Sarepta Therapeutics Inc (SRPT) 2022 Q4 法說會逐字稿

Good afternoon, and welcome to the Sarepta Therapeutics Fourth Quarter and Full Year 2022 Earnings Call. (Operator Instructions) As a reminder, today's conference call is being recorded.

下午好，歡迎參加 Sarepta Therapeutics 2022 年第四季和全年財報電話會議。 （操作員說明）提醒一下，今天的電話會議正在錄音。

At this time, I will turn the call over to Mary Jenkins, Associate Director, Investor Relations. Please go ahead.

此時，我會將電話轉給投資者關係副總監瑪麗‧詹金斯 (Mary Jenkins)。請繼續。

Thank you, Valerie, and thank you all for joining today's call. Earlier this afternoon, we released our financial results for the fourth quarter and full year 2022. The press release is available on our website at sarepta.com, and our 10-K was filed with the Securities and Exchange Commission this afternoon. 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.

謝謝瓦萊麗，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2022 年第四季度和全年的財務業績。新聞稿可在我們的網站sarepta.com 上獲取，我們的10-K 已於今天下午向美國證券交易委員會提交。今天加入我們電話會議的有 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。

I'd like to note that during this call, we will be making a number of forward-looking statements. Please take a moment to review our slide on the webcast which contains our forward-looking statements. 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.

我想指出的是，在這次電話會議中，我們將做出一些前瞻性聲明。請花點時間回顧我們在網路廣播中的幻燈片，其中包含我們的前瞻性陳述。這些前瞻性陳述涉及風險和不確定性，其中許多風險和不確定性超出了 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、營運結果和交易價格產生重大不利影響。

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on Form 10-K filed with the SEC as well as the company's other SEC filings. 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.

有關適用風險和不確定性的詳細說明，我們建議您查看該公司向 SEC 提交的最新 10-K 表格年度報告以及該公司向 SEC 提交的其他文件。該公司不承擔任何義務根據後續事件或情況公開更新其前瞻性陳述，包括今天提供的任何財務預測。

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

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

Thank you, Mary. Good afternoon, everybody, and thank you for joining Sarepta Therapeutics for our fourth quarter and full year 2022 financial results conference call. 2023 may be the most eventful year in Sarepta's event-filled history. Our Biologics License Application, or BLA, for our gene therapy SRP-9001 for Duchenne muscular dystrophy will be a significant bellwether moment: first, for the Duchenne families who are waiting without the luxury of patients for a therapy that might arrest the brutal decline associated with this disease; and next for the promise of gene therapy as a class to deliver meaningful improvements in the lives of patients with rare degenerative diseases, not at some distant vanishing points in the future but in time to do good now.

謝謝你，瑪麗。大家下午好，感謝您參加 Sarepta Therapeutics 參加我們的 2022 年第四季和全年財務業績電話會議。 2023 年可能是 Sarepta 歷史上最重要的一年。我們用於治療杜氏肌肉營養不良症的基因療法SRP-9001 的生物製劑許可申請(BLA) 將是一個重要的領頭羊時刻：首先，對於那些正在等待沒有足夠患者的治療方法的杜氏肌肉營養不良症家庭來說，這種療法可能會阻止相關的嚴重衰退。患有這種疾病；其次，基因療法有望為罕見退化性疾病患者的生活帶來有意義的改善，不是在未來某個遙遠的消失點，而是及時做好事。

And given the keen interest in the 9001 BLA submission, I'm going to comment on the BLA review before I move to quarterly and yearly performance. As you will recall, in the fall of last year, we submitted our BLA for SRP-9001 to treat ambulant Duchenne patients. And in the fourth quarter, the FDA accepted the BLA for filing, granted 9001 priority review and set May 29, 2023, as our action date.

鑑於人們對 9001 BLA 提交的濃厚興趣，我將在討論季度和年度績效之前對 BLA 審查發表評論。您還記得，去年秋天，我們提交了 SRP-9001 的 BLA，用於治療流動性 Duchenne 患者。第四季度，FDA 接受了 BLA 備案，給予 9001 優先審查，並將 2023 年 5 月 29 日定為我們的行動日期。

We have been diligently prosecuting the BLA. We have by now completed a very productive mid-cycle review with the division. At the mid-cycle, the division requested additional CMC information, and we have by now provided answers to all of those questions. The division formally informed us as well at the mid-cycle meeting that they see no significant safety issues that have been identified. And the division has determined that there is no need for an advisory committee meeting for SRP-9001 BLA.

我們一直在努力起訴 BLA。到目前為止，我們已經與該部門完成了非常有成效的中期審查。在周期中期，該部門要求提供額外的 CMC 信息，我們現在已經提供了所有這些問題的答案。該部門也在周期中期會議上正式通知我們，他們認為沒有發現任何重大安全問題。該部門已確定無需就 SRP-9001 BLA 召開諮詢委員會會議。

As you may have read, FDA has announced that the Office of Tissues and Advanced Therapies, or OTAT, is being reorganized and a new super office entitled the Office of Therapeutic Products, or OTP, is being established. The goal is to improve alignment, increase resources and capacity and enhance expertise.

您可能已經讀到，FDA 宣布正在重組組織和先進療法辦公室 (OTAT)，並建立一個名為治療產品辦公室 (OTP) 的新超級辦公室。目標是改善一致性、增加資源和能力以及增強專業知識。

A couple of thoughts. First, Sarepta is delighted by the establishment of OTP. We believe it will enhance reviews and serve Dr. Peter Mark's publicly stated vision to lean in and accelerate the transformative potential of cell and gene therapy. Second, FDA has stated that the reorganization and establishment of OTP will not impact any timelines. And we can confirm that we have not experienced any delay or disruption of any kind as a result of this reorganization. Indeed, we see the establishment of OTP as unequivocally positive and a potentially great benefit to patients.

有幾點想法。首先，Sarepta 對 OTP 的成立感到高興。我們相信它將加強審查並服務於 Peter Mark 博士公開宣稱的願景，即依靠並加速細胞和基因治療的變革潛力。其次，FDA表示OTP的重組和成立不會影響任何時間表。我們可以確認，我們沒有因此次重組而經歷任何形式的延誤或中斷。事實上，我們認為 OTP 的建立無疑是正面的，並且對患者有潛在的巨大好處。

So going forward, we're going to focus on the following: first, answering any remaining questions the FDA may have on the file; second, preparing for and managing pre-approval inspections. The FDA has already scheduled 3 pre-approval manufacturing inspections and along with our manufacturing partner, Catalent, we are preparing to make those inspections a success; third, building inventory for launch; and fourth, of course, completing our launch readiness.

因此，展望未來，我們將重點關注以下事項：首先，回答 FDA 可能對該文件提出的任何剩餘問題；二是審批前檢查準備和管理。 FDA 已安排了 3 項批准前生產檢查，我們正與我們的生產合作夥伴 Catalent 一起準備使這些檢查取得成功；第三，建立上市庫存；第四，當然是完成我們的發射準備工作。

Now I'll provided an update on the mid-cycle today as there has been a significant amount of interest in whether the division would see the need for an advisory committee. However, from here, we will be focusing on prosecuting the BLA, and we'll provide an update on or after the 9001 action date.

現在，我將在今天提供中期週期的最新情況，因為人們對該部門是否需要成立諮詢委員會非常感興趣。不過，從現在開始，我們將重點放在起訴 BLA，並將在 9001 行動日期或之後提供最新資訊。

Moving now to performance. As one ponders how Sarepta may execute the launch of 9001, if given that opportunity, I would ask you to consider the team's consistent performance quarter-over-quarter and year-over-year, serving the Duchenne community with our 3 approved therapies: EXONDYS, VYONDYS and AMONDYS. From an end-market perspective, 2022 was yet another year where our cross-functional team, including commercial, medical affairs, patient services, access and reimbursement and manufacturing and supply chain, to name a few, executed together and delivered for our patients.

現在轉向性能。當人們思考 Sarepta 如何執行 9001 的推出時，如果有機會，我想請您考慮該團隊季度環比和同比的一致表現，透過我們的 3 種批准的療法為 Duchenne 社區服務：EXONDYS 、VYONDYS 和 AMONDYS。從終端市場的角度來看，2022 年是我們的跨職能團隊（包括商業、醫療事務、患者服務、准入和報銷以及製造和供應鏈等）共同執行並為我們的患者提供服務的另一年。

Fourth quarter total revenue stood at $258.4 million, while net product revenue came in at $235.9 million. That is a 32% increase over the same quarter of the prior year. Full year total revenue came in at $933 million, and net product revenue for the year came in at $843.8 million, representing a 38% year-over-year increase. For the last 5 years, we have grown at a consistent 40% compounded annual growth rate, all of which performance comes from serving the Duchenne community and none of which comes from price increases.

第四季總營收為 2.584 億美元，產品淨收入為 2.359 億美元。比去年同期成長 32%。全年總收入為 9.33 億美元，全年產品淨收入為 8.438 億美元，較去年同期成長 38%。在過去的 5 年裡，我們一直以 40% 的複合年增長率成長，所有這些業績都來自於為 Duchenne 社區提供服務，而沒有任何一項來自於價格上漲。

Now as we announced at the JPMorgan conference in January, for 2023, our net product revenue guidance for our 3 currently approved PMO therapies, excluding the impact of a 9001 approval, is $925 million or greater.

現在，正如我們在 1 月的摩根大通會議上宣布的那樣，到 2023 年，我們目前批准的 3 種 PMO 療法的淨產品收入指導（不包括 9001 批准的影響）為 9.25 億美元或更多。

Moving back to SRP-9001 for a moment. We are commencing studies this year to ensure that we have the broadest label for SRP-9001 as is possible, consistent with the science. We have already commenced our study to limit mutation-related exclusions. Further, in the coming months, we will be starting a study in the non-ambulant population called ENVISION or Study 303. And we will commence 2 separate studies with alternative approaches to removing preexisting antibodies to make SRP-9001 available to rh74 NAV-positive patients as well.

暫時回到 SRP-9001。我們今年開始研究，以確保我們擁有盡可能廣泛的 SRP-9001 標籤，且符合科學。我們已經開始研究以限制與突變相關的排除。此外，在接下來的幾個月中，我們將在非流動人群中啟動一項名為ENVISION 或研究303 的研究。我們將開始兩項單獨的研究，採用替代方法去除預先存在的抗體，以使SRP-9001 可用於rh74 NAV 陽性患者也是如此。

Additionally, we are making significant progress with our limb-girdle pipeline as Dr. Louise Rodino-Klapac will discuss in a moment as she provides updates across our research and development activities.

此外，我們的肢帶產品線正在取得重大進展，Louise Rodino-Klapac 博士稍後將討論我們的研發活動的最新情況。

On the RNA platform, we will complete enrollment of the MOMENTUM study this quarter. MOMENTUM, as you know, is our study for our first next-generation peptide-conjugated PMO, also known as PPMO, next SRP-5051 designed to treat Duchenne patients who are exon 51 amenable. MOMENTUM will read out later this year, and if successful, we will discuss a filing for SRP-5051 with the neurology division this year.

在RNA平台上，我們將於本季完成MOMENTUM研究的註冊。如您所知，MOMENTUM 是我們針對第一個新一代勝肽綴合 PMO（也稱為 PPMO）的研究，即下一個 SRP-5051，旨在治療外顯子 51 適合的 Duchenne 患者。 MOMENTUM 將於今年稍後公佈，如果成功，我們將在今年與神經病學部門討論 SRP-5051 的申請。

I am proud of the progress that we have made these last 6 years. And yet it pales in comparison to the good that we can do in the coming years together. We have the potential to improve the lives of countless patients and to greatly reward those who have been committed to and invested in this mission. Indeed, the opportunity in front of us is breathtaking. To realize that opportunity, we will need laser-focused and tenacious execution, but as Sarepta has proven time and again, this is a team that knows how to execute.

我為我們過去六年所取得的進步感到自豪。然而，與我們在未來幾年共同努力所做的善事相比，這顯得相形見絀。我們有潛力改善無數患者的生活，並大大獎勵那些致力於並投資於這項使命的人們。確實，擺在我們面前的機會是令人驚嘆的。為了實現這個機會，我們需要高度專注和頑強的執行力，但正如 Sarepta 一次又一次證明的那樣，這是一支知道如何執行的團隊。

And with that, let me turn the call over to our Head of R&D and Chief Scientific Officer, Dr. Louise Rodino-Klapac. Louise?

接下來，讓我將電話轉給我們的研發主管兼首席科學官 Louise Rodino-Klapac 博士。路易絲？

Thanks, Doug. The accomplishments of 2022 and the opportunities before us in 2023 and beyond speak to the promise of science to fundamentally impact and change the lives of patients around the world. My deepest gratitude to our R&D colleagues across RNA, gene therapy and gene editing for their extraordinary work to get us where we are today. And where we are today represents an important moment in genetic medicine and an important moment for Sarepta.

謝謝，道格。 2022 年的成就以及 2023 年及以後我們面臨的機會表明科學有望從根本上影響和改變世界各地患者的生活。我對 RNA、基因治療和基因編輯領域的研發同事表示最深切的感謝，他們的出色工作使我們取得了今天的成就。我們今天所處的位置代表基因醫學的重要時刻，也是 Sarepta 的重要時刻。

Firstly, we were thrilled to learn last November that the FDA accepted our BLA for review via the accelerated approval pathway for our lead gene therapy candidate, SRP-9001. This decision was based on our ability to show a robust expression of the SRP-9001 dystrophin protein, a shortened functional version of dystrophin serving as a surrogate endpoint reasonably likely to predict clinical benefit in patients with Duchenne muscular dystrophy.

首先，我們很高興去年 11 月獲悉 FDA 透過我們的領先基因治療候選藥物 SRP-9001 的加速審批途徑接受了我們的 BLA 審查。這項決定是基於我們能夠顯示SRP-9001 肌肉營養​​不良蛋白的穩健表達，這是肌營養不良蛋白的一種縮短的功能版本，可作為替代終點，合理地預測杜氏肌肉營養不良症患者的臨床獲益。

Duchenne results from a mutation in the gene that codes for dystrophin. Dystrophin acts as a shock absorber in our muscle, attaching to the muscle membranes and distributing force as we move, thereby protecting our muscles from damage. Individuals with Duchenne lack dystrophin, and as a result, their muscles become progressively worse. Our goal with SRP-9001 is to change the course of the fatal disease by treating the underlying cause of Duchenne with a onetime gene therapy that delivers functional dystrophin to the muscle.

杜興氏症是由編碼肌肉營養不良蛋白的基因突變引起的。肌肉營養不良蛋白在我們的肌肉中充當減震器，附著在肌肉膜上並在我們移動時分散力量，從而保護我們的肌肉免受損傷。患有杜興氏症的人缺乏肌肉營養不良蛋白，因此他們的肌肉變得越來越差。我們對 SRP-9001 的目標是透過向肌肉輸送功能性肌肉營養不良蛋白的一次性基因療法來治療 Duchenne 的根本原因，從而改變這種致命疾病的病程。

Based on well-established precedent, the FDA has approved 4 therapies to date using short and functional dystrophin as a surrogate endpoint. Further, Sarepta has generated the most compelling preclinical biomarker and clinical functional results to date. What is particularly interesting about SRP-9001, but not completely surprising based on the strong scientific underpinning of our construct, is at the early SRP-9001 data provided read-through to our positive clinical experience with the therapy.

根據既定的先例，FDA 迄今已批准了 4 種使用短功能性肌肉營養不良蛋白作為替代終點的療法。此外，Sarepta 還產生了迄今為止最引人注目的臨床前生物標記和臨床功能結果。 SRP-9001 特別有趣的地方在於早期 SRP-9001 數據為我們提供了積極的治療臨床經驗，但基於我們建立的強大科學基礎，這並不完全令人驚訝。

Over the course of 10-plus years, I along with Dr. Jerry Mendell built researched and tested numerous constructs to determine what areas of the protein were functional and protective. We eventually identified an optimal gene cassette that will be able to retain protective and functional elements and fit easily into AAV, thereby enabling its delivery. This gene cassette was packaged into our AAV of choice, rh74, and we chose MHCK7 as our promoter.

在十多年的時間裡，我和 Jerry Mendell 博士一起研究和測試了許多構建體，以確定蛋白質的哪些區域具有功能性和保護性。我們最終確定了一種最佳基因盒，該基因盒將能夠保留保護性和功能性元件，並輕鬆融入 AAV，從而實現其輸送。這個基因盒被包裝到我們選擇的 AAV rh74 中，並且我們選擇 MHCK7 作為我們的啟動子。

We are pleased with the early data, which showed robust expression across skeletal, diaphragm and cardiac muscle. And as a result of that expression as well as the dystrophin protein demonstrating functional benefits, we saw significant restoration of function of the clinical target dose.

我們對早期數據感到滿意，這些數據顯示出骨骼、膈肌和心肌的強烈表達。由於此表達以及肌肉營養不良蛋白顯示出功能益處，我們看到臨床目標劑量的功能顯著恢復。

To understand the significance of the results and their importance in the context of a viable therapy for Duchenne, it's critical to understand the dystrophin-associated protein complex, or DAPC. DAPC is a collection of proteins to which dystrophin attaches. In its absence, these proteins disassemble. Individuals with Duchenne don't have a functioning dystrophin-associated protein complex.

為了了解這些結果的意義及其在 Duchenne 可行療法中的重要性，了解肌肉營養不良蛋白相關蛋白質複合物 (DAPC) 至關重要。 DAPC 是肌肉營養不良蛋白所附著的蛋白質的集合。如果沒有它，這些蛋白質就會分解。杜興氏症患者沒有功能性肌肉營養不良蛋白相關蛋白質複合物。

Understanding this, when we inserted a functional dystrophin protein, we saw up-regulation of the DAPC in animal models. More specifically, we saw an almost 1-for-1 up-regulation of DAPC when there was expression of the SRP-9001 dystrophin, confirming the protective properties of the protein. Further, we saw significant reduction increase in kinase or CK levels. CK is an enzyme associated with muscle damage. The reduction in CK provided further proof that SRP-9001 was reasonably likely to predict clinical benefit.

了解這一點後，當我們插入功能性肌肉營養不良蛋白時，我們發現動物模型中 DAPC 的上調。更具體地說，當 SRP-9001 肌肉營養​​不良蛋白表現時，我們發現 DAPC 幾乎呈現一對一上調，證實了該蛋白質的保護特性。此外，我們發現激酶或 CK 水平顯著降低。 CK 是一種與肌肉損傷相關的酵素。 CK 的降低進一步證明 SRP-9001 有理由預測臨床效益。

The strength of this early work gave us the confidence and conviction to advance SRP-9001 into the clinic. Since 2018 and across multiple studies, we've dosed over 140 patients, more than any other gene therapy being developed for Duchenne, and the clinical results have surpassed our expectations. SRP-9001 demonstrated robust expression of dystrophin far above what literature would suggest is necessary to be protective of muscle. All of it is properly localized at the muscle membrane or sarcolemma where it acts as a shock absorber.

這項早期工作的力量給了我們將 SRP-9001 推進臨床的信心和信念。自 2018 年以來，在多項研究中，我們已經對 140 多名患者進行了給藥，比任何其他針對 Duchenne 開發的基因療法都要多，而且臨床結果超出了我們的預期。 SRP-9001 表現出抗肌肉營養不良蛋白的強勁表達，遠高於文獻顯示的保護肌肉所需的表達水平。這一切都正確地定位在肌肉膜或肌膜上，並起到避震器的作用。

We also developed a cell-based potency assay that shows that SRP-9001 is active, functional and protective at the muscle membrane. And as in the animal models with robust expression of SRP-9001, we saw significant reduction in CK. Finally, expression of SRP-9001 in patients leads to up-regulation of the DAPC.

我們還開發了一種基於細胞的效力測定，顯示 SRP-9001 對肌肉膜具有活性、功能性和保護性。正如在 SRP-9001 強表達的動物模型中一樣，我們看到 CK 顯著降低。最後，患者中 SRP-9001 的表達導致 DAPC 上調。

In addition to all of this compelling evidence, we are also able to show functional benefit versus what natural history would predict. NSAA, or the North Star Ambulatory Assessment, is our primary functional endpoint. We were able to show benefit across 1-, 2- and 4-year time points. In summary, based on the totality of the data, we were able to provide objective evidence that SRP-9001 qualifies as a disease-modifying agent and at the levels of dystrophin expressed based on vast clinical evidence and experience are reasonably likely to predict clinical benefit in patients with Duchenne.

除了所有這些令人信服的證據之外，我們還能夠展示與自然史預測相比的功能益處。 NSAA（即北極星動態評估）是我們的主要功能終點。我們能夠在 1 年、2 年和 4 年的時間點上顯示出好處。總之，根據全部數據，我們能夠提供客觀證據，證明 SRP-9001 有資格作為疾病緩解劑，並且基於大量臨床證據和經驗表達的肌肉營養不良蛋白水平很可能預測臨床獲益Duchenne 患者。

As Doug mentioned in his opening comments, since the agency is not planning on holding an advisory committee for SRP-9001, the team is focused on responding to any remaining requests. As a reminder and because we are in active review with the FDA, we do not anticipate publicly sharing additional data cuts from the SRP-9001 studies leading up to the 2023 regulatory milestones and the EMBARK data readout, which is on track for the fourth quarter of this year.

正如 Doug 在開場白中所提到的，由於該機構不打算為 SRP-9001 成立諮詢委員會，因此該團隊專注於回應任何剩餘的請求。提醒一下，由於我們正在與 FDA 進行積極審查，因此我們預計不會公開分享 SRP-9001 研究中導致 2023 年監管里程碑和 EMBARK 數據讀出的額外數據削減，該數據讀出預計將在第四季度進行今年的。

Continuing now with our gene therapy platform and our limb-girdle muscular dystrophy programs. We were pleased to announce earlier this month the first patient was dosed in study SRP-9003-102, also known as VOYAGENE. VOYAGENE is a Phase I study evaluating SRP-9003 for the treatment of limb-girdle muscular dystrophy type 2E in ambulant adult patients and non-ambulant patients using clinical process SRP-9003 material. Combined with positive expression and functional data shared from our initial study, SRP-9003-101, we believe the data from VOYAGENE will give us insights into a broader patient population as we finalize plans for a global Phase III study using commercially representative process material that we intend to begin later this year.

現在繼續我們的基因治療平台和肢帶型肌肉營養不良症計畫。我們很高興地宣布本月早些時候，第一位患者在研究 SRP-9003-102（也稱為 VOYAGENE）中接受了給藥。 VOYAGENE 是一項 I 期研究，使用臨床過程 SRP-9003 材料評估 SRP-9003 對可行走的成人患者和非可行走的患者治療 2E 型肢帶型肌肉營養不良症的效果。結合我們最初研究SRP-9003-101 中分享的陽性表達和功能數據，我們相信VOYAGENE 的數據將使我們深入了解更廣泛的患者群體，因為我們最終確定了使用具有商業代表性的工藝材料的全球III期研究計劃，我們打算在今年稍後開始。

In addition, we plan to commence a systemic pilot study for our SRP-6004 dual-vector rh74-mediated gene therapy to treat LGMD2B characterized by the absence of the protein dysferlin. We believe our gene therapy platform is well suited to generate medicines for the limb-girdle muscular dystrophies. Our work in this area continues on pace and represents a key priority for Sarepta.

此外，我們計劃針對 SRP-6004 雙載體 rh74 介導的基因療法進行系統性試驗研究，以治療以缺乏 Dysferlin 蛋白為特徵的 LGMD2B。我們相信我們的基因治療平台非常適合生產肢帶型肌肉營養不良症藥物。我們在這一領域的工作仍在繼續進行，並且是 Sarepta 的首要任務。

Turning now to our RNA platform. MOMENTUM study for our next-generation PPMO SRP-5051 is ongoing, and we remain on track to announce data towards the back half of 2023. Further, we were pleased to complete enrollment in the ESSENCE trial, our post-marketing requirement for golodirsen and casimersen. And lastly, we are making good progress with our MIS51ON study, and it continues on pace.

現在轉向我們的 RNA 平台。我們下一代 PPMO SRP-5051 的動量研究正在進行中，我們仍有望在 2023 年下半年公佈數據。此外，我們很高興完成 ESSENCE 試驗的註冊，這是我們對 golodirsen 的上市後要求，卡西默森。最後，我們的 MIS51ON 研究取得了良好進展，並且仍在繼續進行中。

In closing, I want to take a moment to recognize Rare Disease Day and the over 300 million individuals around the world living with a rare disease. This is my life's work and I along with my colleagues at Sarepta will not rest until we do our part in advancing the science and developing the therapies for waiting patients. I would also like to say thank you to the patients and their families whose generously give of their time and commitment to our trials. We could not undertake this important work without you.

最後，我想花點時間向罕見疾病日以及全世界 3 億多人患有罕見疾病表示敬意。這是我一生的工作，我和 Sarepta 的同事們不會休息，直到我們盡自己的一份力量來推進科學發展並為等待的患者開發治療方法。我也要向病人及其家屬表示感謝，他們慷慨地付出了時間並致力於我們的試驗。沒有您，我們就無法承擔這項重要的工作。

I will now turn the call over to Dallan for an update on our commercial activities. Dallan?

我現在將把電話轉給達蘭，以了解我們商業活動的最新情況。達蘭？

Thank you, Louise, and good afternoon. In 2022, the team delivered yet another year of strong double-digit growth across all 3 of our RNA-based PMO therapies. As Doug noted, our full year net product revenue was $843.8 million, which beat the upper end of our upwardly revised 2022 guidance of $825 million to $840 million. This represented more than $230 million in growth over 2021 and a growth rate that approached 40% year-over-year.

謝謝你，路易絲，下午好。 2022 年，該團隊的所有 3 種基於 RNA 的 PMO 療法又實現了兩位數的強勁成長。正如 Doug 指出的那樣，我們的全年淨產品收入為 8.438 億美元，超過了我們向上修訂的 2022 年指導值 8.25 億至 8.4 億美元的上限。這意味著 2021 年的成長超過 2.3 億美元，年成長率接近 40%。

I'll take a moment to highlight some of our full year 2022 achievements for our PMO franchise. The team started the year in a strong position by successfully navigating the beginning of the year insurance changes and reauthorizations. This led to a reauthorization rate in the low to mid-90s throughout 2022. This robust start, coupled with continued high adherence rates and strong ex U.S. revenues, served as the foundation for full year net product revenue growth of approximately 13% generated with EXONDYS 51 and net product revenue of roughly $511 million.

我將花點時間重點介紹我們的 PMO 業務在 2022 年全年取得的一些成就。該團隊成功地應對了年初的保險變更和重新授權，從而在今年伊始處於有利地位。這導致整個 2022 年的重新授權率處於 90 年代中期。這種強勁的開端，加上持續的高遵守率和強勁的美國以外收入，為 EXONDYS 全年淨產品收入增長約 13% 奠定了基礎51，產品淨收入約5.11 億美元。

For VYONDYS 53, we ended 2022 in a strong leadership position and market share. VYONDYS 53 exceeded $100 million in revenues, ending the year with $117.4 million in total net product revenue and over 30% growth compared to 2021. And last but not least, the team's continued execution on AMONDYS 45 produced exceptional growth in 2022 of over 200% with total net product revenue of $214.8 million.

對於 VYONDYS 53，我們在 2022 年結束時保持了強大的領導地位和市場份額。 VYONDYS 53 的收入超過1 億美元，年底產品淨收入總額為1.174 億美元，與2021 年相比增長超過30%。最後但並非最不重要的一點是，該團隊對AMONDYS 45 的持續執行在2022 年實現了超過200% 的超常成長產品淨收入總額為 2.148 億美元。

As we've noted in previous calls, our ex U.S. growth continues to accelerate and represented roughly 11% of our overall net product revenues in 2022. Ex U.S. net product revenue was $96.3 million for the full year of 2022. Our performance in 2022 is the result of a highly committed and effective team focused on serving the nearly 30% of patients [RNA-based via] therapies with the level of urgency that Duchenne requires.

正如我們在先前的電話會議中所指出的，我們在美國以外的成長持續加速，約占我們2022 年整體產品淨收入的11%。2022 年全年，美國以外的產品淨收入為9,630 萬美元。我們2022 年的表現為這是一支高度敬業且高效的團隊的成果，該團隊專注於為近 30% 的患者提供[基於 RNA 的] 療法，並滿足 Duchenne 所需的緊迫程度。

Turning now to our performance in the fourth quarter of 2022. We ended the year on a high note with net product revenues of $235.9 million. Once again, the team executed and grew the RNA-based PMO business by more than 30% over the fourth quarter of 2021 and 13% over the prior quarter.

現在談談我們 2022 年第四季的業績。我們以 2.359 億美元的淨產品收入高調結束了這一年。該團隊再次執行並成長了基於 RNA 的 PMO 業務，較 2021 年第四季成長了 30% 以上，較上一季成長了 13%。

I'll now outline individual net product revenues for the fourth quarter of 2022 for our 3 approved RNA-based PMO therapies. For EXONDYS 51, net product revenue of $146 million represented roughly 22% growth over Q4 of '21. VYONDYS 53 fourth quarter 2022 net product revenue totaled $28.5 million, representing roughly 15% growth versus the fourth quarter of 2021. And finally, AMONDYS 45 net product revenue was $61.4 million in Q4 of 2022, representing nearly 80% growth versus the fourth quarter of 2021.

現在，我將概述 2022 年第四季我們 3 種已批准的基於 RNA 的 PMO 療法的各個淨產品收入。對於 EXONDYS 51，產品淨收入為 1.46 億美元，較 21 年第四季成長約 22%。 VYONDYS 53 2022 年第四季產品淨收入總計2,850 萬美元，較2021 年第四季成長約15%。最後，AMONDYS 45 2022 年第四季產品淨收入為6,140 萬美元，較2021 年第四季成長近80%。2021 年。

As the business evolved and grew throughout 2022, we see more variability in our quarter-over-quarter revenue numbers due mainly to ex U.S. ordering patterns. We have observed lumpy quarter-to-quarter fluctuations and seasonality with our ex U.S. orders. We expect this trend to continue going forward.

隨著 2022 年業務的發展和成長，我們發現季度環比收入數據有更多變化，這主要是由於美國以外的訂購模式所致。我們觀察到美國前訂單的季度波動和季節性波動。我們預計這一趨勢將繼續向前發展。

For example, sales in the fourth quarter of 2022 were robust due to very strong ex U.S. sales of $36.9 million. This strength allowed us to far exceed expectations for the quarter. However, we do not expect the same dynamic to persist into the first quarter of 2023. We want to provide you this level of visibility to help you model our revenues for the year. Our forecast anticipates this dynamic, and it is reflected in our 2023 PMO net product revenue guidance of greater than $925 million, which we issued in January.

例如，由於美國以外地區的銷售額非常強勁，達到 3,690 萬美元，因此 2022 年第四季的銷售額非常強勁。這種優勢使我們遠遠超出了本季的預期。然而，我們預計同樣的動態不會持續到 2023 年第一季。我們希望為您提供這種程度的可見性，以幫助您對我們今年的收入進行建模。我們的預測預見了這種動態，並反映在我們 1 月發布的 2023 年 PMO 淨產品收入指引中，該指引將超過 9.25 億美元。

Despite the quarterly fluctuations, overall, we expect a strong year and are confident in our guidance. Again, I'm proud of what we accomplished in 2022. And most importantly, I'm grateful for our team's enduring commitment to the Duchenne community and the patients we serve. This commitment to operational excellence will serve us in the patient community well as we apply the lessons learned to the upcoming launch of SRP-9001.

儘管存在季度波動，但總體而言，我們預計今年會表現強勁，並對我們的指導充滿信心。我再次為我們在 2022 年所取得的成就感到自豪。最重要的是，我感謝我們的團隊對杜興社區和我們服務的患者的持久承諾。這種對卓越營運的承諾將為我們的患者社群服務，我們將學到的經驗教訓應用於即將推出的 SRP-9001。

In parallel with the team's execution of our existing business in 2022, the customer organization build for SRP-9001 is on track and nearly complete. Importantly, engagement with key gene therapy sites and U.S. payers is well underway. If SRP-9001 is approved, the team is once again prepared to demonstrate their capabilities and hard-fought expertise in our fourth launch into the Duchenne space with the first gene therapy to serve the patient community.

在團隊於 2022 年執行現有業務的同時，SRP-9001 的客戶組織建置也已步入正軌並接近完成。重要的是，與主要基因治療站點和美國付款人的接觸正在順利進行。如果 SRP-9001 獲得批准，團隊將再次準備好在我們第四次向 Duchenne 領域推出首個基因療法來為患者群體提供服務時，展示他們的能力和來之不易的專業知識。

And now I'll turn the call over to Ian Estepan for an update on our financials. Ian?

現在我將把電話轉給伊恩·埃斯特潘 (Ian Estepan)，以了解我們財務狀況的最新情況。伊恩？

Thanks, Dallan. Good afternoon all. This afternoon's financial results press release provided details for the fourth quarter and full year of 2022 on a non-GAAP basis as well as a GAAP basis. Please refer to the press release available on Sarepta's website for a full reconciliation of GAAP to non-GAAP financial results.

謝謝，達蘭。大家下午好。今天下午的財務業績新聞稿提供了按非公認會計原則和公認會計原則計算的 2022 年第四季度和全年的詳細資訊。請參閱 Sarepta 網站上的新聞稿，以了解 GAAP 與非 GAAP 財務表現的全面對帳。

For the 3 months ended December 31, 2022, the company recorded total revenues of $258.4 million, which consists primarily of net product revenues and collaboration revenues compared to revenues of $201.5 million for the same period of 2021, an increase of $56.9 million. Net product revenue for the fourth quarter of 2022 from our PMO exon skipping franchise was $235.9 million compared to $178.7 million for the same period of 2021. The increase in net product revenue primarily reflects increasing demand for our products.

截至2022年12月31日的三個月，該公司的總收入為2.584億美元，主要包括淨產品收入和協作收入，與2021年同期的收入2.015億美元相比，增加了5,690萬美元。 2022 年第四季度，我們的 PMO 外顯子跳躍特許經營權的產品淨收入為 2.359 億美元，而 2021 年同期為 1.787 億美元。產品淨收入的成長主要反映了對我們產品的需求不斷增長。

For the quarters ended December 31, 2022 and 2021, we recognized $22.5 million and $22.7 million of collaboration and other revenues, respectively, which primarily relates to our collaboration arrangement with Roche. The reimbursable co-development costs under the Roche agreement totaled $51.7 million for the fourth quarter of 2022 compared to $29.7 million for the same period of 2021.

在截至2022年12月31日和2021年12月31日的季度中，我們分別確認了2,250萬美元和2,270萬美元的合作和其他收入，這主要與我們與羅氏的合作安排有關。 2022 年第四季羅氏協議下的可報銷共同開發費用總計 5,170 萬美元，而 2021 年同期為 2,970 萬美元。

On a GAAP basis, we reported a net loss of $109.2 million or $1.24 and $122 million or $1.42 per basic and diluted share for the fourth quarter of 2022 and 2021, respectively. We reported a non-GAAP net loss of $46.5 million or $0.53 per basic and diluted share in the fourth quarter of 2022 compared to a non-GAAP net loss of $66 million or $0.77 per basic and diluted share in the fourth quarter of 2021.

根據 GAAP 基礎，我們報告 2022 年第四季和 2021 年第四季的淨虧損分別為 1.092 億美元（即 1.24 美元）和 1.22 億美元（即每股基本股和稀釋股 1.42 美元）。我們報告2022 年第四季的非GAAP 淨虧損為4,650 萬美元，即每股基本股和稀釋股0.53 美元，而2021 年第四季的非GAAP 淨虧損為6,600 萬美元，即每股基本股和稀釋股0.77 美元。

In the fourth quarter of 2022, we recorded approximately $30.8 million in cost of sales compared to $31.7 million in the same period of 2021. The decrease in cost of sales is primarily due to write-off of certain batches of our products not meeting the quality specifications for the 3 months ended December 31, 2021, with no similar activity in the same period of 2022 and a decrease in our royalty payments during the 3 months ended December 31, 2022, due to changes in our BioMarin royalty terms.

2022年第四季度，我們的銷售成本約為3,080萬美元，而2021年同期為3,170萬美元。銷售成本下降主要是由於我們某些批次的品質不合格產品被註銷截至2021 年12 月31 日止3 個月的規格，2022 年同期沒有類似活動，並且由於我們的BioMarin 特許權使用費條款發生變化，截至2022 年12 月31 日止3 個月我們的特許權使用費有所減少。

On a GAAP basis, we recorded $213.8 million and $197.3 million in R&D expenses for the fourth quarter of 2022 and 2021, respectively, a year-over-year increase of $16.5 million. The increase is primarily due to increases in upfront and milestone expenses. On a non-GAAP basis, R&D expenses were $186.8 million for the fourth quarter of 2022 compared to $175.5 million for the same period of 2021, an increase of $11.3 million.

以公認會計原則計算，2022 年第四季和 2021 年第四季的研發費用分別為 2.138 億美元和 1.973 億美元，比去年同期增加 1,650 萬美元。這一增長主要是由於前期費用和里程碑費用的增加。以非公認會計原則計算，2022年第四季的研發費用為1.868億美元，而2021年同期的研發費用為1.755億美元，增加了1,130萬美元。

Now turning to SG&A. On a GAAP basis, we recorded approximately $120.5 million and $78.1 million of expenses for the fourth quarters of 2022 and 2021, respectively, an increase of $42.4 million. The increase was driven primarily by an increase in stock-based compensation expense primarily due to additional expense recognized through the CEO grant modification agreement executed in 2022.

現在轉向SG&A。根據公認會計原則，我們在 2022 年和 2021 年第四季的支出分別約為 1.205 億美元和 7,810 萬美元，增加了 4,240 萬美元。這一增長主要是由於股票薪酬費用的增加，這主要是由於透過 2022 年執行的執行長撥款修改協議確認的額外費用。

On a non-GAAP basis, the SG&A expenses were $86.6 million for the fourth quarter of 2022 compared to $60.1 million for the same period of 2021, an increase of $26.5 million. On a GAAP basis, we recorded $5.5 million in other income net for the fourth quarter of 2022 compared to $16.1 million in other expense net for the same period of 2021. The change is primarily due to an increase in interest income due to the investment mix of our investment portfolio as well as the reduction of interest expense incurred as a result of the repayment of our December 2019 term loan for the 3 months ended December 31, 2022. We expect that both SG&A and R&D expenses will be higher in 2023 as we build inventory and prepare for the launch of SRP-9001. The increases in expenses will however be partially offset by the growth in our revenue.

以非公認會計準則計算，2022 年第四季的銷售、管理及行政費用為 8,660 萬美元，而 2021 年同期為 6,010 萬美元，增加了 2,650 萬美元。根據公認會計原則，我們 2022 年第四季的其他收入淨額為 550 萬美元，而 2021 年同期的其他支出淨額為 1,610 萬美元。這項變更主要是由於投資組合導致利息收入增加我們的投資組合以及因償還截至2022 年12 月31 日止3 個月的2019 年12 月定期貸款而產生的利息費用減少。我們預計2023 年SG&A 和研發費用都會更高，因為我們建立庫存並為SRP-9001的上市做好準備。然而，費用的增加將被我們收入的成長部分抵消。

We had approximately $2 billion in cash, cash equivalents and long-term restricted cash at December 31st. And we've made tremendous progress over the course of 2022, and this upcoming year has the potential to dwarf all that we have previously accomplished. I'm particularly pleased that we are well capitalized to execute on all of our plans that we've outlined today on the call.

截至 12 月 31 日，我們擁有約 20 億美元的現金、現金等價物和長期限制性現金。我們在 2022 年取得了巨大進展，即將到來的一年有可能使我們先前的成就相形見絀。我特別高興的是，我們有充足的資金來執行我們今天在電話會議上概述的所有計劃。

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

然後，我會將電話轉回道格進行問答。道格？

Thank you very much, Ian. Valerie, let's open up the lines for questions and answers.

非常感謝你，伊恩。瓦萊麗，讓我們開始提問和回答。

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

（操作員指令）我們的第一個問題來自摩根大通的 Anupam Rama。

Congrats on all the progress. I noticed in the press release and Doug, in your comments as well that the FDA noted no major safety concerns in the filing for 9001. Was there any commentary on the mid-cycle review on the external control arm and that analysis? If I remember correctly that, that was a prespecified analysis by the FDA? And then quickly on manufacturing. Doug, in your opening comments, did you say that the site inspections have been scheduled?

祝賀所有的進展。我在新聞稿和 Doug 以及您的評論中註意到 FDA 指出 9001 的申請中沒有重大安全問題。對於外部控制臂的中期審查和分析有任何評論嗎？如果我沒記錯的話，那是 FDA 預先指定的分析？然後快速進行製造。道格，在您的開場白中，您是否說過現場檢查已經安排好了？

Yes. Thank you very much for your questions, Anupam. So first, as you noted, on safety, the -- at the mid-cycle review of the division explicitly in writing and informed us that they saw no -- they see no significant safety issues with the filing with 9001. That would -- that should come as a little surprise, I suppose, to those who know our profile, but it was to say the least, gratifying and encouraging that the FDA saw it the way we saw it.

是的。非常感謝您提出問題，阿努帕姆。因此，首先，正如您所指出的，在安全方面，在該部門的中期審查中明確以書面形式通知我們，他們沒有看到 9001 備案沒有重大安全問題。這將——我想，對於那些了解我們概況的人來說，這應該有點驚訝，但至少可以說，FDA 以我們的方式看待它，這令人欣慰和鼓舞。

As -- I'm not going to get into a lot of detail on the review beyond what I've already said. I will say on the clinical side of things, we're in an active review. As you know, there are lots of questions and analyses that we've done and questions we've answered. I can at least say at the mid-cycle review, the division did not identify any significant issues or material deficiencies with the clinical data set at all. So that's where we are as of the mid-cycle. And then finally, as it relates to the site inspections, yes, all of the manufacturing inspections have been scheduled.

因為——除了我已經說過的內容之外，我不會透露有關該評論的更多細節。我想說的是，在臨床方面，我們正在進行積極的審查。如您所知，我們提出了許多問題、進行了分析，也回答了許多問題。我至少可以說，在周期中期審查中，該部門根本沒有發現臨床資料集有任何重大問題或重大缺陷。這就是我們在周期中期所處的情況。最後，由於涉及現場檢查，是的，所有製造檢查都已安排。

(Operator Instructions) Our next question comes from the line of Brian Abrahams of RBC.

（操作員說明）我們的下一個問題來自 RBC 的 Brian Abrahams。

Congrats on all the progress. Is there anything more you can say, at least more broadly, on the nature of the CMC dialogue in preparation for the manufacturing inspections? And I guess I'm curious, your level of manufacturing confidence and overall comfort that there'd be sufficient time post these inspections to rectify any minor issues that might come up and still have sufficient time to build supply. And then just maybe quickly, I'm wondering also if the FDA provided any specific reasons as to why no Adcom would be required. I know sometimes they give specifics on that.

祝賀所有的進展。關於為製造檢查做準備的 CMC 對話的性質，您還有什麼可以說的嗎？至少更廣泛地說？我想我很好奇，你們的製造信心水平和整體舒適度，在這些檢查後有足夠的時間來糾正可能出現的任何小問題，並且仍然有足夠的時間來建立供應。然後也許很快，我也想知道 FDA 是否提供了任何具體原因來說明為什麼不需要 Adcom。我知道有時他們會詳細說明這一點。

Yes. Thank you very much for that, Brian. First on CMC, there -- I think as everyone knows, and certainly we've talked about before with respect to BLAs and I think, in particular, with gene therapy, the CMC part of the submission in the Q&A is some of the most significant ones. As I mentioned before, as it relates to all of the questions that the agencies had, we were current and have answered all of their questions. So we feel like we're in very good shape there. We feel like we're in very good shape with those questions.

是的。非常感謝你，布萊恩。首先是關於 CMC，我想眾所周知，當然我們之前已經討論過 BLA，我認為，特別是在基因治療方面，問答中提交的 CMC 部分是最重要的部分。重要的。正如我之前提到的，由於這涉及到各機構提出的所有問題，我們及時了解並回答了他們的所有問題。所以我們感覺我們在那裡的狀態非常好。我們覺得我們對這些問題的回答非常好。

As it relates to the timing of the pre-approval inspections themselves, yes, we're very, very confident in the timing. So we -- I'm not going to go into detail on the schedules, but we're confident about the schedules and the timing and the ability to adapt ourselves. We don't, as we sit here today, have any reason to believe that there would be a delay in our PDUFA date for this or any other reason right now, at least as of now.

由於這關係到批准前檢查本身的時間安排，是的，我們對時間安排非常非常有信心。所以我們——我不會詳細說明日程安排，但我們對日程安排、時間安排以及適應自己的能力充滿信心。當我們今天坐在這裡時，我們沒有任何理由相信我們的 PDUFA 日期會因為這個或任何其他原因而延遲，至少到目前為止是這樣。

And then as it relates to the decision that there wasn't a need for an advisory committee, there really isn't any additional color other than we had the mid-cycle. They confirmed they saw no safety issues -- significant safety issues with the program. They didn't identify any significant clinical issues or major deficiencies and then determine that they didn't need an Adcom. That's where we are right now.

然後，由於它涉及不需要諮詢委員會的決定，因此除了我們的中期週期之外，實際上沒有任何其他顏色。他們確認沒有發現安全問題——該計劃存在重大安全問題。他們沒有發現任何重大的臨床問題或重大缺陷，然後確定他們不需要 Adcom。這就是我們現在所處的情況。

(Operator Instructions) Our next question comes from the line of Colin Bristow of UBS.

（操作員指令）我們的下一個問題來自瑞銀集團的 Colin Bristow。

Congrats on all the progress. Another one on the Adcom or lack thereof. You -- previously, you had stated that your -- one of the focal points of the outcome you're anticipating would be the surrogacy of truncated dystrophin. Did FDA comment on its comfort around this? Or is this something that's part of an ongoing dialogue that is just part of the review process? And then maybe just on the manufacturing supply side, if you are approved on the PDUFA, can you just talk about the number of patients you expect to be able to supply at launch and how this will build over time?

祝賀所有的進展。 Adcom 上的另一項或缺乏。您—之前，您曾說過，您所預期的結果的焦點之一將是截短的肌肉營養不良蛋白的替代品。 FDA 對此是否感到滿意？或者這是正在進行的對話的一部分，只是審查過程的一部分？然後，也許只是在製造供應方面，如果您獲得了 PDUFA 的批准，您能否談談您期望在啟動時能夠供應的患者數量以及隨著時間的推移，這將如何建立？

Sure. First, I would say that entire discussion, that's kind of the fundamental issue in the review is the use of short and functional dystrophin is reasonably likely to predict a clinical benefit. As it relates to the Adcom comments, we see this -- we obviously see the decision to -- Adcom as a positive. We had a very productive mid-cycle review. We're not going to speculate on what this means from the probability of success.

當然。首先，我想說的是，整個討論的基本問題是，使用短的功能性肌肉營養不良蛋白很可能預測臨床益處。由於它與 Adcom 的評論相關，我們認為這一點——我們顯然認為 Adcom 的決定是積極的。我們進行了一次非常有成效的中期審查。我們不會根據成功的機率來推測這意味著什麼。

But what we would say is that given that we know that there are no significant safety issues, that there isn't going to be an Adcom. We can then spend our time really focusing on answering any remaining questions, preparing for and executing our pre-approval inspections and doing that successfully, making sure that we're launch-ready and building inventory for launch.

但我們想說的是，鑑於我們知道不存在重大安全問題，因此不會有 Adcom。然後，我們可以花時間真正專注於回答任何剩餘的問題，準備和執行我們的批准前檢查並成功完成，確保我們做好啟動準備並建立啟動庫存。

We haven't given exact patient numbers as it relates to manufacturing, but what we've said, and we stand by it, is that our goal is to launch this therapy and serve this community without back orders with all patients getting the therapy as soon as they are able to get it from an access and reimbursement perspective. And we want to be in a position to do that, and we will be.

我們沒有給出與製造相關的確切患者人數，但我們已經說過，並且我們堅持這一點，我們的目標是推出這種療法並為這個社區服務，而不需要延期交貨，所有患者都可以接受該療法一旦他們能夠從訪問和報銷的角度獲得它。我們希望能夠做到這一點，而且我們一定會做到。

Our next question comes from Matthew Harrison of Morgan Stanley.

我們的下一個問題來自摩根士丹利的馬修·哈里森。

I guess 2 just follow-ups for me. I know we've touched on many of the major issues here. But first, just on manufacturing. Can you just talk, to the extent you can, in a bit more detail? Are these multiple facilities or just lines in the same facility that are being inspected? How comprehensive is this inspection versus maybe what you were expecting or thought you might see?

我想 2 對我來說只是後續。我知道我們已經觸及了這裡的許多主要問題。但首先，只是在製造方面。您能否盡可能詳細地談談？正在檢查的是多個設施還是同一設施中的生產線？與您期望或認為可能看到的內容相比，此檢查的全面程度如何？

And then just secondly, on the inventory and the supply that you are building now. Is there any chance or any reason that the supply you've started to build now could not be used? Could you just talk about supply you have now versus supply you're continuing to build.

其次，關於您現在正在建立的庫存和供應。您現在開始建造的供應是否有可能或有任何原因無法使用？您能否談談您現在擁有的供應與您正在繼續建造的供應。

Yes. So first of all, on the inspections, there are 3 separate facilities. They are exactly as we anticipated. In fact, I would say none of the questions that have been posed and none of the inspection notices that we've received have been at all a surprise. We've been very well prepared for them. So we're in good shape there. From an inventory and supply perspective, we're on track. And no, we don't think there's any significant risk that inventory that we build will be able to be used commercially. So we're tracking there.

是的。首先，在檢查方面，有 3 個獨立的設施。它們與我們的預期完全一樣。事實上，我想說，我們所提出的所有問題以及我們收到的所有檢查通知都一點也不令人意外。我們已經為他們做好了充分的準備。所以我們在那裡狀況良好。從庫存和供應的角度來看，我們正步入正軌。不，我們不認為我們建立的庫存能夠用於商業用途有任何重大風險。所以我們正在追蹤那裡。

A lot of work to do as an organization. Site readiness is a significant issue. Building inventory is a significant issue. Completing this review and satisfying any remaining questions or comments or analysis the FDA is extremely important to us, and we need to focus on that as well. But the team is very, very focused on all of this, and we're working overtime to ensure that we have a successful BLA review.

作為一個組織，有很多工作要做。現場準備情況是一個重要議題。建立庫存是一個重要議題。完成本次審查並滿足 FDA 的任何剩餘問題、評論或分析對我們來說極為重要，我們也需要關注這一點。但團隊非常非常專注於所有這一切，我們正在加班以確保 BLA 審核成功。

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

我們的下一個問題來自美國銀行的 Tazeen Ahmad。

Can you give us a sense of how the doctors' offices or facilities that the patients would have to go to might have to make any adjustments? Is the infrastructure already there for high demand for the physicians to be able to meet the potential volume demand that we would expect upon an approval? I don't know what your checks are telling you, but I'd love to hear some color on that.

您能否讓我們了解病人必須去的醫師辦公室或設施可能需要做出哪些調整？基礎設施是否已經存在，對醫生的高需求能夠滿足我們在批准後預期的潛在數量需求？我不知道你的支票告訴你什麼，但我很想聽聽對此的一些看法。

Yes. I mean, I think the first thing I'll say that we start in a very good place, probably in a very privileged place because of SMA and because of Zolgensma. So a significant percentage of the experts -- neuromuscular experts that would be treating patients with Duchenne muscular dystrophy with 9001 have previous experience with Zolgensma. So we're starting with at a good place.

是的。我的意思是，我想我要說的第一件事是，我們從一個非常好的地方開始，可能是因為 SMA 和 Zolgensma 而在一個非常優越的地方。因此，在使用 9001 治療杜氏肌肉營養不良症患者的專家（神經肌肉專家）中，有相當大比例有使用 Zolgensma 的經驗。所以我們從一個好的地方開始。

Now certainly, I'm going to turn this over to Dallan to provide any additional color that I missed, but I would say there's certainly a lot of work still that we need to do to make sure that very specific to 9001, the sites are up, ready to go, properly educated and ready to make this therapy a success.

當然，現在我會將其交給 Dallan，以提供我錯過的任何其他顏色，但我想說，我們仍然需要做很多工作，以確保非常具體地針對 9001，這些站點是站起來，準備出發，接受適當的教育，並準備好使這種療法成功。

Our goal at launch is to have about 50 of those sites up and running. That would serve just about 80% of the Duchenne community, and then over time to be up as high as about 70 sites over the course of the next couple of quarters beyond that. But Dallan, what have I missed there?

我們發佈時的目標是讓其中大約 50 個網站正常運作。這將為大約 80% 的 Duchenne 社區提供服務，然後隨著時間的推移，在接下來的幾個季度中，服務站點數量將增加到約 70 個。但達蘭，我錯過了什麼？

No, I think you covered it, Doug. And I think these sites are really at the forefront of precision genetic medicine. And they have a lot on their plates, but they're absolutely heroic and they are -- we're working already with some -- with whatever we can do from an educational standpoint prior to approval that is compliant and appropriate. So the team is out there today engaging with the sites. Every site is different. But they are -- it's -- these are centers of excellence that are already treating these patients, the Duchenne muscular dystrophy patients. So they'll be ready to go, and we'll be ready to go.

不，我想你已經涵蓋了，道格。我認為這些網站確實處於精準基因醫學的最前線。他們有很多事情要做，但他們絕對是英雄，而且他們——我們已經在與一些人合作——在獲得批准之前，從教育的角度來看，我們能做的都是合規且適當的。因此，該團隊今天正在與這些網站進行接觸。每個網站都不同。但他們是——確實是——這些卓越中心已經在治療這些患者，即杜氏肌肉營養不良症患者。所以他們會準備出發，我們也會準備出發。

Our next question comes from the line of Robert Finke of Guggenheim.

我們的下一個問題來自古根漢的羅伯特芬克。

This is Robert on for Debjit. How quickly can Sarepta reimbursement agreements in place following approval in the race to launch?

這是羅伯特為德布吉特配音。在啟動競賽獲得批准後，Sarepta 報銷協議能多快到位？

I'll turn this over to Dallan as well. The short answer is that we're going to be ready to go on day 1. It doesn't mean kids are going to get infused on day 1. There's a process here, the access and reimbursement process, and having to get tested for neutralizing antibodies and the policies have to get finalized. But the team is already doing an enormous amount of work with not only sites but payers right now so that we're in a position to begin to serve the community day 1 post approval, assuming that we're fortunate and get approved. Dallan?

我也會把這個交給達蘭。簡而言之，我們將在第一天做好準備。這並不意味著孩子們會在第一天就接受輸注。這裡有一個流程，即訪問和報銷流程，並且必須接受測試中和抗體和政策必須最終確定。但該團隊現在不僅與網站，而且還與付款人進行了大量工作，以便我們能夠在批准後的第一天開始為社區提供服務，假設我們很幸運並獲得批准。達蘭？

Yes. Yes, we'll be ready in terms of day 1. And we're already engaging with payers. And so I think we're going to do everything we can do to accelerate that for eligible patients on day 1 and learn the lessons from past launches.

是的。是的，我們會在第一天就做好準備。而且我們已經在與付款人接觸。因此，我認為我們將盡一切努力在第一天為符合條件的患者加速這一進程，並吸取過去推出的經驗教訓。

One thing just to add to that -- I think one thing just to add to that is that you guys have good precedent on what you've seen in terms of our launches for our PMO exon skipping franchise. And obviously, to Doug's and Dallan's point, it takes time to get patients on therapy and through the access and reimbursement system. And obviously, there's state Medicaid and getting through the drug utilization review board process, right?

需要補充的一件事是——我認為補充的一件事是，你們在我們推出 PMO 外顯子跳躍特許經營方面已經看到了很好的先例。顯然，就道格和達倫的觀點而言，讓患者接受治療並透過存取和報銷系統需要時間。顯然，有國家醫療補助並通過藥物利用審查委員會程序，對吧？

So it is going to take a couple of quarters for patients to work through, and you've seen that before. But then once we really work through those reimbursement steps, I think you're going to see very, very strong uptake.

因此，患者需要幾個季度的時間才能恢復正常，而且您以前已經看到過這一點。但一旦我們真正完成這些報銷步驟，我想你會看到非常非常強烈的採用。

Our next question comes from the line of Gena Wang of Barclays.

我們的下一個問題來自巴克萊銀行的 Gena Wang。

I have 2 quick questions. Doug, you mentioned that there are still remaining questions from the FDA. What are the natures of these remaining questions? And do you expect late-cycle review will be mainly focusing on these questions and no new questions remaining? And the second question is regarding the 3 sites. Do any of these 3 sites have established commercial experience with iCELLis manufacturing?

我有兩個簡單的問題。道格，您提到 FDA 仍然存在一些問題。這些剩餘問題的性質是什麼？您是否預計後期審查將主要集中在這些問題上，而不會留下新的問題？第二個問題是關於這三個站點的。這 3 個站點中是否有任何一個已建立 iCELLis 製造的商業經驗？

Well, there's not a lot -- there's not a ton of history. I'll answer the last question first. I remind you that what we're doing is not a first is nearly a first. So you're not going to find a lot of organizations around the world that are going to have an enormous amount of experience with commercial iCELLis unless they happen to be Novartis.

嗯，沒有太多——沒有太多歷史。我先回答最後一個問題。我提醒您，我們正在做的事情不是第一次，也幾乎是第一次。因此，您不會在世界各地找到很多在商業 iCELLis 方面擁有大量經驗的組織，除非它們碰巧是諾華。

What I will say is -- so when we're in an active review, one of the things I tried to make the point of in my script is that we provided detail about the mid-cycle review, frankly, because there was this significant interest in whether we were having an advisory committee or not. We're now in the active review itself. It's an ongoing dialogue and questions and answers.

我要說的是——所以，當我們進行積極的審查時，我試圖在腳本中強調的一件事是，坦率地說，我們提供了有關中期審查的詳細信息，因為有這個重要的內容對我們是否有諮詢委員會有興趣。我們現在正在進行積極的審查。這是一個持續的對話和問答。

And in respect of that discussion and dialogue with the agency item, I'm not going to go into a ton of detail along the way. There will be a late-cycle review, and then we'll see where we are. The inspections will be completed. And then if all goes well, of course, you'll have an answer certainly by May 29. And we hope it's a positive one. We certainly think the patients deserve it.

關於與機構項目的討論和對話，我不會在過程中詳細介紹大量細節。我們將進行後期週期審查，然後我們將了解我們的進展。檢查將完成。當然，如果一切順利，您肯定會在 5 月 29 日之前得到答案。我們希望這是一個積極的答案。我們當然認為患者應得的。

The line of Ritu Baral of Cowen.

考恩的瑞圖·巴拉爾 (Ritu Baral) 系。

Doug, just back to the Adcom for a second. When FDA put in their minutes, they were going to have an Adcom, and now they're saying they don't. It sounds like they had a question around the biomarker that at least they figured out that they can answer on their own at this point.

道格，請回到 Adcom。當 FDA 提交會議記錄時，他們本來打算設立 Adcom，但現在他們說沒有。聽起來他們對生物標記有疑問，至少他們發現現在可以自己回答。

Does that revolve around any additional data sets or analysis around the ongoing or follow-up for 102 or 103 that they've requested that you've submitted? Or is it really just sort of questions as you've discussed? And then just a quick one on CMC. The plants, the Harmon plant and the 2 others, have you done -- completed mark inspections at all of them? Are you inspection-ready?

這是否圍繞著他們要求您提交的 102 或 103 正在進行或後續的任何其他資料集或分析？或者這真的只是您所討論的問題嗎？然後簡單介紹一下 CMC。這些工廠，哈蒙工廠和另外兩家工廠，您是否已經完成了所有這些工廠的標記檢查？您準備好接受檢查了嗎？

I'll answer the last question first. We are undoubtedly inspection-ready. We're just saying that. We're an organization that doesn't want to get surprised. So we are very much inspection-ready, and we've done all the work to put ourselves in a good position.

我先回答最後一個問題。毫無疑問，我們已做好檢查準備。我們只是這麼說。我們是一個不想感到驚訝的組織。因此，我們已經做好了檢查準備，並且已經完成了所有工作以使自己處於有利位置。

And that gets to the first -- to get the first -- the answer to the first question as well. So let me make sure I dispel and perhaps a misunderstanding. There wasn't a point in which the agency said to us in writing that you're going to have an Adcom and then later determined that we didn't need an Adcom. What did occur is that we said in connection with the BLA submission that we should all assume there's going to be an Adcom.

這就是第一個問題——得到第一個——第一個問題的答案。因此，讓我確保我消除了也許是一個誤解。該機構從未以書面形式向我們表示將擁有 Adcom，然後決定我們不需要 Adcom。確實發生的是，我們在提交 BLA 時說過，我們都應該假設將會有一個 Adcom。

And given an opportunity to do this the second time, I would do that exactly the same way a second time. Why? Because we needed to be ready for an advisory committee meeting. There's an enormous amount of work that goes into preparing for an advisory committee meeting, and we wanted to make sure that we had a mindset that had us in a good position. So that to the extent with the FDA, the division determined that it was wise or necessary to take external scientific advice that we'd be well prepared to participate in that Adcom. It was at the mid-cycle review, both in the written agenda and at the mid-cycle that the agency had -- has, for the first time, told us that they don't need an Adcom for this fall. So that's where we are with respect to that.

如果有機會第二次這樣做，我會以完全相同的方式第二次這樣做。為什麼？因為我們需要為諮詢委員會會議做好準備。準備諮詢委員會會議需要做大量的工作，我們希望確保我們的心態能讓我們處於有利的位置。因此，就 FDA 而言，該部門認為採納外部科學建議是明智的或必要的，我們將為參與該 Adcom 做好充分準備。正是在周期中期審查中，無論是書面議程還是周期中期，該機構首次告訴我們，他們今年秋天不需要 Adcom。這就是我們目前的情況。

(Operator Instructions) Our next question comes from the line of Joe Schwartz of SVB.

（操作員說明）我們的下一個問題來自 SVB 的 Joe Schwartz。

This is Beth on for Joe. We are wondering how much precedent you believe that EXONDYS' Accelerated Approval on the basis of dystrophin expression provides for 9001? Specifically, we're also wondering if you've been able to quantify the benefit of higher expression of a less complete micro-dystrophin compared to the lower expression of a more complete shortened dystrophin produced by exon skippers and if this is something that FDA has been considering throughout the review.

這是貝絲為喬代言的。我們想知道您認為 EXONDYS 基於肌肉營養不良蛋白表現的加速審批為 9001 提供了多少先例？具體來說，我們還想知道，與外顯子跳躍者產生的更完整的縮短型肌營養不良蛋白的較低表達相比，您是否能夠量化不太完整的微肌營養不良蛋白的較高表達的益處，以及這是否是FDA 擁有的東西在整個審查過程中一直在考慮。

Okay. Let me -- yes. Let me answer this question. Let me start with the second part of it then work to the first part of it because there's a fundamental misunderstanding, and it's understandable that you have the misunderstanding, but there's a misunderstanding of the underlying science when one assumes that the 9001 dystrophin, which is shortened, is sort of vastly shortened. And then the dystrophin that's made by EXONDYS or VYONDYS or AMONDYS or in the case of one of our competitors, Viltepso is very lightly edited. I think those who might imagine that the resulting dystrophin is one exon smaller. That isn't the case.

好的。讓我——是的。讓我來回答這個問題。讓我從第二部分開始，然後討論第一部分，因為存在一個根本性的誤解，你有這種誤解是可以理解的，但是當人們假設 9001 抗肌營養不良蛋白（即縮短了，有點大大縮短了。然後是由 EXONDYS 或 VYONDYS 或 AMONDYS 製造的抗肌營養不良蛋白，或者我們的競爭對手之一 Viltepso 製造的抗肌萎縮蛋白經過非常輕微的編輯。我想那些可能會想像由此產生的抗肌肉營養不良蛋白會小一個外顯子。事實並非如此。

The exon skipping occurs to place to restore the reading frame and allow the messenger RNA to make dystrophin. That reading frame is restored by the removal of that exon, and then it will naturally include also the removal of the parts of the gene that are associated with a mutation. And so for instance, the resulting dystrophin that you can make can be 40% shorter, smaller and yet very functional versus wild-type dystrophin. And that's the same case in natural history with Becker-like dystrophin. Becker dystrophin can be 50% or more shortened from full-length dystrophin.

發生外顯子跳躍以恢復閱讀框並允許信使 RNA 產生肌肉營養不良蛋白。透過刪除該外顯子來恢復該閱讀框，然後它自然也會刪除與突變相關的基因部分。例如，與野生型肌肉營養不良蛋白相比，您可以製造的肌肉營養不良蛋白可以縮短 40%、更小，但功能非常強大。這與自然史中貝克爾樣肌營養不良蛋白的情況相同。 Becker 肌營養不良蛋白可以比全長肌營養不良蛋白縮短 50% 或更多。

But so long as the reading frame is impacted, it can make dystrophin and it retains the right hinges and repeats and the right anchoring places, then it's functional. And that's the same thing with the 9001 dystrophin. This is a reasonable approximation of another -- any other Becker-like dystrophin, just like EXONDYS and AMONDYS and VYONDYS and Viltepso make.

但只要閱讀框架受到影響，它就可以產生肌肉營養不良蛋白，並保留正確的鉸鍊和重複以及正確的錨定位置，那麼它就可以發揮作用。 9001 肌肉營養​​不良蛋白也是如此。這是另一種的合理近似——任何其他貝克爾樣肌肉營養不良蛋白，就像 EXONDYS、AMONDYS、VYONDYS 和 Viltepso 製造的那樣。

And so that -- so from at least our perspective, the precedent for EXONDYS and VYONDYS and AMONDYS and Viltepso s very relevant here. Those therapies, while there's -- it's a different mechanism to get there because it's the use of exon skipping and [chronic] therapy, it is the same underlying concept, where what you're doing is providing to the patient a shortened but functional dystrophin which will protect them.

因此，至少從我們的角度來看，EXONDYS、VYONDYS、AMONDYS 和 Viltepso 的先例在這裡非常重要。這些療法雖然有不同的機制，因為它使用外顯子跳躍和[慢性]療法，但它的基本概念是相同的，你所做的就是為患者提供一種縮短但功能性的肌肉營養不良蛋白這將保護他們。

The biggest difference in addition to the mechanism of action being different, here, we're using a gene cassette to make the dystrophin. The biggest difference between these 2 is the amount of dystrophin we're making. We are making well over and multiples of an order of magnitude more dystrophin with our gene cassette than we can make with the PMOs today given the delivery limitations there.

除了作用機制不同之外，最大的差異是，我們使用基因盒來製造肌肉營養不良蛋白。這兩者之間最大的差異是我們產生的抗肌萎縮蛋白的量。考慮到那裡的遞送限制，我們用我們的基因盒生產的肌肉營養不良蛋白比我們今天用 PMO 生產的抗肌萎縮蛋白多出好幾個數量級。

And so a couple of things. And then kind of going on here, but so we say, number one, do I think there's a significant amount of precedent? I absolutely do. And I think there's an enormous amount of precedent for the idea that shortened functional dystrophin is the right kind of biomarker recently likely to predict clinical benefit. It's the right kind of upstream biomarker that we should all be looking for.

還有幾件事。然後這裡發生了一些事情，但我們說，第一，我認為有大量的先例嗎？我絕對願意。我認為有大量的先例表明，縮短的功能性肌肉營養不良蛋白是最近可能預測臨床益處的正確生物標記。這是我們都應該尋找的正確的上游生物標記。

And then second of all, there is not a significant difference in what's happening with 9001 and what happens with the PMOs other than the amount of dystrophin we're making.

其次，除了我們製造的抗肌萎縮蛋白的量之外，9001 和 PMO 中發生的情況沒有顯著差異。

And then one final thing I'll say as long as I'm on my soap box on this topic, one must remember that in nature, better dystrophin is the result of mutations. So the fact that these kids can make dystrophin -- kids or adults in the case of Becker, I think the average age -- average mortality rate of Beckers as well into the 60s on average, the fact they can make dystrophin is a happy accident. They still have a reading frame and they can make dystrophin.

最後我要說的一件事是，只要我在談論這個主題，人們就必須記住，在自然界中，更好的肌肉營養不良蛋白是突變的結果。因此，這些孩子可以產生肌肉營養不良蛋白——就貝克爾而言，無論是兒童還是成人，我認為貝克爾人的平均年齡——平均死亡率以及平均60多歲，他們可以產生肌肉營養不良蛋白的事實是一個幸福的意外。它們仍然具有閱讀框架並且可以產生肌肉營養不良蛋白。

9001 is different. Dr. Rodino-Klapac along with her partner, Dr. Jerry Mendell, worked for well over a decade to purpose build a construct that would be shortened, deliverable but functional. And in the end, they were able to not only do that, do it safely and do it in a way that creates a robust amount of expression, and our position is protection. So there's my long-winded answer to your very simple question.

9001則不同。 Rodino-Klapac 博士和她的合作夥伴 Jerry Mendell 博士花了十多年的時間，致力於建造一個縮短、可交付但功能齊全的結構。最終，他們不僅能夠做到這一點，而且能夠安全地做到這一點，並以創造大量表達的方式做到這一點，而我們的立場是保護。這就是我對你這個非常簡單的問題的冗長答案。

Our next question comes from the line of Judah Frommer of Credit Suisse.

我們的下一個問題來自瑞士信貸銀行的 Judah Frommer。

Just curious if EMBARK came up in any way in the mid-cycle communication and if so, in what context? And kind of same question for conversations, pre-commercialization conversations with payers. Is EMBARK coming up as a topic of conversation there?

只是好奇 EMBARK 是否在中期溝通中以任何方式出現，如果是，在什麼背景下出現？對於對話、商業化前與付款人的對話也有同樣的問題。 EMBARK 會成為那裡的話題嗎？

As it relates to the mid-cycle, there was no explicit discussion in the market on mid-cycle. On pre-commercial discussions, certainly, we discussed the entire program and it includes the confirmatory trial, EMBARK. So yes. Dallan, if there's anything I missed there, let me know.

由於涉及中周期，市場上並沒有明確討論中周期。當然，在商業化前的討論中，我們討論了整個計劃，其中包括驗證性試驗 EMBARK。所以是的。達蘭，如果我錯過了什麼，請告訴我。

No, that's exactly right.

不，完全正確。

Our next question comes from the line of Gil Blum of Needham. Our next question comes from the line of Neil -- of Gil Blum of Needham.

我們的下一個問題來自李約瑟的吉爾布魯姆（Gil Blum）。我們的下一個問題來自尼爾（Neil）——來自尼達姆（Needham）的吉爾·布魯姆（Gil Blum）。

One quick technical. Isn't May 29th a holiday? Doesn't that have any effect on the filing? And the other question I have is, do you think the payer pathway is going to follow closely kind of the road map set by Zolgensma?

一項快速技術。 5月29號不是放假嗎？對備案沒有影響嗎？我的另一個問題是，您認為付款人途徑會嚴格遵循 Zolgensma 制定的路線圖嗎？

So on the first of, yes, it is a holiday. Officially, May 29 is our PDUFA date. So we would we assume we could hear on May 29. This is a Memorial Day or we'll hear the business day before then, which would be May 26, if I'm not mistaken, or we would hear the day after May 29. But we're using May 29 because that is indeed the actual PDUFA date.

所以，第一天，是的，這是一個假期。根據官方說法，5 月 29 日是我們的 PDUFA 日期。所以我們假設我們可以在5 月29 日聽到消息。這是陣亡將士紀念日，或者我們會聽到之前的工作日，即5 月26 日，如果我沒記錯的話，或者我們會聽到5月29 日之後的一天. 但我們使用 5 月 29 日，因為這確實是實際的 PDUFA 日期。

So I think the question on the payer approach, I think the payer approach, Zolgensma is probably one construct. I think we have an enormous amount of Duchenne-specific experience with the payer community. Obviously, we've now been supporting 3 therapies. The earliest approval happened over 6 years ago. So I think we're in very good shape to have productive dialogue with payers about access and reimbursement for 9001, assuming that we're able to get approved.

所以我認為關於付款人方法的問題，我認為付款人方法，Zolgensma 可能是一種構造。我認為我們在付款人社群方面擁有大量杜興特定的經驗。顯然，我們現在已經支持 3 種療法。最早的批准發生在 6 年前。因此，我認為，假設我們能夠獲得批准，我們就能夠與付款人就 9001 的使用和報銷問題進行富有成效的對話。

(Operator Instructions) Our next question comes from the line of Danielle Brill of Raymond James.

（操作員說明）我們的下一個問題來自 Raymond James 的 Danielle Brill。

Doug, I have a question on the micro-dystrophin follow-up data. I believe we saw 60-week data from Part 1 of Study 102. Do you have additional expression data at that time point or any expression data at later time points? And then random question, do you see any legal risk for 9001 from REGENXBIO IP claims?

道格，我有一個關於微肌營養不良蛋白追蹤數據的問題。我相信我們看到了研究 102 第 1 部分的 60 週數據。您是否有該時間點的其他表達數據或稍後時間點的任何表達數據？然後隨機提問，您認為 REGENXBIO IP 索賠對 9001 有任何法律風險嗎？

On the second question, I'll answer and say no, we don't. On the first question, I'll turn it over to Louise, if you understand what -- I didn't fully understand the question. Apologies.

關於第二個問題，我會回答說不，我們不會這麼做。關於第一個問題，我會把它交給路易絲，如果你明白的話——我沒有完全理解這個問題。道歉。

Yes. It was just about additional time points. There's no additional biopsy time points in the that we have.

是的。這只是額外的時間點。我們沒有額外的活檢時間點。

(Operator Instructions) Our next question comes from the line of Hartaj Singh of Oppenheimer.

（操作員說明）我們的下一個問題來自奧本海默的 Hartaj Singh。

Congratulations on a very big step forward. Looking forward to many more. Just a question actually on SRP-9003. I know you've got the VOYAGENE trial starting the Phase I. You're doing additional work. Doug, you're also doing a lot of work around characterizing the material -- the clinical material, commercial, et cetera. If you could just talk to that, but also just talk to us a little bit about the Phase III design could look like. I believe you've indicated that could start later this year.

祝賀您向前邁出了一大步。期待更多。其實只是關於 SRP-9003 的問題。我知道你們已經開始了 VOYAGENE 試驗的第一階段。你們正在做額外的工作。道格，您還圍繞著表徵材料做了很多工作——臨床材料、商業材料等等。如果您可以談談這一點，也可以和我們談談第三階段的設計可能會是什麼樣子。我相信您已經表示這可能會在今年稍後開始。

Yes. Louise, do you want to take that?

是的。路易絲，你想接受這個嗎？

Yes. Thanks for that question. Certainly, in -- we're looking at this closely. This is an ultrarare indication, and so we're looking at all the data we have to date in both the ambulatory population and now this new population that we're spending, which is the older ambulatory and non-ambulatory.

是的。謝謝你提出這個問題。當然，我們正在密切關注這一點。這是一個極為罕見的跡象，因此我們正在研究迄今為止在流動人口和現在我們正在花費的新人口（即較老的流動人口和非流動人口）中所擁有的所有數據。

And so the totality of the patient population could be captured in that Phase III design. So we don't have it finalized yet. But all of the results from these 2 trials will be taken into consideration when we have the ultimate study design for that Phase III study.

因此，第三階段設計可以涵蓋所有患者群體。所以我們還沒有最終確定。但是，當我們為此 III 期研究制定最終研究設計時，將考慮這兩項試驗的所有結果。

Our next question comes from Yun Zhong of BTIG.

我們的下一個問題來自 BTIG 的雲忠。

So my question is actually also on the limb-girdle program. And I was wondering, what is the purpose of the Phase I study? And what kind of information are you trying to get? And given the small prevalence of the indication, what's your thinking on the patient allocation enrolled patient into the current study? I don't believe you have disclosed the size of the study versus maybe saving patients for future pivotal study.

所以我的問題其實也是關於肢帶計畫。我想知道第一階段研究的目的為何？您想獲取什麼樣的資訊？鑑於此適應症的盛行率較小，您對納入目前研究的患者分配有何看法？我不認為你已經透露了該研究的規模，也沒有可能為未來的關鍵研究拯救患者。

Yes. I'll touch on it briefly and then I'll -- Louise can answer it and correct me when I get this wrong. I mean the reason that we're doing -- there are 2 reasons why we've done this clinical experience study. The first is that it gives us an opportunity to explore the safety and expression of the therapy in a broader patient population than we would typically do for our pivotal trial itself. So we will glean important information.

是的。我會簡單地談談它，然後我會--路易絲可以回答它，並在我弄錯時糾正我。我的意思是我們這樣做的原因——我們進行這項臨床經驗研究有兩個原因。首先，它讓我們有機會在更廣泛的患者群體中探索該療法的安全性和表達情況，而不是我們通常為關鍵試驗本身所做的事情。所以我們會收集重要的資訊。

And the second reason that we did it is that we had clinical material available to us. So for the pivotal trial, we need to have commercially appropriate material, and that has to be material. That would be appropriate. So the launch of the therapy, we have very appropriate clinical material right now, and it seemed appropriate to make good of it to get additional insight and also, frankly, to provide a benefit at the same time. Louise?

我們這樣做的第二個原因是我們有可用的臨床資料。因此，對於關鍵試驗，我們需要有商業上合適的材料，而且必須是材料。那是合適的。因此，在推出該療法時，我們現在擁有非常合適的臨床材料，似乎應該充分利用它來獲得更多見解，坦白說，同時提供益處。路易絲？

I think you characterized it well. Just emphasizing that this is a different patient population than we've previously studied in older patients where we can look at safety and efficacy in non-ambulatory and older ambulatory, which is an important component of this preplan population.

我認為你描述得很好。只是強調，這是一個與我們之前在老年患者中研究的不同的患者群體，我們可以研究非臥床患者和老年臥床患者的安全性和有效性，這是預先計劃人群的重要組成部分。

Our next question comes from the line of Kristen Kluska of Cantor.

我們的下一個問題來自康托爾的克里斯汀·克魯斯卡（Kristen Kluska）。

This is Rick on for Kristen. In the press release, you mentioned that the Catalent agreement structures how Catalent could support multiple gene therapy candidates in the LGMD pipeline. So could you maybe go into a little detail here on what this might mean in terms of whether this could deal with clinical-grade material or potentially commercial-grade material for later-stage trials in LGMD?

這是克里斯汀的瑞克。在新聞稿中，您提到 Catalent 協議構建了 Catalent 如何支持 LGMD 管道中的多種基因療法候選藥物。那麼，您能否在此詳細說明這可能意味著什麼，即這是否可以處理用於 LGMD 後期試驗的臨床級材料或潛在的商業級材料？

Yes. Relationship with Catalent and our goal is to -- they would potentially have the opportunity to manufacture for us the limb-girdle. Really, our goal going forward is to try to have commercial represented material from the first inpatient clinical trial. Historically, as we evolve from Nationwide Children's Hospital, as you know, the first study with 9001 started with clinical material there. Likewise, 9003 started with clinical material provided by Nationwide. But the fastest pathway forward is to have commercial representative material from the beginning, and that's going to be our goal. And the potential of doing that with Catalent is a significant one.

是的。與 Catalent 的關係以及我們的目標是——他們可能有機會為我們製造肢帶。事實上，我們未來的目標是嘗試從第一個住院臨床試驗中獲得具有商業代表性的材料。從歷史上看，如您所知，隨著我們從全國兒童醫院發展而來，第一項針對 9001 的研究就是從那裡的臨床材料開始的。同樣，9003 也從 Nationwide 提供的臨床資料開始。但最快的前進途徑是從一開始就擁有具有商業代表性的材料，這將是我們的目標。透過 Catalent 實現這一目標的潛力是巨大的。

Our next question comes from Gavin Clark-Gartner of Evercore.

我們的下一個問題來自 Evercore 的 Gavin Clark-Gartner。

Phase II excluded exons 1 through 17. But as you noted, you've been dosing patients inside that range. Have you had any discussion with FDA on getting some of those exons included in the initial label? And is there any chance that something in here could represent a major amendment?

II 期排除了外顯子 1 至 17。但如您所指出的，您一直在該範圍內給予患者藥物。您是否與 FDA 就將其中一些外顯子納入初始標籤進行過討論？這裡的某些內容是否有可能代表重大修訂？

It won't be a major amendment because our BLA went in with the assumption that we would have a narrower exclusion. We already had good scientific rationale for why the label exclusions needed should be narrower, that we were being overly exclusive in those mutations. And then to support that thesis we've started this, and we're nearly done enrolling a study to explore those mutations. It's going quite well right now. But our initial BLA went in with the request that we have a narrower exclusion in our proposed label in connection with our initial BLA submission made that same assumption.

這不會是一個重大修訂，因為我們的 BLA 是假設我們的排除範圍會更窄。我們已經有充分的科學理由來解釋為什麼所需的標籤排除範圍應該更窄，我們對這些突變過於排斥。然後為了支持該論文，我們開始了這一點，並且我們即將完成一項探索這些突變的研究。現在進展順利。但我們最初的 BLA 提出了這樣的要求：我們提議的標籤中的排除範圍更窄，與我們最初提交的 BLA 做出了同樣的假設。

(Operator Instructions) Our next question comes from the line of Salveen Richter.

（操作員說明）我們的下一個問題來自 Salveen Richter。

Tommie on for Salveen. Congrats on the progress. Just wondering how you're thinking about uptake in between that period after the accelerated approval but before EMBARK reads out. Any physician or payer commentary that some might wait to prescribe to see EMBARK? And can you just remind us how long it takes for patients to get tested for eligibility?

湯米替補薩爾文。祝賀取得的進展。只是想知道在加速批准之後和 EMBARK 讀出之前的這段時間裡，您是如何考慮吸收率的。有沒有醫生或付款人評論說有些人可能會等待開處方去看 EMBARK？您能否提醒我們，患者接受資格檢測需要多長時間？

So we don't -- with our current thinking based on all of our discussions both with thought leaders and with certainly patient groups and families is that people wouldn't wait -- waiting is not a viable option for people with this degenerative disease. I would note that by the end of this call, somewhere around the world, a kid with Duchenne would have died and another kid will be going on event. And another kid will go into a wheelchair, never to get back out of a wheelchair.

因此，我們目前的想法是基於我們與思想領袖以及患者團體和家庭的所有討論，人們不會等待——對於患有這種退化性疾病的人來說，等待不是一個可行的選擇。我要指出的是，在這通電話結束時，在世界各地的某個地方，一個患有杜興的孩子可能已經死亡，而另一個孩子將參加活動。另一個孩子會坐上輪椅，永遠不會從輪椅上出來。

So the luxury of patients isn't there for these families. So we don't intend to -- we don't imagine that people would wait for other readouts down the road, put their kids at risk, at least that's not our current assumption nor do we think it's the assumption of the treating physicians either. Certainly, those who have seen what 9001 can do, I don't think would want to wait.

因此，對這些家庭來說，病人的奢侈並不存在。所以我們不打算——我們不認為人們會等待其他讀數，從而將他們的孩子置於危險之中，至少這不是我們目前的假設，我們也不認為這也是治療醫生的假設。當然，那些已經見過 9001 功能的人，我認為不會願意等待。

As far as the process, Dallan, do you want to touch on the process itself.

至於流程，Dallan，您想談談流程本身嗎？

Yes. Yes. And just to underscore what you said about the urgency, Doug. That's what we're seeing out there as well. And I think in terms of what the team has for the process, the data is to have a fully enrolled confirmatory trial at the time of approval is just -- is such an incredible position to be in. And so that's going to inform all of our dialogue going forward on this.

是的。是的。只是為了強調你所說的迫切性，道格。這也是我們所看到的。我認為就團隊在該過程中所擁有的數據而言，在批准時進行完全登記的驗證性試驗的數據是非常令人難以置信的。因此，這將告知所有人我們就此展開對話。

I'm showing no further questions at this time. I'd like to turn the call back over to Doug Ingram for any closing remarks.

我目前沒有提出任何進一步的問題。我想將電話轉回給道格·英格拉姆，請他發表結束語。

Well, thank you very much, everyone, for joining us this evening and for your very good questions. It is a point entity I think as Dr. Rodino-Klapac back noted that today is indeed Rare Disease Day. We are completely committed to using great science and moving as fast as possible to bringing a better life to Duchenne patients and beyond Duchenne patients to other rare disease patients. And I look forward to updating people along the way. Although I will note yet again that as it relates to the BLA for 9001, the next substantive update you'll get is on or around May 29, which is our action date.

非常感謝大家今晚加入我們並提出非常好的問題。我認為這是一個重要的實體，正如 Rodino-Klapac 博士指出的那樣，今天確實是罕見疾病日。我們完全致力於利用偉大的科學，並儘快採取行動，為杜興患者以及杜興患者和其他罕見疾病患者帶來更好的生活。我期待著向人們通報最新情況。儘管我會再次指出，由於它與 9001 的 BLA 相關，您將在 5 月 29 日或前後收到下一次實質更新，這是我們的行動日期。

So thank you all very much, and have a lovely evening.

非常感謝大家，祝您有個愉快的夜晚。

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.

謝謝。女士們、先生們，今天的會議到此結束。感謝大家的參與。您現在可以斷開連線。祝你有美好的一天。