Ultragenyx Pharmaceutical Inc (RARE) 2024 Q2 法說會逐字稿

Good afternoon, and welcome to the Ultragenyx Second Quarter 2024 Financial Results Conference Call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have opportunity to ask questions during the question-and-answer portion of the call. (technical difficulty) Vice President of Investor Relations. Please go ahead.

下午好，歡迎參加 Ultragenyx 2024 年第二季財務業績電話會議。此時，所有參與者都處於只聽模式。在準備好的發言結束時，您將有機會在電話的問答部分提問。 （技術難度）投資人關係副總裁。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. I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

謝謝。我們發布了一份新聞稿，詳細介紹了我們的財務業績，您可以在我們的網站 ultragenyx.com 上找到新聞稿。與我一起參加本次電話會議的還有執行長兼總裁 Emil Kakkis、首席商務長 Erik Harris；霍華德‧霍恩，財務長；和首席醫療官埃里克·克羅姆茲(Eric Crombez)​​。我想提醒大家，在今天的電話會議中，我們將做出前瞻性聲明。這些陳述存在一定的風險和不確定性，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。我現在將把電話轉給艾米爾。

Thanks Josh, and good afternoon, everyone. We've had an incredible first half of the year and look forward to sharing more with you today. On the commercial front, our strong revenue performance puts us on the trajectory to outperform our prior projections and so we're raising our total revenue guidance range. We're happy with what this means for access to our drugs globally and Eric and Howard can share more on the revenue details.

謝謝喬希，大家下午好。我們度過了令人難以置信的上半年，並期待今天與您分享更多。在商業方面，我們強勁的收入表現使我們有望超越先前的預測，因此我們正在提高總收入指導範圍。我們很高興這對於在全球範圍內獲取我們的藥物意味著什麼，而艾瑞克和霍華德可以分享更多有關收入的詳細資訊。

Within our clinical pipeline we have meaningfully advanced our late-stage programs through multiple positive data readouts and successful and critically important regulatory interactions. On the data front in addition to the positive results we shared earlier this year on both UX-111 in Sanfilippo syndrome and GTX-102 in Angelman syndrome, we recently announced positive Phase III results from the DTX401 gene therapy for the treatment of patients with glycosidase Type 1a and additional long-term positive Phase II results from the UX143 antibody for the treatment of patients with Osteogenesis Imperfecta. For GTX102 for Angelman syndrome, we announced the successful completion of an end of Phase II meeting with the FDA where we align on Phase III study design and key endpoints to be evaluated.

在我們的臨床管道中，我們透過多次積極的數據讀數和成功且至關重要的監管互動，有意義地推進了我們的後期專案。在數據方面，除了我們今年早些時候分享的UX-111 治療Sanfilippo 綜合徵和GTX-102 治療Angelman 綜合徵的積極結果外，我們最近還宣布了用於治療糖苷酶患者的DTX401 基因療法的III 期正面結果UX143 抗體用於治療成骨不全症患者，獲得 1a 型和其他長期陽性 II 期結果。對於治療 Angelman 症候群的 GTX102，我們宣布與 FDA 成功完成了 II 期會議，會議上我們就 III 期研究設計和要評估的關鍵終點進行了協調。

Our teams have been working with our study sites to initiate our global Phase III study by the end of this year. On UX-111 for Angelman syndrome Type A we also reached agreement with FDA on a path forward to seek accelerated approval. The FDA has agreed to cerebral spinal fluid heparan sulfate is a reasonable surrogate endpoint to support submission of a BLA supported by our clinical data to date.

我們的團隊一直在與我們的研究中心合作，在今年年底前啟動我們的全球 III 期研究。對於治療 A 型 Angelman 症候群的 UX-111，我們也與 FDA 就尋求加速批准的前進道路達成了協議。 FDA 已同意將腦脊髓液硫酸乙醯肝素作為合理的替代終點，以支持提交由我們迄今為止的臨床數據支持的 BLA。

Our next step is to finalize the details of our submission with the agency in a pre-BLA meeting and we intend to submit this BLA later this year or early next. Selectively this puts us in a position to have; multiple regulatory marketing submissions and key clinical data readouts over the next six to 18 months, which is extraordinary. I spent my career developing therapies in rare disease and I can tell you I've never seen a rare disease company with the breadth and depth of opportunities we have ahead of us, nor with our ability to move all these things forward. These achievements are a direct result of our excellent execution across the company from our committed employees and our best-in-class approach to rare fees drug development.

我們的下一步是在 BLA 預會議上與該機構最終確定提交的細節，我們打算在今年稍後或明年初提交此 BLA。有選擇性地，這使我們能夠：在接下來的 6 到 18 個月內提交了多項監管行銷申請和關鍵臨床數據讀數，這是非同尋常的。我的職業生涯都在開發罕見疾病的療法，我可以告訴你，我從未見過一家罕見疾病公司擁有如此廣泛和深入的機遇，也沒有見過一家有能力推動所有這些事情向前發展。這些成就是我們全公司忠誠的員工的出色執行力以及我們在稀有藥物開發方面採取的一流方法的直接結果。

It's a very exciting time for Ultragenyx. I'll now turn the call over to our Chief Commercial Officer, Erik Harris to provide an update on the momentum across our commercial portfolio that has led us to raise our total revenue guidance for the year.

對於 Ultragenyx 來說，這是一個非常令人興奮的時刻。現在，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投資組合勢頭的最新信息，這促使我們提高了今年的總收入指導。

Thank you, Emil, and good afternoon, everyone. I'll start with Crysvita's performance in the United States. The demand for Crysvita in the US remained strong in Q2 2024. Approximately 60% of the stock forms came from adult patients and were prescribed by community physicians with over 40 new prescribers in the quarter. This is encouraging, given adult penetration is in the low 20s and implies Crysvita has ample room to continue growing.

謝謝你，艾米爾，大家下午好。我先從Crysvita 在美國的表現開始。2024 年第二季度，美國對 Crysvita 的需求依然強勁。大約 60% 的庫存表格來自成年患者，由社區醫生開出處方，本季有 40 多名新處方者。鑑於成人滲透率在 20 多歲左右，這令人鼓舞，並且意味著 Crysvita 有足夠的持續成長空間。

We are confident in our full year US revenue projections given the strength of the underlying demand. Shifting to Crysvita in Latin America where we lead commercialization, our LatAm team delivered another successful quarter by adding approximately 60 new patients to Crysvita, totaling over 620 patients on reimbursed therapy since launch. Brazil is the largest market in Latin America and continues to drive the majority of revenue in the region. That said, we are beginning to see more meaningful contributions from countries like Argentina and Mexico supported by the underlying patient demand.

鑑於潛在需求的強勁，我們對全年美國收入預測充滿信心。轉向拉丁美洲的 Crysvita，我們在那裡領導商業化，我們的拉丁美洲團隊在 Crysvita 上增加了約 60 名新患者，實現了另一個成功的季度，自推出以來總共有超過 620 名患者接受報銷治療。巴西是拉丁美洲最大的市場，並繼續推動該地區的大部分收入。也就是說，我們開始看到阿根廷和墨西哥等國家在潛在患者需求的支持下做出了更有意義的貢獻。

As I mentioned on previous earnings calls, we expect quarter-to-quarter variability in LatAm revenue, due to uneven ordering patterns, but remain confident in the underlying demand growth for our products. Moving on to Dojolvi. Growth of new start forms remained strong. In the US, we added approximately 30 start forms and 30 patients on reimbursed therapy, resulting in approximately 520 reimbursed patients since launch. The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults.

正如我在之前的財報電話會議上提到的那樣，由於訂購模式不均勻，我們預計拉丁美洲收入會出現季度波動，但對我們產品的潛在需求增長仍然充滿信心。繼續前往多約爾維。新開工形式的成長依然強勁。在美國，我們增加了約 30 份起始表格和 30 名接受報銷治療的患者，自推出以來約有 520 名報銷患者。兒童和成人患者之間的比例仍然約為 65% 為兒童，35% 為成人。

The number of new prescribers continue to grow, adding approximately 10 new prescribers in Q2 2024 with half of them writing more than one prescription. For Dojolvi across Europe and the MENA region, revenue is currently driven by named patient sales request. There are approximately 215 patients treated under MPS across 12 countries in the region. The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the EMEA region, including the Middle East.

新開處方者的數量持續成長，2024 年第二季新增約 10 名新開處方者，其中一半開出不只一張處方。對於歐洲和中東和北非地區的 Dojolvi 來說，收入目前由指定患者的銷售需求所驅動。該地區 12 個國家約有 215 名患者接受 MPS 治療。大部分需求來自法國，但我們收到越來越多來自歐洲、中東和非洲地區其他國家（包括中東）的請求。

As I have said before, 2024 is an important launch year for Evkeeza. And in the EMEA region, we added approximately 60 new patients in the second quarter who are being treated through MPS and regular reimbursement processes, where we have approval. In Japan, the launch is starting, but has already gained meaningful contribution following regulatory approval in January and pricing and reimbursement approval in April. The team there has done an excellent job to map and identify a majority of patients in the country and has processed 35 stock forms through the second quarter of 2024.

正如我之前所說，2024 年是 Evkeeza 的重要發布年。在歐洲、中東和非洲地區，我們在第二季度新增了約 60 名患者，他們正在透過 MPS 和定期報銷流程（我們已獲得批准）接受治療。在日本，該產品的推出才剛開始，但在 1 月獲得監管部門批准以及 4 月定價和報銷批准後，已經獲得了有意義的貢獻。該團隊出色地繪製和識別了該國大多數患者的身份，並在 2024 年第二季度處理了 35 份庫存表格。

In our territories, we continue to receive positive feedback from the HOFH physician and patient communities and they are all very excited to have Evkeeza as a treatment option. We expect demand for Evkeeza to continue growing as we bring this important therapy to patients with HOFH. Overall, Q2 2024 was a strong quarter for Ultragenyx. As expected, the second quarter bounced off the first quarter seasonality leading to $147 million in total revenue. The broad strength across the commercial portfolio through the first six months of the year put us on a trajectory that gives us confidence we will exceed the guidance range that we established at the beginning of the year. With that, I'll turn the call to Howard to share more details on our financial results for the quarter and guidance for the year.

在我們的地區，我們繼續收到 HOFH 醫生和患者社群的正面回饋，他們都非常高興將 Evkeeza 作為治療選擇。隨著我們為 HOFH 患者提供這種重要的療法，我們預計對 Evkeeza 的需求將繼續增長。總體而言，2024 年第二季對於 Ultragenyx 來說是一個強勁的季度。正如預期的那樣，第二季的總收入擺脫了第一季的季節性影響，達到 1.47 億美元。今年前六個月商業投資組合的廣泛實力使我們走上了一條軌道，這讓我們有信心我們將超越年初制定的指導範圍。接下來，我將致電霍華德，分享有關我們本季財務表現和今年指導的更多詳細資訊。

Thanks, Erik and good afternoon everyone. I'll start by briefly summarizing our financials that were reported in our press release earlier today. As Erik noted, we reported $147 million in total revenue for the second quarter of 2024. Crysvita contributed $114 million, including $67 million from North America, $40 million from Latin America and Turkey and $6 million from Europe.

謝謝埃里克，大家下午好。首先，我將簡要總結今天早些時候新聞稿中報導的我們的財務狀況。正如 Erik 指出的那樣，我們報告 2024 年第二季的總收入為 1.47 億美元。Crysvita 貢獻了 1.14 億美元，其中 6,700 萬美元來自北美，4,000 萬美元來自拉丁美洲和土耳其，600 萬美元來自歐洲。

Dojolvi revenue in the second quarter was $19 million, Evkeeza revenue in the second quarter was $8 million and Mepsevii revenue in the second quarter was $6 million. Our total operating expenses in the second quarter were $263 million, which included R&D expenses of $162 million, SG&A expenses of $81 million and cost of sales of $21 million. Operating expenses included noncash stock-based compensation of $39 million. In the second quarter, net loss was $132 million or $1.52 per share.

Dojolvi 第二季營收為 1,900 萬美元，Evkeeza 在第二季營收為 800 萬美元，Mepsevii 第二季營收為 600 萬美元。第二季我們的總營運費用為 2.63 億美元，其中包括 1.62 億美元的研發費用、8,100 萬美元的銷售成本和 2,100 萬美元的銷售成本。營運費用包括 3,900 萬美元的非現金股票薪酬。第二季淨虧損為 1.32 億美元，即每股 1.52 美元。

As of June 30, 2024, we had $874 million in cash, cash equivalents and marketable securities, which included net proceeds of $381 million from our offering in June. Net cash used in operations was $77 million for the second quarter and was $268 million in total for the first half of the year. As we discussed on our May call, there is seasonality in the first quarter because it includes items like the payment of annual bonuses. Our guidance for 2024 net cash used in operations remains unchanged and is expected to be less than $400 million for the year.

截至 2024 年 6 月 30 日，我們擁有 8.74 億美元的現金、現金等價物和有價證券，其中包括 6 月份發行的淨收益 3.81 億美元。第二季營運中使用的現金淨額為 7,700 萬美元，上半年總計為 2.68 億美元。正如我們在五月電話會議中討論的那樣，第一季存在季節性，因為它包括年度獎金支付等項目。我們對 2024 年營運中使用的淨現金的指引保持不變，預計全年將低於 4 億美元。

Shifting to revenue guidance, we are increasing our range for total revenue, which is now expected to be between $530 million and $550 million for the year. This reflects strong performance and trajectory across all of our products, including Crysvita globally and the launch of Evkeeza in our territories. Accordingly, we are targeting Crysvita revenue to be towards the upper end of our existing range of $375 million to $400 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. Specifically, it includes Crysvita product revenue from Latin America and Turkey, and cash and non-cash royalties from North America and Europe.

轉向收入指導，我們正在擴大總收入範圍，目前預計今年的總收入在 5.3 億美元至 5.5 億美元之間。這反映了我們所有產品的強勁表現和發展軌跡，包括全球範圍內的 Crysvita 以及在我們地區推出的 Evkeeza。因此，我們的目標是 Crysvita 收入達到現有範圍 3.75 億美元至 4 億美元的上限，其中包括所有地區和所有形式的 Crysvita 給 Ultragenyx 的收入。具體來說，它包括來自拉丁美洲和土耳其的 Crysvita 產品收入，以及來自北美和歐洲的現金和非現金特許權使用費。

We continue to expect the Dojolvi revenue to be between $75 million and $80 million. With that, I'll turn the call to our CMO, Eric Crombez.

我們仍然預計 Dojolvi 的收入將在 7500 萬美元至 8000 萬美元之間。接下來，我會將電話轉給我們的行銷長 Eric Crombez。

Thank you, Howard, and good afternoon everyone. The first half of this year has seen a number of important clinical catalysts for UX-111 for the treatment of MPS IIIA. We announced data demonstrating clinically significant reductions in heparan sulfate that correlated with improved long-term cognitive function. This was followed up with our announcement in June that we reached agreement with the FDA that CSF heparin sulfate can be used as a surge endpoint for accelerated approval.

謝謝你，霍華德，大家下午好。今年上半年，UX-111 治療 MPS IIIA 出現了許多重要的臨床催化劑。我們發表的數據表明，硫酸乙醯肝素的臨床顯著減少與長期認知功能的改善有關。隨後，我們在 6 月宣布與 FDA 達成協議，腦脊髓液硫酸肝素可用作加速核准的激增終點。

We expect to finalize details of our filing package in a pre-BLA meeting later this year with the goal of filing the BLA around the end of 2024. For DTX401 for the treatment of GSDIa, we announced positive top line data from the Phase III study that showed that treatment with DTX401 resulted in a statistically significant reduction in daily cornstarch at week 48 with maintenance of strong glucose control. Results from this study will be discussed with regulatory authorities in a pre-BLA meeting in the second half of 2024. For UX143, for the treatment of Osteogenesis Imperfecta, we announced 14-month data from the Phase II portion of Orbit that showed treatment with setrusumab resulted in a sustained 67% reduction in annual in fracture rate and persistent median annualized fracture rate of zero.

我們預計將在今年稍後的 BLA 預會議上敲定歸檔方案的細節，目標是在 2024 年底左右提交 BLA。對於用於治療GSDIa 的DTX401，我們宣布了來自III 期研究的積極頂線數據，該數據表明，使用DTX401 治療在第48 週時每日玉米澱粉的攝入量在統計學上顯著減少，同時維持了強而有力的血糖控制。這項研究的結果將在 2024 年下半年舉行的 BLA 前會議上與監管機構進行討論。對於治療成骨不全症的 UX143，我們公佈了 Orbit II 期部分的 14 個月數據，顯示 setrusumab 治療使年度骨折率持續降低 67%，持續中位數年化骨折率為零。

There were also continued substantial improvements in bone mineral density with a mean increase from baseline of 22% and a mean improvement in Z score of 1.25. For GTX-102 for the treatment of Angelman syndrome in April, we shared additional Phase I/II data from the expansion cohorts that showed rapid and clinically meaningful improvements across multiple domains. These improvements were consistent or exceeding those of the dose escalation cohorts data at day 170. We also shared that additional long-term data in dose escalation cohorts showed increasing and sustained clinical benefit through day 758.

骨礦物質密度也持續大幅改善，較基線平均增加 22%，Z 評分平均改善 1.25。對於 4 月用於治療 Angelman 症候群的 GTX-102，我們分享了來自擴展隊列的額外 I/II 期數據，這些數據顯示了跨多個領域的快速且具有臨床意義的改善。這些改善與第 170 天劑量遞增隊列數據一致或超過。我們也分享了劑量遞增隊列的其他長期數據顯示，到第 758 天，臨床效益不斷增加且持續。

There's been a lot of news flow in the space recently and we feel very good about the ability of GTX-102 to improve the lives of patients affected by this disorder. We continue to see the patients in the Phase II portion of the study developing new skills across multiple domains with no new serious adverse events, and we believe we are in a strong position as we advance Phase III start-up activities. Last month we completed a successful end of Phase II meeting with the FDA, where we aligned on the design for a global 48-week blinded randomized sham-controlled Phase III study. We expect to enroll approximately 120 patients between four and 17 years of age who have a full UBE3A deletion.

最近該領域有許多新聞報導，我們對 GTX-102 改善受這種疾病影響的患者生活的能力感到非常滿意。我們繼續看到研究第二階段部分的患者在多個領域發展新技能，沒有出現新的嚴重不良事件，我們相信，在推進第三階段啟動活動時，我們處於有利地位。上個月，我們與 FDA 成功結束了 II 期會議，會上我們就一項為期 48 週的全球盲法隨機假對照 III 期研究的設計進行了協調。我們預計招募約 120 名 4 歲至 17 歲之間 UBE3A 完全缺失的患者。

The primary endpoint will be improvement in cognition assessed by Bayley-4 cognition raw score. The study will also include a key secondary endpoint of a multi-domain responder index evaluating cognition, receptive communication, behavior, gross motor and sleep. Individual secondary endpoints were also discussed and aligned on with the FDA for the domains of communication, behavior, motor function and sleep. Phase 3 study start-up activities have been ongoing for some time.

主要終點是透過 Bayley-4 認知原始評分評估的認知改善。該研究還將包括評估認知、接受性溝通、行為、粗大運動和睡眠的多領域反應者指數的關鍵次要終點。也討論了溝通、行為、運動功能和睡眠領域的各個次要終點，並與 FDA 保持一致。第三階段研究啟動活動已經持續了一段時間。

And now with FDA alignment we are focused on initiating the study by year-end. The ongoing Phase 2 study includes 25 phase across eight countries, which allowed us to respond to the significant global demand to participate in the study and for these types to gain experience with GTX-102. With startup activities already in progress and alignment with FDA and design, we are on track to begin enrollment of our Phase III study by the end of this year. While this initial Phase 3 study will focus on patients with full deletions who represent the majority of patients with Angelman syndrome, we are also planning to initiate an open-label study to evaluate GTX-102 for the treatment of patients with other genotype and in other age groups in 2025.

現在，隨著 FDA 的協調，我們的重點是在年底前啟動這項研究。正在進行的 2 期研究包括跨越 8 個國家的 25 個階段，這使我們能夠滿足全球參與研究的巨大需求，並讓這些類型獲得 GTX-102 的經驗。隨著啟動活動已經在進行中並與 FDA 和設計保持一致，我們預計將在今年年底開始 III 期研究的註冊。雖然這項最初的3 期研究將重點關注代表大多數Angelman 綜合徵患者的完全缺失患者，但我們還計劃啟動一項開放標籤研究，以評估GTX-102 對其他基因型和其他疾病患者的治療作用。

We expect to enroll both studies in parallel and plan to include both sets of data in a future BLA application. I'll now turn the call back to Emil to provide some closing remarks.

我們希望同時招募這兩項研究，並計劃將兩組數據納入未來的 BLA 申請中。現在我將把電話轉回給埃米爾，以提供一些結束語。

Thank you, Eric. In the first part of the year, we made significant progress advancing our clinical pipeline and we performed well globally on the commercialization of four products. I'll close quickly by summarizing our key clinical catalysts for the rest of the year. For GTX-102 for Angelman syndrome, we're working to initiate the Phase 3 study by the end of the year and over time plan to share updates on how the Phase 2 patients are doing as they continue receiving maintenance doses. Our long-term data is far superior to any other data presented on ASOs for Angelman to-date and this puts us in excellent position for the future of that program.

謝謝你，埃里克。今年上半年，我們在推動臨床管線方面取得了重大進展，四種產品的商業化在全球範圍內表現良好。最後，我將總結今年剩餘時間的主要臨床催化劑。對於治療 Angelman 症候群的 GTX-102，我們正在努力在今年年底前啟動 3 期研究，並計劃隨著時間的推移分享 2 期患者在繼續接受維持劑量時的最新情況。我們的長期數據遠遠優於 Angelman 迄今為止 ASO 上提供的任何其他數據，這使我們在該計劃的未來中處於有利地位。

For the Phase 3 portion of the UX143 Orbit study, there are two interim analyses planned was the first anticipated by year-end or early 2025. The first analysis will have a stringent threshold of p value less than or equal to 0.001. If the threshold is not met, a second interim analysis will occur a few months later followed by a final Angelman study at 18 months. The first interim analysis will not be reported to the company by the Data Monitoring Committee unless the data have met this very stringent threshold and it's important for study integrity to run these analysis very carefully and rigorously.

對於 UX143 軌道研究的第三階段部分，計劃進行兩項中期分析，第一次預計在年底或 2025 年初進行。第一個分析的嚴格閾值 p 值小於或等於 0.001。如果未達到閾值，幾個月後將進行第二次中期分析，然後在 18 個月時進行最終的 Angelman 研究。資料監測委員會不會向公司報告第一次中期分析，除非資料達到了這個非常嚴格的閾值，並且非常仔細和嚴格地運行這些分析對於研究的完整性非常重要。

In the event of an interim analysis clears the threshold, we would share that outcome but top line results would not be announced immediately as the study would require patients to complete their final visits over a couple of months and then there's time to collect and prepare the data for a formal analysis. For UX701 for Wilson disease, we expect to share Stage 1 data in the second half of the year. In the dose finding stage of data readout, we'll be prompted once the last patient with Cohort three as Angelman therapy for six months or more followed by some additional time to collect and analyze all of the data. All of these are very exciting catalysts and while the teams are executing on these clinical programs we will also be working on two BLA submissions one for UX-111 for Sanfilippo syndrome, which is expected around the end of the year; and the other for DTX401 for glycogen storage disease type 1a which is expected in 2025.

如果中期分析清除了門檻，我們將分享該結果，但不會立即公佈最重要的結果，因為該研究將要求患者在幾個月內完成最終訪問，然後有時間收集和準備用於正式分析的數據。對於治療威爾遜氏症的 UX701，我們預計將在今年下半年分享第一階段的數據。在數據讀出的劑量發現階段，一旦第三組的最後一位患者接受 Angelman 治療六個月或更長時間，我們就會收到提示，然後需要一些額外的時間來收集和分析所有數據。所有這些都是非常令人興奮的催化劑，在團隊執行這些臨床項目的同時，我們還將提交兩項 BLA 申請，其中一項是針對 Sanfilippo 綜合徵的 UX-111，預計將於今年年底提交；另一個是用於治療 1a 型肝醣累積病的 DTX401，預計 2025 年上市。

Ultragenyx is at an incredible inflection point. Over the next 12 to 18 months we expect to have filed two BLAs provide Phase 3 data new UX143 and should be well on our way with the GTX-102 Phase 3 study, all the while we are generating meaningful revenue growth is now expected to be between $530 million and $550 million this year. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Ultragenyx 正處於一個令人難以置信的轉折點。在接下來的12 到18 個月內，我們預計將提交兩份BLA，提供新UX143 的第3 階段數據，並且GTX-102 第3 階段研究應該會順利進行，同時我們正在產生有意義的收入增長，目前預計今年在 5.3 億至 5.5 億美元之間。接下來，讓我們繼續回答您的問題。運營商，請提供問答說明。

(Operator Instructions) Gena Wang, Barclays.

（操作員說明）王吉娜，巴克萊銀行。

Angelman syndrome data update. We also saw quite a few other data update from both Ionis and Roche. Maybe what is your latest thoughts regarding the competitive landscape and the read-through to your trial design especially if we're looking at the loading dose frequency and also, the endpoints such as expressive communication for Bayley?

安格曼症候群資料更新。我們還看到了 Ionis 和羅氏的其他一些數據更新。也許您對競爭格局和試驗設計通讀的最新想法是什麼，特別是如果我們正在考慮負荷劑量頻率以及貝利的表達性溝通等終點？

Emil was your line muted? We can't hear you. All right. It looks like we're having maybe a little bit of technical difficulty and we've lost Emil's line. Eric, are you able to help out with that question?

艾米爾，你的線被靜音了嗎？我們聽不到你的聲音。好的。看起來我們可能遇到了一點技術困難，我們失去了艾米爾的線路。艾瑞克，你能幫我解答這個問題嗎？

Yes. Thanks and certainly we've been following along the important data updates that were released around the time of ASF. So certainly, feel very good about where we stand looking more closely at the data both from Roche and importantly from Ionis. As we've mentioned, we had a very successful end of Phase 2 meeting with the FDA and we really have locked in our plans for Phase 3 as we're looking forward to first patient by end of year. We have done some thought on loading dose and reducing from four to three loading doses, which also gives us the ability to increase our dose and drive to higher doses in a shorter period and really get to a data readout for that Phase 3 under one year of time.

是的。謝謝，當然我們一直在關注 ASF 前後發布的重要數據更新。因此，當然，我們對羅氏和 Ionis 的數據進行了更仔細的觀察，對此感到非常滿意。正如我們所提到的，我們與 FDA 的第二階段會議非常成功地結束了，我們確實已經鎖定了第三階段的計劃，因為我們期待在年底前迎來第一位患者。我們對負荷劑量進行了一些思考，並將負荷劑量從四個減少到三個，這也使我們能夠在更短的時間內增加劑量並達到更高的劑量，並真正在一年內獲得第三階段的數據讀數的時間。

Again, looking across all of the important domains, we've been talking about collectively in the MDRI and individually as secondary endpoints, we're seeing great movement across all of those domains. We are moving forward with cognition raw scores for our primary endpoint but certainly looking at expressive communication as an important secondary endpoint

再次，縱觀所有重要領域，我們一直在 MDRI 中集體討論，並單獨作為次要終點，我們看到所有這些領域都發生了巨大的變化。我們正在推進主要終點的認知原始分數，但肯定將表達性溝通視為重要的次要終點

Hello I'm back.

你好我回來了。

Eric took care of the call. Gena are there any follow-up there that you had for Emil?

埃里克接聽了電話。吉娜（Gena），你對埃米爾（Emil）有什麼後續行動嗎？

Sure. Yes. So maybe regarding the Wilson data in second half this year maybe how many more patients and what kind of data do you on biomarker you wish you with that?

當然。是的。那麼，關於今年下半年的威爾遜數據，可能會有多少患者以及您希望獲得什麼樣的生物標記數據？

Well, there is a total of 15 patients, five in each cohort. So it will be 15 patients worth of data at each dose level. It will be primarily biochemical. There's not enough patients in there that have a lot of clinical information right, so it will be focused on copper levels, distribution levels and other aspects of (inaudible).

嗯，一共有 15 名患者，每組 5 名。因此，每個劑量等級的數據相當於 15 名患者。它將主要是生化的。那裡沒有足夠的患者擁有大量正確的臨床信息，因此它將重點關注銅水平、分佈水平和其他方面（聽不清楚）。

I think it will give us an understanding of is the gene therapy working well. We had certainly an early indication and that was very encouraging. So we're primarily focus on the biochemical part of the story at this point.

我認為這會讓我們了解基因療法是否有效。我們確實有一個早期跡象，這非常令人鼓舞。所以我們現在主要關注故事的生化部分。

Great. Thank you.

偉大的。謝謝。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Hey, Salveen. I am not sure your line is muted, we can’t reach.

嘿，薩爾文。我不確定您的線路是否已靜音，我們無法接通。

Hi. Can you hear me now?

你好。現在你能聽到我說話嗎？

Loud and clear, Salveen. Go ahead.

響亮而清晰，薩爾文。前進。

So sorry about that. Thank you for taking my question. Could you help us understand how you look on OI with regard to the Phase 2 data translating to Phase 3 here? And particularly, as the patients see improvements how that kind of impacts the rate of fractures here for the population and your assumptions around that in the Phase 3 trial?

對此感到非常抱歉。感謝您回答我的問題。您能否幫助我們了解您如何看待 OI 將第 2 階段資料轉換為第 3 階段資料？特別是，當患者看到改善時，這對這裡的人群骨折率有何影響，以及您在第三階段試驗中對此的假設？

Well, I think what we've shown at the 14-month data was in fact that the bone marrow density continues to increase dramatically. And the p-value got much smaller. So remember that's looking at all the patients not just the median, but it tells you the p-value declining substantially tells that all of the patients are moving toward a reduction in fractures. So we feel that the effect is very large. In terms of translating to Phase 3, we know from the data we had in a few placebos that they do not see bone marrow density improvement during this period of time.

嗯，我認為我們在 14 個月的數據中所顯示的實際上是骨髓密度繼續急劇增加。且 p 值變得更小。因此請記住，我們不僅關注中位數，還關注所有患者，它會告訴您 p 值大幅下降，表明所有患者的骨折率都在減少。所以我們覺得作用是非常大的。就轉化為第三階段而言，我們從一些安慰劑的數據中得知，在此期間他們沒有看到骨髓密度改善。

So there will be no placebo effect from that. With regard to fractures, fractures are dependent on both disease severity and also environmental factors like what the patient is doing. Our expectation is that patients when they feel better could start doing more work, but what we have seen is patients that have gotten stronger and have been on treatment for a longer period of time will have falls and not have fractures. So we feel pretty confident that the strength of bones as such to even compensate for any change might occur because patients are more active.

所以不會產生安慰劑效應。關於骨折，骨折取決於疾病的嚴重程度以及環境因素，例如患者正在做的事情。我們的期望是，患者感覺好些時可以開始做更多的工作，但我們看到的是，變得更強壯並且接受治療時間更長的患者會跌倒，而不是骨折。因此，我們非常有信心，由於患者更加活躍，骨骼的強度甚至可以補償任何變化。

But we do think that the way patients feel their activity will bode well for supportive clinical data and how the patients are doing, which I think will support the value of the product and its clinical means for this. Did I hit on the thing you were most interested in Salveen?

但我們確實認為，患者感覺自己活動的方式對於支持性臨床數據以及患者的表現來說是個好兆頭，我認為這將支持該產品及其臨床手段的價值。我是否發現了您對 Salveen 最感興趣的事情？

That's really helpful. Thank you.

這真的很有幫助。謝謝。

Dae Gon Ha, Stifel.

大貢河，斯蒂菲爾。

Hey, good afternoon, guys. Thanks for taking my question. Hope, I'm coming off. Okay. Can you guys hear me?

嘿，下午好，夥計們。感謝您提出我的問題。希望，我要走了。好的。你們聽得到我說話嗎？

Loud and clear, Dae Gon

響亮清晰，大袞

Awesome. So maybe just revisiting or maybe rewording Gena's earlier question, Emil coming out of that ASF and we certainly have some details around the different domains and its impact by the ASOs. I guess now that the Phase III trial design is set, is there a certain strategy you have in terms of maximizing GTX-102's, product differentiation as you feel about the other ASO coming through fairly quickly? And then, just maybe a little bit tangential here, but I was wondering if you guys ever thought about using an numayo reservoir for GTX-102, just thinking about intrathecal administration and its affiliated side effects? I mean wouldn't numayo reservoir be like life cycle management strategy, where you can get more drug a bit more safely perhaps, with greater potency? Thanks so much.

驚人的。因此，也許只是重新審視或重新措辭 Gena 之前的問題，Emil 來自 ASF，我們當然有一些關於不同領域及其 ASO 影響的細節。我想現在第三階段試驗設計已經確定，在最大化 GTX-102 的產品差異化方面，您是否有某種策略，就像您認為其他 ASO 很快就會通過一樣？然後，這裡可能有點離題，但我想知道你們是否考慮過使用 Numayo 儲存庫來治療 GTX-102，只是考慮鞘內給藥及其相關副作用？我的意思是numayo水庫不會像生命週期管理策略一樣，你可以更安全地獲得更多的藥物，或許有更大的效力？非常感謝。

Thanks, Dae Gon. So on the first, I think the thing is to part about looking at our data is that we actually are showing long-term data and showing the Bailey four condition into the double-digit range for the majority of patients, if you look long enough. So we were showing two years plus of data. I haven't seen any of that from anyone. So from right now, we're the only program that's showing that kind of data.

謝謝，大袞。因此，首先，我認為查看我們的數據的一部分是，如果您觀察足夠長的時間，我們實際上正在顯示長期數據，並將大多數患者的貝利四條件顯示為兩位數範圍。所以我們展示了兩年多的數據。我沒有從任何人那裡看到這些。因此，從現在開始，我們是唯一顯示此類數據的程式。

Our drug is more potent than the other drugs. We're operating in the five to 14-milligram range far below that. That tells you the science of what we've been talking about is right. The targeted region that we have added is more potent and more effective. So, we believe will differentiate on superior efficacy. And I'm waiting to see other data from people that will actually, match what we have.

我們的藥物比其他藥物更有效。我們的操作劑量範圍是 5 到 14 毫克，遠低於這個值。這告訴你我們一直在談論的科學是正確的。我們新增的目標區域更加有效。因此，我們相信會因卓越的功效而脫穎而出。我正在等待人們提供的其他數據，這些數據實際上與我們所掌握的數據相符。

With regard to your point, I think it's a good point. I think one of our philosophies in nephrology is that we first make things work and then we make them easy. Our goal is to get a drug approved drug for this Angelman syndrome, as soon as possible. But then we'll look at how do you make this easier for patients, or more potent. But Omya is one thing, it is certainly an invasive approach.

對於你的觀點，我認為這是一個很好的觀點。我認為我們腎臟病學的哲學之一是，我們首先讓事情發揮作用，然後讓事情變得簡單。我們的目標是盡快獲得藥物批准用於治療天使症候群。但接下來我們將看看如何讓患者更容易做到這一點，或更有效。但 Omya 是一回事，它肯定是一種侵入性方法。

It has its upsides and downsides. There are also companies that make lumbar catheter-type devices, which would have catheters inside, which you can access which is a much simpler procedure than a lumber puncture, through a port a similar idea. So certainly those are things we can do, as a life cycle management. Those are things we will consider and we as a company never sit still.

它有其優點和缺點。還有一些公司生產腰椎導管型裝置，該裝置內部有導管，您可以透過類似想法的連接埠進入裝置，這比腰椎穿刺簡單得多。因此，作為生命週期管理，這些當然是我們可以做的事情。這些都是我們會考慮的事情，作為一家公司，我們永遠不會坐以待斃。

If we get approved, we're still going to be constantly looking into ways to improve the patient experience improve the efficacy, and continue to drive forward with the best possible outcome. So we feel like we're in a great position. And after ASF, I haven't seen anything that tells me any different way.

如果我們獲得批准，我們仍將不斷尋找改善患者體驗、提高療效的方法，並繼續努力取得最佳結果。所以我們感覺我們處於一個很好的位置。在非洲豬瘟之後，我沒有看到任何能告訴我任何不同方法的事。

Fair enough. Thank you very much and congrats on the progress.

很公平。非常感謝並祝賀取得的進展。

Tazeen Ahmad, Bank of America.

塔津·艾哈邁德，美國銀行。

Hi, good afternoon. And thanks for taking my question. On Wilson, you're talking about doing that interim Stage 1 readout. And maybe I wanted to get a sense on initially, your thought was that you would have a readout in the first half, and then it's moved a couple of times to now second half of the year. Just curious, the reason for the delay. And then once we do see that data, what should we expect those next steps in the development of that program? Thanks.

嗨，下午好。感謝您提出我的問題。在威爾遜，你正在談論進行臨時第一階段讀數。也許我最初想了解一下，你的想法是你會在上半年得到讀數，然後它已經移動了幾次，現在是下半年。只是好奇，延遲的原因。一旦我們看到這些數據，我們應該期待該程式開發的後續步驟是什麼？謝謝。

Yes. So Tazeen, thank you for the question. I think one of the first thing is that to finish out the cohort three, took longer and we end up having patient that qualifies and something happened, we had ended up dragging out the last patient. And so that was part of one of the problems. One thing, we saw in the Cohort one day that we did put out, is it actually took more time.

是的。塔津，謝謝你的提問。我認為第一件事是，要完成第三組，需要更長的時間，我們最終得到了符合資格的患者，並且發生了一些事情，我們最終拖出了最後一個患者。這就是問題之一。有一天，我們在隊列中看到我們確實推出了一件事，它實際上花了更多時間。

You took more than six months to see the effects of the drug. It's a transporter for copper. It's not going to behave like some of our enzymes. So, we're learning a little bit about it. So our take was we need to go at least six months of data from the last patient in, and that's what the timing is.

您花了六個月多的時間才看到藥物的效果。它是銅的運輸者。它的行為不會像我們的一些酵素那樣。所以，我們正在了解一些關於它的知識。所以我們的看法是，我們需要從最後一位患者那裡獲取至少六個月的數據，這就是時間安排。

I think you have to add on to that, time to clean the data it is an international Phase 2/3 study for prepared in Phase and put it out. So we felt it's important to get this right and make the decisions and so that's where it is. But we're encouraged by the early data we saw. And I think, there is a gene therapy treatment for Wilson on the horizon. And we'll continue to put that data forth and come up, with our plan for heading into Phase 3.

我認為你必須補充一點，是時候清理資料了，這是一項國際 2/3 階段研究，需要在階段中準備並發布。因此，我們認為正確處理並做出決定非常重要，所以這就是它的所在。但我們看到的早期數據令我們感到鼓舞。我認為，針對威爾遜的基因療法即將出現。我們將繼續提供這些數據並提出進入第三階段的計劃。

Thanks. Operator, next question please.

謝謝。接線員，請下一個問題。

Kristen Kluska, Cantor Fitzgerald.

克里斯汀·克魯斯卡，坎托·費茲傑拉。

Hi, congrats on a great quarter. On setrusumab, I wanted to ask if you think that there are any benefits this drug could potentially show as it relates to the pain these patients experience. Is there a reason to think that both reducing those fractures and putting down better bone has the potential to have an impact on pain?

您好，恭喜您度過了一個美好的季度。關於setrusumab，我想問您是否認為這種藥物可能會顯示出任何益處，因為它與這些患者經歷的疼痛有關。是否有理由認為減少骨折和放置更好的骨頭有可能對疼痛產生影響？

Yes. Our impression from the Phase 2 patients particularly with their increased activity they're feeling better. They're having less pain. And while we talk about fractures all the time, OI patients have weak bones. And what that means is lots of micro fractures. So, if they do some strong activity, they'll feel terrible the next day because they probably have induced a bunch of micro fractures. So, it's not a single point fracture.

是的。我們對第二階段患者的印象特別是隨著他們活動的增加，他們感覺好多了。他們的痛苦減輕了。雖然我們一直在談論骨折，但成骨不全患者的骨骼很脆弱。這意味著大量的微裂縫。因此，如果他們做了一些劇烈的活動，第二天他們會感覺很糟糕，因為他們可能誘發了一堆微骨折。所以，這不是單點骨折。

What we can see from the patients treated at the one-year point or beyond patients are having much more activity not needing wheelchairs, not being as afraid of physical activity. So, we have confidence that stronger bones will reduce micro fractures and we'll improve pain. And so we are evaluating both pain quality of life and other measures in the study. And it's a large enough study that should help us power those endpoints. So, we think it's one of the ways that we'll make I think setrusumab a really important therapy for OI.

我們從接受治療一年或一年後的患者身上可以看到，患者不需要輪椅就可以進行更多的活動，也不再害怕體力活動。因此，我們相信，更強健的骨骼將減少微骨折，並改善疼痛。因此，我們正在研究中評估疼痛生活品質和其他指標。這是一項足夠大的研究，應該可以幫助我們為這些終點提供動力。因此，我們認為這是使 setrusumab 成為治療成骨不全症真正重要療法的方法之一。

And then, just on that point I know people sometimes ask if you're feeling better and you're doing more activities does that open the door for any potential fractures? But maybe on the other end of that spectrum if people are exercising and doing more activity could that help even further slowdown any type of bone loss or density loss? Thank you again.

然後，就在這一點上，我知道人們有時會問你是否感覺好些並且你做了更多的活動，這是否為任何潛在的骨折打開了大門？但也許在這個範圍的另一端，如果人們鍛鍊身體並進行更多的活動，這可能有助於進一步減緩任何類型的骨質流失或密度損失嗎？再次感謝您。

Yes, it's a very good point. I think it certainly could increase fracture risk. We did have a patient who started doing sports again and did have a fracture, but I'm not the one to tell a patient you feel great now, now if don't do anything with that, right? It's just not rational to think that.

是的，這是一個非常好的觀點。我認為這肯定會增加骨折風險。我們確實有一位病人再次開始運動，並且確實骨折了，但我不是那個告訴病人你現在感覺很好的人，現在如果不做任何事情，對吧？這種想法是不合理的。

What I will say is these patients if you're sedentary you or I sit in our bed and we don't do enough our bones get weaker. So, the exercise they do will actually stimulate their bones to lay down the bone where their bone is weakest. It will actually enhance their bone strength further. So, I think we'll have a beneficial effect for them to be more active and with sports or anything else.

我要說的是，這些患者如果你久坐不動，你或我坐在床上，而我們做得不夠，我們的骨頭就會變得脆弱。因此，他們所做的運動實際上會刺激他們的骨骼，使骨骼最薄弱的地方放下。它實際上會進一步增強他們的骨骼強度。所以，我認為我們會對他們更積極地參與運動或其他事情產生有益的影響。

So, we're not worried about the moral risk of getting more fractures. We think it's part of a healthy pattern towards more activity stronger bone and better lives for these OI patients.

因此，我們並不擔心更多骨折的道德風險。我們認為這是健康模式的一部分，為這些成骨不全患者提供更多的活動、更強的骨骼和更好的生活。

Thanks Emil.

謝謝埃米爾。

Anupam Rama, JPMorgan.

阿努帕姆‧拉瑪，摩根大通。

Hi everyone. This is Priyanka on for Anupam. Just a quick question from us. For UX-111 even though the BLA filing will be based on available data, are there any gating factors for the BLA filing later this year or into early next year?

大家好。這是 Anupam 的 Priyanka。我們只是問一個簡單的問題。對於 UX-111，儘管 BLA 備案將基於可用數據，但今年稍後或明年初的 BLA 備案是否有任何限制因素？

Well, the one thing we need to make sure is that the CMC put together with our contract manufacturer, they're doing an excellent job. They are derived from the nationwide children's people. They know their stuff they do good work. And so we feel we're pretty much on track to get where we need to go. That would be one thing that has to be in line.

嗯，我們需要確保的一件事是 CMC 與我們的合約製造商合作，他們做得非常出色。他們來自全國兒童人民。他們知道他們的工作，他們做得很好。因此，我們覺得我們已經步入正軌，即將到達我們需要去的地方。這是必須遵守的一件事。

We're having our discussion with agency about exactly what needs to be in a BLA. And agency has shown the proper flexibility on what needs to be now what can be in later. And I think right now I don't see any gating factors. It isn't a lot of work putting a BLA together and but we're expected to get there this year. Answer

我們正在與相關機構討論 BLA 中到底需要包含哪些內容。對於現在需要什麼、以後可以做什麼，代理商展現了適當的靈活性。我認為現在我沒有看到任何限制。制定 BLA 的工作量並不大，但我們預計今年就能實現。回答

Thanks so much for taking our question.

非常感謝您提出我們的問題。

Operator, next question please.

接線員，請下一個問題。

Joon Lee, Truist Securities.

李俊，Truist 證券公司。

Hey congrats on the strong quarter and thanks for taking our question. During Biogen's conference call this morning when asked why they did not opt in to Ionis' Angelman program, Biogen and Piaget data may not have cross the preset go no-go threshold. Knowing what you know about the competing ASO from what's been publicly disclosed. In what ways do you think GTX-102 may be a better option for patients than IONIS 582? In other words, as patients consider enrolling for GTX-102 or IONIS study what would be the selling point for your program? Thank you.

嘿，恭喜季度的強勁表現，感謝您提出我們的問題。在今天早上百健(Biogen) 的電話會議上，當被問及為什麼不選擇加入Ionis 的Angelman 計劃時，百健(Biogen) 和伯爵(Piaget) 的數據可能沒有超過預設的“走不走”閾值。從公開揭露的內容中了解您對競爭 ASO 的了解。您認為 GTX-102 在哪些方面可能比 IONIS 582 更適合患者？換句話說，當患者考慮參加 GTX-102 或 IONIS 研究時，您的專案的賣點是什麼？謝謝。

Well, I think I am sure Biogen is considering looking at all the data that are publicly available. Since we show substantially higher levels of daily condition achievement over longer periods of time and steady growth and in multiple domains in fact, I think that's a strong data set. What we've seen from our Ionis competitor is a limited amount of data through six months. So I'm sure that Biogen has a capability to understand what the data look like and how to compare and they made their choice.

嗯，我想我確信百健（Biogen）正在考慮查看所有公開的數據。事實上，由於我們在較長時間內和穩定成長以及在多個領域中顯示了更高水平的日常狀況成就，因此我認為這是一個強大的數據集。我們從 Ionis 競爭對手那裡看到的是六個月內的數據量有限。因此，我確信百健（Biogen）有能力了解數據是什麼樣子以及如何進行比較，並且他們做出了選擇。

It seems unlikely to me that they wouldn't have opted in, if they had a product that was equal to ours. And at this point we don't think it is equal. And I think our data longer term is substantially stronger. And it didn't meet their criteria and might not have met ours if we were doing their product. But right now, we feel good about our product it's potency and the fact that I think it's the number one ASO for Angelman at this point.

在我看來，如果他們有與我們相同的產品，他們不太可能不會選擇加入。在這一點上，我們認為這是不平等的。我認為我們的長期數據要強得多。它不符合他們的標準，如果我們做他們的產品，也可能不符合我們的標準。但現在，我們對我們的產品感覺良好，它的效力，而且我認為它是目前 Angelman 的第一個 ASO。

Thank you.

謝謝。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特，傑弗里斯。

Hi. Thanks for taking my question. And I'll ask one about Wilson's disease. For your upcoming update, you're assessing global copper metabolism by biomarkers. What would be considered a win or what magnitude of change do you need to see to advance to Phase III? Or what scenarios could require further optimization?

你好。感謝您提出我的問題。我會詢問有關威爾遜氏症的問題。在即將發布的更新中，您將透過生物標記評估全球銅代謝。什麼會被視為勝利，或者您需要看到多大程度的變化才能進入第三階段？或哪些場景需要進一步優化？

Thanks, Maury. I think with Wilson to have an effective gene therapy I think it's necessary to see patients to be able to get off standard of care, right and maintain free copper levels and urinary copper accretion that indicates that they are now top copper through the proper pathway, right? So first off, we have to be able to replace chelators as a weighted detox copper. Secondly, we'd like to see some significant improvement in the majority of patients in copper distribution that is a ceruloplasmin copper levels which are generally very low in these patients and are the source of copper to be distributed to the brain and other places.

謝謝，莫里。我認為威爾遜要進行有效的基因治療，我認為有必要看到患者能夠擺脫標準護理，正確並維持遊離銅水平和尿銅積累，這表明他們現在通過正確的途徑達到最高銅水平，正確的？因此，首先，我們必須能夠將螯合劑替換為加重的排毒銅。其次，我們希望看到大多數患者的銅分佈有顯著改善，即銅藍蛋白銅水平在這些患者中通常非常低，並且是分佈到大腦和其他部位的銅的來源。

And in many patients, we think that copper deficiency is a contributor to the Wilson phenotype. So those are the two things we're looking for a substantial improvement in copper distribution over their background baseline, particularly in those patients were it's low and the ability to remove standard of care and maintain toxicity control.

在許多患者中，我們認為缺銅是導致威爾遜表型的因素。因此，我們正在尋找銅分佈相對於背景基線有顯著改善的兩件事，特別是對於銅分佈較低的患者以及能夠取消護理標準和維持毒性控制的患者。

Got it. That’s helpful. Thanks for taking my question.

知道了。這很有幫助。感謝您提出我的問題。

Joseph Schwartz, Leerink Partners.

約瑟夫‧施瓦茨，Leerink Partners。

Hi, all. This is Will on for Joe. Thanks for taking our questions. Congrats on the progress this quarter. One for us on GTX-102 outside of the study design and endpoints.

大家好。這是威爾為喬做的事。感謝您回答我們的問題。恭喜本季取得的進展。我們在研究設計和終點之外的 GTX-102 上進行了一項研究。

Just wondering if the FDA has provided any color on the bar success for approval? And along the same lines, can you remind us of our understanding of what a clinically meaningful benefit would be on the Bailey four endpoint? Thank you.

只是想知道 FDA 是否已提供任何顏色來批准成功的酒吧？同樣，您能否提醒我們，我們對貝利四終點有何臨床意義的益處的理解？謝謝。

Well, first off, they agreed to a continues variable analysis for the Baily 4, right? So there was no set threshold established or required. They thought variable approach was the right way. So they didn't require responder analysis. We do a responder as part of the MDRI which will support the ceruloplasmin maintenance, so that's what they've required to us.

嗯，首先，他們同意對 Baily 4 進行連續變數分析，對吧？因此，沒有設立或要求設定閾值。他們認為變數方法是正確的方法。所以他們不需要響應者分析。我們做一個響應器作為 MDRI 的一部分，它將支持銅藍蛋白的維持，所以這就是他們對我們的要求。

They haven't set any numbers. In our mind, if we can show what we've already seen in Phase 2 which is achieving a majority of patients into the double-digit range of Baily 4 that's essentially twice what is considered a statistic significant improvement in the Baily 4 I think that's quite important. But I want to be clear about it, while we Baily 4 as a primary. The other end points are part of the story and the value of it as we see it through the MRI the eyes of the is this combination of factors that is a change of life for patients.

他們還沒有設定任何數字。在我們看來，如果我們能夠展示我們在第2 階段已經看到的情況，即大多數患者達到Baily 4 的兩位數範圍，這基本上是Baily 4 中被認為統計顯著改善的兩倍，我認為這就是相當重要。但我想澄清這一點，而我們貝利 4 作為初選。其他終點是故事的一部分，正如我們透過 MRI 看到的，它的價值在於這些因素的組合改變了患者的生活。

So I look at the big picture the Bayley 4 score self doesn't tell the whole story. Knowing the patient sleeps well is not falling down as much, behavior is calmer, is understanding language spoken language instructions better these are all things that are a change of life for patients at home. And we think some of these states have multiple domains of improvement are going to tell you why this drug would be important for patients. So if we can replicate that in Phase III what we're already showing you in Phase II I think we're in good shape.

所以我從大局來看，Bayley 4 得分自我並不能說明一切。了解患者睡眠品質是否良好，是否跌倒得厲害，行為是否更加平靜，是否更能理解語言口語指令，這些都是患者在家生活的改變。我們認為其中一些州有多個領域的改進將告訴您為什麼這種藥物對患者很重要。因此，如果我們能夠在第三階段複製我們在第二階段已經向您展示的內容，我認為我們處於良好狀態。

Yaron Werber, TD Cowen.

亞龍·韋伯，TD·考恩。

Hi. Thanks for including us as well. Maybe I just have one and one follow-up. An age the 48-week endpoint can you give us a little bit of a sense what kind of a delta in terms of powering are you kind of hoping to see and planning to see in the Phase III? And is there going to be a longer look as a secondary end point? And then just on GSDIa we're beginning to get questions kind of how to think about what's feasible in terms of the commercial opportunity here? I think you've kind of talked about price being let's say just in the mid- sort of $1 million or so. I don't want to speak for you but how big of a market can we think here? Thank you.

你好。感謝您也包括我們。也許我只有一項又一項的後續行動。48 週終點年齡，您能否讓我們了解您希望併計劃在第三階段看到什麼樣的動力增量？是否會有較長的觀察作為次要終點？然後就在 GSDIa 上，我們開始收到這樣的問題：如何思考這裡的商業機會什麼是可行的？我想你已經談到了價格，比如說 100 萬美元左右。我不想為你說話，但我們認為這裡的市場有多大？謝謝。

Great. So the 48-week data we actually, if you look at our April AAN terminology deck we actually put a slide on powering in there showing we're well above 90 percentile. Even if you assume the placebo group had the three times the natural history three or four times in natural history we still had well more than 90% power. In fact, with the typical natural history control group in fact we would be well above 95% powered. So it is very well powered to see, the effect size we're seeing right now which were into the double-digit range when you talk about 48 weeks.

偉大的。因此，實際上，如果您查看 4 月的 AAN 術語表，我們實際上會在 48 週的資料中放置一張有關通電的幻燈片，顯示我們遠高於 90%。即使你假設安慰劑組的功效是自然歷史的三倍或四倍，我們仍然擁有超過 90% 的功效。事實上，對於典型的自然史對照組，我們的動力將遠高於 95%。因此，我們現在看到的效果大小非常有說服力，當您談論 48 週時，效果大小已達到兩位數範圍。

One of the reasons we went longer is we felt you accumulate more improvements and that made it a better story overall, so that's the powering on Angelman. With regard to GST1a a commercial opportunity, I think the thing to recognize is for the patients the exact amount of cornstarch is less the issue than the fear of dying if they miss their doses their brittle nature of their disease. And what we're seeing with these patients is a change in their outlook on what's happening to them, because they are no longer highly dependent of cornstarch to survive. We think our data in the Phase 3 because of the blinding and the inability to call patients and doctors what their sugars were didn't get us as strong a reduction as we've seen and we are seeing an extension.

我們花更長的時間的原因之一是我們覺得你累積了更多的改進，這使得整個故事變得更好，所以這就是《天使》的動力。關於 GST1a 的商業機會，我認為需要認識到的是，對於患者來說，玉米澱粉的確切數量並不是問題，而是因為他們疾病的脆弱性，如果他們錯過劑量，就會擔心死亡。我們在這些患者身上看到的是他們對發生在自己身上的事情的看法發生了變化，因為他們不再高度依賴玉米澱粉來生存。我們認為，由於盲法以及無法告知患者和醫生他們的血糖水平，我們在第三階段的數據並沒有讓我們看到像我們所看到的那樣強烈的減少，而且我們正在看到延長。

But we know that number will get better and better as their physiology changes. But the effect of feeling better and having a change of life is very much there. We think there's a high urgency in this disease. I think people hate living, would have gone to the head waiting to die. And the corn starch is just a representation of that risk that occurs for them every day.

但我們知道，隨著生理機能的變化，這個數字會越來越好。但感覺更好和生活改變的效果是非常明顯的。我們認為這種疾病的迫切性很高。我想，人厭惡活著，就會去頭等死。玉米澱粉只是他們每天發生的風險的代表。

And it's nothing like some of the other diseases with regard to the urgency that exists. So we think it will be highly desired in the patient population and we expect patients to want to get dosed. And we think that's a key to gene therapy success commercially has been what's the level of patient urgency that's been defining what's been happening. With regard to pricing, we certainly have not put out pricing at this point.

就其存在的緊迫性而言，它與其他一些疾病完全不同。因此，我們認為患者群體非常渴望這種藥物，我們預計患者希望接受藥物治療。我們認為基因療法在商業上取得成功的關鍵是患者的緊迫程度，這決定了正在發生的事情。關於定價，我們目前當然還沒有公佈定價。

It's a bit too early. We have said in the past that pricing in the $1 million to $2 million range is possible. I think price points have gotten even higher for some programs. But we haven't set down what our plan is. We're going to look carefully at this and come at it. But I think GSDIa is a very reasonable and important opportunity.

有點太早了。我們過去曾說過，定價在 100 萬至 200 萬美元範圍內是可能的。我認為某些項目的價格甚至更高。但我們還沒有確定我們的計劃是什麼。我們將仔細研究並解決這個問題。但我認為GSDIa是一個非常合理且重要的機會。

I think it will do well. And I think it will be an important new therapy. I expect it to perform more like some of the other programs where there's high levels of urgency.

我認為它會做得很好。我認為這將是一種重要的新療法。我希望它的表現更像其他一些緊急程度較高的程序。

from Jeffrey Hung, Morgan Stanley.

來自摩根士丹利的 Jeffrey Hung。

Hi. This is Michael Riad on for Jeff Hung. Going back to setrusumab and thinking about that cycle of fractures leading to bone deformation and then loss of activity. What factors do you think play a bigger on the treatment course? Is it age or OI type? I mean if you think about like the profile do you view it as like a broadly better options for the most pediatric patients regardless of type? Whereas for adults you'd expect more OI type-dependent penetration? Thank you.

你好。我是邁克爾·裡亞德 (Michael Riad) 代表傑夫·洪 (Jeff Hung)。回到setrusumab並思考導致骨變形然後喪失活動的骨折循環。您認為哪些因素對治療過程影響較大？是年齡還是OI類型？我的意思是，如果您考慮一下該概況，您是否認為對於大多數兒科患者（無論類型如何）來說，它是一個更好的選擇？而對於成年人來說，您會期望更多的成骨不全類型依賴性滲透？謝謝。

Well, I think each patient is going to have a reason to be treated. It may be different. If you're a Type 3 patient or Type 4 with a really severe bone disease and your treated when you're one or two years old our hope and we will see with the Phase 3 data show is that we could be transformed in terms of stopping fracture stopping vertical compression and not basically destroying your skeleton before your three or four years of age and ending up in a wheelchair. So that would be what you could do when you're treating kids that are young.

嗯，我認為每個病人都有接受治療的理由。可能會有所不同。如果您是患有嚴重骨病的 3 型或 4 型患者，並且您在一兩歲時接受治療，我們希望透過第 3 階段的數據顯示我們可以在以下方面進行轉變：停止骨折，停止垂直壓縮，並且不會在三四歲之前基本上破壞您的骨骼並最終坐在輪椅上。所以當你治療年幼的孩子時，這就是你可以做到的。

However, when they're all like, even if you're in a wheelchair because you have to form bones you're still fracturing, you're still in pain all the time. Being able to stopping and pain by stopping fracturing even if you can't change the information it's still highly valuable in an adult would Type 3 or Type s4. For Type 1, probably the sphere half of that population, we'll have enough fractures where at any age young or old, it's going to be beneficial. They don't have as much information, but being able to be comfortable participating in sports or activities you might not have been doing before, I think will get Type 1s treated.

然而，當他們都喜歡時，即使你坐在輪椅上，因為你必須形成骨頭，但你仍然會骨折，你仍然會一直感到疼痛。即使您無法更改訊息，也能夠透過停止骨折來停止疼痛，這對成人來說仍然非常有價值，屬於 3 型或 s4 型。對於 1 型，可能是該人群的一半，我們將有足夠的骨折，無論年輕還是年老，這都會是有益的。他們沒有那麼多的信息，但能夠輕鬆地參與你以前可能沒有做過的運動或活動，我認為會得到第一類的治療。

There may be some Type 1s who are milder, don't have as many fractures and there might not be as much addressable need in those patients, so we would expect all Type 1s.What I can say from the data we've shown you though, the Type 1s do really well on the treatment as do the Type 3s and 4s. So we expect that we'd have a good penetration of all three types as well as in all ages, because we think there's a reason to treat at any point in life any of these diseases.

可能有一些1 型患者病情較輕，沒有那麼多骨折，而且這些患者可能沒有那麼多可解決的需求，因此我們期望所有1 型患者都是如此。什麼不過，1 型和 3 型和 4 型在治療方面都表現得非常好。因此，我們期望我們能夠很好地滲透所有三種類型以及所有年齡段，因為我們認為在生命的任何階段都有理由治療任何這些疾病。

Great. Thank you. I appreciate that added color. And then for Angelman, I just want to circle back to something. So obviously we saw like competitor data that showed good responses up to six months and the Phase 3 is out to 48 weeks, but that makes the Phase 1/2 giving a bit of a more unique insight into those longer-term benefits. So I was just wondering how that data like, you think it can be used for evaluating that more like durable clinical aspect and like the developmental gains that have been achieved?

偉大的。謝謝。我很欣賞這種添加的顏色。然後對於《Angelman》，我只想回到一些事情上。顯然，我們看到競爭對手的數據在長達6 個月的時間內顯示出良好的反應，而第3 階段則長達48 週，但這使得第1/2 階段對這些長期效益提供了更獨特的見解。所以我只是想知道這些數據怎麼樣，您認為它可以用於評估更像是持久的臨床方面以及已經取得的發展成果嗎？

Are you asking about or data or someone else's data? I didn't quite understand it--.

你問的是數據還是別人的數據？我不太明白--。

I'm asking about like the Phase 1/2, like how that Phase 1/2, data especially like larger-term data can.

我問的是第 1/2 階段，第 1/2 階段的數據，尤其是長期數據。

Long-term.

長期。

Yes.

是的。

Yeah. Well, I think what's important about the long-term data is to see patients continue to gain ground. They don't like to they continue to gain ground which tells you that 48 weeks is only one point on a longer journey where these kids are going where they can go is still unclear how much better could they get. The other point I would make is that, while you get a brain to start functioning better it does take time for kids to learn things, right? Just like growing up you took time to learn them, right?

是的。嗯，我認為長期數據的重要之處在於看到患者繼續取得進展。他們不喜歡繼續取得進展，這告訴你，48 週只是更長旅程中的一個點，這些孩子將前往他們能到達的地方，但仍不清楚他們能取得多少進步。我要說的另一點是，雖然你的大腦開始更好地運作，但孩子確實需要時間來學習東西，對嗎？就像成長過程中你花時間學習它們一樣，對吧？

So this is a developmental component particularly in receptive communication and repressive communication that we think might take more time as kids have to essentially learn something that they didn't know and they can't understand. So there's complex, control functions that might take more time, but we feel that 48 weeks is a good time point to capture enough improvement to demonstrate the shift from the control group gets the drug approved, but the long-term continued improvement will be why patients stay on drug and why the product will penetrate the population if successful in Phase 3.

因此，這是一個發展的組成部分，特別是在接受性溝通和壓抑性溝通中，我們認為這可能需要更多時間，因為孩子必須本質上學習他們不知道和無法理解的東西。因此，複雜的控制功能可能需要更多時間，但我們認為 48 週是一個很好的時間點，可以捕獲足夠的改進，以證明對照組的轉變獲得藥物批准，但長期持續的改進將是原因患者繼續服用藥物，以及為什麼如果在第三階段取得成功，該產品將滲透到人群中。

Thanks so much for taking my question.

非常感謝您提出我的問題。

Jack Allen, Baird.

傑克艾倫、貝爾德。

Hi. Thanks so much for taking my question and congratulations on the progress over the quarter. I wanted to ask on setrusumab, I guess a few little parts of this question. The first of which I was wondering what we should expect as we look towards the second half of the year and the presentation of additional data for setrusumab? It looks like the BMD and Z scores are continuing to improve overtime.

你好。非常感謝您提出我的問題，並祝賀本季的進展。我想問setrusumab，我猜這個問題的幾個小部分。第一個我想知道，當我們展望今年下半年以及 setrusumab 的額外數據時，我們應該期待什麼？看起來 BMD 和 Z 分數正在持續改善。

Do you expect to provide additional color as it relates to differences in fracture rates over time with setrusumab and how that correlates with the biomarkers we're looking at there? And then I also just wanted to follow-up and ask about any comment as it related to the enrollment in the Orbit study and the types of patients you're seeing in that trial versus the Phase 2 portion of that study?

您是否希望提供額外的顏色，因為它與 setrusumab 隨時間推移骨折率的差異有關，以及它與我們正在研究的生物標記有何關聯？然後我也只是想跟進並詢問任何評論，因為它與 Orbit 研究的招募以及您在該試驗中與該研究的第 2 階段部分相比所看到的患者類型有關？

Sure. So with regard to the second half, we haven't set a plan now a particular set of data that we might prevent or not. I mean honestly right now our goal is to crank Phase 3 and to be prepared as necessary to file a BLA, if we're able to hit in the interim. But right now I'm not sure, if we will put out more data, but the patients clearly have continued improvement overtime. And 14 months is certainly not the end of the story.

當然。因此，關於下半年，我們還沒有製定計劃，現在我們可能會阻止或不阻止一組特定的數據。我的意思是，老實說，我們現在的目標是啟動第三階段，並在必要時做好提交 BLA 的準備（如果我們能夠在過渡期間實現這一目標的話）。但現在我不確定我們是否會提供更多數據，但隨著時間的推移，患者的病情顯然持續改善。14個月當然不是故事的結局。

The patient who have been on the 17 to 24 months have continued to do extremely well and it's very encouraging and it's been transformative. So we definitely think that's true. We may put it out at some point in time, but I think most people are eyes already turned toward interim analyses in 2025. So we haven't committed to other more data yet.

接受治療 17 至 24 個月的患者一直表現得非常好，這非常令人鼓舞，而且具有變革性。所以我們絕對認為這是真的。我們可能會在某個時間點發布它，但我認為大多數人的目光已經轉向 2025 年的中期分析。所以我們還沒有承諾其他更多數據。

With regard to the Orbit type of patients, we did enroll more Type 3s and 4s. We now put up the ratio. But in the first Phase 2 study we had 17 Type 1s and seven Type 3s and 4s. And it's significantly larger Type 3s and 4s in the Orbit study, which is what we wanted. We wanted to get more severe patients that have more fractures that have more medical need and we're able to enroll a lot number of those.

關於眼眶類型的患者，我們確實招募了更多的3型和4型患者。我們現在提出這個比率。但在第一個 2 期研究中，我們有 17 個 1 型和 7 個 3 型和 4 型。在軌道研究中，它的 3 型和 4 型要大得多，這正是我們想要的。我們希望招收更多骨折、有更多醫療需求的重症患者，我們能夠招募其中大量患者。

I think actually the Phase 2 data stimulated them to get involved because before they were apprehensive once they saw data then the doctors started putting in their patients in most need. So there is a little bit of shift there, but I don't think it will be substantially different in what we see compared to our Phase II data.

我認為實際上第二階段的數據刺激了他們參與其中，因為在他們看到數據後感到擔憂之前，醫生開始將最需要的患者救治。因此，那裡有一點變化，但我認為與第二階段的數據相比，我們看到的情況不會有太大不同。

Got it. Thanks so much for the context. Maybe just one brief follow-up. I know you get a lot of questions on how to think about the powering of the Orbit study. But in that context what were your expectations for enrollment when you set out to enroll the Phase III portion of Orbit, and I guess did you enroll potentially more severe patients than expected? Any thoughts on how that may impact the power?

知道了。非常感謝您提供的背景。也許只是一個簡短的後續行動。我知道您對如何思考軌道研究的動力有很多疑問。但在這種情況下，當您開始招募 Orbit 的 III 期部分時，您對招募的期望是什麼？ 我猜您是否招募了比預期更多的重症患者？關於這可能如何影響電源有什麼想法嗎？

Well, we originally started with 195-patient study. And then, when we saw our first look of data at six months, it was pretty clear that the fracture reduction of 67% is way past what's needed. We brought that down to 150, which is not a huge difference in power frankly. But we wanted to keep it that large, because you want to get enough Type 1s, Type 3s and 4, to look at the subset, right?

嗯，我們最初是從 195 名患者的研究開始的。然後，當我們在六個月後第一次看到數據時，很明顯，67% 的骨折減少量遠遠超出了所需的範圍。我們將其降低至 150，坦白說，這在功率上並沒有太大差異。但我們希望保持那麼大，因為您想要獲得足夠的 Type 1、Type 3 和 Type 4 來查看子集，對嗎？

And you also had peds and adults, so you have to look at the age subsets. So the number 150 if you could look at the overall powering, but I also look at it as having enough of each group to be able to look at their data and understand the benefit in young or old or Type 3s, 4s or 1s. So that was one of the drivers in maintaining the number of 150. I think with the fracture reduction rate and assuming a higher fraction rate in the study there was plenty of power, we could have made the study smaller.

而且還有兒童和成人，因此您必須查看年齡子集。所以如果你能看一下整體動力的話，數字是 150，但我也認為每個組都有足夠的人能夠查看他們的數據並了解年輕人或老年人或 3 型、4 型或 1 型的好處。這是維持 150 人數的驅動因素之一。我認為，隨著骨折復位率的提高，並假設研究中有較高的分率率，我們就可以縮小研究規模。

But I think when you try to cover the types and the severities and the age groups what we put, I think was a good design that will capture the amount of data across all types of Hawaii.

但我認為，當你嘗試涵蓋我們所輸入的類型、嚴重性和年齡組時，我認為這是一個很好的設計，可以捕獲夏威夷所有類型的數據量。

Got it. Thanks so much for color, and congrats on all the progress.

知道了。非常感謝您的顏色，並祝賀所有的進展。

Thank you.

謝謝。

Lisa Walter, RBC.

麗莎·沃爾特，加拿大皇家銀行。

Great. Thanks for taking our question. This is Lisa on for Luca. This question is for Emil. More of a big picture question. Wondering, if we can get your thoughts on the future of the rare pediatric disease voucher program, it sounds like this is set to expire on September 30th, unless it is reauthorized by Congress. So if it's not reauthorized how might this affect rare disease drug development going forward? Any color there would be much appreciated. Thanks so much.

偉大的。感謝您提出我們的問題。這是盧卡的麗莎。這個問題是問艾米爾的。更多的是一個大局問題。想知道我們能否了解您對罕見兒科疾病優惠券計劃未來的看法，聽起來該計劃將於 9 月 30 日到期，除非得到國會重新授權。那麼，如果不重新授權，這可能會如何影響罕見疾病藥物的未來開發？任何顏色都會非常感激。非常感謝。

Yeah. So the sun setting of being able to get them being able to apply for new ones is happening later this year and through next year. For us as a company there should be two PRVs available to us or if we file for UX-111 and DTX401, we should be able to get to. So for us it doesn't affect us in the short term in our own financial planning. In the long run, the PRV vouchers really changed the equation on what happens in some of the ultra-rare diseases.

是的。因此，讓他們能夠申請新的申請將在今年晚些時候和明年發生。對於我們作為一家公司來說，應該有兩個 PRV 可供我們使用，或者如果我們申請 UX-111 和 DTX401，我們應該可以到達。所以對我們來說，短期內它不會影響我們自己的財務規劃。從長遠來看，PRV 代金券確實改變了一些極為罕見疾病的情況。

And for us, we've sold two vouchers something like $170 million, $180 million of additional cash for Ultragenyx has had a major impact on our ability to develop other rare disease drugs. We've submitted that information. We're highly supportive of the PRV. We think those bipartisan support on the helm is rarely that for almost anything.

對我們來說，我們已經售出了兩張大約 1.7 億美元的代金券，為 Ultragenyx 提供的 1.8 億美元額外現金對我們開發其他罕見疾病藥物的能力產生了重大影響。我們已經提交了該資訊。我們非常支持 PRV。我們認為，兩黨對掌舵的支持幾乎對任何事情都很少。

So right now I feel that it will get done, but hasn't happened yet and the election year is a crazy time to do things, but we think it's something that rare doesn't matter with regard to what party you are if you have a rare disease. So we hope the PRB will get to support. We are certainly providing it.

所以現在我覺得這會完成，但還沒有發生，選舉年是做事情的瘋狂時機，但我們認為這是罕見的事情，無論你是哪個政黨，如果你有一種罕見的疾病。所以我們希望PRB能夠得到支持。我們當然會提供它。

Thanks, operator. We’ll got to the next.

謝謝，接線生。我們將進行下一個。

Thank you.

謝謝。

Can go to the next question?

可以轉到下一個問題嗎？

Liisa Bayko, Evercore ISI.

莉莎·貝科，Evercore ISI。

This is [Jim Ming] on for Liisa. Thanks so much for taking our questions. So we noticed that Amgen is running an open-label Phase III study for romosozumab in OI and they have indicated that if the Phase III study is positive they may have an opportunity to pursue approval and launch in OI. So I'm just wondering what implications do you think it would have for setrusumab if Amgen decides to pursue approval in OI? Thank you.

這是為莉莎主持的[吉姆·明]。非常感謝您回答我們的問題。因此，我們注意到安進正在進行 romosozumab 治療 OI 的開放標籤 III 期研究，他們表示，如果 III 期研究結果積極，他們可能有機會獲得批准並在 OI 中上市。所以我只是想知道如果安進決定在 OI 領域尋求批准，您認為這會對 setrusumab 產生什麼影響？謝謝。

Well that's news to us. They've already given us the intellectual property access. So I don't think they've had that much interest in it. As a biologic for them not surprise is a huge indication. It's growing. There's a big shift toward anabolic agents in osteoporosis I really think that's their focus. With regard to OI we've seen their Phase II data.

這對我們來說是新聞。他們已經給了我們知識產權訪問權。所以我認為他們對此沒有那麼大的興趣。作為一種生物製劑，對他們來說並不奇怪，這是一個巨大的跡象。它正在增長。在骨質疏鬆症中，合成代謝藥物發生了巨大的轉變，我真的認為這是他們的重點。關於OI，我們已經看到了他們的二期數據。

We understand their dosing from the published comments in the clinicaltrials.gov or the European version of it. Right now they're getting substantially less bone marrow density at the dose levels they're using. So we're a superior treatment in terms of our bone modes improvement and we will then be superior in fracture reduction. So I think you should look at this as an unclear story.

我們從 ClinicalTrials.gov 或其歐洲版本中發表的評論中了解了它們的劑量。目前，在他們使用的劑量水平下，他們的骨髓密度大大降低。因此，就骨骼模式改善而言，我們是一種優越的治療方法，因此我們在骨折復位方面也將具有優越性。所以我認為你應該把這看成一個不明確的故事。

What they've done in their Phase 3 is not optimized the drug or the presentation for OI. And so I really don't have concerns right now because we know our data is far superior for them to get to our data they would have to change your dosing dramatically from Phase III which is not likely to happen at this point. So at this point, I think there will be inferred us and I think that will be a factor. Now, because they use a higher dose of romo potentially but then the differentiation with regard to pricing goes away if you have to give five times or eight times more drug to match our dosing level.

他們在第三階段所做的並沒有優化藥物或成骨不全症的表現。所以我現在真的不擔心，因為我們知道我們的數據對他們來說遠遠優於我們的數據，他們將不得不從第三階段大幅改變你的劑量，這在這一點上不太可能發生。所以在這一點上，我認為我們會做出推斷，我認為這將是一個因素。現在，因為他們可能使用更高劑量的羅莫，但如果你必須給予五倍或八倍的藥物來匹配我們的劑量水平，那麼定價方面的差異就會消失。

So we feel like we're in a good position and I haven't heard anything from Amgen by this before. I believe that the osteoporosis in their main space for us and has been listed as part of their rare disease franchise at all. So I'd be surprised if they're changing that.

所以我們覺得我們處於有利地位，而且我之前沒有從安進那裡聽到任何消息。我相信骨質疏鬆症是我們的主要領域，並且已經被列為他們罕見疾病專營權的一部分。所以如果他們改變這一點我會感到驚訝。

That’s helpful. Thank you.

這很有幫助。謝謝。

Thank you. Ladies and gentlemen, we have reached the end of our question-and-answer session. And I would like to turn the call back to Joshua Higa for closing remarks. Please go ahead sir.

謝謝。女士們先生們，我們的問答環節已經結束了。我想將電話轉回約書亞·比嘉 (Joshua Higa)，讓其致閉幕詞。請先生繼續。

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。如果還有其他問題，請透過電話或造訪 ir.ultragenyx.com 與我們聯絡。感謝您加入我們。

Thank you. Ladies and gentlemen that then concludes today's conference. Thank you for joining us. You may now disconnect your lines.

謝謝。女士們、先生們，今天的會議到此結束。感謝您加入我們。現在您可以斷開線路。