億美元，比 2024 年第二季度成長 13%，2025 年上半年比 2024 年上半年成長 20%。

Crysvita contributed $120 million in the second quarter, including $79 million from North America, $35 million from Latin America and Turkey, and $7 million from Europe.

Crysvita 在第二季貢獻了 1.2 億美元，其中來自北美的 7,900 萬美元，來自拉丁美洲和土耳其的 3,500 萬美元，以及來自歐洲的 700 萬美元。

Dojolvi contributed $23 million, consistent with its expected steady growth trajectory. Evkeeza contributed $15 million, as demand continues to build following launches in our territories outside of the United States. And Mepsevii contributed $8 million, as we continue to treat patients in this ultra-rare indication.

Dojorvi 貢獻了 2300 萬美元，符合其預期的穩定成長軌跡。Evkeeza 貢獻了 1500 萬美元，因為隨著我們在美國以外地區推出產品，需求持續成長。Mepsevii 捐贈了 800 萬美元，用於繼續治療這種極為罕見的疾病患者。

Total operating expenses for the quarter were $274 million, which included R&D expenses of $165 million, SG&A expenses of $87 million, and cost of sales of $23 million. Operating expenses included non-cash stock-based compensation of $39 million.

本季總營運費用為 2.74 億美元，其中包括研發費用 1.65 億美元、銷售、一般及行政費用 8,700 萬美元以及銷售成本 2,300 萬美元。營運費用包括 3,900 萬美元的非現金股票薪酬。

For the quarter, net loss was $115 million or $1.17 per share. As of June 30, we had $539 million in cash, cash equivalents and marketable securities, which included $80 million of net proceeds raised through our ATM facility.

本季淨虧損為 1.15 億美元，即每股 1.17 美元。截至 6 月 30 日，我們擁有 5.39 億美元的現金、現金等價物和有價證券，其中包括透過 ATM 設施籌集的 8,000 萬美元淨收益。

For the three months ended June 30, 2025, net cash used in operations was $108 million. And in total, for the six months ended June 30, 2025, it was $275 million.

截至 2025 年 6 月 30 日的三個月，經營活動所用淨現金為 1.08 億美元。截至 2025 年 6 月 30 日的六個月總計為 2.75 億美元。

We now expect 2025 net cash used in operations to modestly increase compared to 2024, primarily driven by timing delays associated with UX111, DTX401, and UX143. We will remain on our path -- or excuse me, we remain on our path to GAAP profitability in 2027, and we'll continue to focus on growing revenues and rigorously prioritizing our spend, including stopping and delaying certain expenses prior to upcoming potential commercial launches.

我們現在預計 2025 年營運淨現金流將較 2024 年略有增加，主要原因是 UX111、DTX401 和 UX143 相關的時間延遲。我們將繼續走我們的道路——或者對不起，我們將繼續走在 2027 年實現 GAAP 盈利的道路上，我們將繼續專注於增加收入並嚴格確定支出的優先順序，包括在即將到來的潛在商業發布之前停止和推遲某些費用。

Shifting to revenue guidance for 2025, we are reaffirming the guidance we provided in February and May. Total revenue is expected to be between $640 million and $670 million, which represents 14% to 20% growth over 2024.

轉向 2025 年的收入指導，我們重申我們在二月和五月提供的指導。預計總收入將在 6.4 億美元至 6.7 億美元之間，比 2024 年增長 14% 至 20%。

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.

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所有形式的 Crysvita 收入給 Ultragenyx。這一範圍代表 2024 年的成長率為 12% 至 17%。

Dojolvi revenue is expected to be between $90 million and $100 million, which represents 2% to 14% growth over 2024.

Dojorvi 的營收預計將在 9,000 萬美元至 1 億美元之間，比 2024 年成長 2% 至 14%。

With that, I'll turn the call to our COO, Eric Crombez, who will provide operational updates on the clinical programs.

說完這些，我將把電話轉給我們的營運長 Eric Crombez，他將提供有關臨床項目的營運更新。

Thank you, Howard, and good afternoon, everyone.

謝謝你，霍華德，大家下午好。

I'll start with GTX-102 for the treatment of Angelman Syndrome. As Emil mentioned, we completed enrollment in the Phase 3 Aspire study ahead of initial expectations, enrolling 129 patients across six countries in a randomized controlled study in seven months is a remarkable accomplishment. This would not have been possible without the incredible dedication and support from the Angelman community, study site teams, and investigators. The accelerated enrollment of the Phase 3 study underscores the urgent need and strong desire for an infective treatment for these patients.

我將首先使用 GTX-102 來治療天使症候群。正如艾米爾所提到的，我們提前完成了第三階段 Aspire 研究的招募，在七個月內招募了來自六個國家的 129 名患者參與隨機對照研究，這是一項了不起的成就。如果沒有 Angelman 社群、研究現場團隊和研究人員的非凡奉獻和支持，這一切都不可能實現。第三階段研究的加速招募凸顯了這些患者對感染治療的迫切需求和強烈意願。

We will now shift our enrollment efforts to the Aurora study that will target younger and older patients and those with other genotypes. This study is open label and intended to be supportive information on safety and efficacy in this expanded patient population. The protocol has been finalized, and we expect to begin enrollment in the second half of this year. Data from this ongoing study will be included in approval filings after successful completion of the Phase 3 Aspire study.

我們現在將把招募工作轉向 Aurora 研究，該研究將針對年輕、年長患者和其他基因型的患者。這項研究是開放標籤的，旨在為擴大的患者群體提供安全性和有效性的支持資訊。該協議已經最終確定，我們預計將於今年下半年開始招生。這項正在進行的研究的數據將在第三階段 Aspire 研究成功完成後納入批准文件中。

Shifting to UX111 for the treatment of MPS IIIA, or Sanfilippo syndrome type A. We received a complete response letter for our BLA filing last month, and we are actively working with the FDA to resolve the observations through a planned Type A meeting. That should lead to an understanding of what is required for refiling of the BLA. Once resolution has been achieved, we expect to resubmit the BLA and anticipate an up to six-month review.

轉向 UX111 治療 MPS IIIA 或 A 型 Sanfilippo 症候群。上個月我們收到了 BLA 申請的完整回覆信，我們正在積極與 FDA 合作，透過計劃中的 A 型會議解決這些觀察結果。這應該有助於了解重新提交 BLA 的要求。一旦解決問題，我們預計將重新提交 BLA，並預計進行長達六個月的審查。

I think it's important to note that the clinical review has been ongoing and that the FDA acknowledged at the late-cycle review meeting that the neurodevelopmental outcome data is robust and that the biomarker data provided additional supportive evidence. The CRL did not note any review issues related to the clinical data package nor comment on the clinical inspection. There is a request for updated clinical data for specific clinical and biomarker endpoints in safety to be included in the resubmission.

我認為值得注意的是，臨床審查一直在進行中，並且 FDA 在後期審查會議上承認神經發育結果數據是可靠的，並且生物標記數據提供了額外的支持證據。CRL 沒有註意到與臨床資料包相關的任何審查問題，也沒有對臨床檢查發表評論。要求在重新提交的文件中納入安全性方面特定臨床和生物標記終點的更新臨床數據。

Next, DTX401 for the treatment of glycogen storage disease type 1a, where we are now on track to submit a BLA in the fourth quarter of this year. We have been working on the BLA over the last couple of quarters and the non-clinical and clinical sections are ready to cement. We want to proactively resolve any relevant CMC and facility questions that derived from the UX111 CRL that could possibly impact the DTX401 submission before we finalize the CMC section of the BLA. We expect to resolve the observations over the next few months and then finalize the BLA submission.

接下來是 DTX401，用於治療 1a 型肝醣累積疾病，我們目前預計在今年第四季提交 BLA。過去幾季我們一直在致力於 BLA，非臨床和臨床部分已準備好鞏固。在最終確定 BLA 的 CMC 部分之前，我們希望主動解決源自 UX111 CRL 的任何可能影響 DTX401 提交的相關 CMC 和設施問題。我們希望在接下來的幾個月內解決這些問題，然後最終完成 BLA 提交。

Finally, UX701 for the treatment of Wilson disease. Recall, we are in the dose-finding stage of the study, and in Cohort 4, we are evaluating a dose of 4.0e13. All patients in this cohort will receive immunomodulation therapy with rituximab and tacrolimus, in addition to the prophylactic oral corticosteroid regimen patients in Cohorts 1 through 3 received. Enrollment in dosing in Cohort 4 is underway, and we expect to complete enrollment in the next month or two.

最後，UX701用於治療威爾遜氏症。回想一下，我們目前正處於研究的劑量探索階段，在隊列4中，我們正在評估4.0e13的劑量。除了隊列1至3患者接受的預防性口服皮質類固醇治療方案外，該隊列的所有患者都將接受利妥昔單抗和他克莫司的免疫調節治療。第 4 組的給藥招募正在進行中，我們預計在未來一兩個月內完成招募。

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，讓他發表一些結束語。

Thank you, Eric. I'll quickly recap the milestones and catalysts over the second half of the year. For UX143 and osteogenesis imperfecta, we expect to have top line data from the final analyses of the Orbit and Cosmic studies around the end of the year.

謝謝你，埃里克。我將快速回顧下半年的里程碑和催化劑。對於 UX143 和成骨不全症，我們預計將在今年年底左右獲得 Orbit 和 Cosmic 研究最終分析的頂線數據。

For GTX-102 in Angelman syndrome, we will continue treating patients in the 40-week -- 48-week ASPIRE study, and will begin enrollment in support of Aurora study in the second half of 2025.

對於治療 Angelman 症候群的 GTX-102，我們將繼續在 40 週至 48 週的 ASPIRE 研究中對患者進行治療，並將於 2025 年下半年開始招募患者以支持 Aurora 研究。

For UX701 in Wilson, we'll complete enrollment of the fourth cohort in the next couple of months. We expect to make a determination on the Stage two dose in 2026.

對於威爾遜的 UX701，我們將在接下來的幾個月內完成第四批學生的招生。我們預計將在 2026 年確定第二階段的劑量。

For UX 111 in Sanfilippo syndrome, we are working toward a Type A meeting the FDA to get agreement on our plan to revolve their observations, which we believe we can address. Following this, we would work through agreements to resubmit the BLA, which we followed by a review period that could take up to six months.

對於 Sanfilippo 綜合徵中的 UX 111，我們正在努力與 FDA 舉行 A 類會議，以就我們的計劃達成一致，以解決他們的觀察結果，我們相信我們可以解決這個問題。隨後，我們將透過協議重新提交 BLA，隨後進行為期可能長達六個月的審核期。

Lastly, for DTX401 and GSDIa, the BLA submission is on track and should be submitted in the fourth quarter.

最後，對於 DTX401 和 GSDIa，BLA 提交正在按計劃進行，應該在第四季度提交。

These last 15 years at Ultragenyx have been incredibly fulfilling and yet the best is still to come. While the news of last month did delay our approval for UX11 and didn't accelerate the OI program. We're confident in the strong (technical difficulty) in 2027.

在 Ultragenyx 工作的過去 15 年非常充實，但最好的還在後頭。而上個月的消息確實推遲了我們對 UX11 的批准，並且沒有加速 OI 計劃。我們對2027年的強勁（技術難度）充滿信心。

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

好了，讓我們繼續回答您的問題。接線員，請提供問答說明。

(Operator Instructions) Joseph Schwartz, Leerink Partners.

（操作員指示）Leerink Partners 的 Joseph Schwartz。

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

嘿，大家好。我是威爾，代替喬發言。恭喜你本季的進展。所以對我們來說這是一個。考慮到 FDA 的領導層最近變動較大，您能否介紹一下您最近與 FDA 的互動情況，尤其是在[軍刀]？您是否注意到訊息傳遞和/或與您互動的人發生了任何有意義的變化？只是想了解我們所看到的這些標題對 Ultragenyx 的日常互動有多大影響？

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

嗯，我認為我們自 CRL 以來的互動一直很好。我認為他們很有成效，我們正在努力發送我們的 A 類會議包。我們對目前的情況感到滿意。我知道他們在代理機構現場服役，有很多定期換油，但事情進展順利。我們對迄今為止的進展感到滿意。

Great. Thank you.

偉大的。謝謝。

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

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

這是為 Joon 開啟的 [Mibi]。鑑於 GTX-102 和（聽不清楚）都使用 LNA 化學，您能否詳細說明導致這兩種藥物的給藥方案截然不同的非目標位點依賴因素？

Well, the LNA chemistry we're using is primarily chosen because it is substantially more potent. It can have more toxicities which is known, but its potency was dramatically better for the target, on the ore, at least one order of magnitude or more in our hands when we compare it to non-LNA chemistry. So there's a reason for it.

嗯，我們之所以選擇使用 LNA 化學，主要是因為它的效力更強。它可能具有已知的更強的毒性，但與非 LNA 化學品相比，其對目標礦石的效力顯著提高，至少高出一個數量級或更多。所以這是有原因的。

We think the potency gives us a dosing that's in the 5- to 14-milligram range, which I think is a distinct advantage, because the non-chemical or the chemical-based off-target effects will be less since we're operating at a relatively low chemical concentration.

我們認為效力使我們的劑量在 5 至 14 毫克範圍內，我認為這是一個明顯的優勢，因為由於我們在相對較低的化學濃度下操作，非化學或基於化學的脫靶效應會更少。

It's a little hard to compare all the different molecules, the ruginess. The one from Roche is also an LNA, the one from Ionis is a different chemistry. Each of the chemistries has upside to downside. We believe the LNA strategy in this case for this target gives us a much better potency and a better therapeutic window. And I think -- that's why I think we're seeing, we think, better results in our program so far and why we've been given breakthrough therapy designation based on FDA's review of our data.

要比較所有不同的分子和粗糙度有點困難。Roche 的產品也是 LNA，而 Ionis 的產品則採用不同的化學成分。每種化學物質都有其優點和缺點。我們相信，在這種情況下，針對這一目標的 LNA 策略為我們提供了更好的效力和更好的治療窗口。我認為——這就是為什麼我認為我們迄今為止看到的項目結果更好，以及為什麼我們根據 FDA 對我們數據的審查獲得了突破性治療稱號。

Thank you.

謝謝。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you. I have a two steps question. The first one is regarding Cosmic trial. I mean, maybe can you remind us what's the reason to run Cosmic trial? And then what is your assumption for this Fastnet arm? And if trials fail, but orbit is positive. How do you see the payer and the physician uptake of the draw?

謝謝。我有兩個步驟的問題。第一個是關於宇宙審判。我的意思是，也許你能提醒我們進行宇宙試驗的原因是什麼？那麼，您對 Fastnet 臂架的假設是什麼？如果試驗失敗，但軌道是正的。您如何看待付款人和醫生對抽獎的接受程度？

My second question, if I may, just also very quick stats question regarding Phase 3 Aspire, your secondary endpoint, you allocate 10% of alpha. Just want to confirm, is that the 0.005? And why isn't it statistical hierarchy to have full 0.005 allele [key] for the secondary endpoint.

我的第二個問題是，如果可以的話，也只是一個關於第三階段 Aspire 的非常快速的統計問題，您的次要終點，您分配了 10% 的 alpha。只是想確認一下，那是 0.005 嗎？為什麼統計層次結構中沒有完整的 0.005 等位基因 [key] 作為次要終點？

Thank you. Of course, and I would not expect anything more than detailed statistical questions. So thank you for that, diving deep. So the Cosmic study, and the reason for it, is to look at young patients who have severe disease who couldn't go in a placebo-controlled trial. And in this case, they'd want to be on the drug they're on, which they're on bisphosphonates. So they all have been on bisphosphonates. So we're simply randomizing some to go on our drug versus they're on bisphosphonates.

謝謝。當然，除了詳細的統計問題之外，我不會期待任何其他內容。所以，謝謝你的深入探討。因此，Cosmic 的研究及其原因是為了觀察無法參加安慰劑對照試驗的患有嚴重疾病的年輕患者。在這種情況下，他們希望服用他們正在服用的藥物，即雙磷酸鹽。所以他們都服用雙磷酸鹽。因此，我們只是隨機選擇一些人服用我們的藥物，有些人服用雙磷酸鹽。

We didn't assume a change in the fracture rate for those patients with bisphosphonate. We assume that they continue to sustain. The question is, can we get a 50% improvement, which is what we were trying to power for.

我們沒有假設使用雙磷酸鹽的患者的骨折率會改變。我們假設它們會繼續維持下去。問題是，我們能否實現 50% 的改進，這正是我們努力追求的目標。

The one advantage of the study, although you would say a head-to-head may have less power, but I'd also argue that the population is very narrow, they're all very young patients that have a very rapid response to the drug -- very rapid [binaural] density production response to the drug. And we think that that will help power the results.

這項研究的一個優點是，儘管你可能會說面對面的比較可能效力較小，但我還認為研究對象非常狹窄，他們都是非常年輕的患者，對藥物有非常迅速的反應——對藥物有非常迅速的[雙耳]密度產生反應。我們認為這將有助於推動結果。

So if, for example -- we believe the study has the power to succeed. If it perhaps just missed, for example, showed a difference, I think it still would provide supportive data in the age group and supportive data of what the head-to-head looks like. I actually think the study should hit though, because I think of the consistent responsiveness of patients with that age. And the fact that bisphosphonates have a relatively weak and variable bisphosphonate response, we feel good about the fact that the combination mechanism of action of our drug will overcome whatever you might see with bisphosphonates.

例如，如果我們相信這項研究有能力成功。例如，如果它可能只是錯過了顯示出差異，我認為它仍然會提供年齡組的支持數據和頭對頭情況的支持數據。我確實認為這項研究應該會成功，因為我認為這個年齡層的患者反應一致。儘管雙磷酸鹽的反應相對較弱且多變，但我們對我們的藥物的組合作用機制感到滿意，因為它將克服雙磷酸鹽可能遇到的任何問題。

And our read, so far, is that we are not worried about bisphosphonates as a competitor. But we want to have the data to prove to authorities, right, that setrusumab is superior to bisphosphonates.

到目前為止，我們的看法是，我們並不擔心雙磷酸鹽作為競爭對手。但我們希望有數據向當局證明，setrusumab 優於雙磷酸鹽。

With regard to Aspire, we allocated the primary to -- [92] to the power is to the Bayley, and 10% to the MDRI, which is called key secondary, but it's really the primary alpha split.

對於 Aspire，我們將主要部分分配給 -- [92] 給 Bayley，將 10% 分配給 MDRI，這稱為關鍵次要部分，但實際上是主要的 alpha 分割。

The reason for that is the MDRI is a very powerful method, which we see very strong statistical significance. So we didn't need to use much power to do that. But the idea was, if MDRI hits, it gives us a way of having a successful study no matter what happens to Bayley. If Bayley hits, we expect both to hit, then it's fine. Could we done sequential? You could do a sequential, Bayley first and then MDRI, or MDRI first then Bayley and kept all 0.05.

原因在於 MDRI 是一種非常強大的方法，我們看到了非常強大的統計意義。所以我們不需要耗費太多的電力來做到這一點。但我們的想法是，如果 MDRI 成功，無論貝利發生什麼，我們都能找到成功研究的方法。如果貝利擊中，我們預計兩人都會擊中，那就沒問題。我們可以按順序完成嗎？您可以按順序進行，先進行 Bayley，然後進行 MDRI，或先進行 MDRI，然後進行 Bayley，並保持全部 0.05。

But by doing them separately, it means that were not dependent on Bayley. It doesn't have to hit in order to succeed in this design. We can still have a successful trial even with Bayley were not to hit. I think it just provides a more secure approach to statistics here. But we appreciate sequential would be another way to do it. But we think what we've picked gives us the best chance and brings forth a new method.

但透過分別進行這些操作，就意味著我們不依賴貝利。在這個設計中，不一定要擊中才能成功。即使貝利沒有擊中，我們仍然可以成功進行審判。我認為它只是提供了一種更安全的統計方法。但我們認為順序是另一種實作方法。但我們認為我們所選擇的給了我們最好的機會並帶來了一種新的方法。

The MDRI method is a new method for the FDA, but it is a powerful method and we think will become the dominant superior way to look at complex multi-domain neurologic development disorders. And once we start showing this in this study, I think people will understand how much more powerful it is when you're talking about a very heterogeneous population of patients. So we're excited that the FDA has given us a chance to put that forth as one of the primary ways to assess our Phase 3 study.

MDRI 方法對於 FDA 來說是一種新方法，但它是一種強大的方法，我們認為它將成為研究複雜的多領域神經發育障礙的主導方法。一旦我們開始在這項研究中展示這一點，我認為人們就會明白，當你談論一群非常異質的患者時，它有多強大。因此，我們很高興 FDA 給了我們機會，將其作為評估我們第三階段研究的主要方法之一。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

Hi, thank you for taking my question. Emil, for the third and final read for Orbit, there is some debate among investors that if it is statistically significant at that final rate at 18 months, that the level of clinical benefit will also matter more than it might have at 12 months. Because the argument is, if it's taking that long to separate from the bisphosphonates, how much better is it than bisphosphonates?

你好，謝謝你回答我的問題。埃米爾，對於 Orbit 的第三次也是最後一次解讀，投資者之間存在一些爭論，即如果 18 個月時的最終利率具有統計意義，那麼臨床獲益水平也將比 12 個月時更重要。因為爭論的焦點是，如果它需要那麼長時間才能與雙磷酸鹽分離，那麼它比雙磷酸鹽好多少？

So I wanted to get your thoughts on what you think doctors would think about that particular argument. Does it matter the -- as long as the statistically significant, does it matter how much separation is getting at the 18-month time point? Thanks.

所以我想聽聽您的想法，您認為醫生會如何看待這個特定的論點。只要具有統計意義，這重要嗎？在 18 個月的時間點上分離多少重要嗎？謝謝。

I think if you look at the treatment effect estimates, the difference between patients, I think you could have the same difference. But because of more variation, it just might take longer to separate the group. So the treatment effect size could very well be the same.

我認為如果你看一下治療效果評估，看看患者之間的差異，我認為你可能會有同樣的差異。但由於變異較大，可能需要更長的時間來區分群體。因此治療效果的大小很可能是相同的。

But we had to try to caution people that if it's 60%, 67%, 40%, 50%, in this range, it is substantially better than what certainly observed. And I don't think that that percent number is going to have a dramatic impact exactly on what happens. I think any number in that range is a strong benefit to patients.

但我們必須試著提醒人們，如果這個數字是 60%、67%、40%、50%，那麼它就比觀察到的結果好得多。我不認為這個百分比數字會對最終發生的事情產生巨大影響。我認為該範圍內的任何數字對患者來說都是一種很大的益處。

What we can see from Phase 2, though, is that the effect on functional ability and other aspects of the patient health is substantial. And really, that is what's going to drive the benefit.

然而，從第二階段我們可以看出，對功能能力和患者健康其他方面的影響是巨大的。事實上，這才是真正帶來利益的因素。

To give you the parallel, Tazeen, we talk about XLH, the Crysvita story, we had an RSS score that as a primary endpoint, but there's no patient looking at the RSS score change percent telling us whether they're going to put the kit on drug or not. The truth is that proves that it does improve rickets, but the reason it has so successful as patients feel great are more functional, more active, just like we're seeing with OI.

為了給你一個類比，Tazeen，我們談論 XLH，Crysvita 的故事，我們有一個 RSS 分數作為主要終點，但沒有患者查看 RSS 分數變化百分比來告訴我們他們是否要將試劑盒用於藥物。事實證明，它確實可以改善佝僂病，但它之所以如此成功，是因為患者感覺更好，功能更強，更活躍，就像我們在成骨不全症中看到的那樣。

That's what drives prescriptions. That's what drives patient demand. The numbers we have to hit, we will hit the numbers. I think the thing in utilization will come from the overall benefit. And we think what we're seeing in Phase two mix is at least as good as Crysvita and it's that effect on OI. So that's why we're confident about where it goes.

這就是處方的驅動力。這就是推動患者需求的因素。我們必須達到的目標，我們一定會達到。我認為利用的東西會來自於整體效益。我們認為，第二階段混合物至少與 Crysvita 一樣好，並且對 OI 有相同的作用。這就是我們對它的發展充滿信心的原因。

Anupam Rama, JPMorgan.

摩根大通的 Anupam Rama。

Hey, guys. This is Billy on for Anupam. Just will appreciate in the FDA acknowledged the neurodevelopmental outcomes data are robust in the biomarker data as supportive evidence. What additional clinical data is likely to be included in a resubmission? Is this more kind of longer duration data we're thinking or additional biomarkers that would be asked for? Thanks.

嘿，大家好。這是 Billy 為 Anupam 表演的。只是會欣賞 FDA 承認的神經發育結果數據在生物標記數據中作為支持證據的穩健性。重新提交時可能包含哪些額外的臨床數據？我們考慮的是更多類型的長期數據還是需要額外的生物標記？謝謝。

Yeah. So what they specifically asked for was an update on the clinical endpoint data and the biomarker data, just because time will have passed, they just want the latest data we had, which we have data, patients have been on in the study.

是的。因此，他們特別要求更新臨床終點數據和生物標記數據，因為時間已經過去，他們只想要我們擁有的最新數據，即我們擁有的數據，患者一直在研究中。

So we'll collect their Bayley data, and the [biomarker] data of the data, that sort of the developmental data they've seen, which they considered robust. It will include whatever CSF biomarker data we have as well in that assessment as requested.

因此，我們將收集他們的貝利數據和[生物標記]數據，即他們所看到的、他們認為可靠的發育數據。它將包括我們在該評估中根據要求擁有的任何 CSF 生物標記數據。

So it's pretty much an update on the ongoing data. And it was more, because time had passed, they just want to see everything continues as we believe. And we believe patients are doing well, and it will be what I would call a routine update of the clinical data.

因此，這基本上是對正在進行的數據的更新。更重要的是，因為時間已經過去，他們只是希望看到一切都按照我們所相信的那樣繼續下去。我們相信患者的情況良好，這將是我所說的臨床數據的例行更新。

Kristen Kluska, Cantor Fitzgerald.

克里斯汀·克魯斯卡，坎托·費茲傑拉。

Hi, good afternoon, everybody. For the Orbit study reading out later this year, I know you're still very high conviction in the trial being successful. But I wanted to talk about a hypothetical scenario, where maybe the structure data fall slightly under what you were hoping for, but you see really strong benefits on pain.

大家好，下午好。對於今年稍後公佈的 Orbit 研究報告，我知道您仍然非常相信試驗會成功。但我想談論一個假設的情況，其中結構數據可能略低於您所希望的水平，但您會看到疼痛確實有很大的好處。

Do you still think that there is a strong case to make for the FDA here and argue that this will drive higher adoption for patients since they deal with this on a daily basis over the fracture aspect?

您是否仍然認為 FDA 有充分的理由這樣做，並認為這將推動患者採用該療法，因為他們每天都要處理骨折方面的問題？

Well, I think that your point is maybe there's some variation in fractures, and you just missed that and you have other supportive data. I think the FDA will always look at the total totality of the data in our rare disease program. We've had that many times in many programs. Our sense here is that we're seeing a fundamental mechanistic effect on more density.

嗯，我認為你的觀點是骨折可能存在一些變化，但你只是忽略了這一點，而且你還有其他支持數據。我認為 FDA 將始終關注我們罕見疾病計劃的全部數據。我們在很多專案中都多次遇到這種情況。我們的感覺是，我們看到了對更大密度的基本機械效應。

The second has a fracture, it depends on how many fractures that patient have their particular condition. We have a lot more type 3 and type 4s in the study. They have a lot of complex problems. And so I'm sure that the support of other data would help us in any situation, whatever the statistical or treatment size is.

第二種是出現骨折，骨折的多寡要看病人的具體情況。我們的研究中有更多的 3 型和 4 型。他們有很多複雜的問題。因此，我相信無論統計或治療規模如何，其他數據的支持都會對我們有所幫助。

And so that's just generally been the case. We feel confident what the fracture data will be what it is. We're seeing what's going on in Phase 2. We know that as time goes on, there are very few fractures among patients after they've gotten established on the treatment. So we feel good we'll be able to do that.

整體來說，情況就是這樣。我們對骨折數據有信心。我們正在觀察第二階段發生的情況。我們知道，隨著時間的推移，患者在接受治療後很少發生骨折。因此我們很高興能夠做到這一點。

But hypothetically, I think the data will always be more than just fractures in this disease state. And the body of data we have, we think will support its use, however, we come out with on fractures.

但從假設的角度來說，我認為在這種疾病狀態下的數據永遠不只是骨折。我們認為，我們擁有的數據將支持它的使用，然而，我們發現了一些問題。

Yigal Nochomovitz, Citigroup.

花旗集團的 Yigal Nochomovitz。

Hey, thank you. Hi, Emil, and team. I just had a clarifying question firstly regarding GSDIA in the filing. I think Eric, you mentioned that you were making sure that you wanted to resolve any of the outstanding CMC issues on 111 before submitting GSDIA.

嘿，謝謝你。嗨，艾米爾和團隊。我首先想澄清一下有關文件中的 GSDIA 的問題。我認為 Eric，您提到過，在提交 GSDIA 之前，您要確保解決 111 上所有未解決的 CMC 問題。

Could you just clarify, is there a specific question that you're trying to to answer on CMC related to GSDIA by virtue of clarifying something on UX 111? Or is this simply just a matter of taking extra precaution to make sure that you've got everything right before filing the GSDIA?

您能否澄清一下，您是否想透過澄清 UX 111 上的某些內容來回答與 GSDIA 相關的 CMC 上的一個具體問題？或者這只是採取額外的預防措施以確保在提交 GSDIA 之前一切順利？

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

艾瑞克，你想回答這個問題嗎？或是你喜歡我來回答嗎？

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

我會嘗試一下，並且很高興看到後續進展。但重要的是要記住，貝德福德的製造工廠正在生產 MPS IIIA 和 GSDIA 的基因療法。因此，任何與該製造工廠相關的調查結果都可能透過 GSDIA 得到證實。因此，我們只是想確保我們能夠完成所有這些工作以及任何與 GSDIA 相關的工作。

Okay. Thanks. And then on --

好的。謝謝。然後--

No, I think we're going go ahead.

不，我想我們會繼續前進。

Okay. I was going to say on OI, given the first two in terms of -- looking at the final one. I'm just curious if you have any updated thoughts as far as what you believe the expected placebo AFR would be.

好的。我本來想就 OI 說一下，考慮到前兩個，再來看看最後一個。我只是好奇，對於預期的安慰劑 AFR，您是否有任何最新的想法。

Obviously, we've done some work and there are a number of epidermologic studies out there, both in Scandinavia as well as the United States, which point to various ranges for AFR. I'm just wondering if you could comment on what you believe would be the most likely scenario at this point as well as on some of the more specific aspects of the the statistics again, regarding this concept of variance or over dispersion, which, as we know, is a feature of this particular data set given the way the fractures are distributed?

顯然，我們已經做了一些工作，並且有許多流行病學研究，無論是在斯堪的納維亞半島還是在美國，都指出了 AFR 的不同範圍。我只是想知道您是否可以評論一下您認為目前最有可能出現的情況，以及統計數據的一些更具體的方面，關於方差或過度分散的概念，我們知道，考慮到裂縫的分佈方式，這是這個特定數據集的一個特徵？

Yeah. So yes, we're aware of the annualized factor rate available in literature and looking at natural history, the principal investigators have on hand. We really use a lot of the data coming on for pretreatment for baseline for both Orbit and COSMIC to do our modeling. And we were really looking at those patients with the baseline AFR between 0.7 and 1 for our modeling to support both of the work for internally and obviously, the power we did. -- for the primary efficacy analysis period at 18 months.

是的。是的，我們知道文獻中提供的年化因子率，並且研究自然史，主要研究人員已經掌握了這些資料。我們確實使用了大量用於 Orbit 和 COSMIC 基線預處理的資料來進行建模。我們確實在關注基線 AFR 在 0.7 到 1 之間的患者，以便為我們的模型提供內部支持，並且顯然支持我們所做的工作——針對 18 個月的主要療效分析期。

And with the dispersion, yes. I mean, I think while we did not change entry criteria for Orbit Phase 2 going into Orbit Phase 3 -- on the strength of the Phase two data, we had really what I consider to be a self-enrichment of patients with type 3s and type 4s. I think they needed to see that strong safety and efficacy data to take the risk to come into clinic, because remember, they really are at risk just from traveling into sites to sign consents and begin setting participation.

是的，而且存在分散性。我的意思是，我認為雖然我們沒有改變 Orbit 第 2 階段進入第 3 階段的准入標準 - 但根據第 2 階段的數據，我們確實實現了我認為的 3 型和 4 型患者的自我豐富。我認為他們需要看到強有力的安全性和有效性數據，才能冒險進入診所，因為請記住，他們只是前往現場簽署同意書並開始參與就已經面臨風險。

So I will say we did -- we have a greater number of patients with type 3 and type 4 OI in the Phase 3 part of Orbit compared to Phase 2.

所以我想說我們確實做到了——與第 2 階段相比，Orbit 在第 3 階段中患有 3 型和 4 型 OI 的患者數量更多。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

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

這是 Salveen 的 Tommy。從監管和競爭的角度來看，您如何看待明年 Angelman 數據的標準？想知道您是否收到有關使用每日 4 次作為主要終點的任何更新回饋。

Eric, do you want to do it? Go for it.

艾瑞克，你想做這件事嗎？大膽試試吧。

No, sorry, I didn't know if you guys were back online or not. But again, I guess I'll give it a start and you can certainly jump in. But the bar, I think, range man, it hasn't moved for us. So certainly, we had our interactions with the FDA. We do feel like we have full buy-in with the study there. We do work through our statistical analysis plans with them as well, so have been in communication with.

不，抱歉，我不知道你們是否已經重新上線。但是，我想，我會再次開始，當然可以加入。但是我認為，對我們來說，酒吧並沒有動。當然，我們與 FDA 有過互動。我們確實覺得我們完全認同這項研究。我們也與他們一起制定了統計分析計劃，因此一直保持溝通。

Again, following back to the data we generated in Phase 2 and that was quite a few number of patients there who continue to see the attainment of new developmental skills over time, we are not seeing a flat to effect. We are seeing them continue to gain new abilities and that's very important to them and their parents.

再一次，回顧我們在第二階段產生的數據，有相當多的患者隨著時間的推移不斷獲得新的發展技能，我們並沒有看到效果的平穩。我們看到他們不斷獲得新的能力，這對他們和他們的父母來說非常重要。

We have a lot of confidence in our primary endpoint with Bailey cognition. Again, cognition is foundational to everything else you're looking at there, whether it be expressive language, receptive language motor, or anything else there, it is foundational, and we think an appropriate endpoint. Again, we talked about using -- under and really being an ideal tool for these types of indications because you're really looking at all of these aspects on a very straightforward transparent scoring system to really look at the benefit in totality and also allowing some variability between individual patients.

我們對貝利認知的主要終點非常有信心。再說一次，認知是你正在研究的一切事物的基礎，無論是表達性語言、接受性語言運動，還是其他任何東西，它都是基礎，我們認為它是一個合適的終點。再次，我們討論了使用——這確實是這些類型適應症的理想工具，因為您實際上是在一個非常直接透明的評分系統上查看所有這些方面，以真正了解整體效益，同時也允許個體患者之間存在一些差異。

So again, I think that rapid enrollment -- and really, it's not just 129 patients over seven months. It's 129 patients in a very complex study. And that really speaks to the enthusiasm with sites, with patients, and their families to really gain access to this therapy.

所以，我再次認為，快速招募——實際上，不僅僅是七個月內招募 129 名患者。這是一項非常複雜的研究，涉及 129 名患者。這確實體現了治療中心、患者及其家人對獲得這種療法的熱情。

Maxwell Skor, Morgan Stanley.

摩根士丹利的麥克斯韋爾·斯科爾（Maxwell Skor）。

Great. Thank you very much for taking my question. I was just wondering, can you elaborate a bit on how PRV proceeds are being factored into your path to 2027 GAAP profitability? Any insights into your relative confidence in receiving all three PRBs? Thank you.

偉大的。非常感謝您回答我的問題。我只是想知道，您能否詳細說明一下 PRV 收益是如何納入您實現 2027 年 GAAP 盈利能力的路徑中的？您對獲得所有三個 PRB 的相對信心有何見解？謝謝。

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

嗯，顯然，PRB 是其中的重要組成部分，我會讓霍華德談談 PRB 以及我們如何將它們納入我們的現金計劃。

Yeah. We have PRBs from three of our programs, so 11,401 and 143 factored in. There has been a shift in timing on those, but we still think all of them come through. So yes, I think that's where I stop.

是的。我們有三個項目的 PRB，因此將 11,401 和 143 計算在內。雖然時間上有所變化，但我們仍然認為它們都會實現。是的，我想我就到此為止了。

Yeah. If it's reauthorized and makes it easier for the OI one, but if it's not, then the other two certainly could be -- will be done in time to achieve, and we'd expect their value to be higher. So the net of whether it's three with reauthorization or two without, we think we're still up in the same place from a total cash.

是的。如果它被重新授權並且使 OI 變得更容易，但如果不是，那麼另外兩個肯定可以 - 將及時完成以實現，我們預計它們的價值會更高。因此，無論是三家獲得重新授權的公司，還是兩家沒有重新授權的公司，我們認為，從現金總額來看，我們的淨額仍處於同一水平。

Great. Thank you.

偉大的。謝謝。

Yaron Werber, TD Cowen.

Yaron Werber，TD Cowen。

This is Dan on for Yaron. Congrats on the quarter -- you noticed that there's going to be more of a prioritization on controlling spend, including softening delays or expenses. Can you give us a more granularity about what this entails? And are you exploring the options in the event that responding to the CRL for U11 takes longer than expected. Thank you so much.

這是 Dan 代替 Yaron 上場。恭喜本季—您注意到我們將更加優先考慮控制支出，包括減少延誤或費用。您能否更詳細地說明一下這意味著什麼？如果響應 U11 的 CRL 所花的時間比預期的要長，您是否正在探索其他選項？太感謝了。

Yeah, thanks. I think a lot of this is practical stuff that we're focusing on. And maybe Howard can go through it with you. But our expectation on the CRO part is to get through. I mean, I don't -- we've looked through the whole list. We actually had a lot of feedback already, and we've already done a lot of the changes and things. So we don't really see there's anything in there that is undoable, very doable stuff. So we're working through it. So we're not really planning for us not to get it done. I think it will be done.

是的，謝謝。我認為其中很多都是我們關注的實際問題。也許霍華德可以和你一起度過難關。但我們對 CRO 部分的期望是能夠通過。我的意思是，我不知道——我們已經看過整個名單了。實際上我們已經收到了很多回饋，並且已經做了很多改變和事情。所以我們確實沒有看到其中有什麼是不可行、非常可行的事情。所以我們正在努力解決這個問題。所以我們實際上並沒有計劃不去完成它。我認為它會完成的。

And so far, we think the FDA has been responsive in our discussions since then. Maybe, Howard, you can talk about how we're managing costs?

到目前為止，我們認為 FDA 對我們此後的討論做出了積極的回應。霍華德，也許你可以談談我們是如何管理成本的？

Yeah. Our goal has been and remains to be GAAP profitable, full year GAAP profitable in 2027. And so how do you get there, of course, is continuing to grow the top line, but also making sure that we are good stewards of our cash.

是的。我們的目標一直是並將繼續是實現 GAAP 盈利，到 2027 年全年實現 GAAP 盈利。那麼，如何實現這一目標呢？當然，就是繼續增加營業收入，同時確保我們妥善管理現金。

And so with some of the delays that we've experienced this summer, we did the natural thing, which is to delay those expenses and make sure we're being prudent and making sure we're using our money as well.

因此，對於今年夏天遇到的一些延誤，我們採取了自然的做法，即推遲這些開支，確保我們謹慎行事，確保我們也使用好我們的資金。

It involves not hiring people that would have been hired for launches and managing other head count -- and in addition to that, just really scrubbing through all the spend that should be delayed as well and not just continue to add with momentum.

它涉及不僱用那些本來會被雇用來負責發布會的人員和管理其他員工人數——除此之外，還要仔細檢查所有應該推遲的支出，而不是繼續隨意增加。

So we hope that bridge us to the the point in which we will get the cash and manage where we're at. But we're -- I think it's just a prudent part of managing company in these situations. And we've been through this before. So we're actually very facile at making the moves we have to make.

因此，我們希望能夠幫助我們獲得現金並管理好現狀。但我們——我認為這只是在這種情況下管理公司的一個謹慎的部分。我們以前也經歷過這樣的事。因此，我們實際上能夠非常輕鬆地採取我們必須採取的行動。

Great. Thank you so much.

偉大的。太感謝了。

Sami Corwin, William Blair.

薩米·科溫、威廉·布萊爾。

Congrats on the progress. I had one on UX111 and then a broader question on your AAV platform. Do you think that the SEBRA leadership change will be helpful or kind of hinder the CRL resolution for UX111?

恭喜你取得進展。我在 UX111 上有一個問題，然後在您的 AAV 平台上有一個更廣泛的問題。您認為 SEBRA 領導層的變動會對 UX111 的 CRL 決議有幫助還是有阻礙？

And then given the recent safety events was systemically administered AAV, are you thinking about modifying your immunosuppression regimens at all? Or are there any additional precautions you've implemented to decrease the risk of AAV-related SAEs? Thank you.

然後考慮到最近的安全事件是系統性地使用 AAV，您是否考慮過修改您的免疫抑制方案？或者您採取了任何其他預防措施來降低 AAV 相關 SAE 的風險？謝謝。

So look, I think there's a lot of very good people at FDA. They're still there doing their jobs. And our sense is that they won't impact their ability to do their jobs. I think in some ways, it might be simpler for the next period because the team has head down in the work, can do their work and work with us in solving these things. So I think it will stick to a very practical matter of fact, line-by-line resolution of issues raised.

所以，我認為 FDA 有很多非常優秀的人才。他們仍在那裡做他們的工作。我們認為這不會影響他們工作的能力。我認為從某種程度上來說，下一階段可能會更簡單，因為團隊會埋頭工作，做好自己的工作，並與我們一起解決這些問題。因此我認為它將堅持非常實際的事實，逐行解決所提出的問題。

And I think it's very doable without having high-level leadership for these kinds of things, these kinds of resolutions, because the clinical data were felt to be robust and strong, that's a little there's a little less uncertainty in judgment because safety was excellent.

我認為，在沒有高層領導的情況下，這些事情、這些決議也是完全可行的，因為臨床數據被認為是可靠和有力的，這在判斷上就少了一些不確定性，因為安全性非常好。

There are no real question marks there. It's really more about getting the things boxes checked on all the CMC pieces which we think we can do. So we're not so concerned about leadership for that particular aspect of it.

那裡沒有真正的問號。這實際上更多的是關於檢查我們認為可以做的所有 CMC 部分。因此，我們並不太關心這方面的領導力。

With regard to the AAV platform, we're highly supportive AAV as a treatment strategy. We obviously have a lot of investment in it. But for many of the liver-targeted ones we're doing at relatively lower doses compared to others, we have not seen substantial safety issues like you're talking about either death or very serious liver complications. The lower dose that we use, we think are in a very safe range, and we feel very good on them.

關於 AAV 平台，我們非常支持 AAV 作為治療策略。我們顯然對此投入了大量資金。但是對於我們以相對較低的劑量進行的許多針對肝臟的治療，我們還沒有看到重大的安全問題，例如你所說的死亡或非常嚴重的肝臟併發症。我們認為，我們使用的較低劑量處於非常安全的範圍內，我們感覺非常好。

Now we are looking at enhancing immune modulation, but it's more about trying to alter or support more efficacy or managing anti-transgene responses. We are looking at that in our Cohort 4 for UX111 to try to manage the immunological responses.

現在我們正在研究增強免疫調節，但更多的是嘗試改變或支持更多的功效或管理抗基因改造反應。我們正在 UX111 的第 4 組研究中嘗試控制免疫反應。

But the drug worth was just the simple steroids, fine. That's what we can get approved on. And our goal is always to continue to look to optimize. But it's not a central thing to try to prevent a death, it's more about trying to optimize the outcome. And we will look at and be more fast at looking at immune modulation where needed.

但藥物的價值只是簡單的類固醇，很好。這就是我們可以獲得批准的原因。我們的目標始終是不斷尋求優化。但試圖阻止死亡並不是核心問題，更重要的是試圖優化結果。我們將在需要的地方更快地研究免疫調節。

But so far, we don't have any programs that are of the high dose type that have created more complexities. But I want to say that if you have a lethal disease as Duchenne is or others, it is not inappropriate to have a situation that would challenge a patient. And I think parents should have the right to make their decisions about the risk benefit. And we think that a lot of these horrible diseases are a death sentence and a horrible death sentence for families and they should be given the opportunity to make their decision on what's the best health care for their kid.

但到目前為止，我們還沒有任何高劑量類型的計畫造成更大的複雜性。但我想說的是，如果你患有像杜氏肌肉營養不良症或其他疾病那樣的致命疾病，那麼遇到對患者有挑戰的情況也是合適的。我認為父母應該有權利對風險利益做出決定。我們認為，許多可怕的疾病對家庭來說都意味著死亡，他們應該有機會決定什麼是對孩子最好的醫療保健。

And I think they can -- are capable of making that decision with an approved product.

我認為他們能夠——有能力針對已批准的產品做出這項決定。

Maurice Raycroft, Jefferies.

莫里斯·雷克羅夫特（Maurice Raycroft），傑富瑞集團（Jefferies）。

This is Faizan on for Maurice. I wanted to clarify for setrusumab. If you can provide more granular timing on the speed disclosure, that last patient visit should be end of October. So it sounds like there will be no DMC review and you'll be unblinded to the data.

這是 Faizan 代替 Maurice 上場。我想澄清一下 setrusumab。如果您可以提供有關速度披露的更詳細時間，那麼最後一次患者就診應該是在 10 月底。因此聽起來好像不會有 DMC 審查，而且您將無法獲得數據。

So technically, it should be faster than two months than it took for -- so you'd like what day and time the data are coming out?

因此從技術上講，它應該比之前花費的時間快兩個月以上——那麼您想知道數據將在哪一天和什麼時間發布？

I'm sure we can put out that.

我確信我們可以實現這一點。

Well, yeah, the last piece, I don't remember, there's this whole process of getting all the last data sets, the X-rays reviewed finalize, clean no issues. We have to look at blinded to make sure there's nothing wrong to operations. It's a Phase 3 study. So it's not something you want to rush through. It's the final assessment. We want to make sure we do it carefully.

嗯，是的，最後一部分，我不記得了，整個過程包括獲取所有最後的資料集，X 射線審查完成，清理乾淨沒有問題。我們必須進行盲法檢查，以確保操作沒有任何問題。這是一項第三階段的研究。所以這不是一件你想匆匆忙忙完成的事。這是最終考核。我們希望確保我們能謹慎地做這件事。

We've been saying around the end of the year could be before the end of the year, it could be just after the end of the year, somewhere in there. But we don't want to nail it down because, frankly, it's not possible to and we're not trying to be cagey here, it's just that we want to make sure we all the time is provided to get the study closed out absolutely perfectly.

我們一直說是在年底左右，可能是在年底之前，也可能是在年底之後，或是在那段時間的某個時候。但我們不想將其確定下來，因為坦白說，這是不可能的，而且我們也不是想在這裡保持謹慎，我們只是想確保我們有足夠的時間來完美地完成這項研究。

And every aspect with the study is perfect. We owe it to the patients and our investors to make sure that everything is perfectly correct when we go out and release data.

並且學習的各個方面都很完美。當我們發布數據時，我們有責任確保一切完全正確，以造福患者和投資者。

Makes sense. And then for the instrument, the demand is there clearly and these are all deletion patients. But can you talk more about the patient baseline profile relative to your Phase 1/2 enrolled patients? And then should we expect more durability data from the Phase 1/2 cohort of patients maybe this year?

有道理。然後對於儀器來說，需求是明確的，這些都是缺失患者。但是，您能否詳細談談相對於您入選的 1/2 期患者的基線狀況？那麼，我們是否應該期待今年從第 1/2 階段患者群體中獲得更多耐久性數據？

Well, the patients in the Phase 2 and now enrolled in the Phase 3 are essentially the same. They're 4- to 17-year-old deletion only patients. So they're actually identical, the same criteria we used. So they're really very comparable.

嗯，第 2 階段的患者和現在第 3 階段的患者本質上是相同的。他們是 4 至 17 歲的缺失患者。所以它們實際上是相同的，我們使用了相同的標準。所以它們確實非常具有可比性。

So whatever we saw in Phase 2 is probably pretty much what you should see in these Phase 3 patients. So with the Aurora study, we're going to look at younger patients or older patients with deletion will also look at patients that have missense cation or the ICD/UPD type. So we're going to gain knowledge.

因此，我們在第 2 階段看到的情況可能與您在第 3 階段患者身上看到的情況基本相同。因此，透過 Aurora 研究，我們將觀察年輕患者或患有缺失的老年患者，也將觀察患有錯義陽離子或 ICD/UPD 類型的患者。這樣我們就能獲得知識。

The idea was to gain sufficient safety data to show that you can administer the drug and then show that their efficacy, even though in an open-label format that the efficacy is comparable to the effect that we will demonstrate and prove as a cause and effect of the drug in the randomized controlled study. So that's the idea on the approach we're taking.

這樣做的目的是獲得足夠的安全數據，以證明你可以使用該藥物，然後證明其療效，即使在開放標籤形式下，其療效也與我們在隨機對照研究中展示和證明的藥物因果關係相當。這就是我們所採取的方法的想法。

Does that answer your question?

這回答了你的問題嗎？

Yeah. And should we see more follow-up data from the Phase 1 to this year?

是的。我們是否應該看到從第一階段到今年的更多後續數據？

We haven't planned right now. I mean, the team is working on two Phase 3 programs right now. That is our focus. And the last thing I want to do is put another item on their plate of running more. Patients continue to get drug, and are doing fine, and we're encouraged with it. But we hadn't planned another cut of data yet. We got to get the Phase 3 done and do them well.

我們目前還沒有計劃。我的意思是，該團隊目前正在進行兩個第三階段的專案。這是我們的重點。我最不想做的事就是讓他們再多跑一些步。患者繼續接受藥物治療，並且情況良好，我們對此感到鼓舞。但我們尚未計劃另一次數據削減。我們必須完成第三階段，並且做好它。

Got it, thank you so much.

明白了，非常感謝。

Jack Allen, Baird.

傑克艾倫，貝爾德。

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

感謝您回答我的問題。恭喜你取得進展。我想問一對夫婦有關 setrusumab 計劃的問題。就 Orbit 而言，您在看到的任何盲點資料中看到了什麼樣的標準差？您對目前所製定的統計分析計畫有多大信心？您認為有必要更新 SAP 嗎？然後我也會快速跟進。

Yeah. We haven't really talked to stand Aviation. I know everyone is trying to calculate disperse you didn't say dispersion though. So but everyone's else seeing dispersion just to show they're at the level of statistician operating here. I know everyone is trying to do the math for us.

是的。我們還沒有真正與航空業進行過交談。我知道每個人都在嘗試計算分散度，但你沒有說分散度。但其他人看到的離散只是為了表明他們處於這裡統計員的水平。我知道每個人都在盡力為我們計算。

We haven't put out the standard deviation. I don't really even know it off the top of my head right now. But there is a significant amount of variation, because we've said about a third of the patients had fracture rate at baseline up from three or above and about two-thirds below. We also have age range of 5 year-old up to 25.

我們還沒公佈標準差。我現在真的還不知道這一點。但存在很大的差異，因為我們已經說過，大約三分之一的患者在基線時的骨折率高於三分之二或以上，而大約三分之二的患者在基線時的骨折率低於三分之二。我們的年齡範圍為 5 歲至 25 歲。

So there's a bit of range in those things. Those are all factors in the standard deviation, both the standard deviation of the AFR, but also bone BMD response, et cetera.

所以這些事情都有一定的範圍。這些都是標準差的因素，包括 AFR 的標準差，還有骨骼 BMD 反應等等。

We have comp in the SAP in the sense that the negative binomial model actually is the best way to look at this kind of fracture data. And frankly today, I actually did a little AI search, which you can do yourself and look up negative binomial and fractures. And it will tell you, actually, this is the best method. So you can do it yourself.

我們在 SAP 中擁有補償，因為負二項式模型實際上是查看此類裂縫數據的最佳方式。坦白說，今天我實際上做了一些人工智慧搜索，你可以自己做並找到負二項式和骨折。它會告訴你，實際上，這是最好的方法。所以你可以自己做。

And it says, among all the messages and some comparison papers, it's the best method. Now, there are things of details to that, like what co-variables, what are the items that contribute to variation that we can look at? Those are basically tweaks to the model that you can make. And usually, in any stat plan, you offer some flexibility in what covariable you might use, because you have to control for contributions of variation, which included the baseline AFR.

並且它說，在所有訊息和一些比較論文中，這是最好的方法。現在，有一些細節，例如哪些共變量，哪些項目導致了我們可以查看的變化？這些基本上是您可以對模型進行的調整。通常，在任何統計計劃中，您都會在可能使用的協變量方面提供一些靈活性，因為您必須控制變異的貢獻，其中包括基線 AFR。

It could include the type OI who include the age, right? Those are three obvious ones that would be potentially included. So those are some of the tweaks you would do to a final analysis plan, but the basic negative of our normal model is set, and we're confident in it as a strategy. And we just want to make sure we're using the right set of covariable to help control four baseline variation that's not related to actual treatment effect, and that will help assure that we get the best result.

它可能包括年齡在內 OI 型患者，對嗎？顯然，這三個是可能被納入的。因此，這些是您對最終分析計劃所做的一些調整，但我們的正常模型的基本負面因素已經確定，並且我們對它作為策略充滿信心。我們只是想確保使用正確的協變量集來幫助控制與實際治療效果無關的四個基線變化，這將有助於確保我們獲得最佳結果。

Great. Great. That's super helpful context. And then you did mention that the Phase two seems to be trading a very durable effect and even a deepening of response over time, at least that's how I would characterize some of your earlier comments from setrusumab. I just wanted to ask if there are any plans to present updated data from the Phase 2 cohort of 24 patients and when we may see that data set if there are plans.

偉大的。偉大的。這是非常有用的背景資訊。然後您確實提到，第二階段似乎正在產生非常持久的效果，甚至隨著時間的推移反應會加深，至少這就是我對您之前對 setrusumab 的一些評論的描述。我只是想問一下，是否有計劃展示第 2 階段 24 名患者的最新數據，如果有計劃，我們什麼時候可以看到該數據集。

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

嗯，我們還沒有計劃。該研究仍在進行中。病人的情況非常好，我們考慮在某個時候這樣做。我們還沒有製定具體的計劃。

Hannah Way, Guggenheim Partners.

漢娜‧韋 (Hannah Way)，古根漢合夥公司。

This is Hannah for Debjit. We have questions regarding OI program. Could you clarify which spot for net therapy for patients were on prior before entering the audit study? And roughly how many patients were on reclass -- thank you.

我是 Debjit 的 Hannah。我們對 OI 計劃有疑問。您能否澄清一下在進入審計研究之前，患者的網路治療地點在哪個位置？大約有多少名患者需要重新分類？謝謝。

Yes. We haven't disclosed which best phosphate on, but we have said faster, I think it's greater than 90% have had bisphosphonates on board, like a large fraction. So it's primarily because it's enrolling patients with a higher fracture rate the higher ones are in the study. So the fraction on the phosphate were, I think, above 90%. But we haven't said which ones, it's several different ones.

是的。我們還沒有透露哪種磷酸鹽最好，但我們已經說過更快，我認為超過 90% 的患者都使用了雙磷酸鹽，佔很大比例。因此，這主要是因為它招募了骨折率較高的患者，因此研究中的骨折率較高。所以我認為磷酸鹽的比例在 90% 以上。但我們還沒有說是哪些，而是有幾種不同的。

So it wouldn't help you.

所以它不會幫助你。

Raghuram Selvaraju, H.C. Wainwright.

拉古拉姆‧塞爾瓦拉朱 (Raghuram Selvaraju)，H.C.溫賴特。

This is Dan on for Ram. Congrats on the -- so have you noticed or has current mentioned anything notable about the US or Canadian casino market the royalties appeared kind of flat on a Q1 year-over-year basis but increased over 17% Q2 year-over-year. Do you have any rationalization for that? And how much of that increase do you expect to be sustainable in year-over-year quarter comparisons moving forward?

這是丹 (Dan) 代替拉姆 (Ram)。恭喜您——那麼您是否注意到或提到有關美國或加拿大賭場市場的任何值得注意的事情，版稅在第一季度同比持平，但在第二季度同比增長超過 17%。您對此有什麼合理解釋嗎？您預計未來季度將年增幅能維持多少？

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

是的。嗯，我認為這些地區總是會存在一些不平衡現象，這是因為訂購和購買的方式不同。我沒有任何特別的解釋。艾瑞克，我不知道，這是你的一些見解，但我認為，當政府管理發生的事情時，只是存在著地區性的不平衡。

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

是的。不，我們認為潛在的需求在拉動方面一直相當一致。正如 Emil 所提到的，訂購模式有點不均勻。

Luca Issi, RBC Capital Markets.

伊西 (Luca Issi)，加拿大皇家銀行資本市場部。

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

我是謝爾比 (Shelby)，代替盧卡 (Luca) 報道。 ——我們在最近的採訪中聽到了您的消息，您提到 FDA 要求在 Sanfilippo CRL 的運輸驗證中進行更多探測，並要求檢查員對其審查特別嚴格。能詳細闡述嗎？然後也許從更大的角度來看，您能否分享一下您的觀點，您是否認為 FDA 的做法是只見樹木不見森林？任何顏色都值得讚賞。

Well, I think 1 of the FDA's job is actually to check every tree in the forest. That's part of the rigor of the process. So there's a CRO has a lot of bits and pieces because there are a lot of bits and pieces. I think I'd say -- these are all things they need to get taken care of, and there are lots of parts and pieces to it. So they're -- I think they're doing their job with regard to that detail.

嗯，我認為 FDA 的職責之一實際上是檢查森林裡的每棵樹。這是流程嚴謹性的一部分。因此，CRO 有很多零碎部分，因為有很多零碎部分。我想說的是──這些都是他們需要處理的事情，而且涉及很多部分。所以他們——我認為他們正在針對這個細節做好自己的工作。

What should be CRL? Or could we have done it in time?

CRL 應該是什麼？或者我們能及時完成嗎？

Those are questions you could ask, but -- we're going to do the work they ask for. And the inspector and all that, I think it doesn't matter. At the end of the day, we have a CRL listed issues to do, and we're going to do them, and we're doing them -- and I think we'll be able to work that out with the agency and get it done. But there are times when the FDA has to focus on certain details, it's part of the rigor they apply, and we appreciate that particularly in CMC rigor is essential, and there are reasons for a lot of things that relate to things that have happened. And so we are going to comply and improve what we can with everything we do.

這些都是你可以問的問題，但是──我們會完成他們要求的工作。至於檢查員和所有這些，我認為這並不重要。最終，我們有一個 CRL 列出的待辦事項，我們將著手處理這些問題，而且我們正在處理這些問題 —— 我認為我們將能夠與該機構一起解決這個問題並完成它。但有時 FDA 必須關注某些細節，這是他們所採用的嚴謹性的一部分，我們認識到，特別是在 CMC 中，嚴謹性至關重要，並且很多與已經發生的事情有關的事情都是有原因的。因此，我們將盡我們所能，遵守並改進我們所做的一切。

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

謝謝。女士們、先生們，我們的問答環節已經結束。現在我將把電話轉回給 Joshua Higa 做最後發言。

Thank you. This concludes today's call. If there are 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。如果您還有其他問題，請致電或發送郵件至ir@ultragenyx.com與我們聯繫。感謝您的參與。