Sarepta Therapeutics Inc (SRPT) 2024 Q4 法說會逐字稿

Good afternoon, and welcome to the Sarepta Therapeutics fourth-quarter and full-year 2024 financial results conference call. As a reminder, today's program is being recorded.

下午好，歡迎參加 Sarepta Therapeutics 2024 年第四季和全年財務業績電話會議。提醒一下，今天的節目正在錄製中。

At this time, I'd like to turn the call over to Mary Jenkins, Associate Director, Investor Relations and Corporate Communications. Please go ahead.

現在，我想將電話轉給投資者關係和企業傳播部副總監瑪麗·詹金斯 (Mary Jenkins)。請繼續。

Thank you, Lisa, and thank you all for joining today's call. Earlier this afternoon, we released our financial results for the fourth-quarter and full-year 2024. The press release, slides, and supplementary information are available on the Investor section of our website at Sarepta.com. Our 10-K will be filed with the SEC later this week.

謝謝你，麗莎，也謝謝大家參加今天的電話會議。今天下午早些時候，我們發布了 2024 年第四季度和全年財務業績。新聞稿、幻燈片和補充資訊可在我們網站 Sarepta.com 的投資者部分找到。我們的 10-K 報表將於本週稍後提交給美國證券交易委員會 (SEC)。

Joining us on the call today are Doug Ingram, Ian Estepan, Dallan Murray, and Dr. Louise Rodino-Klapac. After our formal remarks, we'll open the call for Q&A. I'd like to note that during this call, we'll be making a number of forward-looking statements. Please refer to slide 2 on the webcast, which contains our forward-looking statements.

今天參加電話會議的有 Doug Ingram、Ian Estepan、Dallan Murray 和 Louise Rodino-Klapac 博士。正式發言後，我們將開始問答環節。我想指出的是，在這次電話會議中，我們將做出一些前瞻性的陳述。請參閱網路廣播中的投影片 2，其中包含我們的前瞻性陳述。

These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements, and any such risks can materially and adversely affect the business, the results of operations, and trading prices for Sarepta's common stock. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent SEC filings.

這些前瞻性陳述涉及風險和不確定性，其中許多超出了 Sarepta 的控制範圍。實際結果可能與這些前瞻性陳述有重大差異，任何此類風險都可能對 Sarepta 普通股的業務、經營績效和交易價格產生重大不利影響。有關適用風險和不確定性的詳細描述，我們建議您查看該公司最新的 SEC 文件。

The company does not undertake any obligation to publicly update its forward-looking statements including any financial projections provided today based on subsequent events or circumstances. As noted on slide 3, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP are included in today's press release and the slide presentation available on the Investor section of our website.

本公司不承擔根據後續事件或情況公開更新其前瞻性聲明（包括今天提供的任何財務預測）的任何義務。如投影片 3 所述，我們將在本次網路廣播中討論非 GAAP 財務指標。這些非公認會計準則 (non-GAAP) 財務指標的描述以及 GAAP 與非 GAAP 的對帳均包含在今天的新聞稿和我們網站投資者部分提供的幻燈片簡報中。

And now I'll turn the call over to our President and CEO, Doug Ingram, who will provide an overview of our recent progress. Doug?

現在，我將把電話轉給我們的總裁兼執行長道格·英格拉姆 (Doug Ingram)，他將概述我們最近的進展。道格？

Thank you, Mary. Good afternoon, everyone, and thank you for joining Sarepta Therapeutics' fourth-quarter and full-year 2024 financial results conference call. As you may know, back in late 2017, we created an expansive strategic plan that we called Project Moonshot, one that would require that we raise billions of dollars, chart a course through the unknown, and overcome multiple unforeseen obstacles, obstacles that would have deterred a less committed team, but also a strategic plan, if achieved, which would ensure a better life for thousands of Duchenne patients and cement the durable future of Sarepta.

謝謝你，瑪麗。大家下午好，感謝您參加 Sarepta Therapeutics 2024 年第四季和全年財務業績電話會議。您可能知道，早在 2017 年末，我們就制定了一項廣泛的戰略計劃，我們稱之為“登月計劃”，這項計劃要求我們籌集數十億美元，規劃未知領域的路線圖，並克服多重不可預見的障礙，這些障礙可能會阻礙一個不夠投入的團隊，但如果能夠實現，這項戰略計劃將確保成千上萬的杜氏肌營養不良症患者過上更好的生活，鞏固未來的持久性生活，鞏固。

After years of work and reams of new insight into the treatment of Duchenne in 2024, we achieved all of the goals laid out in Project Moonshot. We obtained approval for the broadest possible label for ELEVIDYS, achieving our goal of a transformative therapy that could serve the vast majority of Duchenne patients. We worked with the FDA to reframe the approach to the development of rare and ultra-rare diseases so that therapies previously rendered unviable by FDA requirements now have the potential to help patients.

經過多年的努力以及對 2024 年杜氏肌肉營養不良症治療的大量新見解，我們實現了「登月計畫」中列出的所有目標。我們獲得了 ELEVIDYS 最廣泛標籤的批准，實現了我們為絕大多數杜氏肌肉營養不良症患者提供轉化療法的目標。我們與 FDA 合作，重新制定罕見疾病和極罕見疾病的研發方法，以便先前因 FDA 要求而不可行療法現在有可能幫助患者。

And as a result, our LGMD franchise is moving with renewed speed towards three potential approvals over the next three years. We broadly launched the ELEVIDYS in 2024 and achieved results greater than all other in vivo gene therapies combined. At the same time, we continue to serve the community with our PMOs, which grew even in the face of a robust gene therapy launch.

因此，我們的 LGMD 特許經營權將以新的速度向前邁進，在未來三年內獲得三項潛在批准。我們在 2024 年廣泛推出了 ELEVIDYS，並取得了比所有其他體內基因療法總和還要好的成果。同時，我們繼續透過我們的 PMO 為社區提供服務，即使在基因療法蓬勃發展的背景下，我們的 PMO 仍在不斷發展。

We became sustainably profitable and cash flow positive in 2024. Indeed, by the end of 2030, we will do over $16 billion cumulatively in operating income and over $13 billion in free cash flow. And this is after we have closed and made our initial investment in the Arrowhead transaction.

2024年，我們實現了持續獲利，現金流為正。事實上，到 2030 年底，我們的累計營業收入將超過 160 億美元，自由現金流將超過 130 億美元。這是在我們完成 Arrowhead 交易並進行初始投資之後。

We have secured a durable and even more diversified future through our Arrowhead collaboration, pursuant to which we now add to our gene therapy pipeline a broad platform of siRNA, including four clinical programs, three preclinical programs, and six research programs across neuromuscular, CNS, cardiomyopathy, and pulmonary. In addition to multiple gene therapy launches in the coming few years, we will have multiple potential blockbuster siRNA launches before the end of this decade.

透過與 Arrowhead 的合作，我們確保了持久且更加多樣化的未來，根據該合作，我們現在為基因治療產品線添加了廣泛的 siRNA 平台，包括四個臨床項目、三個臨床前項目和六個研究項目，涵蓋神經肌肉、中樞神經系統、心肌病變和肺部。除了未來幾年推出多種基因療法外，我們還將在本世紀末推出多種潛在的重磅 siRNA。

Now speaking more specifically of performance, we had an exceptionally strong fourth-quarter and full-year performance with our four approved therapies. For the fourth quarter, our net product revenues stood at $638 million, growing at 75% over the same quarter prior year. This represents more than $60 million in overperformance to our prior guidance. Our full-year net product revenues stood at $1.8 billion, representing year-over-year growth of 56%, and this over-performed to our guidance by over $100 million.

現在更具體地談論業績，我們四種獲批療法在第四季度和全年的業績表現異常強勁。第四季度，我們的淨產品收入為 6.38 億美元，比去年同期成長 75%。這比我們之前的預期高出 6,000 多萬美元。我們的全年淨產品收入為 18 億美元，年增 56%，超出我們的預期 1 億美元以上。

Turning to ELEVIDYS, in 2024, we had by a wide margin the most successful launch of a gene therapy yet in history. For the fourth quarter, ELEVIDYS sales stood at $384 million, representing a 112% increase over the prior sequential quarter. And while we have already achieved over $1 billion in sales since our initial approval in 2023, this represents less than 5% of the on-label addressable opportunity, so clearly this is just the beginning.

談到 ELEVIDYS，2024 年，我們以巨大的優勢成功推出了歷史上最成功的基因療法。第四季度，ELEVIDYS 銷售額為 3.84 億美元，較上一季成長 112%。儘管自 2023 年首次獲批以來，我們的銷售額已超過 10 億美元，但這還不到標籤上可尋址機會的 5%，所以顯然這只是個開始。

Our three PMOs, EXONDYS 51, AMONDYS 45, and VYONDYS 53, achieved $254 million in the fourth quarter and $967 million for the full year. We were profitable on a GAAP and non-GAAP basis in the fourth quarter, and we were cash flow positive. Dallan Murray, our Chief Customer Officer, will provide more color on commercial performance in a moment. And then to round out the call, our CFO, Ian Estepan, will discuss our financials in more detail.

我們的三個 PMO，EXONDYS 51、AMONDYS 45 和 VYONDYS 53，在第四季度實現了 2.54 億美元的收入，全年實現了 9.67 億美元的收入。第四季度，我們按照 GAAP 和非 GAAP 計算均實現盈利，且現金流為正。我們的首席客戶長達蘭·莫瑞 (Dallan Murray) 稍後將提供有關商業表現的更多詳情。然後，為了結束電話會議，我們的財務長 Ian Estepan 將更詳細地討論我們的財務狀況。

Looking forward, in 2025, we will capitalize on the successes of 2024. As you know, our net product revenue guidance for 2025, excluding royalties from Roche, is between $2.9 billion and $3.1 billion, approximately one-third of which will come from the PMOs and a bit over two-thirds of which will come from ELEVIDYS. This represents year-over-year growth of 70% for total net product revenue; and for ELEVIDYS, this represents over 160% year-over-year growth.

展望2025年，我們將充分利用2024年的成功。如您所知，我們對 2025 年淨產品收入的預期（不包括羅氏的特許權使用費）在 29 億美元至 31 億美元之間，其中約三分之一將來自 PMO，略多於三分之二將來自 ELEVIDYS。這意味著總淨產品收入年增 70%；對於 ELEVIDYS 來說，這意味著同比增長超過 160%。

On the R&D and tech ops sides, we have more upcoming milestones this year than any other time in our history. As you know, we already met our important ELEVIDYS milestone in late January. We reported the two-year and one-year crossover results for ELEVIDYS from our pivotal trial in [BARC] and in all pre-specified measures. That includes all functional measures, muscle health, and biomarkers. Those on ELEVIDYS did strongly statistically, significantly better than untreated natural history would have predicted.

在研發和技術營運方面，我們今年即將實現的里程碑比歷史上任何時候都多。如您所知，我們在一月底就已經實現了重要的 ELEVIDYS 里程碑。我們報告了 ELEVIDYS 在 [BARC] 的關鍵試驗的兩年和一年交叉結果以及所有預先指定的措施。其中包括所有功能測量、肌肉健康和生物標記。服用 ELEVIDYS 的患者在統計上表現強勁，明顯優於未接受治療的自然病史所預測的結果。

We have passed 600 patients now on therapy across a broad range of ages and weights. These data are further proof of the transformative potential of ELEVIDYS to change the future course of this disease for patients. To continue to serve the global market and improve COGS, we are planning for a move to suspension manufacturing. And after completing our GMP runs, we intend to commence our suspension manufacturing bridging study this year.

目前，我們已經為超過 600 名年齡和體重各異的患者提供治療。這些數據進一步證明了 ELEVIDYS 改變患者未來疾病進程的轉化潛力。為了繼續服務全球市場並改善 COGS，我們正計劃轉向懸吊製造。在完成 GMP 運行後，我們打算今年開始懸浮液製造橋接研究。

As noted, we are now moving rapidly with our LGMD platform. We are continuing to dose our study for SRP-9004 to treat LGMD type 2D, and we have initiated our registration study for SRP-9005 to treat LGMD type 2C. We have completed dosing in our pivotal trial for SRP-9003 to treat LGMD type 2E, and we will be submitting our BLA for approval later this year. We also intend to file our IND for SRP-9010 to treat LGMD Type 2A later this year. If successful, we will launch SRP-9003 next year, we will launch SRP-9004 the following year, and SRP-9005 will be launched the year after that.

如上所述，我們現在正在快速推進我們的 LGMD 平台。我們正在繼續對 SRP-9004 進行劑量研究，以治療 2D 型 LGMD，並且我們已經啟動了 SRP-9005 治療 2C 型 LGMD 的註冊研究。我們已經完成了 SRP-9003 治療 2E 型 LGMD 的關鍵試驗劑量，並將於今年稍後提交 BLA 以供批准。我們還打算在今年稍後提交 SRP-9010 的 IND，用於治療 LGMD 2A 型。如果成功的話，我們明年會推出SRP-9003，後年會推出SRP-9004，後年會推出SRP-9005。

As you know, we have closed our transaction with Arrowhead this month, and already there will be several very significant milestones in 2025. This year, we will have our initial readout for cohorts for ARO-DUX4 to treat FSHD type 1. Again, this could be a very significant proof of biology. We will be looking at muscle concentration, downstream gene correction, and safety.

如你所知，我們本月已完成與 Arrowhead 的交易，2025 年將迎來幾個非常重要的里程碑。今年，我們將對 ARO-DUX4 治療 1 型 FSHD 的隊列進行初步讀數。再一次，這可能是一個非常重要的生物學證明。我們將研究肌肉濃度、下游基因校正和安全性。

We're also very excited about the potential to directly measure knockdown of the aberrant protein of interest DUX4. No other program to date has been able to achieve this, and this would be a very powerful result if successful. Likewise, we will have a readout of our initial cohorts for ARO-DM1 to treat DM1, where we could obtain proof of biology looking at muscle concentration, knockdown, gene splicing, and safety.

我們也對直接測量感興趣的異常蛋白質 DUX4 的敲低的潛力感到非常興奮。到目前為止，還沒有其他程式能夠實現這一點，如果成功的話，這將是一個非常強大的成果。同樣，我們將讀取 ARO-DM1 治療 DM1 的初始隊列，從中我們可以獲得觀察肌肉濃度、敲除、基因剪接和安全性的生物學證據。

If successful, we could launch our therapy for DM1 in 2029. Our clinical programs for MMP7 and SCA2 are progressing well as well. We intend to initiate our first in-human clinical study before the end of this year for ARO-HTT, which is intended to treat Huntington's disease. And finally, we have a significant number of siRNA and gene therapy pipeline programs underway, and so we intend to schedule an R&D Day later this year to discuss all of them in more detail. Our Head of R&D and Chief Scientific Officer, Dr. Louise Rodino-Klapac, will discuss our pipeline progress in a moment.

如果成功的話，我們可以在 2029 年推出針對 DM1 的治療方法。我們針對 MMP7 和 SCA2 的臨床項目也進展順利。我們計劃在今年年底前啟動針對 ARO-HTT 的首次人體臨床研究，該藥物旨在治療亨廷頓氏症。最後，我們有大量 siRNA 和基因治療管道項目正在進行中，因此我們打算在今年稍後安排研發日，以更詳細地討論所有這些項目。我們的研發主管兼首席科學官 Louise Rodino-Klapac 博士稍後將討論我們的管道進度。

With grit and operational excellence, we achieved all of our multi-year objectives in 2024. In 2025, we will continue to execute. We will build on our foundation as one of the very few fully integrated, profitable, and cash-flow positive biotechs in the world today, and we will achieve our next ambition, which is to become the next globally relevant big biotech focused on improving the lives of those among us with life-limiting rare disease.

憑藉堅韌不拔的精神和卓越的運營，我們在 2024 年實現了所有多年目標。2025年，我們將繼續執行。我們將在此基礎上再接再厲，成為當今世界上為數不多的完全整合、盈利且現金流為正的生物技術公司之一，並實現我們的下一個目標，即成為下一個全球性的大型生物技術公司，專注於改善我們當中患有限制生命的罕見疾病的人的生活。

And with that, I will turn the call to Dallan Murray for more detail on commercial performance and plans. Dallan?

接下來，我將把電話轉給達蘭·默里 (Dallan Murray)，以了解有關商業表現和計劃的更多詳細資訊。達蘭？

Thank you, Doug, and good afternoon. I'm delighted by the exceptional performance the team delivered in the fourth-quarter and for the full-year 2024. As we pre-announced in January, net product revenue for 2024 totaled $1.79 billion, consisting of roughly $967 million from our PMO franchise and approximately $821 million for ELEVIDYS. 2024 marked the eighth year of our PMO franchise, which continues to perform well and grew modestly year over year, even in the face of the transformation brought about by ELEVIDYS.

謝謝你，道格，下午好。我對團隊在第四季和 2024 年全年的出色表現感到非常高興。正如我們在 1 月預先宣布的那樣，2024 年的淨產品收入總計 17.9 億美元，其中來自我們的 PMO 特許經營權的約 9.67 億美元和來自 ELEVIDYS 的約 8.21 億美元。 2024 年是我們 PMO 特許經營業務的第八年，即使面對 ELEVIDYS 帶來的轉型，該業務仍然表現良好，並且逐年小幅增長。

As in prior years, the team delivered this growth organically without taking price increases on any of our approved PMO products. As such, this growth speaks to the increase in patients we are serving in the Duchenne community. For 2025, the PMOs remain an integral part of our guidance. And even in the face of strong ELEVIDYS performance, we are only seeing modest US net cannibalization. We are comfortable with the current consensus estimates as they stand today for the PMOs.

與往年一樣，該團隊有機地實現了這一增長，而沒有提高任何我們批准的 PMO 產品的價格。因此，這種增長表明我們在杜氏肌肉營養不良症社區服務的患者數量有所增加。到 2025 年，PMO 仍將是我們的指導方針中不可或缺的一部分。即使 ELEVIDYS 表現強勁，我們也只看到美國淨蠶食幅度不大。我們對目前 PMO 的一致估計感到滿意。

For the fourth quarter, net product revenues for the PMOs totaled roughly $254 million, growing at approximately 9% compared to the fourth quarter of 2023. Individual PMO net product revenues were $137.6 million for EXONDYS 51, $40.2 million for VYONDYS 53, and $76.2 million for AMONDYS 45.

第四季度，PMO 的淨產品收入總計約為 2.54 億美元，與 2023 年第四季相比成長約 9%。單一 PMO 淨產品收入分別為 EXONDYS 51 1.376 億美元、VYONDYS 53 4020 萬美元和 AMONDYS 45 7620 萬美元。

Now turning to the ELEVIDYS launch and performance, Q4 was our second full quarter with an expanded label, and we could not be more pleased with the launch execution. In particular, for the fourth quarter, ELEVIDYS revenue totaled $384.2 million, exceeding our quarterly guidance by over $60 million.

現在談談 ELEVIDYS 的發布和表現，第四季度是我們推出擴展品牌的第二個完整季度，我們對發布的執行情況感到非常滿意。特別是第四季度，ELEVIDYS 的營收總計 3.842 億美元，超出我們的季度預期超過 6,000 萬美元。

And please bear in mind, even with this impressive growth, at this point in the launch, we have treated approximately 5% of the on-label addressable patient population for a ELEVIDYS. So the opportunity ahead of us remains significant. And we have the wind in our sails at the moment. The recent findings from the part two of the EMBARK study adds to the existing robust body of clinical evidence. This will undoubtedly help the team with their efforts going forward.

請記住，即使取得如此令人印象深刻的成長，在推出的這個階段，我們只治療了約 5% 的 ELEVIDYS 標籤可尋址患者。因此，我們面前的機會依然龐大。目前我們正順風順水。EMBARK 研究第二部分的最新發現進一步充實了現有的堅實臨床證據。這無疑將有助於球隊未來的努力。

As the launch progresses, we remain confident in our understanding of the launch dynamics and the key drivers, which continue to be robust patient demand for both the ambulant and non-ambulant populations, ample site capacity for both the infusion and follow-up, positive trends in access and reimbursement for both ambulatory and non-ambulatory patients, and consistent conversion rates as we continue to see patients gaining access within the three- to five-month conversion timeline.

隨著發布的進展，我們仍然對發布的動態和關鍵驅動因素充滿信心，這些驅動因素仍然是門診和非門診患者對藥物的強勁需求、充足的輸液和隨訪場地容量、門診和非門診患者在獲取藥物和報銷方面的積極趨勢，以及一致的轉化率，因為我們繼續看到患者在三到五個月的轉化時間內獲得藥物獲取。

Doug took some time at the recent JP Morgan meeting to give more detail on that conversion timeline. Understanding this process is essential to understanding our business model and the confidence we have in our success and ability to execute both quarter to quarter and in the coming years. Five launches and a decade of working in partnership with the key neuromuscular institutions gives us a deep line of sight into the cadence of dosing each patient in each center, in each region, and across the country.

道格在最近的摩根大通會議上花了一些時間詳細介紹了該轉換時間表。了解這個過程對於理解我們的業務模式以及我們對季度和未來幾年的成功和執行能力的信心至關重要。五次發布以及與主要神經肌肉機構十年的合作使我們深入了解了每個中心、每個地區和全國範圍內每個患者的用藥節奏。

For each and every gene therapy patient, roughly 20 to 25 people within each institution play an important part in making that dose happen. And those folks are across each institution, from the executive team to the pharmacy department, as well as the medical finance and various administrative teams. And that's only the people within the institution. We also rely on additional people from our distribution and manufacturing partners, along with others from various internal Sarepta teams. All need to do their individual parts with perfection and under tight timelines to successfully dose each patient.

對於每一位基因治療患者，每個機構內約有 20 到 25 個人在實現該劑量方面發揮重要作用。這些人遍布各個機構，從執行團隊到藥房部門，以及醫療財務和各個行政團隊。而這還只是機構內部的人員。我們也依賴來自分銷和製造合作夥伴的額外人員，以及來自 Sarepta 內部各個團隊的其他人員。每個人都需要在緊迫的時間內完美地完成各自的工作，以成功地給每位患者服藥。

Why is this important? There are two reasons. The first and most critical is that we've now shown as a team we can do this reliably and successfully for over six quarters now since our initial launch. We've built the model and shown we can reliably execute, which has been challenging for others to accomplish. Secondly, it gives us a great deal of confidence in our revenue projections, which are driven by our understanding of the patient journey.

為什麼這很重要？有兩個原因。首先也是最關鍵的是，我們現在已經證明，作為一個團隊，自首次推出以來，我們已經在六個多季度內可靠且成功地做到了這一點。我們已經建立了模型並證明我們可以可靠地執行，這對其他人來說是一個挑戰。其次，它讓我們對收入預測充滿信心，而收入預測則源自於我們對病患旅程的理解。

There are several factors that contribute to the cadence of patients being treated, and we have a good line of sight into each of these factors. With over eight years of commercial experience comes a good understanding where the patients are and their pathway to treatment. We are also pleased with the continued progress in getting broad coverage for ELEVIDYS and continue to see patients gaining access who are in plans with more restrictive policies. To date, not a single patient has been permanently denied coverage.

影響患者治療節奏的因素很多，我們對每個因素都有很好的了解。憑藉超過八年的商業經驗，我們能夠充分了解患者的狀況以及他們的治療途徑。我們也很高興看到 ELEVIDYS 在獲得廣泛覆蓋方面不斷取得進展，並繼續看到那些計劃中政策更嚴格的患者能夠獲得該藥物。到目前為止，還沒有一位患者被永久拒絕承保。

And as you can see from our performance, this is a disease state that we understand extremely well. We are very confident in our growth trajectory, and I'd like to reiterate a point that Doug made in January that puts our performance into broader context. We project that in the first 30 months of our ELEVIDYS launch, ELEVIDYS net product revenue will outperform every other in vivo gene therapy combined over that same period of time. Our success of the ELEVIDYS shows that one-time gene therapy could be commercially viable, providing hope for those with Duchenne and for all those with genetic conditions with unmet need.

從我們的表現可以看出，我們非常了解這種疾病狀態。我們對我們的成長軌跡非常有信心，我想重申道格在一月份提出的觀點，將我們的表現放在更廣泛的背景下。我們預計，在 ELEVIDYS 推出後的前 30 個月內，ELEVIDYS 的淨產品收入將超過同一時期內所有其他體內基因療法的總和。ELEVIDYS 的成功表明一次性基因療法具有商業可行性，為杜氏肌肉營養不良症患者以及所有患有未滿足需求的遺傳疾病的人帶來了希望。

As a reminder, our 2025 net product revenue guidance is $2.9 billion to $3.1 billion, which represents approximately 70% growth over 2024. Thus far, the launch has played out in line with our projections, and we remain comfortable with this guidance given our strong finish to 2024 and our long track record of accurately predicting our performance. In summary, we are comfortable with our guidance for the year. And with Q1 consensus, we expect to deliver sequential growth quarter over quarter throughout 2025.

提醒一下，我們對 2025 年淨產品收入的預期為 29 億美元至 31 億美元，比 2024 年成長約 70%。到目前為止，發表會的進展符合我們的預期，鑑於我們在 2024 年的強勁表現以及我們長期以來準確預測業績的記錄，我們對這一預期仍然感到滿意。總而言之，我們對今年的指導感到滿意。根據第一季的共識，我們預計 2025 年全年將逐季連續成長。

And now I have to call over to Dr. Louise Rodino-Klapac for the R&D update. Louise?

現在我必須打電話給 Louise Rodino-Klapac 博士來了解研發最新情況。路易絲？

Thanks, Dallan. Building on the accomplishments of 2024, I'm thrilled with the promise before us and the vast opportunities there are to continue to make a difference in patients' lives. Firstly, ELEVIDYS. Late last month, we announced positive follow-up data from EMBARK for study SRP-9001-301, our global randomized double-blind placebo-controlled Phase 3 clinical study of ELEVIDYS. Specifically, we shared crossover results from those who received therapy in part two of the study. And we also shared the two-year results of those treated in part one of the study as compared to an external control.

謝謝，達蘭。基於 2024 年的成就，我對我們面前的承諾以及繼續為患者的生活帶來巨大改變的巨大機會感到非常興奮。首先是ELEVIDYS。上個月底，我們公佈了 EMBARK 對 SRP-9001-301 研究的積極後續數據，這是我們對 ELEVIDYS 進行的全球隨機雙盲安慰劑對照 3 期臨床研究。具體來說，我們分享了研究第二部分接受治療的患者的交叉結果。我們也分享了研究第一部分中接受治療的患者與外部對照者的兩年結果。

Given what we know about ELEVIDYS, what the science and data have shown us, and what we have observed in the large population of patients that have been treated with ELEVIDYS, we were not surprised by such overwhelmingly positive data from the study, which demonstrated that ELEVIDYS impacts the trajectory of Duchenne and offers an early treatment option intended to avoid unnecessary and unavoidable muscle damage.

鑑於我們對 ELEVIDYS 的了解、科學和數據向我們展示的情況以及我們在接受 ELEVIDYS 治療的大量患者中觀察到的情況，我們對該研究得出的如此壓倒性的積極數據並不感到驚訝，這表明 ELEVIDYS 會影響杜氏肌營養不良症的發展軌跡並提供一種早期治療選擇，旨在避免不必要和不可避免的肌肉損傷。

Speaking to the therapy's durability, the data are clear. Those not on therapy decline in their functional abilities faster than those on therapy, who stay healthier longer versus the natural history would predict. Intervention is critical in maintaining precious muscle before it's lost. With that, I'd like to pause for a moment and reiterate the significance of the MRI muscle data.

談到這種療法的持久性，數據很清楚。未接受治療的人的功能能力下降速度比接受治療的人更快，而且接受治療的人比自然史預測的更能保持健康。幹預對於在寶貴的肌肉流失之前維持它至關重要。說到這裡，我想暫停一下，重申一下 MRI 肌肉數據的重要性。

As mentioned on last month's call, these data support long-term function and healthier muscle. Specifically, we saw modest to no increase in fat fraction from baseline to two years. And levels at two years were well below what was seen at one year in the placebo patients. This is consistent across muscle groups. We look forward to publishing data from EMBARK at forthcoming scientific meetings and in peer-reviewed journals.

正如上個月電話會議中提到的，這些數據支持長期功能和更健康的肌肉。具體來說，我們發現從基線到兩年內脂肪分數略有增加甚至沒有增加。兩年後的水平遠低於服用安慰劑的患者一年後的水平。這對於各個肌肉群而言都是一致的。我們期待在即將舉行的科學會議和同行評審期刊上發表來自 EMBARK 的數據。

In summary and evidenced by the data, ELEVIDYS demonstrated a clinically meaningful response across all of Sarepta's studies with increasing divergence from natural history over time that supports the durability of the therapy. Toward our goal of providing ELEVIDYS to all eligible patients, we are advancing the ENVISION study, or Study SRP-9001-303, a global randomized double-blind placebo-controlled two-part trial evaluating the safety and efficacy of ELEVIDYS in non-ambulatory and older ambulatory individuals with Duchenne.

綜上所述，數據表明，ELEVIDYS 在 Sarepta 的所有研究中都表現出了具有臨床意義的反應，並且隨著時間的推移與自然史的差異越來越大，這支持了該療法的持久性。為了實現向所有符合條件的患者提供 ELEVIDYS 的目標，我們正在推進 ENVISION 研究（或 SRP-9001-303 研究），這是一項全球隨機雙盲安慰劑對照的兩部分試驗，評估 ELEVIDYS 對患有杜氏肌肉營養不良症的非行走能力患者和老年行走能力患者的安全性和有效性。

ENVISION's progressing well, and as previously mentioned, enrollment in the United States is complete. And our last patient last visit is expected in 2027, following an 18-month placebo-controlled period. In addition, for the approximately 15% of patients who are screened out for pre-existing anti-AAVrh74 antibodies, we've commenced two studies, one with imlifidase, or Study 104, to cleave antibodies, and a second with plasmapheresis, or Study 105, to remove antibodies. We expect to have expression data from both of these studies in the second half of 2025.

ENVISION 進展順利，如前所述，在美國的招生工作已經完成。經過 18 個月的安慰劑對照期後，我們的最後一位患者預計將於 2027 年進行最後一次就診。此外，對於大約 15% 被篩檢出存在抗 AAVrh74 抗體的患者，我們已經開始了兩項研究，一項是使用 imlifidase（研究 104）來裂解抗體，另一項是使用血漿置換（研究 105）來去除抗體。我們預計將在 2025 年下半年獲得這兩項研究的表達數據。

Moving now to our programs to the limb girdle muscular dystrophies or LGMDs, we were thrilled to announce in December 2024 that we completed enrollment and dosing of EMERGENE, or Study SRP-9003-301, our Phase 3 clinical trial of SRP-9003 to treat LGMD type 2E, or beta-sarcoglycanopathy. EMERGENE is a global study, and the primary endpoint is biomarker expression of the beta-sarcoglycan protein, the absence of which is the sole cause of LGMD2E. Data from EMERGENE are expected in the first half of 2025.

現在轉到我們的肢帶型肌肉營養不良症或 LGMD 項目，我們很高興地於 2024 年 12 月宣布，我們完成了 EMERGENE 或研究 SRP-9003-301 的招募和給藥，這是我們的 SRP-9003 治療 2E 型 LGMD 或 β-肌聚醣試驗的 3 期臨床試驗。EMERGENE 是一項全球性研究，其主要終點是 β-肌聚醣蛋白的生物標記表達，該蛋白的缺失是 LGMD2E 的唯一原因。EMERGENE 的數據預計將於 2025 年上半年公佈。

Further, we were pleased with the outcomes of our pre-biologics license application meeting with FDA, including endorsement for a rolling BLA submission. We are on track to submit our BLA filings seeking accelerated approval for SRP-9003 in the second half of 2025. We're also encouraged by the progress of our other LGMD programs. At the end of 2024, we initiated Phase 1 of SRP-9004 in development to treat LGMD2D. And in early 2025, we will initiate our Phase 1/3 seamless design clinical trial for SRP-9005, which is in development for the treatment of LGMD2C.

此外，我們對與 FDA 舉行的生物製品許可申請前會議的結果感到滿意，包括對滾動 BLA 提交的批准。我們預計在 2025 年下半年提交 BLA 文件，尋求加速批准 SRP-9003。我們其他 LGMD 專案的進展也令我們感到鼓舞。2024 年底，我們啟動了 SRP-9004 的第一階段開發，用於治療 LGMD2D。2025 年初，我們將啟動 SRP-9005 的 1/3 期無縫設計臨床試驗，該藥物正在開髮用於治療 LGMD2C。

This March, we look forward to sharing with you a wealth of data from our Duchenne and LGMD programs at the MDA Clinical and Scientific Conference taking place March 16 through the 19th in Dallas, Texas. And we also look forward to highlighting our impressive pipeline at an upcoming R&D Day in 2025. As a preview, we have numerous programs in various stages of development across neuromuscular, central nervous system, cardiac, and pulmonary indications, many of which are nearing INDs.

今年 3 月，我們期待在 3 月 16 日至 19 日於德克薩斯州達拉斯舉行的 MDA 臨床和科學會議上與您分享來自杜氏肌肉營養不良症和 LGMD 計畫的大量數據。我們也期待在 2025 年即將到來的研發日上重點展示我們令人印象深刻的產品線。作為預覽，我們有許多處於不同開發階段的項目，涉及神經肌肉、中樞神經系統、心臟和肺部適應症，其中許多項目已接近 IND。

Of note, for neurotrophin 3 or NT3, we have optimized the construct for Charcot-Marie-Tooth type 1A or CMT1A using AAVrh74 and are now rapidly advancing to the clinic following exciting preclinical data. As a reminder, we are using a surrogate approach for delivery of the NT3 gene to improve myelination and nerve regeneration in CMT1A. This pipeline-in-the-product approach has applicability to other CMTs as well as other demyelinating indications.

值得注意的是，對於神經營養因子 3 或 NT3，我們已經使用 AAVrh74 優化了 Charcot-Marie-Tooth 1A 型或 CMT1A 的構建體，並且現在正在根據令人興奮的臨床前數據迅速推進到臨床階段。提醒一下，我們正在使用替代方法傳遞 NT3 基因，以改善 CMT1A 中的髓鞘形成和神經再生。這種產品管道方法也適用於其他 CMT 以及其他脫髓鞘適應症。

On the research side, we've continued to innovate across platforms. We've optimized, developed, and characterized new AEV capsids that will change the landscape for neuromuscular gene therapy and unlock potential in cardiac and CNS disease areas. We are also driving innovation in gene editing, enhanced delivery for RNA, and are pioneering new mechanisms to upregulate gene expression. The future cannot be brighter for genetic medicine.

在研究方面，我們不斷跨平台創新。我們已經優化、開發並表徵了新的 AEV 衣殼，這將改變神經肌肉基因療法的模式並釋放心臟和中樞神經系統疾病領域的潛力。我們也正在推動基因編輯、增強 RNA 傳遞的創新，並開拓上調基因表現的新機制。基因醫學的前景十分光明。

Further, we look forward to sharing data with you later this year around our FSHD1 and DM1 programs. As a reminder, SRP-1001, formerly known as ARO-DUX4, is currently in clinical development to treat FSHD1, an autosomal dominant disease associated with the failure to maintain complete epigenetic suppression of DUX4 expression in differentiated skeletal muscle, leading to overexpression of DUX4, which is myotoxic and can lead to muscle degeneration. We are encouraged by the non-clinical data generated thus far and look forward to the data readout later this year.

此外，我們期待今年稍後與您分享有關我們的 FSHD1 和 DM1 計劃的數據。提醒一下，SRP-1001（以前稱為 ARO-DUX4）目前正在進行臨床開發，用於治療 FSHD1，這是一種常染色體顯性遺傳疾病，與無法維持分化骨骼肌中 DUX4 表達的完全表觀遺傳抑制有關，從而導致 DUX4 過度表達，這具有肌肉毒性並可能導致肌肉退化。我們對迄今為止產生的非臨床數據感到鼓舞，並期待今年稍後的數據讀數。

Turning to myotonic dystrophy type 1, or DM1., DM1 is driven by an expanded CUG trinucleotide repeat in the 3 prime untranslated region of DMPK transcripts. These abnormal transcripts cause misregulated splicing known as spliceopathy for certain messenger RNAs, which are directly linked to the clinical manifestations of DM1. We believe that silencing the inherently transcribed DMPK mRNA using SRP-1003, formerly known as ARO-DM1, may halt CUG expansion-related splice defects in patients with DM1 and thereby improve muscle strength and function. We look forward to sharing the data from the SAD study later this year as well.

談到 1 型肌強直性營養不良症 (DM1)，DM1 是由 DMPK 轉錄本的 3 個主要非翻譯區中的擴展 CUG 三核苷酸重複驅動的。這些異常轉錄本會導致某些信使 RNA 發生錯誤調節的剪接（稱為剪接疾病），這與 DM1 的臨床表現直接相關。我們相信，使用 SRP-1003（以前稱為 ARO-DM1）沉默固有轉錄的 DMPK mRNA 可能會阻止 DM1 患者的 CUG 擴展相關剪接缺陷，從而改善肌肉力量和功能。我們也期待今年稍後分享 SAD 研究的數據。

Now to discuss our RNA PMO platform. The ESSENCE trial, our post-marketing requirement for Golodirsen and Casimersen, as well as MISSION, our post-marketing commitment for EXONDYS, are both fully enrolled and remain on track. We look forward to sharing data as soon as the studies are completed. In summary, I'd like to take the opportunity to thank the patient community, investigators, and my Sarepta colleagues. All this progress would not be possible without you.

現在討論我們的 RNA PMO 平台。ESSENCE 試驗（我們對 Golodirsen 和 Casimersen 的上市後要求）以及 MISSION（我們對 EXONDYS 的上市後承諾）均已完全入組並繼續按計劃進行。我們期待研究完成後立即分享數據。總而言之，我想藉此機會感謝患者群體、研究人員和我的 Sarepta 同事。如果沒有你們，所有這些進步都不可能實現。

And finally, I'd like to recognize this Friday is Rare Disease Day. There are more than 7,000 rare diseases, only a small percent of which have any treatment. As a company dedicated to bringing forth new treatments for rare disease, it's an important day for our employees and the patients we serve. It's a day to reflect on the impact of rare disease on the affected individuals and their families, and to acknowledge all the work that still needs to be done, and to celebrate the progress that we've made.

最後，我想指出本週五是罕見疾病日。罕見疾病有 7,000 多種，其中只有一小部分可以治療。作為一家致力於研發罕見疾病新療法的公司，這對我們的員工和我們服務的患者來說都是重要的一天。這一天是為了反思罕見疾病對受影響個人及其家庭的影響，承認仍需做的所有工作，並慶祝我們已經取得的進展。

With that, I'll turn the call over to Ian for an update on the financials. Ian?

說完這些，我會把電話轉給伊恩，讓他回報一下財務狀況的最新情況。伊恩？

Thanks, LRK. Well said. Good afternoon, everyone. This afternoon's financial results press release provided details for the fourth quarter of 2024 on a GAAP as well as a non-GAAP basis. Please refer to the press release and slide deck available on Sarepta's website for a full reconciliation of GAAP to non-GAAP financial results.

謝謝，LRK。說得好。大家下午好。今天下午的財務業績新聞稿提供了 2024 年第四季度的 GAAP 和非 GAAP 詳細資訊。請參閱 Sarepta 網站上的新聞稿和幻燈片，以了解 GAAP 與非 GAAP 財務結果的完整對照組。

For the three months ended December 31, 2024, the company recorded total revenues of $658.4 million, which consists of net product revenues and collaboration and other revenues, compared to revenues of $396.8 million for the same period of 2023, an increase of $261.6 million. Net product revenue for the fourth quarter of 2024 from ELEVIDYS was $384.2 million compared to $131.2 million for the same period of 2023.

截至 2024 年 12 月 31 日的三個月，該公司的總收入為 6.584 億美元，其中包括淨產品收入以及合作和其他收入，而 2023 年同期的收入為 3.968 億美元，增加了 2.616 億美元。ELEVIDYS 2024 年第四季的淨產品收入為 3.842 億美元，而 2023 年同期為 1.312 億美元。

Net product revenue for the fourth quarter of 2024 from our PMO exon-skipping franchise was $254 million compared to $233.8 million for the same period of 2023. The increase in net product revenue primarily reflects the net product revenue from sales of ELEVIDYS. In the quarter ended December 31, 2024, we recognized $20.3 million of collaboration and other revenues compared to $31.7 million for the same period of 2023. This revenue primarily relates to our commercial ELEVIDYS supply delivered to Roche, royalty revenue, and our collaboration arrangement with Roche.

2024 年第四季度，我們 PMO 外顯子跳躍特許經營權的淨產品收入為 2.54 億美元，而 2023 年同期為 2.338 億美元。淨產品收入的增加主要反映了 ELEVIDYS 銷售帶來的淨產品收入。在截至 2024 年 12 月 31 日的季度中，我們確認了 2,030 萬美元的合作和其他收入，而 2023 年同期為 3,170 萬美元。該收入主要與我們向羅氏公司交付的商業 ELEVIDYS 供應、特許權使用費收入以及我們與羅氏公司的合作安排有關。

The reimbursable co-development costs under the Roche agreement totaled $26 million for the fourth quarter of 2024 compared to $23.5 million for the same period of 2023. As a reminder, these reimburseable co-development costs are an offset to operating expenses. On a GAAP basis, we reported a net income of $159 million, or $1.65 per basic share and $1.50 per diluted share, and a net income of $45.7 million. or $0.49 cents per basic share and $0.47 per diluted share for the fourth quarter of 2024 and 2023 respectively.

根據羅氏協議，2024 年第四季可報銷的共同開發成本總計 2,600 萬美元，而 2023 年同期為 2,350 萬美元。提醒一下，這些可報銷的共同開發成本可以抵銷營運費用。根據 GAAP 計算，我們報告的淨收入為 1.59 億美元，即每股基本收入 1.65 美元，每股稀釋收入 1.50 美元，淨收入為 4,570 萬美元。或 2024 年第四季每股基本收益 0.49 美分，2023 年第四季每股稀釋收益 0.47 美元。

We reported a non-GAAP net income of $206 million or $1.90 per diluted share in the fourth quarter of 2024 compared to a non-GAAP net income of $86.6 million or $0.82 per diluted share in the fourth quarter of 2023. In the fourth quarter of 2024, we recorded approximately $132.3 million in cost of sales, compared to $44.2 million in the same period of 2023. The increase primarily reflects cost of sales related to ELEVIDYS during the three months ended December 31, 2024, following the label expansion in June of 2024.

我們報告 2024 年第四季的非 GAAP 淨收入為 2.06 億美元或每股攤薄收益 1.90 美元，而 2023 年第四季的非 GAAP 淨收入為 8,660 萬美元或每股攤薄收益 0.82 美元。2024 年第四季度，我們的銷售成本約為 1.323 億美元，而 2023 年同期為 4,420 萬美元。這一增長主要反映了 2024 年 6 月標籤擴展之後，截至 2024 年 12 月 31 日的三個月內與 ELEVIDYS 相關的銷售成本。

On a GAAP basis, we recorded $200 million and $195.5 million in R&D expenses for the fourth quarter of 2024 and 2023, respectively, a year-over-year increase of $4.5 million. The increase is primarily due to an increase in our manufacturing expenses related to a ramp up of batches produced for our limb-girdle program, partially offset by a decrease in clinical trial expenses related to the discontinuation of the PPMO program. On a non-GAAP basis, R&D expenses were $172.7 million for the fourth quarter of 2024 compared to $165.1 million for the same period of 2023, an increase of $7.6 million.

依照 GAAP 標準，我們在 2024 年第四季和 2023 年第四季的研發費用分別為 2 億美元和 1.955 億美元，年增 450 萬美元。增加的主要原因是，隨著我們的肢帶計畫生產批次的增加，製造費用也隨之增加，但 PPMO 計畫停止後，臨床試驗費用的減少部分抵消了增加。以非公認會計準則計算，2024 年第四季研發費用為 1.727 億美元，而 2023 年同期為 1.651 億美元，增加了 760 萬美元。

Now turning to SG&A, on a GAAP basis, we recorded approximately $163.9 million and $131.7 million of expenses for the fourth quarter of 2024 and 2023, respectively, an increase of $32.2 million. The increase was driven primarily by an increase in professional services used to support the continued efforts to commercialize ELEVIDYS and ongoing litigation matters, and an increase in compensation and other personnel expenses primarily related to changes in headcount.

現在談談銷售、一般及行政費用，按照 GAAP 計算，我們分別在 2024 年和 2023 年第四季記錄了約 1.639 億美元和 1.317 億美元的費用，增加了 3,220 萬美元。成長的主要原因是用於支持持續努力將 ELEVIDYS 商業化和正在進行的訴訟事宜的專業服務費用增加，以及主要與員工人數變化有關的薪酬和其他人員費用增加。

On a GAAP basis, the SG&A expenses were $131.6 million for the fourth quarter of 2024, compared to $105.7 million for the same period of 2022, an increase of $25.9 million. On a GAAP basis, we recorded $10.1 million in other income net for the fourth quarter of 2024 compared to $15.7 million for the same period of 2023. The change was primarily due to a decrease in interest income and accretion of investment discount net as a result of lower interest rates and a mix of our investment portfolio.

依照 GAAP 標準，2024 年第四季的銷售、一般及行政費用為 1.316 億美元，而 2022 年同期為 1.057 億美元，增加了 2,590 萬美元。以 GAAP 計算，2024 年第四季我們的其他收入淨額為 1,010 萬美元，而 2023 年同期為 1,570 萬美元。這項變更主要是由於利率降低和投資組合混合導致利息收入減少和投資折扣淨額增加所致。

As mentioned earlier, we're maintaining our 2025 total product revenue guidance which reflects a 68% growth from 2024 at the midpoint. We also are introducing expense guidance for 2025. We anticipate combined 2025 non-GAAP R&D and SG&A expenses to be in the range of $1.2 billion to $1.3 billion. The incremental expense is almost exclusively related to Arrowhead development programs. Excluding these costs, our expenses would be essentially flat compared to the prior year.

如前所述，我們維持 2025 年總產品收入指引，該指引較 2024 年中期成長 68%。我們也將推出 2025 年的費用指導。我們預計 2025 年非 GAAP 研發與銷售、一般及行政費用總額將介於 12 億至 13 億美元之間。增加的費用幾乎全部與 Arrowhead 開發計劃有關。除去這些成本，我們的支出與前一年相比基本持平。

And to conclude, we had approximately $1.5 billion in cash, cash equivalent, investments, and restricted cash as of December 31, 2024. As Doug said, now that the Arrowhead transaction is now closed, which was fully funded by our existing cash reserves, we project returning to similar cash levels by year end of 2025, driven by the strong ELEVIDYS launch. Further bolstering our financial position, we secured a $600 million revolving credit facility. The combination of a positive business outlook and our strong financial -- position us really well to execute on our 2030 strategic goal.

總而言之，截至 2024 年 12 月 31 日，我們擁有約 15 億美元的現金、現金等價物、投資和受限現金。正如 Doug 所說，Arrowhead 交易現已完成，資金完全來自我們現有的現金儲備，我們預計在 ELEVIDYS 強勁發布的推動下，到 2025 年底將恢復到類似的現金水平。為了進一步增強我們的財務狀況，我們獲得了 6 億美元的循環信貸額度。積極的商業前景和強大的財務狀況相結合，使我們能夠很好地實現 2030 年策略目標。

And with that, I'll turn the call back over to Doug for Q&A. Doug?

說完這些，我將把電話轉回給 Doug 進行問答。道格？

Thank you very much for that, Ian. And Lisa, let's open the call for questions.

非常感謝你，伊恩。麗莎，讓我們開始提問吧。

(Operator Instructions) Tazeen Ahmad, Bank of America Securities.

（操作員指示） Tazeen Ahmad，美國銀行證券。

Okay, great. Thank you for taking my question. I wanted to ask, Doug, about the cadence of what you're seeing in 1Q so far with regards to patients that are being onboarded. You've talked extensively about certain things that cannot be changed, and you've reiterated your confidence about guidance for 2025. But can you give us a little bit more granularity on, again, what you're seeing in 1Q and how we should be thinking about the cadence of uptake for the rest of the quarters this year? Thanks.

好的，太好了。感謝您回答我的問題。道格，我想問一下，到目前為止，您在第一季看到的入院患者的情況如何。您已經廣泛談論了某些無法改變的事情，並重申了對 2025 年指導的信心。但是，您能否再向我們詳細介紹一下您在第一季看到的情況，以及我們應該如何考慮今年剩餘幾季的成長節奏？謝謝。

Yes, thank you very much for your question, Tazeen. A couple things first, let me reiterate my confidence on the guidance for the year. We feel very good about the guidance that we have. And I would remind everyone, we have a very good track record of setting reasonable guidance in meeting or very often exceeding that guidance.

是的，非常感謝您的提問，Tazeen。首先，讓我重申幾件事，我對今年的指導充滿信心。我們對所得到的指導感到非常滿意。我想提醒大家，我們在製定合理指導方面有著良好的記錄，能夠達到甚至經常超越指導。

The only thing I'll say about quarters going forward is that we will continue to see growth quarter over quarter as we ramp this launch. Things obviously are going very well for this launch through 2024, and I think our guidance should imply it's going very well in 2025 as well. There is a certain cadence to all of this, everything from the start form, the single case contracts that I've talked about before, the infusions, the need for pre-existing neutralizing antibody assays, and the like that describes their cadence.

關於未來幾個季度，我唯一要說的是，隨著我們加強推出力度，我們將繼續看到逐季度的成長。顯然，到 2024 年，這次發射的進展非常順利，我認為我們的指導應該意味著 2025 年的發射也會進展順利。所有這一切都有一定的節奏，從開始的形式、我之前談到的單例合約、輸液、預先存在的中和抗體檢測的需要等等，都描述了它們的節奏。

But it's going very well. And what we'll see over the course of this year is growth quarter over quarter over quarter to achieve our guidance for the full year, which of course is $3 billion in total. A little over two-thirds of that will be coming from ELEVIDYS and the remainder from our three PMOs. So thank you for that.

但一切進展順利。我們將看到今年的銷售額逐季成長，最終實現我們對全年的預期，即總額 30 億美元。其中三分之二多一點的資金來自 ELEVIDYS，其餘的資金則來自我們的三個 PMO。謝謝你。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）。

Hey, guys, thanks so much for taking the question. For limb girdle, just from your work in the space, what's the latest on what you see for the prevalence of 2E and how many in the US are diagnosed today, and the mix of ambulatory versus non-ambulatory patients? Basically, if you will be launching here next year, how should we be thinking about the contribution potentially to revenue and how many patients there might be kind of waiting for therapy? Thanks.

嘿，夥計們，非常感謝你們回答這個問題。對於肢帶症，僅從您在該領域的工作來看，您對 2E 的流行有何最新看法？目前美國有多少人被診斷出患有肢帶症，以及可行走和不能行走的患者的比例是多少？基本上，如果您明年要在這裡推出這項服務，我們應該如何考慮對收入的潛在貢獻以及有多少患者可能在等待治療？謝謝。

I'll give you the broadest strokes, then I'm going to turn the call over to Louise if she has any information on the split between ambulatory and non-ambulatory. Obviously, type 2E is a very rare disease. It's an ultra-rare disease. In fact, all of the three sarcoglycan launches that we'll have over the next three years are individually very rare. But collectively, they will represent about 25% of the Duchenne ELEVIDYS opportunity.

我會給你最廣泛的介紹，然後我會把電話轉給路易絲，看看她是否有關於步行和非步行之間區別的任何信息。顯然，2E 型是一種非常罕見的疾病。這是一種極為罕見的疾病。事實上，未來三年內我們將推出的三種肌聚醣單獨來看都是非常罕見的。但總體而言，它們將佔據 Duchenne ELEVIDYS 約 25% 的市場份額。

So they will be important contributors, first and foremost, to be clear. They'll be enormous contributors in the lives of patients living with and being degenerated from these really devastating muscular dystrophies. And then they will be important for the organization as well. But they'll be modest. They'll be about 25% of Duchenne, so they'll be important but modest. With that said, an additional question that had been asked was the split of ambulatory and non-ambulatory, specifically as it relates to type 2E. And I don't know, Louise, if you have any information on that, please.

因此，首先要明確的是，他們將是重要的貢獻者。他們將為患有和遭受這種極其嚴重的肌肉萎縮症的患者的生活做出巨大貢獻。那麼它們對於組織來說也將非常重要。但他們會很謙虛。它們約佔杜氏肌肉營養不良症的 25%，因此它們很重要，但作用不大。話雖如此，有人提出的另一個問題是可行走和不可行走的區分，特別是與 2E 型相關的區分。我不知道，路易絲，如果你有任何相關信息，請告訴我。

Yes, there's generally an even split. I would say as genetic diagnosis, especially if the limb girdles, has come along, we're seeing more of the ambulatory population. I think, historically, you would have said it would be geared towards the ambulatory, but now it's generally a 50-50 split.

是的，一般來說，是均等分割。我想說，隨著基因診斷，特別是肢帶症候群的出現，我們會看到更多的可行走的人群。我認為，從歷史上看，你會說它會面向門診，但現在它一般是 50-50 的比例。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you for taking my questions. I have one question regarding the data update later this year for both FSHD and the DM1. If I hear correctly, DM1 will be the SAD data. Is FSHD also SAD data? And if they are the SAD data, how many cohorts and how long follow up? And what kind of data you will share with us?

感謝您回答我的問題。我有一個關於今年稍後 FSHD 和 DM1 數據更新的問題。如果我沒聽錯的話，DM1 將是 SAD 資料。FSHD 也是 SAD 資料嗎？如果是 SAD 數據，那麼有多少隊列以及需要多長時間的追蹤？您會與我們分享什麼樣的數據？

Yes, I will turn this to Dr. Rodino-Klapac to provide some color on that.

是的，我將把這個問題交給 odino-Klapac 博士來提供一些說明。

Yes, for both FSHD1 and DM1, it will be the SAD data, so it will be early. We'll be focusing on single-ascending dose study data, which will be focused on safety, some early signals of biomarker efficacy, which will be muscle concentration, knockdown, essentially splicing, restoration as well. So it will be early data, but we look forward to showing that in the second half of the year for both.

是的，對於 FSHD1 和 DM1 來說，它都將是 SAD 數據，所以還為時過早。我們將重點放在單次遞增劑量研究數據，這些數據將專注於安全性、生物標記功效的一些早期訊號，包括肌肉濃度、擊倒、基本剪接和恢復。因此這將是早期數據，但我們期待在今年下半年展示這兩項數據。

Also really excited with FSHD as well that our hope, and of course we'll only know when the data comes in, is that we'll be able to show through an assay the actual direct knockdown of DUX4, which of course is the goal of the therapy for FSHD. If we can do that, that is a really significant proof of biology because no program before has been able yet to achieve that goal. So we're very excited to see that as well.

我們對 FSHD 也感到非常興奮，我們希望能夠透過分析證明 DUX4 的實際直接敲低，當然，只有在數據出來後我們才會知道，這當然是 FSHD 治療的目標。如果我們能夠做到這一點，那將是生物學的一個真正重要的證明，因為之前還沒有任何程式能夠實現這一目標。所以我們也很高興看到這一點。

Brian Abrahams, RBC.

布萊恩·亞伯拉罕斯，RBC。

Hi, this is Kevin on for Brian. Thanks for taking our questions. So maybe just on limb-girdle type 2E, can you maybe tell us a little bit about what you think the bar is for your upcoming 2E data? And then maybe how do you think that bar translates to other LGMD subtypes that we'll eventually see data from? Thanks so much.

大家好，我是凱文，代表布萊恩。感謝您回答我們的問題。因此，也許只是關於肢帶型 2E，您能否告訴我們一些您認為即將到來的 2E 數據的標準是什麼？那麼，您認為該條如何轉化為我們最終會看到資料的其他 LGMD 亞型？非常感謝。

We've done -- I'll comment on it, and then Louise, you update with any more precision. Broadly speaking, we have been working with the agency over a very long period of time, in essence, to help educate the agency on the bar that should exist for these sorts of ultra-rare diseases, particularly diseases and therapies like SRP-9003 for limb-girdle type 2E where you're dealing with the replacement of the native protein unaltered, which the absence of that protein is the sole and exclusive cause of the disease.

我們已經完成了——我會對此發表評論，然後路易絲，您可以更精確地更新。廣義上講，我們與該機構合作了很長一段時間，本質上是為了幫助該機構了解針對這些極其罕見的疾病應該設立的標準，特別是像用於治療 2E 型肢帶綜合徵的 SRP-9003 這樣的疾病和療法，其中需要處理的是未經改變的天然蛋白質的替換，而該蛋白質的缺失是導致疾病的唯一原因。

So I'm very proud to say we have very small end studies. They're single-arm studies. They look to expression and safety. So in the broadest of strokes, the bar will be that we're getting nice expression, and I would hope largely consistent with the expression that we've seen in the past. Because remember, we've actually dosed on SRP-9003 in prior cohorts. And of course, a good safety profile.

因此，我很自豪地說，我們的最終研究規模非常小。它們是單臂研究。他們尋求表達和安全。因此，從最廣泛的角度來看，標準就是我們得到良好的表達，我希望這與我們過去看到的表達基本上一致。因為請記住，我們實際上已經在先前的群組中對 SRP-9003 進行過劑量給藥。當然，還有良好的安全性。

We have a lot of conviction around this, as you can well imagine, first because we've already actually dosed patients with SRP-9003, but also because SRP-9003 stands on the shoulders of all of the work that we've done with 9001, now ELEVIDYS. We have dosed hundreds and hundreds and hundreds of patients with ELEVIDYS. We understand the law, the safety profile, and we understand the power of our constructs and our promoter to get really good expression and get it safely. So that's sort of the bar, and we're very confident about where we're going to go with that.

正如您所想像的，我們對此充滿信心，首先因為我們已經為患者服用了 SRP-9003，而且因為 SRP-9003 建立在我們對 9001（現在的 ELEVIDYS）所做的所有工作的基礎之上。我們已經為數以百計的患者服用了 ELEVIDYS。我們了解法律、安全概況，也了解我們的構造和我們的發起人的力量，以獲得真正良好的表達並安全地獲得它。這就是標準，我們對於要實現的目標非常有信心。

And on your other question, this will be similar across the limb-girdle programs that we have already aligned with the agency on the approach that we're taking for 9003 and 9004 and 9005. And we're confident that this affects a modernization in the way the agency's looking at transformative therapies for ultra-rare diseases. Louise, is there any more detail that I have omitted?

關於您的另一個問題，這對於我們已經與該機構就 9003、9004 和 9005 採取的方法達成一致的肢帶計劃來說是類似的。我們相信，這將影響該機構對極為罕見疾病的轉化療法的現代化研究方式。路易絲，我還遺漏了什麼細節嗎？

You summarized it well. Maybe I'll just linger on one point in the fact that for the sarcoglycans, LGMD2E being the first, these are the full-length genes. So in this case, beta-sarcoglycan is both the gene therapy. It's also the biomarker. We've demonstrated extensively preclinically how the biomarker expression leads to functional improvement. And then that translated in our studies clinically, and we saw two different doses. We saw improvements in both expressions that led to functional improvements over time.

你總結得很好。也許我只想強調一點，對於肌聚醣來說，LGMD2E 是第一個，這些是全長基因。因此在這種情況下，β-肌聚醣既是基因療法。它也是一種生物標記。我們已經在臨床前廣泛證明了生物標記的表達如何導致功能改善。然後，我們在臨床研究中看到了兩種不同的劑量。我們看到兩種表達方式都有改善，隨著時間的推移，功能也得到了改善。

Those patients will be sharing five-year safety follow-up data for those patients continuing to do well. So that will be our first study, and then the other sarco-glycans will follow suit. We're using RH74 across that platform, so not only are we leveraging the 9001 data, but then also the other sarcoglycans. So we're in good position in terms of the outcomes of these studies and the outcome of the BLA.

這些患者將分享那些繼續表現良好的患者的五年安全追蹤數據。這將是我們的第一個研究，然後其他肌聚醣也會跟著做。我們在整個平台上使用 RH74，因此我們不僅利用 9001 數據，還利用其他肌聚醣數據。因此，就這些研究的結果和 BLA 的結果而言，我們處於有利地位。

Andrew Tsai, Jefferies.

安德魯·蔡（Andrew Tsai），傑富瑞（Jefferies）。

Thanks. I appreciate the update. Congrats on all the progress. Maybe one more question on the DM1 FSHD data you'll be sharing later this year. Do you think the initial SAD data will be conclusive to the point where investors can determine whether these programs are looking superior or not, or do you need MAD data? And how would you define superiority in these two programs? Thank you.

謝謝。我很感謝你的更新。祝賀你取得的所有進展。也許您今年稍後會分享有關 DM1 FSHD 數據的另一個問題。您是否認為初始 SAD 數據將具有決定性作用，使投資者能夠確定這些項目是否看起來更優秀，或者您是否需要 MAD 數據？您如何定義這兩個程式的優勢？謝謝。

I'm going to turn this over broadly to Louise to talk about it. Let me say at the inception -- first of all, I don't want to do what other small biotech companies often do, which is oversell early data. The data has to evolve. These are, however, very, very important proofs of biology.

我將把這個問題交給 Louise 來詳細討論。首先，我不想像其他小型生技公司那樣過度銷售早期數據。數據必須不斷發展。然而，這些都是非常非常重要的生物學證據。

So I want to be very clear, both from a safety perspective, a muscle concentration perspective, a knockdown perspective, a downstream gene-splicing perspective, and as it relates to FSHT, whether you can actually directly see the knockdown of DUX4. So while there will still be lots of work to do from there, and we don't want to oversell the data, this is a really, really important moment. And it should give at least signals of potential future product profiles versus other potential approaches to FSHD and DM1. But Louise, you can provide more detail.

因此，我想非常清楚地說明，無論是從安全角度、肌肉濃度角度、敲低角度、下游基因剪接角度，還是與 FSHT 相關的角度，您是否真的可以直接看到 DUX4 的敲低。因此，儘管還有很多工作要做，而且我們也不想過度銷售數據，但這是一個非常非常重要的時刻。並且它至少應該給出與 FSHD 和 DM1 的其他潛在方法相比未來潛在產品概況的訊號。但 Louise，你可以提供更多細節。

Yes. Just to add to that, I would say that what we know from the Arrowhead platform, what we've seen in their other programs, and from the preclinical data is the translation from preclinical to clinical. And so we've been excited to see that, and that's what we'll be looking for is that translation into the clinic.

是的。補充一點，我想說，我們從 Arrowhead 平台了解到的情況、我們在他們的其他項目中看到的情況以及從臨床前數據中了解到的情況是從臨床前到臨床的轉化。所以我們很高興看到這一點，而這正是我們所尋求的，將其轉化為臨床應用。

So it will certainly be a good indicator in terms of the knockdown that we're seeing, the muscle concentration. Those are the things we'll be looking for. As robust clinical developers, we're obviously looking to the MAD data to come following that, but certainly we're excited to see the SAD data and the translation from preclinical and just an extension of their already promising data across the platform for Arrowhead.

因此，就我們所看到的擊倒效果和肌肉集中度而言，這肯定是一個很好的指標。這些就是我們要尋找的東西。作為強大的臨床開發商，我們顯然期待著隨後的 MAD 數據，但我們當然很高興看到 SAD 數據和臨床前轉化，以及他們在 Arrowhead 平台上已經很有前景的數據的延伸。

Kostas Biliouris, BMO Capital Markets.

Kostas Biliouris，BMO 資本市場。

Thanks for taking our question and congrats on the progress. A question on ELEVIDYS from us, given that it's been about eight months now since the label expansion, can you comment on whether you have seen any reimbursements for PMOs in ELEVIDYS-treated patients? And if not, are you hearing anything from payers around their willingness to reimburse PMOs following ELEVIDYS treatment? Thank you.

感謝您回答我們的問題，並祝賀取得的進展。我們有一個關於 ELEVIDYS 的問題，鑑於標籤擴展已經過去了大約八個月，您能否評論一下您是否看到過接受 ELEVIDYS 治療的患者對 PMO 有任何報銷？如果沒有，您是否聽到付款人表示願意在接受 ELEVIDYS 治療後向 PMO 償還費用？謝謝。

Yes, so let me say, Kostas, thank you for your question. In broad strokes, I will still note that it's still very early days. And so trying to draw broad conclusions is challenging. As we've noted, one of the most interesting, I think, data points we should linger on for a second is while we've had all this success, we're still only treated less than 5% of the addressable on-label patient population for ELEVIDYS.

是的，科斯塔斯，謝謝你的提問。總體來說，我仍然會注意到現在還處於早期階段。因此，試圖得出廣泛的結論是很有挑戰性的。正如我們所指出的，我認為最有趣的數據點之一是，儘管我們取得了所有這些成功，但我們仍然只治療了不到 5% 的 ELEVIDYS 可尋址標籤患者群體。

And so you've got to both have to really test this issue. You've got to have ELEVIDYS, and then you have to have the fact that a ELEVIDYS is treating a patient previously on a PMO. But we do have instances of reimbursement of both. So we've already seen that. I don't want to oversell it right now, and I'm sure we also have instances where that was impossible. But it's not black or white or binary right now.

所以你們雙方都必須真正檢驗這個問題。您必須擁有 ELEVIDYS，然後您必須知道 ELEVIDYS 之前正在 PMO 上治療患者。但我們確實有同時報銷這兩項費用的例子。我們已經看到了這一點。我現在不想過度推銷它，而且我確信我們也遇到過不可能的情況。但現在它不是黑色、白色或二進制的。

What I will reiterate, one of the things that we're very excited about is that so far, we haven't seen significant net cannibalization. We'll see some cannibalization in the US. We're seeing very good growth of our PMOs ex-US. Of course, the overlap is modest given that we only treat 29% of patients with Duchenne muscular dystrophy with our PMOs. And it's nice to see that we have seen some payers interested and willing to put kids on sequential therapy, post-gene therapy. But it's still very early days, and I wouldn't overread that. Dallan?

我要重申的是，讓我們非常興奮的事情之一是，到目前為止，我們還沒有看到嚴重的網路蠶食。我們將會看到美國出現一些蠶食現象。我們看到美國以外的 PMO 成長非常好。當然，考慮到我們僅使用 PMO 治療 29% 的杜氏肌肉營養不良症患者，重疊程度不大。我們很高興看到一些付款人感興趣並願意讓孩子們接受序貫治療和基因治療。但現在還為時過早，我不會過度解讀。達蘭？

No, that's absolutely right. That's absolutely right, yes.

不，完全正確。是的，完全正確。

Mike Ulz, Morgan Stanley.

摩根士丹利的麥克烏爾茲。

Hey, guys. Thanks for taking the question. Maybe just a quick one on the $500 million share repurchase program. Can you just remind us what the timeframe is there? And then some of the considerations as you decide when you might deploy that. Thanks.

嘿，大家好。感謝您回答這個問題。也許只是對 5 億美元股票回購計畫做一個簡短的介紹。您能提醒我們一下時間框架嗎？然後，當您決定何時部署時，需要考慮一些因素。謝謝。

So I'll turn this to Ian for his thoughts.

因此我將把這個問題交給伊恩，聽聽他的想法。

Sure. So the time period is 18 months. Like I said, obviously, we just completed the Arrowhead transaction and so we're going to be quickly building back our cash reserves over the course of the year. Like I said in our prepared remarks, we're going to be back to the same level at the end of '25 as where we started -- where we ended in '24. So it just talks to the strength of the launch.

當然。所以時段是18個月。就像我說的，顯然，我們剛剛完成了 Arrowhead 交易，因此我們將在今年內迅速恢復我們的現金儲備。正如我在準備好的演講中所說的那樣，我們將在 2025 年底回到與 2024 年開始時相同的水平。所以這只是談論發射的強度。

And so as we continue to build our cash reserves, we're going to look to be opportunistic around potentially deploying that capital and buying shares. So obviously, we're not going to telegraph when we will be doing it specifically, but we certainly have it at our disposal, and we're looking at the right time to execute.

因此，隨著我們繼續建立現金儲備，我們將尋求機會部署這些資本併購買股票。因此，顯然，我們不會透露具體何時會這樣做，但我們肯定可以自行決定，並且正在尋找合適的時間來執行。

Joe Schwartz, Leerink Partners.

Leerink Partners 的 Joe Schwartz。

Great. Thanks very much. So since approval in '23, it seems like the ELEVIDYS launch has had a few different stages with great growth early on following accelerated approval, then a couple of flat-to-down quarters in early 24, followed by a really nice return to growth following the expanded label in mid '24.

偉大的。非常感謝。因此，自 2023 年獲得批准以來，ELEVIDYS 的推出似乎經歷了幾個不同的階段，在加速批准後初期實現了巨大增長，然後在 2024 年初經歷了幾個持平至下降的季度，隨後在 2024 年中期擴大品牌後恢復了非常好的增長。

So since your '25 guidance seems to imply that growth this year should be more moderate, I'm just wondering if you can give us your view about the stage of the launch that we're in now and how you see it evolving this year. Are there any important constraints to growth that we should keep in mind this year?

因此，由於您的 25 年指導似乎暗示今年的成長應該更加溫和，我只是想知道您是否可以告訴我們您對我們目前所處的發布階段的看法，以及您認為今年它將如何發展。今年有哪些重要的成長限制值得我們記住？

So Joe, thank you for your question. And I will say, with due respect, I do not characterize our launch exactly the way you do. I would say we had a brilliant launch in '23 with a very thin label. Then we achieved something that I achieved, which is a very, very broad label. But of course, the cadence for that broader launch requires the natural cadence of kids getting on therapy, which, to remind everyone, even though we had done a brilliant job in site readiness and accident reimbursement were all ready, there's just a cadence to getting the kids on therapy.

喬，謝謝你的提問。我要說的是，恕我直言，我對我們的發布會的描述與您並不完全一樣。我想說，我們在 2023 年推出了一款非常出色的產品，儘管標籤很薄。然後我們取得了我所取得的成就，這是一個非常非常廣泛的標籤。但當然，更廣泛的啟動節奏需要孩子們接受治療的自然節奏，需要提醒大家的是，儘管我們在場地準備和事故賠償方面做得非常出色，但讓孩子們接受治療還是需要一個節奏。

It takes about four months, and there's really no magic to fixing that because it's the cadence of the single-case contract and the scheduling and the infusion beds and the amount of follow up and the assay work and the like. So there's a certain cadence. We had anticipated exactly what we saw in '24, which was we would see this hockey stick ramp towards the back half of the year, which is exactly what we saw. And as you know, we grew in the fourth quarter by 112%.

這需要大約四個月的時間，而且真的沒有什麼魔法可以解決這個問題，因為這是單一病例合約的節奏、時間安排、輸液床位、後續工作量和檢測工作等等。所以有一定的節奏。我們之前準確預測到了 24 年將會出現的情況，也就是我們會看到下半年出現曲棍球棒式增長，而我們也確實看到了這樣的情況。如您所知，我們第四季度的成長率為 112%。

And then I would note for this year, I mean, with respect against the statement that the growth is modest this year, we're going to grow with ELEVIDYS of over 160% year over year. And I would put that up -- well, first, I can't put it up against any other gene therapy, let's be clear, because we have blown away every other gene therapy cumulatively. But also, I think for launches, this is just about as successful a launch as one could have imagined. And we're still in the robust, robust growth phase of this launch.

然後我想指出的是，對於今年的成長溫和的說法，我們今年的 ELEVIDYS 成長率將超過 160%。我想說的是——首先，我不能把它與任何其他基因療法進行比較，讓我們明確一點，因為我們累積已經擊敗了所有其他基因療法。但同時，我認為，就發布而言，這次發布幾乎是人們所能想像的最成功的一次發布。我們仍處於此次發布的強勁成長階段。

Gil Blum, Needham & Company.

吉爾·布魯姆（Gil Blum），Needham & Company。

Hi, good afternoon, everyone. And again, congrats on all the progress. So maybe a question here on the move to suspension manufacturing with the bridging study later this year. Can you remind us what are the potential associated cost savings? And also, how broadly applicable is this? I mean, you guys use a lot of different programs for this in gene therapy. Is this translatable just outside of DMV, or is this very narrow? Thank you.

大家好，下午好。再次恭喜您取得的所有進展。因此，這裡可能有一個問題，關於今年稍後透過橋接研究轉向懸吊製造。您能否提醒我們潛在的相關成本節省哪些？而且，它的適用範圍有多廣？我的意思是，你們在基因治療中使用了很多不同的程序。這可以在 DMV 外面翻譯嗎，還是說這非常狹窄？謝謝。

Yes, so let me answer the last question first. So our goal, if successful, is to evolve almost all of our gene therapy programs to suspension. In fact, if I'm not mistaken, Louise, you'll correct me if I am, the only program that will remain in adhering is just the timing of it, and we didn't want to slow down the approval as kids are waiting for it. It's 9003. Even all the other sarcoglycans will be in suspension.

是的，那麼讓我先回答最後一個問題。因此，如果成功的話，我們的目標是將幾乎所有的基因治療項目都發展為暫停治療。事實上，如果我沒有弄錯的話，路易絲，如果我錯了，你會糾正我，唯一會繼續堅持的計劃只是時間問題，我們不想因為孩子們在等待而放慢批准的速度。是 9003。甚至所有其他的肌聚醣都會處於懸浮狀態。

And broadly speaking, of course, it's very dangerous to try to estimate the cost impact. We've got more work to do, but it will be very, very significant. We're seeing upwards of 5 times to even greater times more yield efficiency, so you could envision a margin significantly over 90% eventually with this and also the ability to really bring this therapy to the far reaches of the world. And that's, of course, one of our big goals.

當然，從廣義上講，試圖估計成本影響是非常危險的。我們還有很多工作要做，但這些工作將非常非常重要。我們看到產量效率提高了 5 倍甚至更多倍，因此你可以預見最終利潤率將遠超 90%，並且能夠真正將這種療法推廣到世界各地。當然，這是我們的一大目標。

So to remind everyone, we said it already in our prepared remarks, but our goal is to complete our GMP runs and to start our bridging study before the end of this year, certainly. And then the goal, of course, is if all goes well and we're successful to evolve to suspension in 2027, which would be a really, really elegant timing for us as we think about our global plans.

因此，提醒大家，我們在準備好的發言中已經說過了，但我們的目標是在今年年底之前完成 GMP 運行並開始橋接研究。當然，我們的目標是，如果一切順利的話，我們能夠在 2027 年成功實現懸掛，這對我們考慮全球計畫來說是一個非常非常有利的時機。

Ritu Baral, TD Cowen.

Ritu Baral，TD Cowen。

Hi, guys. Thanks for taking the question. Doug and Louise, I wanted to ask your current thoughts as you understand the landscape on the potential for splicing biomarker-based accelerated approval for your FSHD and DM1 programs. I know it's far in the future. But obviously, this is a hot topic of the space. And then, actually, if I could follow up on Gil's question. He asked about the bridging study. Can you describe what that bridging study is? It sounds like it's going to go fast.

嗨，大家好。感謝您回答這個問題。道格和路易絲，我想問你們目前的想法，因為你們了解基於拼接生物標誌物的 FSHD 和 DM1 專案的加速批准的可能性。我知道這還很遙遠。但顯然，這是該領域的熱門話題。然後，實際上，如果我可以跟進吉爾的問題。他詢問了有關橋接研究的情況。您能描述一下那項銜接研究是什麼嗎？聽起來它會進展得很快。

Yes, the bridging study, it's a relatively -- I don't know if he was given the actual data. It's a relatively small study looking at -- empirically looking at expression and safety to confirm that it's substantially similar to the adherent approach. So it should go relatively fast. Everything's at work, but it should go relatively fast, and we intend to start that bridging study later this year. And then with that, I'll turn it over to Louise if you have any thoughts or comments on the potential for an accelerated approval approach with either FSHC or DM1.

是的，這項橋接研究相對來說——我不知道他是否獲得了實際數據。這是一項相對較小的研究，透過實證研究來觀察表達和安全性，以確認它與黏附方法基本相似。所以它應該會相對較快。一切都在進行中，但進展應該相對較快，我們打算在今年稍後開始這項銜接研究。然後，如果您對 FSHC 或 DM1 加速審批方法的可能性有任何想法或意見，我將把問題交給 Louise。

We're in the early stages, I would say, for FSHD. Doug alluded to it, but we're in a unique position with FSHD where we have an assay that actually can quantify the knockdown of the primary effect in the indication, which is DUX4. And so that gives us unique opportunity in terms of potential biomarkers as well.

我想說，對於 FSHD 來說，我們尚處於早期階段。道格提到了這一點，但我們在 FSHD 方面處於一個獨特的地位，我們有一個檢測方法，可以實際上量化該適應症中主要效應的敲除，即 DUX4。因此，這也為我們在潛在生物標記方面提供了獨特的機會。

In these early studies, we are looking at multiple biomarkers and functional outcomes. And that's really what these Phase 1 studies are intended to do, so then you can optimize and pick the best path forward. I think it's an opportunity to evaluate as far as splicing. I think it is one of many biomarkers, so whether it would be the sole biomarker is something left to be explored.

在這些早期研究中，我們正在觀察多種生物標記和功能結果。這正是第一階段研究的目的，讓您可以優化並選擇最佳的前進道路。我認為這是一個評估拼接的機會。我認為它是眾多生物標誌物中的一種，因此它是否是唯一的生物標誌物還有待探索。

And, of course, we recognize -- we know amongst others there's a lot of open discussion and dialogue and even some differences of opinion regarding the pathway for approval. This is one of these really rare moments. Maybe in my time, and Sarepta the first time, where we get to be informed by others.

當然，我們認識到——我們知道，在批准途徑方面存在大量公開的討論和對話，甚至存在一些意見分歧。這是一個非常罕見的時刻。也許在我的時代，以及在 Sarepta 的第一次，我們可以從別人那裡獲得資訊。

And so we're going to get informed by, not only our direct conversations with the FDA, but what others are seeing when they're looking with the FDA. And that will help inform our path forward. So it's an interesting place to be where we get to be informed by others as opposed to with most of our other therapies having been the one to inform the world and chart the path forward.

因此，我們不僅可以透過與 FDA 的直接對話來獲取訊息，還可以透過其他人向 FDA 了解的情況獲取資訊。這將有助於我們指引前進的道路。因此，這是一個有趣的地方，我們可以從其他人那裡獲得信息，而我們的大多數其他療法都是自己向世界通報信息並規劃前進的道路。

Brian Skorney, Baird.

布萊恩·斯科尼，貝爾德。

Hey, good afternoon. Thanks for taking my question. I was hoping you could kind of walk through what you sort of perceive as the current order of potential rate-limiting steps to commercial ELEVIDYS revenue recognition. I'm just trying to understand. It doesn't seem like it's demand in any sense right now. So what's sort of the step-throughs that are kind of creating blocks from realizing the full demand. Is it like -- would one be like insurance authorization? Would it be center capacity? Could you like kind of rank order those?

嘿，下午好。感謝您回答我的問題。我希望您能大致介紹一下您認為的當前對商業 ELEVIDYS 收入確認的潛在限速步驟順序。我只是想了解一下。從目前來看，這似乎根本不是需求。那麼，是哪些步驟阻礙了全部需求的實現呢？它是否像保險授權？這會是中心容量嗎？你能按某種順序排列它們嗎？

Rank ordering is hard. I'm going to turn this over to Dallan and force him to rank order. But let me say a couple things. I don't want to call them blocks because it's just a cadence issue. It would be like saying Dallan often uses a metaphor that this is often like -- think of this more than -- this is not like prescribing a drug. This is almost more like an organ transplant. There's just a lot of steps that have to go through to get from here to a kid dose. That's why it's about a four-month process.

排序很難。我要把這個交給達蘭並強迫他進行排序。但請容許我說幾件事。我不想稱它們為障礙，因為這只是節奏問題。這就像說達蘭經常使用一個比喻，這通常就像——多想想——這不像開藥。這幾乎更像是器官移植。從現在到兒童劑量還需要經過許多步驟。這就是為什麼這是一個大約四個月的過程。

I'll give you some data on that. There are something like 25 individuals at a site of care that touched this therapy moving from the start form to the infusion. And that goes through lots of different departments. It's not just the internal pharmacy and the institutions that are the nurses and the physicians. It's also all the way back into the financial area and the CFO of the organization and the like. And so there's just a cadence.

我會給你一些相關的數據。在一個護理點，大約有 25 個人從開始形式到輸液階段接受過這種療法。這需要經過許多不同的部門。不僅僅是內部藥房和護士和醫生所在的機構。它也一直延伸到財務領域和組織的財務長等。所以這只是一個節奏。

I mean, to give you an example, Brian, that there is -- it's about a -- it can be as much as a four-week or longer process to do the single case contract. Almost every time a patient gets dosed, the site and the payer enter into a specific site contract. It's an administrative step that has to be done. It is done. It's done very well. We understand the process exceptionally well. I'm quite confident now I can say it without fear of being arrogant. There's no organization in the world that understands this process as well as we do, but there's just a cadence to this.

我的意思是，布萊恩，給你舉個例子，簽訂單案合約可能需要大約四周甚至更長時間。幾乎每次患者服藥時，治療點和付款人都會簽訂特定的治療點合約。這是必須採取的行政措施。完成了。做得很好。我們非常了解這個過程。現在我很有自信，我可以毫無顧忌地說出這些話。世界上沒有任何組織像我們一樣了解這個過程，但這其中有一個節奏。

And it is all the things you're mentioning. It's the very process of getting the first meeting and then getting to the assay and then getting the infusion site ready. At the same time, it's the start form and the single case contract. It's negotiating with the payers if you have to. It's the, when necessary, negotiating with the payers around it. Remember, I will comment on this, there's been certainly some misunderstanding regarding payers and some and other relatively superficial surveys that were done.

這就是您提到的所有事情。這是第一次會議、然後進行分析、然後準備輸液部位的過程。同時，它是啟動形式和單案合約。如果有必要的話，就與付款人進行談判。必要時，就要與付款人進行談判。請記住，我會對此發表評論，對於付款人以及進行的一些其他相對膚淺的調查肯定存在一些誤解。

Look, we're doing really great with payers right now. We're doing better with payers with the ELEVIDYS than we did with the PMOs. And I would note, we've done really, really well with the PMOs over time, I think, as anyone would agree. The policies really set themselves into three buckets. Policies, there's a lot of policies that are just dose to label, give access to label more than there were with the PMO. So we're really excited about that. Some of our bigger payers are in that camp. There are some payers that have restrictions and there are some payers that have a lot of restrictions.

瞧，我們現在在付款方面做得非常好。我們與 ELEVIDYS 付款人的關係比與 PMO 的關係更好。我想指出的是，長期以來，我們與 PMO 的合作一直非常出色，我想，這一點任何人都會同意。這些政策其實分為三類。政策，有許多政策只是為了標記，比 PMO 給予更多的標記存取權。所以我們對此感到非常興奮。我們的一些大額付款人就屬於這一類。有些付款人有限制，有些付款人有很多限制。

The interesting thing is that those different policies will not affect today the ultimate kid getting on a therapy. What they do is internally, they define the amount of time to get a kid on therapy and the amount of work that needs to be done to get a kid on therapy, but they get on therapy. So I just want to get everyone's head around that idea.

有趣的是，這些不同的政策不會影響今天的孩子接受最終的治療。他們所做的是內在的，他們定義讓孩子接受治療的時間和讓孩子接受治療所需的工作量，但他們還是接受了治療。所以我只是想讓每個人都理解這個想法。

And our PMOs, with eight years of battle-hardened experience, our win rate if a payer is going to be very resistant and take us to an internal or external appeal is over 90%. With ELEVIDYS right now, we're sitting right now at 100%. So no kid has been permanently denied therapy thus far. So in any event, all of these things describe this broad cadence that is about a four-month process. But Dallan, if you want to rank order them for Brian.

我們的 PMO 擁有八年的豐富經驗，如果付款人非常抵觸並向我們提出內部或外部上訴，我們的勝率將超過 90%。現在有了 ELEVIDYS，我們的效率已經達到 100%。因此，到目前為止還沒有孩子被永久拒絕接受治療。因此，無論如何，所有這些事情都描述了這個大約四個月的過程的大致節奏。但是達蘭，如果你想為布萊恩對他們進行排序。

Yes. Well, Brian, I think you can summarize everything that Doug is saying with one word, which is time, right? Everything here takes time. And so, you really, therefore, cannot point to one thing. As I said in my prepared remarks, we have robust patient demand. We have more demand than can be treated today. We have ample site capacity. We have enough site capacity to treat our peak forecast.

是的。好吧，布萊恩，我認為你可以用一個詞來概括道格所說的一切，那就是時間，對嗎？這裡的一切都需要時間。因此，你實際上無法指出一件事。正如我在準備好的演講中所說，我們有強勁的患者需求。我們的需求超出了目前能夠處理的範圍。我們的場地容量充足。我們擁有足夠的場地容量來應對我們的高峰預測。

We've got positive trends in access and reimbursement that we're allowing to convert patients within that consistent three- to five-month timeframe. So those together, then, when you layer in what Doug said, it's just a game of time to get these patients on therapy, and that is all fact. Because we've got a deep and very detailed line of sight into all of this, this is what informs our quarter-to-quarter growth and our guidance for the year.

我們在獲取和報銷方面呈現了積極的趨勢，我們允許在三到五個月的固定時間內轉化患者。所以綜合起來，當你把道格所說的話放在一起時，讓這些病人接受治療只是一場時間遊戲，而這都是事實。因為我們對所有這些都有深入和非常詳細的了解，所以這為我們的季度成長和全年指導提供了依據。

And I will say, it's probably two things. It's time and an insane attention to detail, which Sarepta is really good at. I am sitting here, I will tell you, at our national training meeting today with all of our folks focused on this, and the amount and attention -- obsession into detail and the passion to make sure a kid never slips through the cracks but can get on this therapy and benefit from ELEVIDYS is insane.

我想說，這可能是兩件事。是時候了，而且非常注重細節，而這正是 Sarepta 所擅長的。我坐在這裡，我可以告訴你，今天在我們的全國培訓會議上，我們所有人都專注於這一點，我們對細節的痴迷和熱情是瘋狂的，以確保孩子永遠不會被忽視，而是可以接受這種治療並從 ELEVIDYS 中受益。

And that explains why we've been so successful, and it explains why we are so comfortable with our guidance for 2025, which I would say is very robust guidance. $3 billion is a 70% growth overall for the year; and as relates to ELEVIDYS, over 160% growth year over year, which speaks to the execution ability of this team out here in Sarepta.

這也解釋了為什麼我們如此成功，也解釋了為什麼我們對 2025 年的指導如此滿意，我想說這是非常穩健的指導。 30億美元，全年整體成長70%；就 ELEVIDYS 而言，其年增長率超過 160%，證明了 Sarepta 團隊的執行能力。

David Hoang, Deutsche Bank.

德意志銀行的 David Hoang。

Hi there. Thanks for taking my question. So I just had one on if you have any thoughts on a recent data set that was generated by a next-generation DMV gene therapy competitor, and do you have any insights from your field force on how a family of patients might think about receiving treatment with commercial ELEVIDYS versus enrolling in a clinical trial for one of these other products. Thank you.

你好呀。感謝您回答我的問題。因此，我只是想問一下，您是否對下一代 DMV 基因治療競爭對手生成的最新數據集有任何看法，並且您是否從您的實地團隊那裡獲得了關於患者家屬如何考慮接受商業 ELEVIDYS 治療而不是參加其他產品之一的臨床試驗的見解。謝謝。

Well, first, there are no next-generation gene therapy programs, so I'm going to correct the record on that. That's a misstatement. But look, a couple thoughts on it. You know, we do understand that [Zolin] put out some very, very early first-in-human data. A couple thoughts. First, fantastic. We are thrilled. that a number of organizations are looking at researching new therapies for kids with Duchenne Muscular Dystrophy.

嗯，首先，沒有下一代基因治療計劃，所以我要糾正這方面的記錄。這是錯誤的陳述。但請看，對此有幾點想法。你知道，我們確實了解到 [Zolin] 發布了某些非常非常早期的人體首次數據。一些想法。首先，太棒了。我們非常激動。許多組織正在研究杜氏肌肉營養不良症兒童的新療法。

And to be honest, we take a lot of pride in it because I think but for the success that we've had with our PMOs and with the ELEVIDYS, they wouldn't have this robust focus on finding new therapies for kids. So we're very excited about that. I do want to note that we have to remember that the families with Duchenne muscular dystrophy have to make difficult decisions today, and they need accurate information to make them. That's for the families to make.

說實話，我們對此感到非常自豪，因為我認為，如果我們的 PMO 和 ELEVIDYS 沒有成功，他們就不會如此專注於為兒童尋找新的治療方法。所以我們對此感到非常興奮。我確實想指出，我們必須記住，杜氏肌肉營養不良症患者的家庭今天必須做出艱難的決定，他們需要準確的資訊來做出決定。這是由家人決定的。

Clearly, there is one absolute overarching fact which is there is one approved therapy that is transformative in nature that is a disease-modifying gene therapy, and that is the ELEVIDYS. And that can treat 80% of children with Duchenne muscular dystrophy and young men and occasionally women with Duchenne muscular dystrophy. And our goal is to ensure that families have the right information so they can make the right decisions, which is often a very difficult decision.

顯然，有一個絕對的首要事實，那就是有一種經過批准的療法具有變革性，是一種改變疾病的基因療法，那就是 ELEVIDYS。這可以治療 80% 的杜氏肌肉營養不良症兒童和年輕男性，偶爾還有女性。我們的目標是確保家庭獲得正確的訊息，以便他們能夠做出正確的決定，而這通常是一個非常艱難的決定。

Do you go -- do you get the current therapy? Do you look at a clinical trial and take a therapy that's been tested less and the like? But I just want to make sure the only thing I -- I'm very thrilled with the others focusing on this. I think it's a really positive for the Duchenne community and everybody should applaud it.

你會去－你會接受目前的治療嗎？您是否會關注臨床試驗並採取較少測試的治療方法等？但我只是想確保唯一的事情——我很高興其他人關注這一點。我認為這對杜氏肌肉營養不良症社群來說是一件非常積極的事情，每個人都應該為此鼓掌。

But I do want to make sure people are providing the right, balanced, reasonable information so people can make intelligent decisions and not make the wrong decisions. And the actual decision that people make between entering into a clinical trial for a new experimental therapy versus getting on an approved therapy that's been shown to be safe and efficacious is a difficult decision that's going to be made between the families and their healthcare provider, hopefully properly informed with all the current data.

但我確實想確保人們提供正確、平衡、合理的訊息，以便人們能夠做出明智的決定，而不是錯誤的決定。人們在參加新的實驗療法的臨床試驗和接受已被證明安全有效的批准療法之間做出的實際決定是一個艱難的決定，這個決定將由家庭和醫療保健提供者之間做出，希望他們能夠充分了解所有當前數據。

Maybe just one thing to add to that, and I'll turn it to Louise to go into more depth. But I do think it's important for people to recognize -- and certainly Louise has done a lot of work, empirical work, for over many years looking at constructs and seeing their functionality.

也許只需要補充一點，然後我會把它交給 Louise 進行更深入的探討。但我確實認為讓人們認識到這一點很重要——當然，路易絲多年來做了大量的工作，實證工作，研究結構並了解它們的功能。

And certainly, as we've seen with other development programs that different constructs have different efficacy and safety profiles; and therefore, when Louise tested all these programs to really move forward with the optimized construct from a functional perspective, and that's why we were able to see data based on our expression lead to functional outcomes.

當然，正如我們在其他開發項目中看到的那樣，不同的結構具有不同的功效和安全性；因此，當 Louise 測試所有這些程序時，真正從功能角度推進優化構造，這就是為什麼我們能夠看到基於我們的表達的數據導致功能結果。

And so that's really important when patients are thinking about therapies that -- it's not just only expression, but actually the functionality of the construct. And to Doug's point, we've been able to show that in clinical studies. But Louise, since you did the work, you probably have the best point of view on that.

因此，當患者考慮治療方法時，這一點非常重要——這不僅僅是表達，而且實際上還涉及結構的功能。正如 Doug 所說，我們已經能夠在臨床研究中證明這一點。但是路易絲，既然你做了這項工作，你可能對此有最好的看法。

Yes, thanks for that. Yes, I think it's important in the fact that the dystrophin space is unique for gene therapy and that in the small space that you are looking are different functional contributions from these constructs. And so the quality of the dystrophin that you're producing is extremely important. Just one of the things that we noted in our studies when we compared to other constructs was the inclusion of [Spectrum Repeat 3] for stability of the construct. And we found that over time that this was critical to the functionality of our construct and the corresponding functional improvement that we saw that corresponded from preclinical work to clinical work.

是的，謝謝。是的，我認為重要的是，肌肉營養不良蛋白空間對於基因療法來說是獨一無二的，並且在您尋找的小空間中，這些構造具有不同的功能貢獻。因此，生產的肌肉營養不良蛋白的品質極為重要。當我們與其他構造進行比較時，我們在研究中註意到的一件事是加入了 [Spectrum Repeat 3] 來提高構造的穩定性。我們發現，隨著時間的推移，這對於我們構造的功能以及從臨床前工作到臨床工作所看到的相應功能改進至關重要。

And so it was -- as you all know, you've been on this journey with us, hundreds of patients over many years and multiple clinical studies showing the same thing in terms of the expression leading to functional benefit and obviously with a traditional approval now and over 600 patients treated both clinically and commercially. So certainly, the quality of the construct and the functional data that's demonstrated in the clinic is critical to making a decision about the therapy that a patient chooses with their family.

事實就是這樣 — — 大家都知道，你們和我們一起走過了這段旅程，多年來對數百名患者進行了多項臨床研究，結果顯示，在表達方面，該療法可帶來功能益處，顯然現在已獲得傳統批准，並且已有超過 600 名患者接受了臨床和商業治療。因此，毫無疑問，結構的品質和臨床所展示的功能數據對於患者及其家人選擇的治療方法做出決定至關重要。

[Rai Forsett], Guggenheim Securities.

[Rai Forsett]，古根漢證券。

Hi, this is Rai from Debjit's team. We have two questions. Number one, how is Sarepta modeling the impact of competitive gene therapies in DMD, especially on the annual incidence population under the assumption that the prevalence pool is saturated? And number two, for the 2E program, should we expect higher vector genomes per nucleus relative to historical Sarepta data and protein expression above 50%? And is there a threshold for regulatory submission?

大家好，我是 Debjit 團隊的 Rai。我們有兩個問題。第一，在盛行率飽和的假設下，Sarepta 如何模擬競爭性基因療法對 DMD 的影響，特別是對年發病率人口的影響？第二，對於 2E 計劃，我們是否應該預期相對於歷史 Sarepta 數據和 50% 以上的蛋白質表達，每個細胞核的載體基因組數會更高？監管提交是否有門檻？

I think I've answered the threshold question. Thank you for that. I think if we get expression consistent with what we've seen before with 9003 and before that with 9001 -- and I would remind you, we got really extraordinary vector genome copies per nucleus, and we do it with a very rigorous approach, fairly unassailable approach to looking at things like vector genome copies and expression, ones that we worked on for years and years with input from the FDA. We might have to be very careful about that because it's very easy to do these things in ways that give false information.

我想我已經回答了門檻問題。謝謝你。我認為，如果我們獲得的表達與之前在 9003 和更早的 9001 中看到的一致 - 我要提醒您，我們在每個細胞核中獲得了非常非凡的載體基因組拷貝，並且我們採用非常嚴格的方法，相當無懈可擊的方法來觀察基因組拷貝和表達等事物，這是我們在 FDA 的投入下多年來一直致力於研究的。我們可能必須對此非常小心，因為以提供虛假資訊的方式做這些事情很容易。

But if we get those levels of vector genome copies per nucleus and we get the kind of expression that we've seen both in 9003 and 9001, we're very confident that we'll get and approval assuming the safety is there and we're very confident about that. As far as modeling, it's way too early to be modeling competition from people that have one, two, and three patients in these early experimental therapies. Probably haven't even figured out manufacturing at that point. Certainly, we wouldn't be modeling anything this decade in any event. It's something we can look to if people will actually start progressing.

但是如果我們獲得每個細胞核的載體基因組拷貝數達到這些水平，並且獲得我們在 9003 和 9001 中看到的那種表達，我們非常有信心我們會獲得批准，前提是安全性是存在的，我們對此非常有信心。就建模而言，現在對這些早期實驗療法中擁有一、二、三名患者的人群進行建模競爭還為時過早。那時可能還沒弄清楚製造業。當然，無論如何，我們都不會在未來十年內對任何東西進行建模。如果人們真的開始進步，我們可以看看這一點。

Although I would say, thank you for that question, because the size of that incident population is really underappreciated. It's really double the size of the Zolgensma market currently. We'll be ready for any competition when it comes. As Doug said, it's going to be a long time coming, and we really are excited about the possibility of treating patients earlier and preserving function earlier in that patient journey. So it's a great question from the perspective of a very underappreciated part of the Duchenne market opportunity.

不過我想說，謝謝你提出這個問題，因為這事件的人口規模確實被低估了。它實際上是目前 Zolgensma 市場規模的兩倍。當任何比賽到來時，我們都會做好準備。正如道格所說，這將是一個漫長的過程，我們真的很高興能夠更早治療患者並在患者康復過程中更早保留功能。因此，從杜氏肌肉營養不良症市場機會中未被充分重視的部分的角度來看，這是一個很好的問題。

Anupam, JP Morgan.

Anupam，摩根大通。

Hi, guys. This is Priyanka on for Anupam. Thank you for taking our quick question. As the R&D Day is in the second half of the year, can we assume potential new data could be presented there from Arrowhead or other non-Arrowhead pipeline programs? Thank you.

嗨，大家好。這是 Priyanka 為 Anupam 表演的。感謝您回答我們的簡短問題。由於研發日是在下半年，我們是否可以假設 Arrowhead 或其他非 Arrowhead 管道項目可能會在那裡展示潛在的新數據？謝謝。

I'll turn that to Louise to comment.

我將把此問題轉交給 Louise 進行評論。

I don't think we said exactly the timing of when we will present the Arrowhead data. It all depends on the timing of the data release and how that lines up with R&D Day. We're excited to talk about the platform generally. I would say that as part of R&D Day and our deep pipeline that we haven't really been able to share in detail. So we look forward to that. As we have more timing, we'll share with you.

我認為我們並沒有明確說明何時展示 Arrowhead 數據。這一切都取決於數據發布的時間以及與研發日的配合。我們很高興談論這個平台。我想說，作為研發日和深度管道的一部分，我們還無法真正詳細分享。所以我們對此充滿期待。當我們有更多時間時，我們會與您分享。

Biren Amin, Piper Sandler.

比倫阿明、派珀桑德勒。

Yes. Hi, guys. Thanks for taking my questions. For the EMERGENE trial, I think you're enrolling both ambulatory and non-ambulatory patients, while the Phase 1 enrolled ambulatory. So should we express -- should we expect expression would be similar in non-ambulatory patients to what was observed in the Phase 1 ambulatory data? And then, when you report these data, will you be comparing these to the NCH national history cohort?

是的。嗨，大家好。感謝您回答我的問題。對於 EMERGENE 試驗，我認為您招募了能夠行走和不能行走的患者，而第一階段招募了能夠行走的患者。那麼我們是否應該表達－我們是否應該預期非臥床患者的表達與第一階段臥床資料中觀察到的表達相似？然後，當您報告這些數據時，您會將這些數據與 NCH 國家歷史隊列進行比較嗎？

Louise?

路易絲？

Yes, a couple of things in there. So we've treated both ambulatory and non-ambulatory patients, and we see similar levels of expression. So the EMERGENE, the analysis will analyze those two populations separate from a functional perspective. That will be the follow-on study, the confirmatory study. But from an expression level, yes, we will evaluate both. In terms of what we're comparing it to, we have our own journey natural history study, and that will be the comparator for the confirmatory study.

是的，裡面有幾件事。因此，我們對能夠行走和不能行走的患者都進行了治療，並且看到了相似的表現水平。因此，EMERGENE 分析將從功能角度分別分析這兩個群體。這將是後續研究，即驗證性研究。但從表達層面來說，是的，我們會對兩者進行評估。就我們所比較的對象而言，我們有自己的旅程自然史研究，這將是驗證性研究的比較對象。

Yes, and just our history has shown that we get great expression across the continuum of disease from very young to very advanced.

是的，我們的歷史表明，從非常年輕到非常晚期的整個疾病過程中，我們都能得到很好的表達。

Gavin Clark-Gartner, Evercore.

加文·克拉克-加特納（Gavin Clark-Gartner），Evercore。

Hey, guys. Thanks for taking the question. I just wanted to focus on terminal value. So if I look at the outer year of consensus estimates, take 2033, I see about $2.2 billion in US ELEVIDYS sales. So that implies about 850 to 900 treated patients annually. Maybe, Dallan, you could just remind us specifically what you're seeing on US incidents. But more broadly, do you believe this consensus estimate is plausible? And maybe explain what has to happen for ELEVIDYS to reach and stay into that range into the next decade. Thank you.

嘿，大家好。感謝您回答這個問題。我只是想專注於最終價值。因此，如果我看一下普遍預期的外部年份，以 2033 年為例，我看到美國 ELEVIDYS 的銷售額約為 22 億美元。這意味著每年約有 850 到 900 名患者接受治療。也許，達蘭，你可以具體提醒我們你在美國事件中看到的情況。但更廣泛地說，您是否認為這個一致估計是合理的？或許可以解釋一下 ELEVIDYS 要達到並在未來十年保持這一範圍需要做些什麼。謝謝。

This is the -- the incident population is sort of looking at what the terminal incident population would be. In the US, the incident population will be somewhere in the low 400s, 420, 430. So you can do the math on that. And then, of course, we'll have the PMOs on top of it because the PMOs are enduring as well. And then by that point, although this might be speculative until we've solved it, we will likely have solved the redosing issue by the 2030s as well. So you'll have to add to that concept as well.

這就是——事件人口正在研究終端事件人口是多少。在美國，發病人口將在 400 出頭、420 ​​或 430 左右。所以你可以對此進行計算。當然，我們會將 PMO 置於其之上，因為 PMO 也是持久的。然後到那時，雖然在我們解決這個問題之前這可能只是推測，但我們很可能也會在 2030 年代解決重複使用問題。所以你也必須加入這個概念。

And of course, if you're talking about the terminal value on ELEVIDYS, it's not the terminal value on the company, as you know. If all goes well, we'll be launching three limb-girdle programs in the next literally every year for the next few years. We have new ones coming. We have new INDs. And if all goes well, we'll be launching FSHD in 2028. We'll be launching DM1 in 2029. Both of those are multi-billion-dollar peak-year sales opportunities. Obviously, the terminal value will be significant on the organization as a whole.

當然，如果您談論的是 ELEVIDYS 的最終價值，那麼它並不是公司的最終價值，正如您所知。如果一切順利的話，我們將在接下來的幾年裡每年推出三個肢帶計畫。我們又有新產品了。我們有新的 IND。如果一切順利的話，我們將在 2028 年推出 FSHD。我們將於 2029 年推出 DM1。這兩個都是數十億美元的高峰年銷售機會。顯然，最終價值對整個組織來說具有重要意義。

Sami Corwin, William Blair.

薩米·科溫、威廉·布萊爾。

Great. Thank you. Congrats on the progress, and thanks for taking my questions. I was curious how you're thinking about the evolution of your gross margins in 2025 and 2026 as ELEVIDYS begins to compromise a larger percentage of your revenue. And then a quick question on your FSHD program. Is this DUX4 assay new, or was it developed in-house, and could you just elaborate on it a little more? Thank you.

偉大的。謝謝。恭喜您取得進展，並感謝您回答我的問題。我很好奇，當 ELEVIDYS 開始佔據您更大比例的收入時，您如何看待 2025 年和 2026 年毛利率的變化。然後是關於您的 FSHD 程式的一個快速問題。這個 DUX4 檢測方法是新的嗎？還是內部開發的？能否詳細說明一下？謝謝。

Sure. I'll turn the evolution question to Ian, and then Louise can touch on the DUX4 assay issue.

當然。我將把進化問題轉給伊恩，然後路易絲可以談談 DUX4 分析問題。

Yes, so from a margin perspective, what we've said is that, obviously, we've already expensed the inventory already, and so that's starting to come off. And then over time, as we continue to treat heavier patients, you're going to see the margin go down. We expect it to be in the kind of high 70s as we continue to penetrate into the non-ambulant patient population. But as Doug said, as we continue to work on our suspension manufacturing, process, we expect that to start getting much significantly higher, trending towards 90%. So as we're treating the heavier population, we expect the margins to improve in the '27 timeframe.

是的，從利潤率的角度來看，我們所說的是，顯然我們已經將庫存費用化了，所以這開始減少了。隨著時間的推移，隨著我們繼續治療體重較重的患者，你會看到利潤率下降。隨著我們繼續滲透到無法行走的患者群體中，我們預計這一數字將達到 70 多歲。但正如道格所說，隨著我們繼續致力於懸吊製造工藝，我們預計這一比例將開始大幅上升，趨向於 90%。因此，隨著我們治療的人群越來越重，我們預計利潤率將在 27 年內提高。

And just on the DUX4 assay, this is a quantitative assay developed by Arrowhead. As we've mentioned, DUX4 is expressed at low levels, somewhere around the incidence of one in 1,000 nuclei, so it's difficult to measure, but Arrowhead has successfully done that. And so this is an assay that we'll be onboarding as well, but we're excited to see it because it's not something that's been able to be accomplished in the field.

僅在 DUX4 檢測中，這是 Arrowhead 開發的定量檢測方法。正如我們所提到的，DUX4 的表達水平較低，大約每 1,000 個細胞核中就有 1 個出現，因此很難測量，但 Arrowhead 已成功做到了這一點。因此，這也是我們將要進行的分析，但我們很高興看到它，因為它不是在該領域能夠完成的事情。

Mitchell Kapoor, H.C. Wainwright.

米切爾·卡普爾，H.C.溫賴特。

Good afternoon. This is Dan on for Mitch. Thanks for taking our question. Congratulations on the positive cash flow for the year. So payers we've spoken with have said that they have had patients experience two rounds of appeals and were ultimately denied. Would an IRO denial not count as permanent denial? And if not, what qualifies as a permanent denial? Thank you.

午安.這是丹代替米奇上場。感謝您回答我們的問題。恭喜您今年的現金流為正。我們採訪過的付款人表示，他們的患者已經經歷了兩輪上訴，但最終都被拒絕了。IRO 拒絕不算永久拒絕嗎？如果不是，什麼情況才算永久拒絕？謝謝。

I'm not sure. I know that you did -- I'm not sure who you spoke to. I know you did a survey. One was actually not a payer. It was PBM, and I think you might have talked to one today. We have no kids that have been permanently denied therapy. I'm not suggesting it will always be 100%. Our PMOs trend above 90% over the last eight years, but we're seeing even a better response than the PMOs of the ELEVIDYS, so we're doing quite well. We don't have any kid that's been permanently denied therapy. Some are still in process, but no kid's been permanently denied therapy.

我不知道。我知道你說過——但我不確定你和誰談過。我知道你做過調查。其中一人其實並不是付款人。它是 PBM，我想你今天可能已經和它談過了。我們沒有孩子被永久拒絕接受治療。我並不是說它會一直維持 100%。在過去八年中，我們的 PMO 趨勢超過 90%，但我們看到的回應甚至比 ELEVIDYS 的 PMO 還要好，所以我們做得相當不錯。我們沒有任何孩子被永久拒絕接受治療。有些治療仍在進行中，但沒有孩子被永久拒絕治療。

Yes, Dan, we've dosed patients in the plan that you're talking about. We're not going to provide you any more details other than that.

是的，丹，我們已經按照你所說的計劃給病人用藥了。除此之外，我們不會向您提供任何其他詳細資訊。

Uy Ear, Mizuho.

尤伊·厄爾，瑞穗。

Hi, guys. This is Leo on for Uy. Thanks for taking our question. Could you provide some detail on the learnings from the pre-BLA meeting with the FDA on 9003 and how these learnings might be applied to the follow-on limb girdle programs? And then also, based on the recent changes within the agency, how do you think FDA interactions might change going forward? Thanks.

嗨，大家好。這是 Leo 為 Uy 所做的表演。感謝您回答我們的問題。您能否詳細介紹一下與 FDA 就 9003 舉行的 BLA 前會議的經驗教訓，以及這些經驗教訓如何應用於後續的肢帶計劃？此外，根據該機構最近的變化，您認為 FDA 的互動未來會發生怎樣的變化？謝謝。

So Louise, do you want to touch on the sort of pre-BLA discussions broadly?

那麼，路易絲，你想廣泛地談談 BLA 之前的討論嗎？

Yes, broadly, it was an extremely positive meeting, I think, across all of the different things that you would speak to in terms of the non-clinical data. The clinical plan for the clinical trial was endorsed, CMC in terms of our plan. So that was endorsed. Using beta-sarcoglycan as a surrogate biomarker for accelerated approval was endorsed.

是的，總的來說，我認為這是一次非常積極的會議，涉及了您在非臨床數據方面談到的所有不同事項。臨床試驗的臨床計劃已獲得批准，CMC 符合我們的計劃。因此，我們同意了。使用 β-肌聚醣作為替代生物標記以獲得加速批准已獲得批准。

So it was a very positive meeting that the agency certainly understands in ultra-rare diseases the challenges that are faced with that in terms of trial design, in terms of manufacturing. So we've already set the stage for the other follow-on sarcoglycan, so I think it bodes well for the entire platform. And we were certainly encouraged by it and certainly seen a change in the agency over the last two years and really promising. And that's something we look forward to as we complete the other two sarcoglycans as well.

因此，這是一次非常積極的會議，該機構肯定了解極罕見疾病在試驗設計和製造方面所面臨的挑戰。因此，我們已經為其他後續的肌聚醣做好了準備，所以我認為這對整個平台來說是個好兆頭。我們確實為此感到鼓舞，也確實看到該機構在過去兩年裡發生了變化，而且確實很有希望。這也是我們期待的事情，因為我們也完成了另外兩種肌聚醣的研究。

I do want to say, we are very proud of -- I am very proud of the work that Louise and her team have done working with the agency to evolve and modernize the approach to ultra-rare disease, and it's paid dividends for the limb girdle programs, not only 9003B and beyond. But I also want to give credit to the division itself. I have to say, the center director, [Dr. Marks], has had a vision for being thoughtful and modernizing the division and comporting with modern science and not creating barriers that make it unviable to treat ultra rare disease patients.

我想說的是，我們非常自豪——我為路易絲和她的團隊與該機構合作開展的工作感到非常自豪，他們共同努力發展和現代化了治療極其罕見疾病的方法，並且它不僅為 9003B 及其他項目，也為肢帶項目帶來了回報。但我也想對該部門本身表示讚賞。我必須說，中心主任 [Dr.馬克斯博士一直致力於深思熟慮，使該部門現代化，與現代科學相適應，並且不會製造障礙，使治療極其罕見的疾病患者變得不可行。

And I think that [Dr. Verdun], the Head of OTP, has done really an exceptional job of taking that vision and operationalizing it in ways that we're seeing and I think others are seeing as well, which is as we think about Rare Disease Day coming up on Friday, and I think we said some really brilliant thoughts on that. I mean, it's just poignant that I think we're moving in the right direction as a people to be able to bring a better life to patients with ultra-rare disease. And I give an enormous kudos to OTP for playing their part in that.

我認為 [Dr. OTP 負責人凡爾登 (Verdun) 確實出色地完成了這一願景，並以我們看到的和我認為其他人也看到的方式將其付諸實踐，也就是當我們想到週五即將到來的罕見病日時，我認為我們對此提出了一些非常精彩的想法。我的意思是，我認為我們正在朝著正確的方向前進，能夠為患有極其罕見疾病的患者帶來更好的生活，這真是令人感動。我對 OTP 在這方面所扮演的角色表示崇高的敬意。

Salveen Richter, Goldman Sachs. Your line is open.

薩爾文·里克特，高盛。您的線路已開通。

Thanks for taking our questions. This is Tommie for Salveen. Just overall, what do you see as Arrowhead's differentiation in terms of kind of their chemistry or structure versus some other RNA approaches in DM1 and FSHD? And on ELEVIDYS, is there flexibility to expand upon existing infusion center capacity, including, for instance, staffing needs? Thank you.

感謝您回答我們的問題。這是 Salveen 的 Tommie。總的來說，您認為 Arrowhead 在化學或結構方面與 DM1 和 FSHD 中的其他 RNA 方法有何不同？ELEVIDYS 是否可以靈活地擴展現有的輸液中心容量，例如人員配備需求？謝謝。

I'm going to turn the first part of the question to Louise. Let me briefly talk about ELEVIDYS. So what we really need to understand is that this is a very detailed cadence from beginning to get a kid dosed. So site capacity isn't alone the issue. People often say, well, what if you found a way to have more infusion days? That would be great. But then you need infusion nurses. Then you need follow ups. Then you need more single-case contracts. Then you need to think about, back in the finance function, what are the credit limits associated with all of that?

我要把問題的第一部分轉給路易絲。我先簡單說一下ELEVIDYS。所以我們真正需要了解的是，從開始給孩子服藥到服藥，這是一個非常詳細的節奏。因此，場地容量並不是唯一的問題。人們常說，如果你找到一種方法來增加輸液天數會怎麼樣？那太好了。但你需要輸液護士。那你需要跟進。那你需要更多的單案合約。然後您需要思考一下，回到財務功能中，與所有這些相關的信用額度是多少？

So it really is just a certain cadence. The thing that I'm excited about is this team has unlocked this opportunity and really become experts in that cadence, and that's why we're able to provide guidance of $3 billion for the year, because the team's figured it out. But the cadence is the cadence. And I don't think the opportunity for dramatically changing that exists. And with that, I'll turn the first part of the question over to Louise.

所以它實際上只是一種特定的節奏。令我興奮的是，這個團隊已經抓住了這個機會，並真正成為這個節奏的專家，這就是為什麼我們能夠為今年提供 30 億美元的指導，因為團隊已經找到了答案。但節奏就是節奏。我不認為有徹底改變這一現狀的機會。現在，我將把問題的第一部分交給路易絲。

Yes, on Arrowhead, I think the comprehensive answer is that Arrowhead is focused on every aspect of the construct, and so we like the diligence of their approach. I would like to call out their targeting lag as being a differentiator. Because getting to the right tissue in the case of muscle for FSHD and DM1 using the alpha -- the beta-targeting ligand that we use, the same one with myo-AAV, for example, we know that it works well in muscle, so that's a differentiator.

是的，關於 Arrowhead，我認為全面的答案是 Arrowhead 專注於結構的每個方面，因此我們喜歡他們方法的勤奮。我想指出他們的目標定位滯後是一個差異化因素。因為在 FSHD 和 DM1 的肌肉情況下，使用 alpha——我們使用的 beta 靶向配體（與 myo-AAV 相同）可以到達正確的組織，例如，我們知道它在肌肉中效果很好，所以這是一個區別因素。

But they focus on the design from the siRNA, from the targeting ligands, from every aspect of the construct. And so we just like their comprehensive, diligent approach. It's something that we model with gene therapy, for example. And so I think it's all of the above, but we certainly appreciate their targeting ligands for the various tissues.

但他們專注於從 siRNA、從靶向配體以及從構建體的各個方面進行設計。因此，我們喜歡他們全面、勤奮的態度。例如，這是我們用基因療法建模的。所以我認為以上都是原因，但我們當然很欣賞它們針對各種組織的標靶配體。

Thank you. And that concludes today's Q&A session. I would like to turn the call back over to Doug Ingram for closing remarks. Please go ahead.

謝謝。今天的問答環節到此結束。我想將電話轉回給道格·英格拉姆 (Doug Ingram) 來做最後發言。請繼續。

Well, thank you, everyone, for your questions this evening. We appreciate them. We've had a really tremendous 2024 and a great Q4 of 2024. And as we track into 2025, things are going very well. A couple things. We're obviously going to continue to drive this launch of ELEVIDYS, and the team's done a really great job on that, and I think they will continue to do that. We're going to continue to focus on our PMOs and ensuring that patients are benefiting from our PMOs over this year.

好吧，謝謝大家今晚的提問。我們感謝他們。我們度過了非常輝煌的 2024 年，並且度過了非常出色的 2024 年第四季。當我們展望 2025 年時，一切進展順利。有幾件事。我們顯然會繼續推動 ELEVIDYS 的推出，團隊在這方面做得非常出色，我認為他們會繼續這樣做。我們將繼續關注我們的 PMO，並確保患者今年能夠從我們的 PMO 中受益。

We have more milestones to read out in 2025 than any other time in our history, and so I look forward to updating folks across this year as we move forward with our limb-girdles as an example, and we get the FSHD data and we get the DM1 data, and we keep driving as an organization. So thank you all very much and have a wonderful evening.

2025 年我們要宣讀的里程碑比我們歷史上任何時期都要多，因此，我期待著在今年向大家通報最新情況，因為我們將以肢帶為例向前邁進，我們將獲得 FSHD 數據，我們將獲得 DM1 數據，我們將繼續作為一個組織前進。非常感謝大家，祝大家有個美好的夜晚。

This concludes today's program and thank you for joining this conference call. You may all disconnect.

今天的節目到此結束，感謝您參加本次電話會議。你們都可以斷開連線。