WAVE Life Sciences Ltd (WVE) 2023 Q3 法說會逐字稿

Good morning, and welcome to Wave Life Sciences Third Quarter 2023 Financial Results Conference Call. (Operator Instructions) As a reminder, this call is being recorded and webcast. Now I'll turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

早安，歡迎參加 Wave Life Sciences 2023 年第三季財務業績電話會議。 （操作員說明）謹此提醒，本次通話正在錄音並進行網路直播。現在我將把電話轉給投資者關係和公司事務副總裁 Kate Rausch。請繼續。

Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review the third quarter 2023 financial results. Joining me today are Dr. Paul Bolno, President and Chief Executive Officer; Kyle Moran, Chief Financial Officer; Anne-Marie Li-Kwai-Cheung, Chief Development Officer; Dr. Ginnie Yang, SVP Translational Medicine; and Dr. Chandra Vargeese, Chief Technology Officer. The press release issued this morning is available on the Investors Section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements.

謝謝你，接線生。早安，感謝您今天加入我們討論我們最近的業務進展並回顧 2023 年第三季的財務業績。今天與我一起出席的還有總裁兼執行長 Paul Bolno 博士；凱爾‧莫蘭，財務長； Anne-Marie Li-Kwai-Cheung，首席開發長； Ginnie Yang 博士，轉譯醫學資深副總裁；和技術長 Chandra Vargeese 博士。今天早上發布的新聞稿可在我們網站 www.wavelifesciences.com 的投資者部分取得。在我們開始之前，我想提醒您，本次電話會議期間的討論將包括前瞻性陳述。這些陳述受到多種風險和不確定性的影響，可能導致我們的實際結果與這些前瞻性陳述中所述的結果有重大差異。

The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2022, and our quarterly report on Form 10-Q for the quarter ended September 30, 2023. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

今天發布的新聞稿和我們向 SEC 提交的文件中討論了可能導致實際結果存在差異的因素，包括我們截至 2022 年 12 月 31 日的年度 10-K 表格年度報告以及 10-Q 表格季度報告截至2023年9 月30 日的季度。我們不承擔以任何理由更新或修改任何前瞻性聲明的義務。我現在想把電話轉給保羅。

Thanks, Kate. Good morning, and thank you all for joining us on today's call. I will begin with opening remarks. Next, Anne-Marie will provide an update on our clinical trials. And finally, Kyle will review our financials. We will then open up the call for questions. Chandra and Ginnie will also be available for questions. In the third quarter, our team made tremendous progress advancing our pipeline of novel RNA medicine.

謝謝，凱特。早安，感謝大家參加今天的電話會議。我先致開幕詞。接下來，安妮瑪莉將提供我們臨床試驗的最新情況。最後，凱爾將審查我們的財務狀況。然後我們將開放提問。錢德拉和吉妮也將接受提問。第三季度，我們的團隊在推動新型 RNA 藥物的研發管線方面取得了巨大進展。

Since our last update, we have brought our first-in-class RNA editing therapeutic program, WVE-006 for AATD into the clinic. We outlined our strategy for growth at our Annual R&D Day, including announcing a new wholly owned siRNA program, targeting INHBE for metabolic disorders, including obesity, and we continue to advance our clinical trials in DMD and HD. Looking ahead to 2024, we are approaching a transformative year for Wave, where we will deliver key data sets for all three of our clinical programs and SELECT and INHBE clinical candidate.

自上次更新以來，我們已將用於 AATD 的一流 RNA 編輯治療項目 WVE-006 引入臨床。我們在年度研發日概述了我們的成長策略，包括宣布一項新的全資 siRNA 計劃，針對 INHBE 治療肥胖等代謝性疾病，並且我們繼續推進 DMD 和 HD 的臨床試驗。展望 2024 年，我們即將迎來 Wave 變革的一年，我們將為所有三個臨床項目以及 SELECT 和 INHBE 臨床候選藥物提供關鍵數據集。

Starting with WVE-006, today, we are announcing the approval of multiple clinical trial applications or CTAs and the initiation of our restoration program. which will investigate WVE-006, the industry's first ever clinical RNA editing candidate for alpha-1 antitrypsin deficiency, or AATD. This is another significant milestone for Wave, patients and the field of nucleic acids. We remain on track to begin dosing healthy volunteers this quarter, and as Anne-Marie will describe in more detail later, the restoration program is designed to enable a highly efficient path to prove the mechanism. Our excitement for WVE-006 is grounded in the strong preclinical profile we have observed to date.

從 WVE-006 開始，今天我們宣布多項臨床試驗申請或 CTA 獲得批准，並啟動我們的修復計劃。本計畫將研究 WVE-006，這是業界首個針對 alpha-1 抗胰蛋白酶缺乏症（AATD）的臨床 RNA 編輯候選藥物。這對於 Wave、患者和核酸領域來說是另一個重要的里程碑。我們仍有望在本季度開始對健康志願者進行給藥，正如安妮瑪麗稍後將更詳細地描述的那樣，恢復計劃旨在提供一條高效的途徑來證明該機制。我們對 WVE-006 的興奮是基於我們迄今為止觀察到的強大的臨床前概況。

We have achieved remarkable potency and durability of editing with convenient subcutaneous dosing in our preclinical studies because of our unique, fully chemically modified oligonucleotides and their ability to effectively (inaudible). WVE-006 precisely corrects the PiZ mutation on the transcript with no bystander editing. In contrast, genome editing technologies rely on hyperactive exogenously delivered artificial enzymes that can result in significant and irreversible collateral bystander editing with DNA, yielding not only the potential for permanent off-target edits to DNA but isoforms of protein with differential function. 006 contains a GalNAc conjugate, a highly specific and elegant delivery tool that is well validated through multiple approved silencing therapeutics on the market.

由於我們獨特的、完全化學修飾的寡核苷酸及其有效（聽不清楚）的能力，我們在臨床前研究中透過方便的皮下給藥實現了顯著的編輯效力和持久性。 WVE-006 精確修正了轉錄本上的 PiZ 突變，無需旁觀者編輯。相較之下，基因組編輯技術依賴於高度活躍的外源性人工酶，這些酶可以對DNA 進行顯著且不可逆的旁觀者編輯，不僅有可能對DNA 進行永久性脫靶編輯，而且可以產生具有差異功能的蛋白質亞型。 006 含有 GalNAc 綴合物，這是一種高度特異性和優雅的遞送工具，經過市場上多種批准的沉默療法的充分驗證。

For AATD, it is a significant advantage to have a stable and optimized candidate that can leverage GalNAc and avoid (inaudible) particles, which have their own challenges and require intravenous dosing. With current therapies largely confined to treating either pulmonary or in the future hepatic manifestations of the disease, the unmet need in AATD remains high.

對於 AATD 來說，擁有一個穩定且優化的候選藥物是一個顯著的優勢，它可以利用 GalNAc 並避免（聽不清楚）顆粒，這些顆粒有其自身的挑戰並且需要靜脈給藥。由於目前的療法主要局限於治療該疾病的肺部或未來的肝臟表現，因此 AATD 的未滿足需求仍然很高。

Even with the limitations of available therapies, the pharmaceutical market for AATD is substantial, with augmentation therapy alone accounting for over $1 billion in sales per year. Our partner, GSK, has a long history and clear leadership in respiratory medicine, development and commercialization and together with WVE-006's differentiated profile, we believe this program is in a strong position, and we look forward to delivering proof of mechanism data next year. As a reminder, under the terms of our collaboration, Wave is also eligible to receive meaningful near-term clinical milestones starting this year, which have the potential to add substantially to our balance sheet.

即使現有療法有局限性，AATD 的醫藥市場仍然巨大，僅增強療法每年的銷售額就超過 10 億美元。我們的合作夥伴 GSK 在呼吸醫學、開發和商業化方面擁有悠久的歷史和明確的領導地位，再加上 WVE-006 的差異化特徵，我們相信該計劃處於有利地位，我們期待明年提供機制數據證明。提醒一下，根據我們的合作條款，從今年開始，Wave 還有資格獲得有意義的近期臨床里程碑，這有可能大幅增加我們的資產負債表。

Clinical proof of mechanism with 006 would serve to meaningfully derisk this novel modality and will continue to unlock value for our emerging pipeline of RNA editing programs. As we shared at our R&D Day, we are actively building a pipeline of wholly owned therapeutic candidates designed to either correct or upregulate mRNA across a range of high-impact targets. We presented both in vivo and in vitro data on several of these targets, which all offer efficient path to clinical proof of concept and represent meaningful commercial opportunities for both rare and common disease indications.

006 機制的臨床證明將有助於有意義地消除這種新穎模式的風險，並將繼續為我們新興的 RNA 編輯計畫管道釋放價值。正如我們在研發日分享的那樣，我們正在積極建構一系列全資候選治療藥物，旨在糾正或上調一系列高影響目標的 mRNA。我們提供了其中幾個目標的體內和體外數據，這些數據都為臨床概念證明提供了有效的途徑，並代表了罕見和常見疾病適應症的有意義的商業機會。

We look forward to continuing to share data on these exciting programs over the course of 2024. Beyond WVE-006, our strategic collaboration with GSK continues to make meaningful progress. The Wave and GSK teams continue to work to advance multiple targets. And as our partner shared during our R&D day, this work spans multiple modalities beyond RNA editing, including silencing using siRNA. As a reminder, GSK pays 100% of the costs related to target validation of these partner programs, and Wave is eligible for up to $2.8 billion in milestones, not inclusive of 006 and additional tier royalty payments.

我們期待在 2024 年繼續分享這些令人興奮的項目的數據。除了 WVE-006 之外，我們與葛蘭素史克的戰略合作繼續取得有意義的進展。 Wave 和 GSK 團隊繼續努力推進多個目標。正如我們的合作夥伴在研發日分享的那樣，這項工作涵蓋了 RNA 編輯以外的多種模式，包括使用 siRNA 進行沉默。需要提醒的是，GSK 支付了與這些合作夥伴計劃的目標驗證相關的 100% 費用，並且 Wave 有資格獲得高達 28 億美元的里程碑費用，不包括 006 和其他級別的特許權使用費。

At R&D Day, we also announced our first wholly owned program to emerge from the collaboration, a GalNAc conjugated siRNA program, targeting INHBE to treat metabolic disorders, including obesity. INHBE is a particularly exciting target, given its strong supporting genetic evidence. INHBE loss-of-function heterozygous carriers exhibit a healthy metabolic profile, including reduced hip-to-waist ratio, improved lipid profile, reduce odds of coronary artery disease and type 2 diabetes.

在研發日，我們也宣布了我們在合作中推出的第一個全資項目，即 GalNAc 綴合 siRNA 項目，以 INHBE 為靶點來治療包括肥胖在內的代謝性疾病。鑑於其強有力的支持遺傳證據，INHBE 是一個特別令人興奮的目標。 INHBE 功能喪失雜合子帶因者表現出健康的代謝特徵，包括降低臀腰比、改善血脂、降低冠狀動脈疾病和 2 型糖尿病的幾率。

GLP-1 therapeutics have established a substantial market opportunity for weight loss therapeutics. We estimate there are more than 47 million people in the United States and Europe with metabolic disorders, including obesity. While GLP-1s are becoming standard of care for weight loss, they come with several drawbacks, including loss of muscle mass, suppression of the general reward system and poor tolerability. With discontinuation rates as high as 70%, there is a need for more therapeutic options, including long-term maintenance. We believe a therapeutic approach for obesity that improves metabolism, increases fat loss while maintaining muscle mass offers the potential for infrequent dosing and does not affect the general reward system would be ideal.

GLP-1療法已經為減肥療法建立了巨大的市場機會。我們估計，美國和歐洲有超過 4700 萬人患有代謝紊亂，包括肥胖症。雖然 GLP-1 正在成為減肥護理的標準，但它們也有一些缺點，包括肌肉質量損失、一般獎勵系統抑制和耐受性差。由於停藥率高達 70%，因此需要更多的治療選擇，包括長期維持。我們相信，改善新陳代謝、增加脂肪減少同時保持肌肉質量的肥胖治療方法提供了不頻繁給藥的潛力並且不影響一般獎勵系統，這將是理想的。

This is what we aim to achieve with our INHBE Program. At R&D Day, we presented the first in vivo data supporting preclinical proof of concept for this target. We achieved INHBE silencing well beyond the 50% therapeutic threshold, which led to substantially lower body weight, a substantial reduction of visceral fat in DIO mice as compared to control.

這就是我們透過 INHBE 計劃實現的目標。在研發日，我們展示了第一個體內數據，支持該目標的臨床前概念驗證。我們實現了遠超過 50% 治療閾值的 INHBE 沉默，與對照組相比，DIO 小鼠的體重顯著降低，內臟脂肪顯著減少。

These are the first in vivo data to demonstrate in INHBE silencing and is consistent with the phenotype of heterozygous loss-of-function carriers. Since R&D Day, we have identified potent and highly specific leads using our new chemistry format and are rapidly advancing towards our goal of selecting an INHBE clinical candidate by the fourth quarter of 2024. Notably, because the levels of INHBE protein and other relevant clinical biomarkers can be readily measured in serum, we believe the path to assessing target engagement and clinical efficacy can be straightforward and achieved in a relatively short period of time. As a reminder, our collaboration allows way to leverage GSK's genetically validated targets to advance at least three programs, meaning we have an additional 2 slots open for new wholly owned programs (inaudible).

這些是首次證明 INHBE 沉默的體內數據，並且與雜合功能喪失攜帶者的表型一致。自研發日以來，我們已經使用新的化學形式確定了有效且高度特異性的先導化合物，並正在快速推進我們的目標，即在2024 年第四季度之前選擇INHBE 臨床候選藥物。值得注意的是，因為INHBE 蛋白和其他相關臨床生物標記的水平可以很容易地在血清中測量，我們相信評估目標參與和臨床療效的途徑可以很簡單，並且可以在相對較短的時間內實現。提醒一下，我們的合作允許利用葛蘭素史克的基因驗證目標來推進至少三個項目，這意味著我們為新的全資項目開放了另外 2 個位置（聽不清楚）。

Turning to WVE-N531 and WVE-003, we continue to advance our clinical DMD and HD programs and are on track to deliver key data from both programs in 2024. For DMD with WVE-N531, we aim to provide a treatment option that delivers convenient, safe production of endogenous (inaudible) and ultimately meaningful clinical benefit for all patients amenable to exon 53 skipping. There remain significant questions around the functional benefit of micro- or mini-dystrophin and we recognize the urgency to deliver more therapeutic options to these patients. We look forward to evaluating the translation of our best-in-class exon skipping to functional dystrophin protein in 2024.

轉向WVE-N531 和WVE-003，我們繼續推進我們的臨床DMD 和HD 項目，並有望在2024 年提供這兩個項目的關鍵數據。對於使用WVE-N531 的DMD，我們的目標是提供一種治療方案，可實現為所有適合外顯子 53 跳躍的患者帶來方便、安全的內源性（聽不清楚）和最終有意義的臨床益處。關於微型或小型肌肉營養不良蛋白的功能益處仍然存在重大問題，我們認識到為這些患者提供更多治療選擇的迫切性。我們期待在 2024 年評估我們一流的外顯子跳躍到功能性肌肉營養不良蛋白的轉化。

In Huntington's disease, we believe WVE-003 is the most promising asset in the field. To date, we have demonstrated a successful translation of our compelling preclinical data to the clinic with the reduction of mutant huntingtin and preservation of wild-type huntingtin after a single dose in humans. We have robust evidence from multiple preclinical studies, including NHP studies that support the ability of our oligonucleotide to achieve significant exposure levels throughout the CNS.

在亨廷頓舞蹈症方面，我們相信 WVE-003 是該領域最有前途的資產。迄今為止，我們已經證明了我們令人信服的臨床前數據成功轉化為臨床，在人類單次劑量後突變亨廷頓蛋白減少並保留野生型亨廷頓蛋白。我們從多項臨床前研究中獲得了強有力的證據，包括 NHP 研究，這些研究支持我們的寡核苷酸在整個中樞神經系統中達到顯著暴露水平的能力。

As we look ahead to the first multi-dose data from our SELECT-HD clinical trial next year, we anticipate potent and durable knockdown of mutant huntingtin while sparing wild-type protein, similar to what we observed in (inaudible) reduction in our WVE-004 program when we transitioned from single to multi-dose. Anne-Marie will speak more on SELECT-HD and our other clinical development programs. And I'd now like to turn the call over to her. Anne-Marie?

當我們展望明年SELECT-HD 臨床試驗的第一個多劑量數據時，我們預期突變亨廷頓蛋白會被有效且持久地敲低，同時保留野生型蛋白，類似於我們在WVE 減少（聽不清楚）中觀察到的情況-004 計劃，當我們從單劑量過渡到多劑量時。 Anne-Marie 將更多地談論 SELECT-HD 和我們的其他臨床開發項目。我現在想把電話轉給她。安妮瑪麗？

Thank you, Paul. It's a really exciting time to be at Wave as we are continuing to validate the translation of our platform in the clinic. I'll begin with WVE-006, our GalNAc conjugated AIMer or RNA editing oligonucleotide for AATD. We have now received approval for multiple clinical trial applications or CTA. This accomplishment affirms that RNA editing oligonucleotide can leverage established regulatory pathways and where 006 has officially become the first RNA editing oligonucleotide to enter the clinical trial.

謝謝你，保羅。在 Wave ，這是一個非常令人興奮的時刻，因為我們正在繼續驗證我們平台在診所中的翻譯。我將從 WVE-006 開始，它是我們用於 AATD 的 GalNAc 綴合 AIMer 或 RNA 編輯寡核苷酸。我們現已獲得多項臨床試驗申請或 CTA 的批准。這項成就證實了RNA編輯寡核苷酸可以利用已建立的監管途徑，006已正式成為第一個進入臨床試驗的RNA編輯寡核苷酸。

Today, we are announcing the initiation of our restoration clinical program, which is comprised of two interconnected portions. Restoration-1 for healthy volunteers and Restoration-2 for individuals with AATD who have the homozygous PiZZ mutation. The healthy volunteer cohorts along with our PD modeling can (inaudible) dose that can rapidly enable initiation in DD patients at the level expected to engage target, thereby enabling efficient delivery of proof of mechanism as defined by detection of additive protein in serum.

今天，我們宣布啟動我們的修復臨床計劃，該計劃由兩個相互關聯的部分組成。 Restoration-1 適用於健康志願者，Restoration-2 適用於具有純合子 PiZZ 突變的 AATD 個體。健康志願者群體和我們的 PD 模型可以（聽不清楚）劑量能夠在 DD 患者中快速啟動，達到預期參與標靶的水平，從而能夠有效地提供透過檢測血清中的附加蛋白所定義的機制證明。

In Restoration-2, patients will have multiple assessments of serum (inaudible) throughout the low, medium and high dose cohorts, meaning it is possible to achieve proof of mechanism before completion of the whole trial and potentially prior to completion of the first cohort. Restoration-1 is now underway and we can expect to initiate dosing in healthy volunteers this quarter and delivery of proof of mechanism data in patients with AATD in 2024. Moving on to DMD. I'll start with a quick reminder of the clinical data that drives our excitement in this program.

在Restoration-2 中，患者將對整個低、中和高劑量組的血清進行多次評估（聽不清楚），這意味著有可能在整個試驗完成之前以及可能在第一個組完成之前獲得機制證明。 Restoration-1 目前正在進行中，我們預計本季開始對健康志願者進行給藥，並於 2024 年向 AATD 患者提供機制數據證明。接下來討論 DMD。我將首先快速提醒我們對這個計畫感到興奮的臨床數據。

In patient muscle biopsies collected from our proof-of-concept study, we observed the mean 53% exon skipping at 6 weeks following 3 doses of WVE-N531 every other week. Since exon skipping and results in dystrophin production improve the cellular environment to enable more skipping and dystrophin, significant nonlinear increases in dystrophin may be expected given the amount of exon skipping we see. This non-linear relationship between exon skipping and dystrophin production has been observed (inaudible).

在我們的概念驗證研究中收集的患者肌肉活檢中，我們觀察到每隔一周服用 3 劑 WVE-N531 後 6 週時平均有 53% 的外顯子跳躍。由於外顯子跳躍和肌肉營養不良蛋白產生的結果改善了細胞環境，以實現更多的跳躍和肌肉營養不良蛋白，考慮到我們看到的外顯子跳躍量，預計肌肉營養不良蛋白會顯著非線性增加。已經觀察到外顯子跳躍和肌肉營養不良蛋白產生之間的這種非線性關係（聽不清楚）。

Furthermore, high tissue concentrations of N531 (inaudible) speak to promise of achieving best-in-class dystrophin protein expression. We are advancing FORWARD-53, our potentially registrational Phase III trial of N531. This open-label trial is evaluating 10 mg per kg doses of N531 and limited every other week and is powered to assess functional indulgence dystrophin expression after 24 and 48 weeks of treatment, which will be the trial's primary endpoint. The trial will also evaluate safety and tolerability, pharmacokinetics and digital and functional endpoints. We remain on track to deliver dystrophin protein data in 2024, which is positive, and would support our plans to file for accelerated approval in the U.S.

此外，N531 的高組織濃度（聽不清楚）顯示有望實現一流的肌肉營養不良蛋白表現。我們正在推進 FORWARD-53，這是我們可能註冊的 N531 III 期試驗。這項開放標籤試驗正在評估每公斤體重10 毫克的N531 劑量，每隔一周限制一次，旨在評估治療24 週和48 週後的功能性縱欲肌營養不良蛋白表達，這將是該試驗的主要終點。該試驗還將評估安全性和耐受性、藥物動力學以及數字和功能終點。我們仍有望在 2024 年提供肌肉營養不良蛋白數據，這是積極的，並將支持我們在美國申請加速批准的計劃。

This data would also accelerate our clinical development plan to build a wholly owned multi-exon DMD franchise beyond Exon 53. We have generated in vitro dystrophin restoration data for follow-on excellent skipping compounds that together would address up to 40% of the DMD population.

這些數據還將加速我們的臨床開發計劃，以建立外顯子53 以外的全資多外顯子DMD 特許經營權。我們已經為後續優秀的跳躍化合物生成了體外肌肉營養不良蛋白恢復數據，這些化合物總計將解決高達40% 的DMD 族群問題。

These follow-on compounds are all defined with PN chemistry and have demonstrated high levels of exon skipping and dystrophin production restoration in, in vitro studies. Turning to WVE-003, our first-in-class, allele-selective candidate for Huntington's disease, or HD (inaudible) is a devastating disease and where 003 offers an optimal treatment approach and reduces the toxic mutant huntingtin protein while preserving the healthy wild-type huntingtin protein.

這些後續化合物均透過 PN 化學進行定義，並在體外研究中表現出高水平的外顯子跳躍和肌肉營養不良蛋白產生恢復。談到WVE-003，我們針對亨廷頓氏症或HD（聽不清楚）的一流等位基因選擇性候選藥物是一種毀滅性的疾病，003 提供了最佳的治療方法，減少了有毒的突變亨廷頓蛋白，同時保留了健康的野生環境。型亨廷頓蛋白。

As a reminder, this program is part of an active collaboration with Takeda. In the third quarter, we achieved a milestone from this collaboration, which pertained to the positive results from a nonclinical study of 003 in nonhuman primates. This study showed significant tissue exposure levels of 003 in the deep brain regions, including striatum and bolstered our existing data sets that confirm the ability of our oligonucleotides to distribute to the areas of CNS important for HD.

提醒一下，該計劃是與武田積極合作的一部分。第三季度，我們在這次合作中取得了一個里程碑，這與 003 在非人類靈長類動物中的非臨床研究取得的積極成果有關。這項研究顯示，包括紋狀體在內的大腦深部區域中003 的組織暴露水平顯著，並支持了我們現有的數據集，這些數據集證實了我們的寡核苷酸分佈到對HD 重要的CNS 區域的能力。

Coupled with the already demonstrated mean mutant Huntington's CSF, single dose reduction of approximately 35% compared to placebo, these new NHP results further reinforce our confidence in this program. I'm excited to share that we've now completed enrollment for the 30-milligram multi-dose q.8 week cohort comprised of 24 HD patients. Having enrolled patients from the single-dose cohorts and fully enrolled the multi-dose cohort which is critical to inform further decisions on this program, we will now evaluate the completed single-dose and multi-dose cohorts simultaneously. We expect to report the 30-milligram multi-dose data with extended follow-up along with all single-dose data in the second quarter of 2024.

再加上已經證明的平均突變亨廷頓氏腦脊髓液，與安慰劑相比，單劑量減少約 35%，這些新的 NHP 結果進一步增強了我們對該計劃的信心。我很高興地告訴大家，我們現在已經完成了由 24 名 HD 患者組成的 30 毫克多劑量 q.8 週隊列的入組。在從單劑量隊列中入組患者並完全入組多劑量隊列（這對於為該計劃的進一步決策提供資訊至關重要）之後，我們現在將同時評估已完成的單劑量和多劑量隊列。我們預計將在 2024 年第二季報告 30 毫克多劑量數據以及所有單劑量數據，並進行長期追蹤。

We also expect these data to enable decision-making on the program and support our option package for Takeda. In summary, I'm proud of our team's accomplishments this year and truly look to the year ahead, during which we will have high-impact (inaudible) across all 3 of our clinical trials. And with that, I'd like to turn the call over to our CFO, Kyle Moran, to provide an update on our financials.

我們還希望這些數據能夠促進該計劃的決策並支持我們為武田提供的選項包。總而言之，我為我們團隊今年的成就感到自豪，並真正展望未來的一年，在此期間，我們的所有 3 項臨床試驗將產生巨大影響（聽不清楚）。說到這裡，我想將電話轉給我們的財務長凱爾·莫蘭（Kyle Moran），以提供有關我們財務狀況的最新資訊。

Thanks, Anne-Marie. We recorded $7.3 million of net income for the third quarter of 2023 as compared to a net loss of $39.0 million in the prior year quarter. This year-over-year change was primarily driven by increased revenue under both our GSK and Takeda collaborations. Under the Takeda collaboration, we earned $7.0 million for the achievement of a nonclinical milestone for WVE-003. Additionally, we recognized $28.0 million from Takeda related to the discontinuation of WVE-004 and $14.3 million under the GSK collaboration. Research and development expenses in the third quarter of 2023 were $31.6 million as compared to $27.6 million in the prior year quarter.

謝謝，安妮瑪麗。 2023 年第三季度，我們錄得 730 萬美元的淨利潤，而去年同期淨虧損為 3,900 萬美元。這一同比變化主要是由於我們與葛蘭素史克和武田合作的收入增加所致。在與武田的合作下，我們因實現 WVE-003 的非臨床里程碑而獲得了 700 萬美元的收入。此外，我們也確認了武田 (Takeda) 與 WVE-004 停產相關的 2,800 萬美元，以及與葛蘭素史克 (GSK) 合作的 1,430 萬美元。 2023 年第三季的研發費用為 3,160 萬美元，而去年同期為 2,760 萬美元。

This increase was primarily driven by increased external expenses related to all 3 of our clinical programs. SG&A expenses in the third quarter were $13.1 million as compared to $11.6 million in the prior year quarter, primarily due to increased spending on professional and consulting expenses. We ended the third quarter with $139.9 million in cash and cash equivalents. Subsequent to the end of the quarter, we received $7.0 million for the achievement of the previous discussed milestone. We expect that our cash and cash equivalents will be sufficient to fund operations into 2025. As a reminder, we do not include any future milestones and are cash friendly. But we do have the potential to receive meaningful near-term milestone payments this year and beyond, including clinical development milestones related to WVE-006. I'll turn the call back over to Paul.

這一增長主要是由於與我們所有 3 個臨床項目相關的外部費用增加所致。第三季的銷售、管理及行政費用為 1,310 萬美元，而去年同期為 1,160 萬美元，這主要是由於專業和諮詢費用的增加。第三季末，我們擁有 1.399 億美元的現金和現金等價物。本季末後，我們收到了 700 萬美元，用於實現先前討論的里程碑。我們預計我們的現金和現金等價物將足以為 2025 年的營運提供資金。提醒一下，我們不包括任何未來的里程碑，並且現金友好。但我們確實有可能在今年及以後獲得有意義的近期里程碑付款，包括與 WVE-006 相關的臨床開發里程碑。我會把電話轉回給保羅。

Thank you, Kyle. With the most versatile RNA medicine platform in the industry, best-in-class chemistry and a pipeline of transformative medicines, Wave is approaching an exciting inflection point. As we approach 2024, I'd like to recap the many near-term milestones we expect to deliver next year. We expect to deliver and share the first ever clinical proof of mechanism data for RNA editing with WVE-006.

謝謝你，凱爾。憑藉業內最通用的 RNA 醫學平台、一流的化學技術和一系列變革性藥物，Wave 正在接近一個令人興奮的轉折點。隨著 2024 年的臨近，我想回顧一下我們預計明年將實現的許多近期里程碑。我們期望透過 WVE-006 提供並分享第一個 RNA 編輯機制資料的臨床證明。

We expect to deliver dystrophin data from our potentially registrational FORWARD-53 clinical trial, and we expect to deliver data from the multi-dose SELECT-HD cohort with extended follow-up along with all single-dose data. We also expect to select a clinical candidate for INHBE by the fourth quarter of 2024, thereby supporting our goal of selecting 5 new clinical candidates by year-end 2025. Together, we are reimagining (inaudible) and we look forward to continuing to share our progress with you. And with that, we'll turn it over to the operator for Q&A.

我們期望提供來自我們潛在註冊的 FORWARD-53 臨床試驗的肌肉營養不良蛋白數據，並且我們期望提供來自多劑量 SELECT-HD 隊列的數據以及所有單劑量數據的長期隨訪。我們也預計在2024 年第四季之前選擇INHBE 的臨床候選藥物，從而支持我們在2025 年底選擇5 名新的臨床候選藥物的目標。我們正在共同重新構想（聽不清楚），並期待繼續分享我們的成果與你一起進步。然後，我們會將其交給操作員進行問答。

(Operator Instructions) Our first question comes from the line of Steven Seedhouse from Raymond James.

（操作員說明）我們的第一個問題來自 Raymond James 的 Steven Seedhouse。

I wanted to first ask about the satellite cell histology that you spoke about and showed at R&D Day (inaudible) program, of course. I'm curious if that's something that -- like can you look for dystrophin protein as well directly in those cells by IHC or something? And is that something that you would do in the ongoing Phase II clinical study and lastly, do you think DMD experts or regulators would view that as a meaningful clinical biomarker at this point? Or is it still sort of academic and speculative, what the meaning of that is?

當然，我想先詢問您在研發日（聽不清楚）節目中談到並展示的衛星細胞組織學。我很好奇是否可以透過 IHC 或其他方法直接在這些細胞中尋找肌肉營養不良蛋白？這是您在正在進行的 II 期臨床研究中會做的事情嗎？最後，您認為 DMD 專家或監管機構目前會認為這是一個有意義的臨床生物標記嗎？或者說它仍然是一種學術性和思辨性，這意味著什麼？

Thank you for the question. So I think if we think about the importance of the satellite cell data, we do think it helps to drive dystrophin production along the full muscle. So muscles are composed of the myoblasts but also the satellite cells, which repopulate those muscle cells. So if we do think about looking for dystrophin and in terms of assessing immunohistochemistry staining for dystrophin, that will obviously be something we look for in the next study. However, the most important meaningful biomarker for us will be Western blot dystrophin and we can quantitatively assess against our peers.

感謝你的提問。因此，我認為如果我們考慮衛星細胞數據的重要性，我們確實認為它有助於推動整個肌肉產生抗肌萎縮蛋白。因此，肌肉由成肌細胞和衛星細胞組成，衛星細胞重新填充這些肌肉細胞。因此，如果我們確實考慮尋找肌肉營養不良蛋白並評估肌肉營養不良蛋白的免疫組織化學染色，那麼這顯然將是我們在下一項研究中尋找的內容。然而，對我們來說最重要的有意義的生物標記將是蛋白質印跡肌肉營養不良蛋白，我們可以針對同行進行定量評估。

But I think in the totality of the treatment, and I think this is what's really important around the satellite cell production is with newborn screening growing in the U.S., we now know newborn screening is growing in Europe. If you think about screening patients much earlier in the disease process or before the loss of ambulation and before the point before the disease would historically have been diagnosed, anyone who treats those boys earier and get exposure to the repopulating cells in the body, we think is a critical part of the treatment paradigm. So it's -- I think it's an exciting piece because it demonstrates the potential of our N531 and PN chemistry distribute broadly in the muscle, not just the select cells.

但我認為，從治療的整體角度來看，隨著美國新生兒篩檢的不斷發展，衛星細胞生產的真正重要之處在於，我們現在知道歐洲的新生兒篩檢也在不斷發展。如果您考慮在疾病過程的早期或喪失行走能力之前以及歷史上診斷出疾病之前對患者進行篩檢，那麼任何較早治療這些男孩並接觸體內再生細胞的人，我們認為是治療範式的關鍵部分。所以我認為這是一個令人興奮的作品，因為它證明了我們的 N531 和 PN 化學物質的潛力廣泛分佈在肌肉中，而不僅僅是選定的細胞。

We think long term, it treats to the totality of the treatment of the disease. But it will obviously be something that will be assessed in the subsequent study. And I think it's important that it was also identified in all three boys. So this wasn't a unique finding in a particular boy in the original study. So I think it's going to be compelling as we look at it in the FORWARD-53 study.

我們認為從長遠來看，它可以治療疾病的整體。但這顯然將在後續研究中進行評估。我認為重要的是在所有三個男孩身上也發現了這一點。因此，這並不是最初研究中某個男孩的獨特發現。所以我認為當我們在 FORWARD-53 研究中看到它時，它會很引人注目。

Okay. That's great. And I want to ask separately also about the alpha-1 antitrypsin program. Just to preface the question, I noticed (inaudible) development of their knockout approach targeting liver phenotype. They're advancing their lung phenotype program only. And then, of course, the RNAi approach is focused on liver. So it seems like there's an opportunity here for Wave and for RNA editing to really demonstrate that you can hit two birds with one stone, so to speak, and treat both lung and liver phenotype, maybe even within the same patient.

好的。那太棒了。我還想單獨詢問有關 alpha-1 抗胰蛋白酶計劃的問題。作為問題的前言，我注意到（聽不清楚）他們針對肝臟表型的敲除方法的發展。他們只是在推進他們的肺表型計劃。當然，RNAi 方法的重點是肝臟。因此，Wave 和 RNA 編輯似乎有機會真正證明一石二鳥，可以治療肺和肝表型，甚至可以治療同一患者。

So I'm curious if that's a focus of maybe the initial patients you would enroll if that's even possible to sort of enrich for that? And really, in general, thinking about the market, how many patients kind of fit into this category where they could benefit from a therapy that addresses both lung and liver phenotypes at once?

所以我很好奇這是否是您最初招募的患者的焦點，如果這有可能豐富這一點的話？實際上，總的來說，考慮到市場，有多少患者屬於這一類別，他們可以從同時解決肺部和肝臟表型的療法中受益？

No. It's a phenomenal question. Obviously, an interesting update today. I think the other interesting nuance that we're also trying to expect from that and then the announcement today of our regulatory filings where we can say, actually, we think RNA editing is being treated very similarly to other oligonucleotide with a shift from an IND filing to a CTA filing for lung. So I think there's a lot of questions still around DNA editing versus RNA editing. But to your point on liver versus lung, I think we agree from the beginning, your important point that it's about the totality of treatment for AATD. We don't want to exclude patients, they go on particularly (inaudible) patients to have both manifestations of the disease.

不，這是一個了不起的問題。顯然，今天有一個有趣的更新。我認為我們也試圖從中期待另一個有趣的細微差別，然後今天宣布我們的監管文件，我們可以說，實際上，我們認為RNA 編輯的處理方式與其他寡核苷酸非常相似，但與IND 有所不同。向 CTA 提交肺部申請。所以我認為關於 DNA 編輯和 RNA 編輯仍然存在很多問題。但對於您關於肝臟與肺部的觀點，我認為我們從一開始就同意您的重要觀點，即這是關於 AATD 的整體治療。我們不想排除患者，特別是（聽不清楚）患者會同時出現這種疾病的兩種表現。

So obviously, there's a protein expression threshold. So again, beating two birds with the same hand, being able to elevate that restored protein function lets us protect lung. But obviously, as we've shown over time, too, that wild-type protein allows the Z protein to come out of the liver and improve liver function. The other thing we've seen, and I think this is an important point, again, for the repeat dosing that comes with RNA editing is, we have shown that cells get healthier.

顯然，存在一個蛋白質表現閾值。再說一次，用同一隻手擊敗兩隻鳥，能夠提高恢復的蛋白質功能可以讓我們保護肺部。但顯然，正如我們隨著時間的推移所證明的那樣，野生型蛋白可以使 Z 蛋白從肝臟中出來並改善肝功能。我們看到的另一件事，我認為這是很重要的一點，對於 RNA 編輯帶來的重複劑量，我們已經證明細胞變得更健康。

And so visibility when you repeat dose that you don't have to try to capture all of the cells on that single infusion and then watch the other hepatocytes necrose as they're injured, you get to restore healthy hepatocytes over time, which continues to make more protein and improve the production over time as well. So I think if we think about again, the totality of the treatment for this important disease, so there are 100,000 patients in the U.S. and Europe, having a treatment that singularly treats both liver and lung, and we're going after, I think is a really exciting promise for these patients.

因此，當您重複劑量時，您不必嘗試捕獲單次輸注中的所有細胞，然後觀察其他肝細胞因受傷而壞死，隨著時間的推移，您可以恢復健康的肝細胞，這將繼續隨著時間的推移，可以產生更多的蛋白質並提高產量。所以我想如果我們再考慮一下這種重要疾病的治療整體，那麼美國和歐洲有 100,000 名患者正在接受一種單獨治療肝臟和肺部的治療，我認為我們正在追求對於這些患者來說，這是一個非常令人興奮的承諾。

And our next question comes from the line of Salim Syed from Mizuho.

我們的下一個問題來自 Mizuho 的 Salim Syed。

Great. Good morning, Paul. Thanks for the update and the question. A little one for me on DMD since it's an important year for you next year, '24 in this space. Just curious to get your views, just generally on the DMD space as a whole, just given everything that we've seen lately with -- if you can talk about -- to the time you talked about the Sarepta compound (inaudible) and it failed to hit on the primary embark and then it does $70 million in sales in quarter 1, right? Just curious, any implications there or nuances to your updated thoughts on either regulatory or commercial as it relates to the space?

偉大的。早安，保羅。感謝您的更新與提問。我想談談 DMD，因為明年（24 年）對這個領域來說是重要的一年。只是想知道您對整個 DMD 領域的看法，以及我們最近看到的一切（如果您可以談論的話）到您談論 Sarepta 化合物（聽不清）及其時的情況未能成功首發，但第一季度銷售額達到7000 萬美元，對吧？只是好奇，您對與該領域相關的監管或商業的最新想法有何影響或細微差別？

I mean I think this is an important point you bring up, which is that patients need new treatment, whether or not that was gene therapy coming to market, I think over the existing skippers, I think patients need new treatments and recognized that they are underserved. We had very interesting discussions with (inaudible) with the patient community and I think there is a hunger for improved functional dystrophin. And so I think as we look at the space, I obviously can't comment on Sarepta's individual regulatory discussions.

我的意思是，我認為這是你提出的一個重要觀點，即患者需要新的治療，無論基因療法是否上市，我認為相對於現有的船長，我認為患者需要新的治療，並認識到他們是服務不足。我們與患者群體（聽不清楚）進行了非常有趣的討論，我認為人們渴望改善功能性肌肉營養不良蛋白。因此，我認為，當我們審視這個領域時，我顯然無法對 Sarepta 的個人監管討論發表評論。

But what I can say is we are resolutely focused on driving as much functional dystrophin protein as possible and seeing that translate to functional benefit for these boys, not just in the U.S. And I think that's another thing we routinely hear is the frustration outside the United States, where we're engaged with the patient community, who watched in the U.S. as these accelerated approvals from medicines, as you point out, are getting on to market.

但我能說的是，我們堅決致力於驅動盡可能多的功能性肌肉營養不良蛋白，並看到這轉化為這些男孩的功能益處，而不僅僅是在美國。我認為這是我們經常聽到的另一件事，那就是曼聯以外的挫敗感正如您所指出的，我們與患者群體接觸的各州，他們在美國看到這些加速批准的藥物正在進入市場。

But because they haven't finished the complete study, are not going to treat patients outside the United States. So as we think about the totality of our program, both a U.S. strategy, but ultimately delivering functional protein so that we can see that translation to boys globally, not just those that are amenable to 53, but again, our thesis of being able to expand that beyond 53 across 40% of DMD, I think that's our core focus. So we've seen that with the initial data. We're excited about FORWARD-53 in terms of delivering protein data and really providing substantial opportunities for these boys with DMD.

但由於他們尚未完成完整的研究，因此不會治療美國以外的患者。因此，當我們思考我們的計劃的整體性時，這既是美國的戰略，但最終提供功能性蛋白質，以便我們可以看到對全球男孩的翻譯，而不僅僅是那些適合53 的男孩，而且我們的論點是能夠將其擴展到 53 個以上，涵蓋 40% 的 DMD，我認為這是我們的核心重點。我們已經透過初始數據看到了這一點。我們對 FORWARD-53 感到興奮，因為它提供了蛋白質數據，並真正為這些患有 DMD 的男孩提供了大量機會。

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

我們的下一個問題來自 Truist Securities 的 Joon Lee。

This is (inaudible) on for Joon Lee. I'm just wondering, do you plan to analyze the guide molecules for Cas12a or Cas9 using your platform, now that you've demonstrated progress in ASOs, RNAi and RNA editing. And then just on INHBE, the time line is (inaudible) I'm just wondering, do you think you could have progressed faster with an ASO?

這是為李俊 (Joon Lee) 準備的（聽不清楚）。我只是想知道，既然您已經在 ASO、RNAi 和 RNA 編輯方面取得了進展，您是否計劃使用您的平台分析 Cas12a 或 Cas9 的引導分子。然後就在 INHBE 上，時間線是（聽不清楚）我只是想知道，您認為透過 ASO 可以進步得更快嗎？

So can you repeat the second question? I just want to make sure.

那你能重複一下第二個問題嗎？我只是想確定一下。

Yes. I'm just wondering if you could just elaborate a little bit on if you think you could progress faster within antisense oligonucleotide as opposed to an RNAi approach for the INHBE program?

是的。我只是想知道您是否可以詳細說明您是否認為反義寡核苷酸（而不是 RNAi 方法）在 INHBE 專案中可以取得更快的進展？

Okay. Sorry, I'll take the last one. So I just want to make sure for INHBE because it was not clear with AATD or INHBE. So you're saying could we have gone faster for an ASO. No, I think actually, our experience in siRNA and as we shared earlier in our collaboration with (inaudible), we've been working in double-strand siRNA for a while now with our format. So I don't think that there is any speed disadvantage by pursuing siRNA for the INHBE program. In fact, I think we're quite on track and, I think, competitive in the field right now in siRNA, and I think as we've always said, having multiple modalities, lets us really evaluate what is the best modality for treating this given disease.

好的。抱歉，我拿最後一張。所以我只是想確定一下 INHBE，因為 AATD 或 INHBE 還不清楚。所以您是說我們是否可以加快 ASO 的速度。不，我認為實際上，我們在 siRNA 方面的經驗以及我們之前在與（聽不清楚）合作中分享的經驗，我們已經在雙股 siRNA 方面以我們的格式進行了一段時間的研究。因此，我認為 INHBE 程序使用 siRNA 不會帶來任何速度劣勢。事實上，我認為我們已經步入正軌，並且目前在 siRNA 領域具有競爭力，而且我認為正如我們一直所說的那樣，擁有多種治療方式可以讓我們真正評估什麼是治療的最佳方式這種特定的疾病。

And I think what we've seen in not just potency, but durability, the GalNAc in hepatocytes on silencing, I think we actually have the best modality and format, frankly, to treat this where we can think about potential for biannual or annual dosing. So I think we've got a competitive program here. I think our goal is to stay ahead in the space, and we'll continue to watch it. As to your first question, it's an interesting one because as we think about the power of guide trends, and we have discussed with numerous companies around our GMP manufacturing capability and process development, I do think we have the ability to work in these spaces. What I don't want that to be translated to on this call is that Wave is going to work on RNA-controlled guide strands for CRISPR right now. But I think the capability we have in collaboration to apply our chemistry and apply our manufacturing know-how and our process development across multiple formats in oligonucleotides, is definitely translatable.

我認為我們不僅看到了效力，還看到了持久性，肝細胞中的GalNAc 沉默，坦率地說，我認為我們實際上擁有最好的方式和形式來治療這一問題，我們可以考慮每年兩次或每年一次給藥的潛力。所以我認為我們這裡有一個有競爭力的計劃。我認為我們的目標是在該領域保持領先地位，我們將繼續專注。至於你的第一個問題，這是一個有趣的問題，因為當我們思考引導趨勢的力量時，我們已經與許多公司圍繞我們的GMP 製造能力和工藝開發進行了討論，我確實認為我們有能力在這些領域開展工作。我不希望在這次電話會議上翻譯成 Wave 現在將致力於 CRISPR 的 RNA 控制的引導鏈。但我認為，我們合作應用我們的化學、應用我們的製造技術和寡核苷酸多種形式的製程開發的能力絕對是可以轉化的。

I think our focus right now is RNA editing in the case as we shared earlier, has a lot of advantages. But the approach we're taking our chemical modifications, again, proprietary way, are definitely transferable across other oligonucleotides in the space.

我認為我們現在的重點是 RNA 編輯，正如我們之前分享的那樣，它有很多優點。但我們採用的化學修飾方法，同樣是專有的方法，絕對可以在該領域的其他寡核苷酸之間轉移。

And then just one more. So I noticed that the single dose data was that originally you were going to get it this quarter. And now it's going to come out with the multi-dose data in the second quarter of 2024. If you could just elaborate a little bit on that?

然後還有一個。所以我注意到單劑量數據是最初您將在本季度獲得的。現在它將在 2024 年第二季度公佈多劑量數據。您能詳細說明一下嗎？

(inaudible).

（聽不清楚）。

Yes, sure. So the single dose data are not informative for our next step. And as we've rolled over the single dose data into the multi-dose cohort and fully enrolled multi-dose cohort, we're reading them out together because these are the important data enabling decision-making.

是的，當然。因此單劑量數據對我們下一步沒有提供資訊。當我們將單劑量資料轉入多劑量隊列並完全登記多劑量隊列時，我們將它們一起讀出，因為這些是支持決策的重要數據。

Yes. I mean just to follow up on that. I mean the single dose is complete. When we cut data and I think this has been discussed before, it is critical when you do assessments of data, particularly on studies as they go to evaluate all patients simultaneously to avoid any discrepancies across the assay in comparison. And so with that complete to Anne-Marie's point, with those patients having rolled over in a fully enrolled 30-milligram repeat dose cohort, those repeat dose data, as we shared earlier on prior calls, are going to be critical in informing the next step of the program.

是的。我的意思是跟進此事。我的意思是單劑量已完成。當我們削減數據時，我認為這已經討論過，當你進行數據評估時，特別是在研究中，這是至關重要的，因為他們要同時評估所有患者，以避免比較過程中出現任何差異。因此，隨著Anne-Marie 的觀點的完成，這些患者已經轉入完全登記的30 毫克重複劑量隊列，正如我們之前在之前的電話會議中分享的那樣，這些重複劑量數據對於通知下一次治療至關重要。程序的步驟。

Thank you. One moment for our next question. And our next question comes from the line of Joseph Schwartz from Leerink Partners.

謝謝。請稍等一下我們的下一個問題。我們的下一個問題來自 Leerink Partners 的 Joseph Schwartz。

So given what we recently saw from EMBARK, I was wondering if we could get your opinion on the merit of NSAA as a functional assessment. And what other endpoints do you think could be more informative, if any? And what functional assessments will you be focusing on now in the FORWARD-53 study? And what is the bar for success on each? And then I have a follow-up.

因此，鑑於我們最近從 EMBARK 看到的情況，我想知道我們是否可以徵求您對 NSAA 作為功能評估的優點的看法。您認為還有哪些其他端點可以提供更多資訊（如果有）？您現在在 FORWARD-53 研究中將重點放在哪些功能評估？每個專案成功的門檻是什麼？然後我有一個後續行動。

I think the first -- and it's a great question, Joe. I mean, I think when we look at these data at the beginning, for us, the translation between and we think about Becker-like functional dystrophin -- making functional dystrophin should translate to a functional benefit. It was always a question, we remember the AdCom that was one of the FDA's questions, but would micro-dystrophin actually translate to a functional benefit. And I think consensus across the reviewers is no. So I don't think this is necessarily the application of saying, well, how do you make the North Star, the endpoint better, our focus is on how do you make the protein better, and that's been creating functional protein. So our view is we're not changing our functional endpoints. We're going to look at North Star. We're going to look at other digital endpoints.

我認為第一個——這是一個很好的問題，喬。我的意思是，我認為當我們一開始查看這些數據時，對我們來說，我們會想到貝克爾樣功能性肌肉營養不良蛋白——製造功能性肌肉營養不良蛋白應該轉化為功能性益處。這始終是一個問題，我們記得 AdCom 是 FDA 的問題之一，但微肌營養不良蛋白實際上會轉化為功能性益處嗎？我認為審稿人的共識是否定的。所以我不認為這一定是說，嗯，你如何讓北極星，終點更好，我們的重點是如何讓蛋白質更好，而這一直在創造功能性蛋白質。所以我們的觀點是我們不會改變我們的功能端點。我們要去看看北極星。我們將研究其他數字端點。

We're going look at a whole host of endpoints on function, but it gets back to the primary driver of the biology of the disease. The reason we're developing exon skipping, oligonucleotide for DMD is because the premise of the biology foundationally was, how can you create Becker-like functional protein that has all of the properties that are required there. So I think our goal is to deliver on that protein and then look at the translation of that into function.

我們將研究一系列功能終點，但它又回到了疾病生物學的主要驅動因素。我們開發用於 DMD 的外顯子跳躍寡核苷酸的原因是因為生物學的基本前提是，如何創建具有所需所有特性的貝克爾樣功能蛋白。所以我認為我們的目標是提供該蛋白質，然後研究將其轉化為功能。

And when you do your muscle histology biopsy analysis, do you think there's any potential to see evidence of a differentiated profile from having more activity in the satellite cells on the muscle cell architecture, given what you said about the actual protein that could be produced as a result?

當您進行肌肉組織學活檢分析時，考慮到您所說的可以產生的實際蛋白質，您是否認為有可能看到肌肉細胞結構上衛星細胞中更多活性的差異化特徵的證據結果？

It's a really interesting question. So obviously, one, we have longer duration, right, a follow-up in terms of the FORWARD-53 than the 3 doses at 6 weeks, which is a more static time point. And so there are opportunities to see the evolution of satellite cells, the evolution of where dystrophin is located. The important thing, obviously, is the quantitative functional protein and then looking at endpoints beyond that. But there are interesting discussions happening.

這是一個非常有趣的問題。很明顯，第一，我們對 FORWARD-53 的追蹤時間比 6 週時的 3 劑劑量更長，對吧，這是一個更靜態的時間點。因此，我們有機會看到衛星細胞的演化，以及抗肌萎縮蛋白所在位置的演化。顯然，重要的是定量功能蛋白，然後觀察除此之外的終點。但正在發生一些有趣的討論。

I know in muscle biology thinking about population and translation of satellite cells into how that dystrophin translates onto the myoblasts and how do you actually expand dystrophin coverage of myoblast again, a lot of that work being academic, I think the fact is -- the fact that we get there actually should let us be able to look at dystrophin architecture over time. And those are interesting continued academic experiments to really think about that translation to function.

我知道在肌肉生物學中，思考衛星細胞的數量和翻譯，即肌肉營養不良蛋白如何翻譯到成肌細胞上，以及如何真正擴大肌營養不良蛋白對成肌細胞的覆蓋範圍，其中許多工作都是學術性的，我認為事實是——事實我們到達那裡實際上應該讓我們能夠隨著時間的推移觀察肌肉營養不良蛋白的結構。這些都是有趣的持續學術實驗，可以真正思考將功能轉化為功能。

I think again, the most important endpoints for us should be the quantity of dystrophin that we produce and the translation to function endpoints. But again, when you see that, that opens up a lot of possibilities to then continue to look and understand better the dystrophin biology and ultimately the translation of that.

我再次認為，對我們來說最重要的終點應該是我們產生的肌肉營養不良蛋白的數量以及功能終點的翻譯。但同樣，當你看到這一點時，這就開啟了許多可能性，可以繼續更好地研究和理解抗肌萎縮蛋白生物學以及最終的翻譯。

And our next question comes from the line of Eun Yang from Jefferies.

我們的下一個問題來自 Jefferies 的 Eun Yang。

Another question on DMD. So when you produce dystrophin protein and obviously, it's close to full length versus a micro-dystrophin. I mean you mentioned there is -- there are like academic testing to assess functionality of a protein itself. But when you measure the protein levels, do you assume that the protein is all functional?

另一個關於DMD的問題。因此，當你產生肌肉營養不良蛋白時，顯然，它與微肌營養不良蛋白相比接近全長。我的意思是你提到有--有類似的學術測試來評估蛋白質本身的功能。但是，當您測量蛋白質水平時，您是否認為該蛋白質具有全部功能？

Yes. So when dystrophin protein is translated to the outside of the cell, at that point, that's the functional protein. That's after -- I mean that's why this protein takes time to both produce and then locate itself onto the external part of the cell, right? So I think that's the piece over time. That is the functional protein. When I was talking about the academic work, that's more on how that distribution takes place over time.

是的。因此，當抗肌營養不良蛋白被翻譯到細胞外部時，這就是功能蛋白。那是之後——我的意思是，這就是為什麼這種蛋白質需要時間來產生然後將其自身定位到細胞的外部，對嗎？所以我認為這就是隨著時間的推移而發生的事情。那就是功能性蛋白質。當我談論學術工作時，更多的是關於隨著時間的推移如何進行分配。

Our view, and obviously, it will be important as we study this, and we have longitudinal both the 24- and 48-week opportunities to really look at the progress, not just in the quantity, but in distribution, I think those are the points that were interesting to assess over time. Obviously, the key metric as we think about the potential for accelerated approval filing will be the quantitative as that's been (inaudible) of the protein. But functionality of the protein is definitely something where we will obviously look at the distribution of the protein in the cell.

我們的觀點，顯然，在我們研究這個問題時，這很重要，我們有縱向的 24 週和 48 週機會來真正觀察進展，不僅是數量，而且是分佈，我認為這些是隨著時間的推移，值得評估的要點。顯然，當我們考慮加速批准申請的潛力時，關鍵指標將是蛋白質的定量（聽不清楚）。但蛋白質的功能肯定是我們要觀察蛋白質在細胞中的分佈的地方。

I would just add, just from a logical point of view, you would expect that a protein, which is as close as possible to the native dystrophin in length is most likely to be functional. And I think with these data, we can see the EMBARK data really significant questions as to whether micro-dystrophin has the ability to deliver function benefit.

我想補充一點，從邏輯的角度來看，您會期望長度盡可能接近天然肌肉營養不良蛋白的蛋白質最有可能具有功能。我認為透過這些數據，我們可以看到 EMBARK 數據對於微肌營養不良蛋白是否有能力提供功能性益處來說確實是一個重要的問題。

And then you mentioned that obviously, there is the need for new treatment for DMD patients. So given what's out there, what we are seeing, what level of the dystrophin levels do you think you would need in order to file for approval to be differentiated commercially?

然後您提到，顯然 DMD 患者需要新的治療方法。那麼，考慮到現有情況、我們所看到的情況，您認為您需要什麼水平的抗肌營養不良蛋白水平才能申請批准進行商業差異化？

To be differentiated commercially, I think there are several ways to be differentiated. Obviously, one, for Exon 53, which is the immediate commercial space we'd be entering. We are powering the study to a show that we can deliver greater than 5%, that's the commercial threshold within the Exon 53. We believe based on our levels of transcript and the time and duration we're treating that, we should be able to see that level of protein above that current threshold.

要在商業上做到差異化，我認為有幾個方面可以做到差異化。顯然，其中之一是 Exon 53，這是我們即將進入的商業空間。我們正在推動這項研究，以證明我們可以提供超過 5% 的效果，這是外顯子 53 內的商業閾值。我們相信，根據我們的轉錄本水平以及我們治療的時間和持續時間，我們應該能夠看到蛋白質水平高於當前閾值。

As we talk to patients and physicians, there's other areas of points of differentiation even amongst the current programs. So we're already less frequent in terms of dosing administration as we talk to these patients about impact on their life in terms of travel, transit costs, having weekly IV infusions versus whether it's biweekly and as we saw in our data from Part A, 25-day half-life means the potential for monthly or less frequent treatment.

當我們與患者和醫生交談時，即使在目前的計劃中也存在其他方面的差異點。因此，當我們與這些患者討論旅行、交通費用、每週靜脈輸液與是否每兩週一次對他們生活的影響時，我們在給藥方面已經不太頻繁了，正如我們在A 部分的數據中看到的那樣， 25 天的半衰期意味著每月一次或更低頻率的治療的可能性。

That in and of itself as we talk to families is a huge advantage. So we see that in the profile of the stability of our drug. We have a profile in terms of safety, too, at least in the early pieces that tells us that we shouldn't look differently than the existing standard of care. So we can provide these patients an opportunity to switch with less frequent administration and substantially more protein, which is what we are powered to see and the ability to get the satellite cells and the fact that we see higher levels, and I think you need to go back to remember that data, 53% transcript was seen in skeletal muscle. We've shared data that shows that we see substantially (inaudible) transcript production in both our NHPs and in our double knockout mice in heart and diagram.

當我們與家人交談時，這本身就是一個巨大的優勢。所以我們在藥物的穩定性方面看到了這一點。我們在安全方面也有一個概況，至少在早期的文章中，它告訴我們我們不應該與現有的護理標準不同。因此，我們可以為這些患者提供一個機會，以更少的給藥頻率和更多的蛋白質進行轉換，這是我們有能力看到的，也是獲得衛星細胞的能力，而且我們看到了更高水平的事實，我認為你需要回頭記住那個數據，53%的轉錄物是在骨骼肌中看到的。我們共享的數據表明，我們在 NHP 以及心臟和圖表中的雙敲除小鼠中看到了大量（聽不清楚）轉錄產物的產生。

So we think about the overall profile, differentiated profile from the existing standard. And what's going to be important to patients, it's high levels of cardiac distribution and muscle dystrophin protein, high levels of diaphragmatic protein expression that treats the underlying respiratory and cardiopulmonary complications that these patients suffer from, in addition to the high levels of skeletal muscle concentration. So the totality of the profile, and I know people tend to think about all exon skipping as being the same.

所以我們考慮整體輪廓，與現有標準的差異化輪廓。對於患者來說，重要的是高水平的心臟分佈和肌肉營養不良蛋白、高水平的橫膈膜蛋白表達，除了高水平的骨骼肌濃度之外，還可以治療這些患者患有的潛在呼吸和心肺併發症。因此，總體而言，我知道人們傾向於認為所有外顯子跳躍都是相同的。

The profile and the reason we started this program after our prior experience this year is not just because of the quantity of dystrophin but the localization, the exposure, the profile, it's differentiated from the existing exon skipping therapies without the need for conjugates and other modalities that potentially impact liabilities on those molecules compared to standard care.

我們在今年的經驗之後開始這個計畫的原因不僅是因為肌肉營養不良蛋白的數量，而且是因為其定位、暴露、概況，它與現有的外顯子跳躍療法不同，不需要結合物和其他方式與標準護理相比，這可能會影響這些分子的責任。

And then last question is on AATD, RNA. So when you deliver a proof of mechanism data sometime in 2024. Can you kind of talk about the level of data we see in terms of number of patients? What kind of data we would see in order to determine proof of mechanism?

最後一個問題是關於 AATD、RNA。因此，當您在 2024 年的某個時候提供機制數據證明時。您能談談我們在患者數量方面看到的數據水平嗎？為了確定機制證明，我們會看到什麼樣的數據？

I'll let Anne-Marie define kind of -- I think it's important that we benchmark proof of mechanism. Obviously, a lot more updates to your other questions in terms of numbers and designed as the study progresses. But do you want to talk about that?

我會讓 Anne-Marie 來定義——我認為我們對機制證明進行基準測試很重要。顯然，隨著研究的進展，您的其他問題在數量和設計上會有更多更新。但你想談談這個嗎？

Sure. So proof of mechanism is detection of additive protein in serum. And that will be a very significant milestone because it will be first evidence that (inaudible) editing can translate into humans. And in our study, we have multiple assessments of (inaudible) throughout the cohorts, low, medium and low, and so we can achieve proof of mechanism as soon as we detect it. And that's before the completion of the trial and potentially before completion of the first cohort.

當然。因此，機制的證據是檢測血清中的添加蛋白。這將是一個非常重要的里程碑，因為這將是（聽不清楚）編輯可以轉化為人類的第一個證據。在我們的研究中，我們對整個隊列（低、中、低）進行了多次評估（聽不清楚），因此一旦我們檢測到它，我們就可以實現機制證明。那是在試驗完成之前，並且可能在第一批完成之前。

(Operator Instructions) Our next question comes from the line of Luca Issi from RBC.

（操作員說明）我們的下一個問題來自 RBC 的 Luca Issi。

Great. This is Lisa on for Luca. Just a couple on A1AT. You mentioned that multiple CTAs have been accepted. Just wondering if you can share which geographies you have cleared the CTAs. And on the SAD data, I know you're expecting to dose healthy volunteers soon. Given there's no mutation to correct in healthy volunteers, what clinical information are you hoping to gain from these subjects? And what will help inform further treatment in A1AT patients?

偉大的。這是盧卡的麗莎。 A1AT 上只有一對。您提到多個 CTA 已被接受。只是想知道您是否可以分享您已通過 CTA 的地理位置。根據 SAD 數據，我知道您預計很快就會對健康志願者進行給藥。鑑於健康志願者中沒有需要糾正的突變，您希望從這些受試者中獲得哪些臨床資訊？什麼有助於為 A1AT 患者的進一步治療提供資訊？

Sure. Well, the first clinical trial sites are Australia and U.K. with more coming. And to your question about what we expect to get from the volunteer study? Well, the volunteer study has been designed to enable us to most rapidly achieve (inaudible) patients that we would expect to see target engagement. And so it's really designed for efficiency and speed. So the healthy volunteer study will inform progress in the patient study and also, of course, safety and tolerability.

當然。嗯，第一個臨床試驗地點是澳洲和英國，還會有更多的臨床試驗地點。關於我們期望從志工研究中得到什麼的問題？嗯，志願者研究的目的是使我們能夠最快速地實現（聽不清楚）我們期望看到目標參與的患者。所以它確實是為了效率和速度而設計的。因此，健康志願者研究將告知患者研究的進展，當然還有安全性和耐受性。

If you think about it, the goal is to get very quickly to the first low-dose cohort in the patient arm, which is where we modeled to anticipate initially engaging target. So there's a combination of how quickly can we enroll and establish both safety and PK and tie that over to our preclinical modeling on PD, which is translated across multiple clinical programs to date.

如果您考慮一下，我們的目標是非常快速地達到患者組中的第一個低劑量隊列，這就是我們建模以預測最初參與目標的地方。因此，我們要多快地註冊並確定安全性和 PK，並將其與我們的 PD 臨床前模型聯繫起來，該模型迄今為止已在多個臨床項目中進行了翻譯。

And to be able to affirm how do we get quickly to starting in a patient cohort where we would expect to anticipate engaging targets. So this idea of kind of rapidly starting as opposed to building up in patients to get to a part where you eventually engage target, I think the team has done a really elegant job of bringing those pieces together to expedite getting to that proof of mechanism (inaudible) as quickly as possible.

並且能夠確認我們如何快速開始在患者群中預期參與目標。因此，這種想法是快速啟動的，而不是在患者身上建立起來，以達到最終參與目標的部分，我認為該團隊做得非常出色，將這些部分整合在一起，以加快獲得機制證明（聽不見清）盡快。

One more, if I may. Just on the milestones. Can you give us a sense of the cadence of the milestone payments from GSK for the A1AT program?

如果可以的話，再來一張。就在里程碑上。您能否向我們介紹一下葛蘭素史克 (GSK) 為 A1AT 專案支付里程碑付款的節奏？

Sure. I mean I think, obviously, we can't break it down. But we can say is, as we've said publicly, we have milestones for the program as we move through the clinic. Some of these are execution milestones and some of these are data inflection milestones. We anticipate milestone payments in 2023 and then 2024 and beyond. So that's the most I can say. But given the progress the team is making, I think it's pretty clear to see a path to how we're going to move through that cadence of potential milestones.

當然。我的意思是，我認為，顯然，我們無法將其分解。但我們可以說，正如我們公開表示的那樣，隨著臨床試驗的進展，我們已經實現了該計畫的里程碑。其中一些是執行里程碑，一些是資料拐點里程碑。我們預計里程碑付款將在 2023 年、2024 年及以後實現。這就是我能說的最多的話。但考慮到團隊正在取得的進展，我認為很清楚我們將如何完成潛在里程碑的節奏。

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Dr. Paul Bolno for any further remarks.

今天節目的問答環節到此結束。我想將該程式交還給保羅·博爾諾博士以供進一步評論。

Thank you all for joining the call this morning. I also want to thank our employees for their efforts towards delivering life-changing treatments for people (inaudible) devastating diseases. We have an exciting year on the horizon, and we look forward to keeping you all updated on our progress. Have a great day.

感謝大家今天早上參加電話會議。我還要感謝我們的員工為為人們（聽不清楚）毀滅性疾病提供改變生活的治療方法所做的努力。我們即將迎來激動人心的一年，我們期待向大家通報我們的最新進展。祝你有美好的一天。

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

女士們、先生們，感謝你們參加今天的會議。這確實結束了該程式。您現在可以斷開連線。再會。