Ultragenyx Pharmaceutical Inc (RARE) 2022 Q4 法說會逐字稿

Good afternoon, and welcome to the Ultragenyx Fourth Quarter and Full Year 2022 Financial Results Conference Call. (Operator Instructions) It is now my pleasure to turn the call over to Joshua Higa, Executive Director and Head of Investor Relations.

下午好，歡迎參加 Ultragenyx 第四季度和 2022 年全年財務業績電話會議。 （操作員說明）現在我很高興將電話轉給執行董事兼投資者關係主管 Joshua Higa。

Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Erik Harris, Chief Commercial Officer; Camille Bedrosian, Chief Medical Officer; Aaron Olsen, Senior Vice President of Corporate Strategy and Finance; and Ted Huizenga, Chief Accounting Officer.

謝謝。我們發布了一份詳細介紹我們財務業績的新聞稿，您可以在我們的網站 ultragenyx.com 上找到該新聞稿。與我一起參加此次電話會議的還有首席執行官兼總裁 Emil Kakkis；首席商務官 Erik Harris；首席醫療官 Camille Bedrosian；公司戰略與財務高級副總裁 Aaron Olsen；和首席會計官 Ted Huizenga。

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，在今天的電話會議上，我們將發表前瞻性陳述。這些陳述受某些風險和不確定因素的影響，我們的實際結果可能存在重大差異。請參閱我們最新提交給美國證券交易委員會的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 Emil。

Thanks, Josh, and good afternoon, everyone. Some of you may have listened in on my presentation at the recent JPMorgan Healthcare Conference where I talked about our focus for areas for 2023. Over last year, we completed several strategic investments, aligned our teams and resources around the highest value-generating programs for the company. This year, we'll continue to focus on operational efficiency while generating data from our key clinical programs in Angelman, osteogenesis imperfecta and our pivotal gene therapy studies.

謝謝，喬希，大家下午好。你們中的一些人可能已經聽過我在最近的摩根大通醫療保健會議上的演講，我在會上談到了我們 2023 年的重點領域。去年，我們完成了幾項戰略投資，圍繞創造最高價值的計劃調整了我們的團隊和資源公司。今年，我們將繼續關注運營效率，同時從 Angelman、成骨不全症和關鍵基因治療研究的關鍵臨床項目中生成數據。

In 2022, we generated more than $350 million of global revenue in our fifth year as a commercial company. This year, we expect revenue to be in the $420 million to $450 million range from our 4 products across 5 indications. We expect a steady revenue growth to continue as the existing products are still in relatively early phase of commercialization. At the same time, the investments made over the last few years have positioned us to drive meaningful value from large opportunity programs like GTX-102 for Angelman and UX143 for osteogenesis imperfecta, and we have more recently bolstered our business with additional strategic steps. Specifically, we secured a license and collaboration agreement to commercialize Evkeeza for clinical homozygous familial hypercholesterolemia in countries outside of the U.S., which will leverage our global commercial infrastructure and capabilities.

2022 年，我們作為商業公司的第五個年頭創造了超過 3.5 億美元的全球收入。今年，我們預計 5 種適應症的 4 種產品的收入將在 4.2 億美元至 4.5 億美元之間。由於現有產品仍處於相對早期的商業化階段，我們預計收入將繼續穩定增長。與此同時，過去幾年的投資使我們能夠從大型機會項目（如 Angelman 的 GTX-102和成骨不全症的 UX143）中獲得有意義的價值，並且我們最近通過額外的戰略步驟來支持我們的業務。具體來說，我們獲得了許可和合作協議，在美國以外的國家將 Evkeeza 商業化用於臨床純合子家族性高膽固醇血症，這將利用我們的全球商業基礎設施和能力。

We acquired global rights to UX111 in AAV gene therapy for the treatment of Sanfilippo syndrome from Abeona based on the strength of the pivotal marker data and clinical data generated in the Transfer A study. We also exercised our option to acquire GeneTx following interim data from the Phase I/II of GTX-102 for the treatment of Angelman syndrome. The GeneTx acquisition gives us full control over that program. And we completed the build-out of our gene therapy manufacturing plant in Bedford, Massachusetts, which is expected to begin production this spring. This facility and our manufacturing capabilities grant us the ability to better control the timing, cost and scale of the production of our gene therapies, establishing us as a commercial-ready gene therapy company.

基於 Transfer A 研究中產生的關鍵標誌物數據和臨床數據的優勢，我們從 Abeona 獲得了用於治療 Sanfilippo 綜合徵的 AAV 基因療法中 UX111 的全球權利。根據 GTX-102 I/II 期治療 Angelman 綜合徵的中期數據，我們還行使了收購 GeneTx 的選擇權。對 GeneTx 的收購使我們能夠完全控制該程序。我們完成了位於馬薩諸塞州貝德福德的基因治療製造廠的擴建，預計將於今年春天開始生產。該設施和我們的製造能力使我們能夠更好地控制基因療法生產的時間、成本和規模，使我們成為一家商業化基因療法公司。

Within our pipeline, we made strong progress over the past year in addition to progressing our Angelman program. We initiated a pivotal Phase II/III program for UX143 and OI and have completed enrollment of the Phase II portion of the study. We advanced DTX401 in 2 pivotal Phase III study for GSDIa and have enrolled the last patient into the baseline screening period. We also initiated a Phase III study of DTX301 in OTC, where we have randomized and dosed the first patient in this study with additional patients in the baseline screening period. And we initiated dose patients in the pivotal seamless study of UX701 for Wilson disease.

在我們的管道中，除了推進我們的 Angelman 計劃之外，我們在過去一年中取得了長足的進步。我們啟動了 UX143 和 OI 的關鍵 II / III 期計劃，並完成了該研究的 II 期部分的註冊。我們在 GSDIa 的 2 項關鍵 III 期研究中推進了 DTX401，並將最後一名患者納入基線篩選期。我們還在 OTC 中啟動了 DTX301 的 III 期研究，在該研究中，我們隨機分配了本研究中的第一位患者，並在基線篩選期間向其他患者給藥。我們在 UX701 治療威爾遜病的關鍵無縫研究中啟動了劑量患者。

As a commercial company with growing revenue in a diverse late-stage clinical pipeline, we recently evaluated ways to improve our operating efficiencies. We will focus on leveraging our established global infrastructure, actively managing expenses and headcount to drive value from the commercial launches and execute on our most important clinical programs.

作為一家在多元化的後期臨床管道中收入不斷增長的商業公司，我們最近評估了提高運營效率的方法。我們將專注於利用我們已建立的全球基礎設施，積極管理費用和員工人數，以推動商業發布的價值並執行我們最重要的臨床項目。

With that, I'll turn the call over to Erik to provide more specifics on the commercial programs and their successes last year.

有了這個，我將把電話轉給埃里克，以提供有關商業計劃及其去年成功的更多細節。

Thank you, Emil, and good afternoon, everyone. 2022 was an important year for the commercial and field teams. Across all the products, they delivered 35% year-over-year growth overcoming some of the early challenges presented by the omicron variant.

謝謝你，埃米爾，大家下午好。 2022 年對於商業和現場團隊來說是重要的一年。在所有產品中，他們實現了 35% 的同比增長，克服了 omicron 變體帶來的一些早期挑戰。

Revenue from Crysvita in our territories grew 34%; Dojolvi grew 41%; and Mepsevii, our ultrarare product, grew 29%. The team's efforts are proving rare disease products can generate meaningful revenue growth 5-plus years after launch. 2022 was also the first year where global sales of Crysvita exceeded $1 billion. Crossing the threshold we made possible through the Ultragenyx team's efforts that led to approximately $700 million in total product sales across North America and Latin America and also the efforts of Kyowa Kirin in Europe and Asia.

Crysvita 在我們地區的收入增長了 34%； Dojolvi 增長了 41%；我們的超稀有產品 Mepsevii 增長了 29%。該團隊的努力正在證明，罕見病產品可以在推出 5 年多後產生有意義的收入增長。 2022年也是Crysvita全球銷售額突破10億美元的第一年。通過 Ultragenyx 團隊的努力，跨越北美和拉丁美洲的產品總銷售額約為 7 億美元，以及 Kyowa Kirin 在歐洲和亞洲的努力，我們實現了這一目標。

Since launching Crysvita in April 2018, we have established a strong base of business that we expect will continue to grow as we transition the primary commercialization responsibilities to Kyowa Kirin in April of this year. In the U.S., we added approximately 110 start forms in the fourth quarter and approximately 90 patients on reimbursed therapy, along with 50 new unique prescribers. These metrics are nearing their pre-pandemic levels and support the 26% annual revenue growth in this region. This is particularly impressive as the team has shifted efforts to finding adults into harder-to-reach community clinics where more than 50% of our start forms are generated.

自 2018 年 4 月推出 Crysvita 以來，我們已經建立了強大的業務基礎，我們預計隨著我們在今年 4 月將主要商業化責任移交給 Kyowa Kirin，業務基礎將繼續增長。在美國，我們在第四季度增加了大約 110 份開始表格和大約 90 名接受報銷治療的患者，以及 50 名新的獨特處方醫生。這些指標已接近大流行前的水平，並支持該地區 26% 的年收入增長。這尤其令人印象深刻，因為該團隊已將努力轉移到更難到達的社區診所尋找成年人，我們超過 50% 的開始表格都是在這些診所生成的。

With combined Kyowa Kirin and Ultragenyx build teams in Q4, we have started to reach many more prescribers in the community and raising awareness of XLH, which has helped us in our patient find efforts. In Latin America, Crysvita continues to grow, supported by additional regulatory and reimbursement approvals and also from steady demand in the pediatric and adult setting. We ended 2022 with approximately 300 patients on reimbursed therapy in this region, and we expect this will continue to grow as more and more prescribers to the benefits their patients experience from Crysvita.

通過在第四季度聯合 Kyowa Kirin 和 Ultragenyx 構建團隊，我們已經開始在社區中接觸到更多的處方藥，並提高了對 XLH 的認識，這有助於我們在尋找患者方面做出努力。在拉丁美洲，Crysvita 繼續增長，得到額外的監管和報銷批准以及兒科和成人環境的穩定需求的支持。到 2022 年底，該地區約有 300 名患者接受報銷治療，我們預計隨著越來越多的開處方者從 Crysvita 中獲益，這一數字將繼續增長。

As is common in this region, ordering patterns drive some quarter-to-quarter variability in revenue, but the underlying demand continues to grow at a steady pace. In 2023, we updated the regions for which we will issue Crysvita guidance. This does a better job of representing the broad reach of Crysvita and the total revenue to Ultragenyx. At the beginning of the year and reaffirmed today, we issued guidance of $325 million to $340 million for Crysvita in North America, Latin America and Europe. This is inclusive of all types of revenue, but our profit share, royalty, cash or noncash. Compared to 2022 for the same regions and types of revenue, this range represents between 16% and 22% growth.

正如該地區常見的那樣，訂購模式會導致收入出現一些季度變化，但潛在需求繼續以穩定的速度增長。 2023 年，我們更新了將發布 Crysvita 指南的區域。這更好地代表了 Crysvita 的廣泛影響和 Ultragenyx 的總收入。今年年初並在今天重申，我們為 Crysvita 在北美、拉丁美洲和歐洲發布了 3.25 億至 3.4 億美元的指導。這包括所有類型的收入，但不包括我們的利潤分成、特許權使用費、現金或非現金。與 2022 年相同地區和類型的收入相比，這一範圍代表了 16% 至 22% 的增長。

Turning now to Dojolvi, where I'll begin with the team's work in the U.S. In 2022, we were encouraged by truly strong patient demand. We ended the year with approximately 425 completed start forms with approximately 375 patients on reimbursed therapy. The number of unique prescribers continues to grow, now with approximately 190 health care providers writing at least one prescription for Dojolvi.

現在轉向 Dojolvi，我將從團隊在美國的工作開始。2022 年，我們受到真正強大的患者需求的鼓舞。我們在年底完成了大約 425 份開始表格，其中大約 375 名患者接受了報銷治療。獨特處方者的數量繼續增長，現在大約有 190 名醫療保健提供者至少為 Dojolvi 開出一份處方。

In 2023, we will be focused on continuing to educate health care providers on the benefits of the dose titration supported by our clinical studies to ensure patients are able to achieve optimal dose titration. In Europe, demand for Dojolvi continues to be led by the name patient and early access programs, particularly in France and Italy. We have also begun to see requests come in from Germany, Austria and certain Middle East countries. In Latin America, we are continuing to work through the process, leveraging our existing infrastructure to expand across the region.

2023 年，我們將專注於繼續教育醫療保健提供者，讓他們了解我們的臨床研究支持的劑量調整的好處，以確保患者能夠實現最佳劑量調整。在歐洲，對 Dojolvi 的需求繼續以患者和早期訪問項目為主導，尤其是在法國和意大利。我們也開始看到來自德國、奧地利和某些中東國家的請求。在拉丁美洲，我們正在繼續推進這一進程，利用我們現有的基礎設施在整個地區擴張。

In Brazil, Dojolvi is currently approved, and we are working through the process to get full reimbursement approval from the Ministry of Finance. We also anticipate additional country regulatory filings in the region later this year. Across all regions, we expect 2023 Dojolvi revenue to be between $65 million and $75 million, reaffirming the range we announced last month. This represents between 17% and 35% growth over 2022. At the beginning of the year, we also issued guidance for total revenue, which we are reaffirming today, the range of $425 million to $450 million represents 20-plus percent growth versus 2022. It includes estimates for Crysvita and Dojolvi that I just mentioned and also includes Mepsevii and Evkeeza.

在巴西，Dojolvi 目前已獲得批准，我們正在努力爭取獲得財政部的全額報銷批准。我們還預計今年晚些時候該地區會提交更多的國家監管文件。在所有地區，我們預計 2023 年 Dojolvi 的收入將在 6500 萬美元至 7500 萬美元之間，重申了我們上個月宣布的範圍。這比 2022 年增長了 17% 到 35%。今年年初，我們還發布了總收入指南，我們今天重申，4.25 億美元到 4.5 億美元的範圍比 2022 年增長了 20% 以上。它包括我剛才提到的 Crysvita 和 Dojolvi 的估計值，還包括 Mepsevii 和 Evkeeza。

With that, I'll turn the call to Aaron to share more details on the financial results for the quarter.

有了這個，我會把電話轉給亞倫，分享有關本季度財務業績的更多細節。

Thanks, Erik. Earlier today, we issued a press release that included financial results for the quarter, which I will briefly summarize. Company revenue for the 12 months ended December 31, 2022, totaled $363 million, Crysvita revenue in Ultragenyx territories was $258 million, including $215 million in the North American profit share territory and net product sales of $43 million in other regions.

謝謝，埃里克。今天早些時候，我們發布了一份新聞稿，其中包含本季度的財務業績，我將對其進行簡要總結。截至2022年12月31日的12個月，公司收入總計3.63億美元，Crysvita在Ultragenyx地區的收入為2.58億美元，其中包括北美利潤分成地區的2.15億美元和其他地區的產品淨銷售額4300萬美元。

Total royalty revenue related to the sales of Crysvita in the European territory was $22 million, Dojolvi revenue for 2022 was $56 million, Mepsevii revenue for the same time period was $21 million. Our total operating expenses for the year ended December 31, 2022, were $1 billion, which included R&D expenses of $706 million, SG&A expenses of $278 million and cost of sales of $28 million.

與 Crysvita 在歐洲地區銷售相關的特許權使用費總收入為 2200 萬美元，2022 年 Dojolvi 收入為 5600 萬美元，同期 Mepsevii 收入為 2100 萬美元。截至 2022 年 12 月 31 日止年度，我們的總運營費用為 10 億美元，其中包括 7.06 億美元的研發費用、2.78 億美元的 SG&A 費用和 2800 萬美元的銷售成本。

Operating expenses for the year include noncash stock-based compensation expense of $130 million and a onetime R&D expense of approximately $75 million related to our acquisition of GeneTx. For the year ended December 31, 2022, net loss was $707 million or $10.12 per share. We ended the year with approximately $900 million in cash, cash equivalents and marketable securities.

本年度的運營費用包括 1.3 億美元的非現金股票補償費用和與我們收購 GeneTx 相關的約 7500 萬美元的一次性研發費用。截至 2022 年 12 月 31 日止年度，淨虧損為 7.07 億美元或每股 10.12 美元。年底，我們擁有約 9 億美元的現金、現金等價物和有價證券。

In 2023, our net uses of cash are expected to decrease significantly as we leverage our established infrastructure and continue to grow the top line. This will be enabled by financial discipline, revenue growth and operational focus on our late-stage clinical portfolio. While these improvements in net cash use will be partially offset by the portion of our Crysvita North America royalty that will now go to our financing partner. We are confident that the continuing strength of our business fundamentals will allow us to drive towards profitability in the coming years.

到 2023 年，隨著我們利用已建立的基礎設施並繼續增加收入，我們的現金淨使用量預計將大幅減少。這將通過財務紀律、收入增長和對我們後期臨床產品組合的運營重點來實現。雖然這些淨現金使用的改善將部分被我們的 Crysvita 北美特許權使用費部分所抵消，這些特許權使用費現在將轉到我們的融資合作夥伴。我們相信，我們業務基礎的持續強勁將使我們能夠在未來幾年實現盈利。

Now I'll turn the call back to Emil to read the recap the 2023 clinical catalyst.

現在，我將把電話轉回給 Emil，閱讀 2023 年臨床催化劑的回顧。

Thank you, Aaron. I'll summarize the catalysts from our broad and diverse clinical portfolio before we open up for the Q&A. Starting with UX143 for osteogenesis imperfecta, setrusumab's anti-sclerostin mechanism provides a unique dual action to address the body's maladaptive response to the bad collagen. If unique maximum stimulates more osteoblast to mature into bone making cells and makes those cells increase their bone production while also limiting bone resorption.

謝謝你，亞倫。在開始問答環節之前，我將總結我們廣泛多樣的臨床產品組合中的催化劑。從用於成骨不全症的 UX143 開始，setrusumab 的抗硬化蛋白機制提供了獨特的雙重作用，以解決身體對不良膠原蛋白的適應不良反應。如果獨特的最大值刺激更多的成骨細胞成熟為造骨細胞並使這些細胞增加它們的骨生成，同時也限制骨吸收。

The Phase II portion of the study has been fully enrolled, and we expect to share these data in transition to the Phase III in mid-2023. Separately, we are playing initiate a young pediatric study that compares setrusumab to bisphosphonates to assess total fractures in a younger patient population, which have a much higher fracture frequency.

該研究的 II 期部分已全部入組，我們預計將在 2023 年年中共享這些數據以過渡到 III 期。另外，我們正在發起一項年輕的兒科研究，該研究將 setrusumab 與雙膦酸鹽進行比較，以評估骨折頻率高得多的年輕患者群體的總骨折情況。

Next, GTX-102 in Angelman syndrome. We are continuing to see encouraging signs of clinical activity across the patients who have been dosed under the amended and expanded access protocols. We recently began screening patients in both expansion cohorts and expect to provide the next data update based on a larger number of patients in the program later this year.

接下來，天使綜合症中的 GTX-102。我們繼續看到根據修訂和擴展的訪問協議接受給藥的患者的臨床活動令人鼓舞的跡象。我們最近開始在兩個擴展隊列中篩查患者，並期望在今年晚些時候根據該計劃中的更多患者提供下一次數據更新。

Turning to the gene therapy programs. With UX111 for Sanfilippo syndrome, we're expecting to have a meeting with FDA in the first half of 2023 to discuss the plan to file for accelerated approval based on a biomarker endpoint. For DTX401 for GSDIa, we enrolled the last patient in the baseline screening period for the pivotal study earlier this year. Once this patient has been dosed, the 48-week clock will begin, we expect to share this Phase III data in the first half of 2024. DTX301 for OTC deficiency dosed the first patient in the Phase III study earlier this year, we anticipate enrollment in this study will increase momentum as more patients make it through the baseline screening period. UX701 for Wilson disease enrolling patients in the dose-finding stage, we expect this to be complete mid-2023 with the data on safety and initial signs of clinical activity expected in early 2024.

轉向基因治療計劃。對於 Sanfilippo 綜合徵的 UX111，我們預計將在 2023 年上半年與 FDA 舉行會議，討論根據生物標誌物終點申請加速批准的計劃。對於 GSDIa 的 DTX401，我們在今年早些時候的關鍵研究的基線篩選期招募了最後一名患者。一旦這名患者服藥，48 週的時鐘將開始，我們預計將在 2024 年上半年分享該 III 期數據。今年早些時候，針對 OTC 缺陷的 DTX301 給 III 期研究中的第一名患者服藥，我們預計招募在這項研究中，隨著更多患者通過基線篩選期，勢頭將增加。 UX701 用於 Wilson 病在劑量探索階段招募患者，我們預計這將在 2023 年年中完成，並在 2024 年初獲得有關安全性和臨床活動初步跡象的數據。

Finally, UX053, our mRNA program for GSDIII has completed enrollment in the single ascending dose cohorts of the Phase I/II study, and we expect to have these data in the first half of 2023. Based on these analyses and other work, we'll then review our plans for the next steps in the program.

最後，我們針對 GSDIII 的 mRNA 項目 UX053 已經完成了 I/II 期研究的單次遞增劑量隊列的註冊，我們預計將在 2023 年上半年獲得這些數據。基於這些分析和其他工作，我們然後，我們將審查我們對該計劃後續步驟的計劃。

I founded Ultragenyx in 2010. 13 years later, we have 4 commercial products and are approaching revenue of $450 million. We also have one of the most robust late-stage clinical pipelines in rare diseases. We're now poised for the next phase of the company with growing revenues, fueling our development of new pipeline priorities. In the coming years, a growing revenue base, financial discipline and larger indication opportunities will allow us to reach profitability while also leading the future of rare disease medicine.

我於 2010 年創立了 Ultragenyx。13 年後，我們擁有 4 種商業產品，收入接近 4.5 億美元。我們還擁有最強大的罕見病後期臨床管道之一。我們現在正準備迎接公司下一階段的收入增長，推動我們開發新的管道優先事項。在未來幾年，不斷增長的收入基礎、財務紀律和更大的適應症機會將使我們能夠實現盈利，同時引領罕見病醫學的未來。

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

有了這個，讓我們繼續你的問題。運營商，請提供問答說明。

(Operator Instructions) Our first question comes from the line of Gena Wang from Barclays.

（操作員說明）我們的第一個問題來自巴克萊銀行的 Gena Wang。

I will ask one question each for Angelman program and also osteogenesis imperfecta. For Angelman program, what are the doses you selected for the expansion cohort A and B? And then for the osteogenesis imperfecta, in the midyear update, how would you use, first, can you remind us the 2 doses you used in the obvious Phase II portion? And how would you use the biomarker response in bone mineral density to establish those algorithm for Phase III portion?

我會針對 Angelman 程序和成骨不全症各問一個問題。對於 Angelman 計劃，您為擴展隊列 A 和 B 選擇的劑量是多少？然後對於成骨不全症，在年中更新中，您將如何使用，首先，您能否提醒我們您在明顯的 II 期部分中使用的 2 劑？您將如何使用骨礦物質密度中的生物標誌物反應來為 III 期部分建立這些算法？

Great. Thank you, Gena. So in the Angelman, we have been, of course, evaluating higher doses and through a dose titration period. We haven't put out what doses we are using, but we've established some doses that we believe have an appropriate benefit risk that we'll be using the expansion in both loading patients and their maintenance levels. We've put some information out of the range of doses that we've been trying, but we'll put out more information when we have it on the exact doses we're using.

偉大的。謝謝你，吉娜。因此，在 Angelman 中，我們當然一直在評估更高的劑量並通過劑量滴定期。我們還沒有公佈我們正在使用的劑量，但我們已經確定了一些我們認為具有適當益處風險的劑量，我們將在負荷患者和他們的維持水平上使用擴展。我們已經將一些信息放在了我們一直在嘗試的劑量範圍之外，但是當我們獲得有關我們正在使用的確切劑量的信息時，我們會提供更多信息。

With regard to osteogenesis imperfecta, we're comparing 2 doses in both children from ages 5 to adults of 25, and we're comparing 20 to 40. Our expectation is that the younger children may need more drug in order to get enough concentration of antibodies using pharmacokinetic analysis to achieve the optimal results. So we'll look at the concentrations of drug in the young and the old, and we'll also look at the biomarkers for bone production P1NP, and we'll have also some bone mineral density data as well, and the goal is to compare those and determine do we need to use a higher concentration of drug in the younger patients to achieve the optimal effect or not?

關於成骨不全症，我們正在比較 5 歲到 25 歲成人的 2 劑，我們正在比較 20 到 40 歲。我們的預期是，年幼的孩子可能需要更多的藥物才能獲得足夠的濃度抗體使用藥代動力學分析來達到最佳效果。因此，我們將研究年輕人和老年人的藥物濃度，我們還將研究骨骼生成 P1NP 的生物標誌物，我們還將獲得一些骨礦物質密度數據，目標是比較這些並確定我們是否需要在年輕患者中使用更高濃度的藥物以達到最佳效果？

So look at this as dose tuning rather than dose finding. We know the dose. The question is do we need to go a little higher in the younger patients and -- you'll get a little read on what this drug does in young patients at that time, which I think will be more responsive patients than the older patients that have been treated before, at least our expectation based on bone disease we've treated in the past.

因此，將此視為劑量調整而不是劑量發現。我們知道劑量。問題是我們是否需要在年輕患者中使用更高一點的藥物——你會了解到當時這種藥物對年輕患者的作用，我認為年輕患者的反應會比老年患者更敏感以前接受過治療，至少我們基於過去治療過的骨病的預期。

(Operator Instructions) And our next question comes from the line of Chris Ramsey (sic) [Christopher Raymond] from Piper Sandler.

（操作員說明）我們的下一個問題來自 Piper Sandler 的 Chris Ramsey（原文如此）[Christopher Raymond]。

Just one question on a collaboration that I don't think I've heard you guys talk about. So Inozyme today mentioned that they just started a collaboration with you guys to find misdiagnosed ENPP1 patients. It seems XLH seems to overlap maybe phenotypically with that disease. Emil, this asset would seem to be something that would, I would think, fit in within your wheelhouse developmentally. Just kind of curious if you had any thoughts on this collaboration and maybe any thoughts on the drug itself, especially in light of the data that these guys had at least top line today and how you're thinking about this relationship going forward?

只是一個關於合作的問題，我認為我沒有聽過你們談論過。所以 Inozyme 今天提到他們剛剛開始與你們合作，尋找誤診的 ENPP1 患者。 XLH 似乎在表型上可能與該疾病重疊。埃米爾，我認為這項資產似乎適合您的發展方向。只是想知道您是否對這種合作有任何想法，也許對藥物本身有任何想法，特別是考慮到這些人今天至少有頂線的數據，以及您如何看待這種關係的發展？

Yes. We work with a lot of companies on the issue of diagnosis and not just other companies, we're all trying to help find patients and share that information with each other. At this point, we are not planning on bringing any more products into our portfolio. And we continue to watch the field, including what Inozyme is doing and others with regard to new opportunities for rare diseases. But at this point, we have on our plate all we need to manage and -- but finding patients and working with our partners and others in the field is something we do routinely.

是的。我們在診斷問題上與很多公司合作，而不僅僅是其他公司，我們都在努力幫助尋找患者並相互分享這些信息。目前，我們不打算將更多產品納入我們的產品組合。我們繼續關注該領域，包括 Inozyme 正在做的事情以及其他與罕見疾病的新機會有關的事情。但在這一點上，我們已經掌握了我們需要管理的所有東西——但是尋找病人並與我們的合作夥伴和該領域的其他人合作是我們經常做的事情。

And our next question comes from the line of Joon Lee from Truist.

我們的下一個問題來自 Truist 的 Joon Lee。

[How should be aware] the biomarker data for setrusumab, is there a level of bone formation you wouldn't want to exceed. Are there potential safety issues, particularly in young patients, growing bones where too much bone formation could lead to potential safety issues, maybe hearing loss, for example.

[應如何注意]setrusumab 的生物標誌物數據，是否存在您不想超過的骨形成水平。是否存在潛在的安全問題，特別是在年輕患者中，骨形成過多可能會導致潛在的安全問題，例如，可能會導致聽力損失。

So the question is whether you can stimulate too much bone growth and kind of impinge nerves like in hearing or otherwise, I think the truth is these patients are very deficient in their bone production. So we're starting from a place of deficiency. And while if you had a genetic defect of sclerostin, you might get these problems, the ability for us to knock down the level of cost to the degree required, I think, is very different from a genetic deficiency state. Secondly, I would say, the patients are beginning at a position of very deficient bone quantity, as we treat them and grow, we'll look at -- after we've improved their bone strength at a point of establishing a maintenance dosing. And based on the asteroid study where we -- the treatment was stopped and we looked at resorption, it looks like we can establish, let's say, less frequent maintenance dosing once we get patients fully loaded and having their bone strength improved, which I think would mitigate, for example, if there was a long-term risk of that kind.

所以問題是你是否可以刺激過多的骨骼生長並像聽力或其他方面那樣刺激神經，我認為事實是這些患者的骨骼生成非常不足。所以我們從一個不足的地方開始。雖然如果你有硬化蛋白的遺傳缺陷，你可能會遇到這些問題，但我認為，我們將成本水平降低到所需程度的能力與遺傳缺陷狀態有很大不同。其次，我要說的是，患者開始時骨量非常不足，隨著我們對他們的治療和成長，我們會看看——在我們提高他們的骨強度後，確定維持劑量。根據小行星研究，我們停止了治療並觀察了再吸收，看起來我們可以確定，比方說，一旦我們讓患者完全負荷並且他們的骨強度得到改善，我認為我們可以降低維持劑量的頻率例如，如果存在這種長期風險，就會減輕。

But let's face it, right now, these patients are suffering every day. Their bones are disintegrating and that's first order of business, but we'll always watch out for managing the effect of our drugs going forward. But at this point, we're not concerned about it in the beginning of this program.

但讓我們面對現實吧，現在，這些患者每天都在受苦。他們的骨頭正在分解，這是首要任務，但我們將始終注意管理我們藥物的影響。但是在這一點上，我們在這個程序的開頭並不關心它。

And our next question comes from the line of Yigal Nochomovitz from Citi.

我們的下一個問題來自花旗的 Yigal Nochomovitz。

So obviously, we are getting a lot of questions lately on the OI program and Romo comes up quite a lot in that conversation, which obviously, as you know, is anti-sclerostin. So if you could help us with the quick elevator pitch on why setrusumab is differentiated from Romo, and why your antibody will be the preferred option, potentially NOI?

很明顯，我們最近收到了很多關於 OI 計劃的問題，而 Romo 在那次談話中出現了很多，正如你所知，這顯然是抗硬化素。因此，如果您能幫助我們快速說明為什麼 setrusumab 與 Romo 不同，以及為什麼您的抗體將成為首選，可能是 NOI？

Sure. First of all, Romo was designed and developed for treatment of osteoporosis and approved and labeled in that area. What we're going to be doing is dose optimizing for the osteogenesis imperfecta indication, not the osteoporosis indication. They have a limit of 12 months of treatment, we will not have that limit. We will be able to have chronic dosing, which will be very important in this disease, which is lifelong. And secondly, by optimizing the dosing regimen, we'll be able to treat patients in an optimal way as a rare disease company will also be able to support patients specifically. So the combination of the dose, the regimen and support programs will differentiate setrusumab from what out there at Romo right now. So those are some of the factors, I think, that will be important.

當然。首先，Romo 是為治療骨質疏鬆症而設計和開發的，並在該領域獲得批准和標記。我們要做的是針對成骨不全適應症而不是骨質疏鬆症適應症進行劑量優化。他們有 12 個月的治療時間限制，我們不會有這個限制。我們將能夠進行慢性給藥，這對於這種終生疾病非常重要。其次，通過優化給藥方案，我們將能夠以最佳方式治療患者，因為罕見病公司也將能夠專門為患者提供支持。因此，劑量、方案和支持計劃的組合將使 setrusumab 與 Romo 目前的產品區分開來。所以我認為這些是一些重要的因素。

And just to follow-up on Gena's earlier question regarding the dose selection for the OI study that you're going to read out in the middle of the year. Once you select that dose, will that be the same dose that is used in the younger patients in the 2- to 5-year-old when you're comparing head-to-head versus bisphosphonates?

只是為了跟進 Gena 之前關於您將在年中宣讀的 OI 研究的劑量選擇的問題。一旦你選擇了那個劑量，當你比較頭對頭與雙膦酸鹽時，它是否與 2 至 5 歲的年輕患者使用的劑量相同？

Well, if that dose, for example, turns out to be higher, if 20 isn't the dose, it needs to be higher, we'll then adapt that over to the other study dose as well. We would expect to.

好吧，例如，如果那個劑量結果更高，如果 20 不是劑量，它需要更高，然後我們也會將其調整到另一個研究劑量。我們希望。

And our next question comes from the line of Tazeen Ahmad from Bank of America.

我們的下一個問題來自美國銀行的 Tazeen Ahmad。

Emil, I just wanted to follow up maybe on the opportunity in Sanfilippo syndrome for UX111. Can you just remind us what the competitive landscape looks like today? And how many patients do you think there are in the U.S. and abroad? And then a quick follow-up, on your manufacturing facility, on the new one, would that support all of your gene therapy programs going forward?

Emil，我只是想跟進 UX111 的 Sanfilippo 綜合症的機會。您能否提醒我們今天的競爭格局是什麼樣的？您認為美國和國外有多少患者？然後快速跟進，在你的製造設施上，在新的上，它會支持你所有的基因治療項目向前發展嗎？

Thanks, Tazeen. So with Sanfilippo IIIa, one of the decisions we had to make in picking up the program was whether there was a very good option around that we could do just as well. And our view was there wasn't really. The other program in life team, they are actually -- they're going out of business. This product was better than that product, I think, from a standpoint of biomarker reductions in effect. There is a lentivirus approach, which I think has its own challenges, it's fairly early on. But really, there isn't another, I think, effective AAV gene therapy out there that's at the stage that says. So our feeling was that this would be the lead program and had the best efficacy that I've seen from at least a biomarker standpoint. So that was our decision.

謝謝，塔贊。因此，對於 Sanfilippo IIIa，我們在接受該計劃時必須做出的決定之一是，是否有一個非常好的選擇可以讓我們做得同樣好。而我們的觀點是真的沒有。生活團隊中的另一個項目，他們實際上——他們要倒閉了。我認為，從生物標誌物減少效果的角度來看，該產品優於該產品。有一種慢病毒方法，我認為它有其自身的挑戰，它還處於早期階段。但實際上，我認為目前還沒有另一種有效的 AAV 基因療法。所以我們的感覺是，這將是領先的項目，並且至少從生物標誌物的角度來看具有我所見過的最好的療效。所以這是我們的決定。

With regard to the population of the world, there's probably a few thousand patients, but the -- you have to think of this as a little bit more of an incident population, right? Because the best effect appears to be in kids that are under 2 years old, so it was a little bit like Zolgensma, they need to be young to get the best benefit. Would we treat older patients? Perhaps, it depends on what happens in the regulatory process. I think there may be benefit in older patients, but it's clearly the optimal benefit happens when you treat young. So I would look at it that way.

關於世界人口，可能有幾千名患者，但是 - 你必須將其視為更多的事件人口，對吧？因為最好的效果似乎出現在 2 歲以下的孩子身上，所以它有點像 Zolgensma，他們需要年輕才能獲得最好的效果。我們會治療老年患者嗎？也許，這取決於監管過程中發生的事情。我認為老年患者可能會獲益，但顯然最佳獲益發生在治療年輕患者時。所以我會這樣看。

What I was saying to you about this gene therapy and unlike some of the other diseases where there are other treatments. If we add a gene therapy that's doing what we believe we see is doing right now, we think essentially every sample patient won't want to get treated because the other options are just none at this point in time. And so it has the kind of devastating impact that you have with SMA, and I think the adoption rate would be very high if we can get it approved promptly.

我對你說的是關於這種基因療法，它與其他一些有其他治療方法的疾病不同。如果我們添加一種基因療法，它正在做我們認為我們現在正在做的事情，我們認為基本上每個樣本患者都不想接受治療，因為此時其他選擇都沒有。因此，它具有與 SMA 一樣的破壞性影響，我認為如果我們能夠迅速獲得批准，採用率將會非常高。

Now the other question was the manufacturing plant and capacity. The plant has 2 suites that can run 30 runs a year. One suite is operating right now. We will -- we can operate a second suite. 30 runs a year gets a lot of what we need done. I don't know that we'll handle 100% of the needs because it depends on which programs you're talking about to achieve that. Our plan has always been to have some hybrids, some contract manufacturing and some of our own. And if necessary, we do have a green space, a greenfield plant space next to our plant that we could double the plant further. But right now, I think 30 runs will take us a long way in the future. And if we're at that high-level success rate, treating that many gene therapies, we can then invest in expanding that capacity further. But it will take us a long way for what we need at the moment.

現在另一個問題是製造工廠和產能。該工廠有 2 個套間，每年可以運行 30 次。一間套房正在運營。我們將 - 我們可以經營第二間套房。每年 30 次運行可以完成很多我們需要完成的工作。我不知道我們是否會處理 100% 的需求，因為這取決於您所討論的實現該需求的計劃。我們的計劃一直是擁有一些混合動力車、一些合同製造車和一些我們自己的車。如果有必要，我們確實有一個綠地，一個靠近我們工廠的綠地工廠空間，我們可以將工廠進一步擴大一倍。但是現在，我認為 30 次跑步會讓我們在未來走得更遠。如果我們能達到如此高的成功率，治療那麼多基因療法，我們就可以投資進一步擴大這種能力。但是，我們目前需要的東西還需要很長的路要走。

And our next question comes from the line of Jeff Hung from Morgan Stanley.

我們的下一個問題來自摩根士丹利的 Jeff Hung。

I guess for setrusumab, you talked about the 2 doses. What kind of incremental benefit would you expect or want to see with the 40-milligram per kilogram dose over the 20? And then can you talk about the feedback that you've been hearing on the launch of Evkeeza in Europe?

我想對於 setrusumab，您談到了 2 劑。在 20 天后，每公斤 40 毫克的劑量，您期望或希望看到什麼樣的增量收益？然後你能談談你在歐洲推出 Evkeeza 時聽到的反饋嗎？

So with setrusumab, we haven't set precise criteria. We really want to look at the gradations of drug concentration and drug effect as we go along. But to give you a rough idea, if there were -- if doubling the dose gave you 10% more bone production, I don't think it's worth it. But if it gave you 50% more bone production, then I would say that's worth it. So if that gives you kind of a rough idea. I think that would be what we would be looking for is something more meaningful to warrant spending and giving that much more drug.

所以對於 setrusumab，我們還沒有設定精確的標準。隨著我們的進行，我們真的很想看看藥物濃度和藥物作用的等級。但是給你一個粗略的想法，如果有——如果劑量加倍可以使你的骨量增加 10%，我認為這是不值得的。但如果它能讓你的骨骼產量增加 50%，那麼我會說這是值得的。所以如果這給了你一個粗略的想法。我認為這將是我們要尋找的更有意義的東西來保證支出和提供更多的藥物。

With regard to Evkeeza, we've had tremendously positive feedback from doctors on it, both in Europe and we've had a few compassionate use requests and patients treated. And I think that we're excited about potential in every -- [each patients], really the first really good drug that doesn't depend on LDL receptor at all and can be given just as a monthly IV and -- so if we can get it reimbursed and get access out there, I think we will see a strong uptick because there is great interest in it. And part of the reason we decided to partner with Regeneron on the program in the first place.

關於 Evkeeza，我們從歐洲的醫生那裡得到了非常積極的反饋，我們也收到了一些富有同情心的使用請求和治療的患者。而且我認為我們對每個 - [每個患者] 的潛力感到興奮，這真的是第一個完全不依賴於低密度脂蛋白受體並且可以每月靜脈注射的真正好的藥物 - 所以如果我們可以得到報銷並在那裡獲得訪問權限，我認為我們會看到強勁的增長，因為人們對它很感興趣。這也是我們決定與 Regeneron 合作開展該計劃的部分原因。

Our next question comes from the line of Salveen Richter from Goldman Sachs.

我們的下一個問題來自高盛的 Salveen Richter。

This is Tommie on for Salveen. So for the UX053 data coming this year, can you remind us what some of the details here are in terms of duration, number of patients and any bars or benchmarks where you would see a positive signal?

這是 Salveen 的 Tommie。因此，對於今年即將發布的 UX053 數據，您能否提醒我們這裡的一些細節，包括持續時間、患者數量以及您會看到積極信號的任何條形圖或基準？

Certainly, the UX053 program is an mRNA LNP that's producing this enzyme that will help restore glycogen metabolism. We'll be looking for changes in biomarkers and glucose release and biomarkers of glucose fragments that are accumulating as well as safety branders around liver or immune response, et cetera. So it will be primarily a biochemical kind of look at both glucose control as well as release of glycogen fragments. So those 2 things should help us get an idea about dose. These are all single-dose patients that were escalated at single-dose ascending dose kind of cohort. So it will be a first indication of what we can achieve in terms of metabolic correction based on -- primarily biochemical measures.

當然，UX053 程序是一種 mRNA LNP，它會產生這種有助於恢復糖原代謝的酶。我們將尋找生物標誌物和葡萄糖釋放的變化以及正在積累的葡萄糖片段的生物標誌物，以及圍繞肝臟或免疫反應等的安全標記。因此，這將主要是一種生化類型的觀察，既可以控制葡萄糖，也可以觀察糖原片段的釋放。所以這兩件事應該可以幫助我們了解劑量。這些都是在單劑量遞增劑量隊列中升級的所有單劑量患者。因此，這將是我們在基於主要生化措施的代謝校正方面可以取得的成果的第一個跡象。

And our next question comes from the line of Maury Raycroft from Jefferies.

我們的下一個問題來自 Jefferies 的 Maury Raycroft。

I was wondering for the setrusumab Phase II update, can you clarify if you'll have all patients at each of the 2 doses and the age range is 5 to 25. But are you breaking out what proportion are older versus younger?

我想知道關於 setrusumab II 期更新，您能否澄清一下是否所有患者都接受了 2 種劑量，並且年齡範圍是 5 到 25 歲。但是您是否要說明老年人和年輕人的比例是多少？

Yes. So for -- what we'll have is for those 24 patients will have all their data through at least 2 months, including the last patients in. For some of the patients that were started last year will have maybe 6 months of data, which will include BMDs that were done at interim time points. So that will be kind of a broad set of data. We will look at different age groups, and we haven't decided how much we need to disclose. We'll have -- we have ages that are distributed around the age range that will allow us to look at different ages and use both PK and the biomarker modeling to try to determine whether we need to increase the drug exposure at the lower doses.

是的。所以——我們將擁有的是，這 24 名患者將擁有至少 2 個月的所有數據，包括最後一名患者。對於去年開始的一些患者，可能會有 6 個月的數據，這將包括在臨時時間點完成的 BMD。所以這將是一組廣泛的數據。我們會考慮不同的年齡段，我們還沒有決定需要透露多少。我們將 - 我們的年齡分佈在年齡範圍內，這將使我們能夠觀察不同的年齡並使用 PK 和生物標誌物建模來嘗試確定我們是否需要在較低劑量下增加藥物暴露。

Our next question comes from the line of Dae Gon Ha from Stifel.

我們的下一個問題來自 Stifel 的 Dae Gon Ha 系列。

Maybe a question on GTX-102. Can you maybe provide any updates on the scoliosis patient? Has that patient resolved fully to continue receiving the dose? And any update to the time line of FDA submission of the package for the protocol harmonization?

也許是關於 GTX-102 的問題。您能否提供有關脊柱側彎患者的任何最新信息？該患者是否已完全決定繼續接受該劑量？ FDA 提交協議協調包的時間表是否有任何更新？

Yes. The patients, as we said before, resolved -- essentially resolved the problems they had. I think that we're continuing to evaluating him. He's not redosed yet. We have to wait until his -- we will wait until his protein levels have resolved, which we will do at intervals and measure, but we're encouraged how that's gone.

是的。正如我們之前所說，患者解決了 - 基本上解決了他們遇到的問題。我認為我們正在繼續評估他。他還沒有恢復。我們必須等到他的——我們將等到他的蛋白質水平得到解決，我們將每隔一段時間進行一次測量，但我們對這種情況如何消失感到鼓舞。

And the second question was on -- yes. So we're planning that discussion shortly, and we'll be presenting how to approach moving ahead with expansion cohorts in the U.S. And we're expecting a good meeting. We think we've gotten good responses through discussions with them lately. And I feel like there's an opportunity to move ahead. But we still need to have that formal discussion in order to open up the protocol in the U.S., which we think will be important in being able to rapidly expand the study and put us in position to get a large enough amount of data to be confident about designing a Phase III.

第二個問題是-- 是的。因此，我們計劃很快進行討論，我們將介紹如何在美國推進擴張隊列。我們期待一次愉快的會議。我們認為我們最近通過與他們的討論得到了很好的回應。我覺得有機會繼續前進。但我們仍然需要進行正式討論，以便在美國開放該協議，我們認為這對於能夠迅速擴大研究並使我們能夠獲得足夠多的數據以確保信心非常重要關於設計第三階段。

And our next question comes from the line of Liisa Bayko from Evercore.

我們的下一個問題來自 Evercore 的 Liisa Bayko。

Could you run through just with the change in -- to the royalty. Can you just remind us of that? And how you're seeing kind of the net profit from that changing is the royalty somewhat equivalent to what you'd be getting from the profit split, that would be helpful.

你能否通過更改 - 對版稅的更改來完成。你能提醒我們一下嗎？你如何看待這種變化帶來的淨利潤是特許權使用費，這在某種程度上相當於你從利潤分配中獲得的收益，這會有所幫助。

Yes. So to be clear, you're talking about the switch from a profit share with our partner, Kirin to the royalty period. Is that correct? That's what you're talking about?

是的。所以要明確一點，你是在談論從與我們的合作夥伴麒麟的利潤分成到特許權使用費期的轉變。那是對的嗎？你說的就是這個？

Yes. Exactly, yes.

是的。沒錯，是的。

Well, in general, that crossover will essentially be even. There won't be a significant change, really. The way we structured it originally made was actually pretty well modeled in terms of predicting what our share should be. So the 29%, the top tier of the royalty will cover and expect to cover some commercial costs. We are sharing some costs with them. But at this point, if you look at the total picture of how the profit share was designed and how this is -- it's pretty flat, pretty similar. And so we feel very good that you wouldn't see a significant step off or change in the revenue stream. I don't know if there's anything more, Aaron, you don't want to say to that.

好吧，一般來說，這種交叉基本上是均勻的。不會有太大的變化，真的。我們最初構建它的方式實際上在預測我們的份額應該是多少方面得到了很好的建模。所以 29%，最高層的特許權使用費將支付並期望支付一些商業成本。我們正在與他們分攤一些費用。但在這一點上，如果你看一下利潤分成的總體情況以及它是如何設計的——它非常平坦，非常相似。因此，我們感覺非常好，您不會看到收入流發生重大變化或變化。我不知道還有什麼，Aaron，你不想對那個說。

No, that was well summarized. Thanks, Emil.

不，總結的很好。謝謝，埃米爾。

(Operator Instructions) Our next question comes from the line of Anupam Rama from JPMorgan.

（操作員說明）我們的下一個問題來自摩根大通的 Anupam Rama。

Two quick ones from me. Following up on Tazeen's question on UX111 and MPS III, has been meeting with the FDA been calendared? And maybe walk us through the scenarios that could play out here. And if you are able to go with an accelerated path forward for that program, is there any read-through to your broader gene therapy programs. And then question 2, maybe could you expand on the statement in the press release that with GTX-102, there continues to be a dose and time-dependent clinical activity in the population. And maybe if you could provide any type of color on what type of benefit you're seeing over what time period? That would be helpful.

我的兩個快速的。跟進 Tazeen 關於 UX111 和 MPS III 的問題，是否已安排與 FDA 的會議？也許可以帶我們了解可能在這裡上演的場景。如果您能夠加快推進該計劃的步伐，是否可以通讀更廣泛的基因治療計劃。然後是問題 2，也許你可以擴展新聞稿中關於 GTX-102 的聲明，在人群中繼續存在劑量和時間依賴性臨床活動。也許您可以提供任何類型的顏色，說明您在什麼時間段內看到的是什麼類型的好處？那會很有幫助。

Yes. Normally, with regulatory authority discussions, we don't precisely put out the exact timing of meetings and events that degree the meeting is set, and we're planning to meet with them shortly. But does the point of the meeting is that the FDA had already agreed on a clinical endpoint and with a longer period of time to evaluate. However, of late, they have started showing some acceptance of heparan sulfate as a biomarker, that is predictive. And we believe in our public discussion with Peter Marks and in other settings as the heparan sulfate marker may be possible as the primary, which would allow us to file earlier than waiting for the clinical data. So our discussion will focus on can we use heparan sulfate of the particular high-quality assay that's being used for purposes of filing with a commitment to complete the clinical follow-up data, of course, to verify the clinical benefit. And so that will come relatively soon. And we'll let you know as soon as we know what the answer is to that question.

是的。通常情況下，隨著監管機構的討論，我們不會準確地公佈會議和活動的確切時間安排，我們計劃盡快與他們會面。但會議的重點是 FDA 已經就臨床終點和更長的評估時間達成一致。然而，最近，他們開始表現出對硫酸乙酰肝素作為生物標誌物的接受程度，這具有預測性。我們相信我們與 Peter Marks 的公開討論和其他設置，因為硫酸乙酰肝素標記物可能作為主要標記物，這將使我們能夠在等待臨床數據之前提交文件。因此，我們的討論將集中在我們是否可以使用用於提交目的的特定高質量測定的硫酸乙酰肝素，並承諾完成臨床隨訪數據，當然，以驗證臨床益處。所以這會相對較快地到來。我們會在知道該問題的答案後立即通知您。

It doesn't mean the program is -- it just means we can go a little faster. If we can go faster, it just allows us to file earlier. We still have to set up the CMC manufacturing pieces of the program. And we're trying to run that in a capital efficient way as possible because we do have a lot on our plate.

這並不意味著該計劃是——它只是意味著我們可以走得更快一點。如果我們能走得更快，它只會讓我們更早提交文件。我們還是要設置CMC製造件的程序。我們正在嘗試以盡可能節省資本的方式來運行它，因為我們確實有很多事情要做。

So GTX-102, we disclosed that there was some dose and time-dependent differences. We have actually mentioned this before. When we put out information earlier, we had talked about the fact that the quantitative endpoints around the Bayley were better with the higher dose groups and with the lowest dose group at 2 mg in the U.S. So that was the dose-dependent piece. And we've said that patients seem to improve over time, and that's the time-dependent piece. So it's information we've been seeing, it's in the -- the main drivers are the ones we've already disclosed, which are -- we're talking about in the Bayley's course and language and sleep. And we're evaluating multiple things and looking at many things, but we feel good about the pattern of response we're seeing with both dose and time-dependent and that's why we're moving into expansion cohorts.

所以 GTX-102，我們透露存在一些劑量和時間依賴性差異。我們之前實際上已經提到過這一點。當我們早些時候發布信息時，我們談到了這樣一個事實，即在美國，較高劑量組和最低劑量組 2 mg 的 Bayley 周圍的定量終點更好，所以這是劑量依賴性的部分。我們已經說過，患者似乎會隨著時間的推移而好轉，這是時間依賴性的部分。所以這是我們一直在看到的信息，它在——主要驅動因素是我們已經披露的那些——我們在 Bayley 的課程、語言和睡眠中談論的。我們正在評估多項事情並研究很多事情，但我們對劑量和時間依賴性方面的反應模式感到滿意，這就是我們進入擴展隊列的原因。

And our next question comes from the line of Joel Beatty from R W. Baird.

我們的下一個問題來自 R W. Baird 的 Joel Beatty。

For revenue, are there any seasonal effects from Q4 of last year and Q1 of this year to be aware of?

對於收入，去年第四季度和今年第一季度是否有任何季節性影響需要注意？

Well, there are always seasonal effects, but I think actually, I think we did well last year in terms of hitting our marks. And I'm not sure, Erik, would have anything more to say. But I think you can always expect some lumpiness particularly with Latin America because the orders come in burst and off and on. And so it's a little bit harder to predict. It's just part of the nature of the rare disease business. But I think things are well. Erik, did you have anything else to add on lumpiness?

好吧，總是有季節性影響，但我認為實際上，我認為我們去年在達到目標方面做得很好。 Erik，我不確定還有什麼要說的。但我認為你總是可以預料到一些不穩定的情況，尤其是在拉丁美洲，因為訂單突然斷斷續續地來了。因此，預測起來有點困難。這只是罕見病業務的一部分。但我認為一切都很好。埃里克，你還有什麼要補充的嗎？

You covered it as far as Latin America is concerned, I mean, I think it's important to recognize that we've had steady growth over the last 5 years for Crysvita. It establishes the gold standard for treatment of XLH and we expect it to continue to grow as we've seen consistent increases in key performance indicators, such as patient finding, start forms, reimbursed patients and unique prescribers. So demand remains strong. That said, we do experience some seasonality increasing ordering patterns in Q4 and Q1, which has been consistent year-over-year, if you look back over the previous years. Q1 being a little lighter as expected as patients work through the reauthorization and changeable insurance process. So it just takes a little longer [for me] to get on. But we remain confident in the underlying demand and which is why we reaffirmed our guidance.

就拉丁美洲而言，你涵蓋了它，我的意思是，我認為重要的是要認識到我們在過去 5 年中為 Crysvita 取得了穩定的增長。它建立了 XLH 治療的黃金標準，我們預計它會繼續增長，因為我們已經看到關鍵績效指標的持續增長，例如患者發現、開始表格、報銷患者和獨特的處方者。因此需求依然強勁。也就是說，如果您回顧前幾年，我們確實在第四季度和第一季度經歷了一些季節性增加的訂單模式，這與去年同期相比一直保持一致。隨著患者完成重新授權和可變保險流程，Q1 比預期的要輕一些。所以 [對我來說] 只需要更長的時間才能繼續下去。但我們對潛在需求仍然充滿信心，這就是我們重申我們的指引的原因。

And our next question comes from the line of Yaron Smith (sic) [Yaron Werber] from Cowen.

我們的下一個問題來自 Cowen 的 Yaron Smith（原文如此）[Yaron Werber]。

This is Brendan on for Yaron. Sorry, if you just answer my phone call for just a second. But for Crysvita, I noticed Q4 sales really did jump up a bit. I was hoping you can maybe give us any color as to what was really underlying that just in Q4 relative to Q3. And if this is kind of some trends that you're expecting to hold forward -- hold moving forward? And then I just wanted to ask on Angelman. I know there's a lot of questions here on dosing and things like this. But can you just give us a sense of what we could expect in the next day to readout in terms of really how many patients you're thinking to include whether they'll include them from the expansion cohorts and maybe over how long really kind of just trying to get a sense of where the internal bar is for you all in terms of when you want to put out the data.

這是 Yaron 的 Brendan。抱歉，如果你只是接聽我的電話一秒鐘。但對於 Crysvita，我注意到第 4 季度的銷售額確實有所上升。我希望你能給我們任何關於第四季度相對於第三季度的真正基礎的顏色。如果這是您希望保持的某些趨勢 - 保持前進？然後我只想問一下 Angelman。我知道這裡有很多關於劑量和類似事情的問題。但是你能告訴我們我們在第二天可以期望讀出的內容嗎？你正在考慮包括多少患者，他們是否會從擴展隊列中包括他們，以及可能需要多長時間？只是想了解在何時發布數據方面適合你們的內部標準。

Sure. Well, I'll answer the Angelman question first. And then maybe, Erik, you can touch on the Crysvita and the strong Q4 question. So on Angelman, we've been releasing. We've been doing these dose titration course, which were just relatively small for patient groups. But it's clear we need to have something like at least 10 patients in each group to kind of give us the kind of data that we can do statistics on and at least do enough projection to understand how to power a study. So I'm looking for the announced to have maybe 20 patients or about half of what we need to enroll. That's giving you a rough idea.

當然。好吧，我先回答天使的問題。然後也許，埃里克，你可以談談 Crysvita 和強大的 Q4 問題。所以在 Angelman 上，我們一直在發布。我們一直在進行這些劑量滴定課程，這些課程對於患者群體來說相對較小。但很明顯，我們需要在每組中至少有 10 名患者，才能為我們提供可以進行統計的數據，並且至少可以進行足夠的預測以了解如何為研究提供動力。所以我正在尋找宣布可能有 20 名患者或大約一半的我們需要註冊的患者。這給了你一個大概的想法。

And now in addition, we would have the patients we've already treated who will have been titrated in maintenance mode, and I would expect that would be the kind of volume of data that would allow us to accurately project what Phase III will look like, which is I think what investors ask for us is to have confident data that will allow them to see the future for the program in a Phase III program. So that's that. And for Crysvita Q4, I think it's a pattern we've seen before, Erik. Perhaps you want to add to the pattern.

現在此外，我們將有我們已經治療過的患者，他們將在維持模式下進行滴定，我希望這將是一種數據量，可以讓我們準確地預測 III 期的情況，我認為投資者要求我們的是擁有自信的數據，使他們能夠在 III 期項目中看到該項目的未來。就是這樣。對於 Crysvita Q4，我認為這是我們以前見過的模式，Erik。也許您想添加到模式中。

Yes. We had expected a strong second half of the year as we were hampered in early 2022 with the Omicron variant. We saw continued increase in patient volumes in the offices as they opened up more and more as well as participation in live educational meetings and programs. And I think consistently growing demand throughout the year was one of the main factors driving the strong Q4.

是的。我們曾預計今年下半年會表現強勁，因為我們在 2022 年初受到 Omicron 變體的阻礙。我們看到辦公室的病人數量持續增加，因為他們越來越多地開放以及參與現場教育會議和項目。我認為全年持續增長的需求是推動第四季度強勁增長的主要因素之一。

So it's a bit of a rebound out of the hampered first part of the year, but it generally has been strong in Q4.

因此，從今年上半年的受阻中略有反彈，但在第四季度總體上表現強勁。

This does conclude the question-and-answer session of today's program. I'd like to turn the program back to Joshua Higa for any further remarks.

今天節目的問答環節到此結束。我想將程序轉回 Joshua Higa 以徵求進一步意見。

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，請通過電話或發送電子郵件至 ir@ultragenyx.com 與我們聯繫。感謝您加入我們。

Ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

女士們，先生們，感謝你們參加今天的會議。這確實結束了程序。您現在可以斷開連接。再會。