WAVE Life Sciences Ltd (WVE) 2025 Q1 法說會逐字稿

Good morning, and welcome to the Wave Life Sciences first quarter 2025 earnings conference call. At this time, all participants are on listen-only mode. As a reminder, this call is being recorded and webcasted. (Operator Instructions)

早安，歡迎參加 Wave Life Sciences 2025 年第一季財報電話會議。此時，所有參與者都處於只聽模式。提醒一下，本次通話將會被錄音並進行網路直播。（操作員指示）

I now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

現在我將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, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our first quarter 2025 earnings update, including progress updates for obesity and AATD clinical trials.

謝謝接線員，各位電話裡的各位早安。今天早些時候，我們發布了一份新聞稿，概述了我們 2025 年第一季的收益更新，包括肥胖症和 AATD 臨床試驗的進展更新。

Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Erik Ingelsson, Chief Scientific Officer; and Kyle Moran, Chief Financial Officer. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

今天與我一起發表準備好的演講的還有總裁兼首席執行官保羅·博爾諾博士、首席科學官埃里克·英格爾松博士和首席財務官凱爾·莫蘭。今天早上發布的新聞稿可在我們網站 www.wavelifesciences.com 的投資者部分查閱。

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. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statements for any reason.

在我們開始之前，我想提醒您，本次電話會議中的討論將包括前瞻性陳述。這些聲明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聲明中所述的結果有重大差異。今天發布的新聞稿和我們提交給美國證券交易委員會的文件中討論了可能導致實際結果不同的因素。我們不承擔因任何原因更新或修改任何前瞻性陳述的義務。

I'd now like to turn the call over to Paul.

現在我想把電話轉給保羅。

Thanks, Kate. Good morning, and thank you all for joining us on today's call. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. With our clinical pipeline progress over the last 12 months, we've made significant strides towards realizing this vision as we've rapidly advanced our INHBE obesity, AATD, DMD and HD programs, demonstrating the impact of our novel and proprietary oligonucleotide chemistries in the clinic.

謝謝，凱特。早安，感謝大家參加今天的電話會議。十多年來，我們一直堅持不懈地致力於釋放 RNA 藥物的巨大潛力，以改善人類健康。隨著過去 12 個月臨床管線的進展，我們在實現這一願景方面取得了重大進展，因為我們迅速推進了 INHBE 肥胖症、AATD、DMD 和 HD 項目，展示了我們新穎的專有寡核苷酸化學在臨床中的影響。

It is our unique platform that has enabled us to assemble our multimodal pipeline, pioneer RNA editing and most recently, advance oligonucleotides into common diseases such as obesity. In just the past two months since our fourth quarter update, we've continued the positive momentum across our pipeline by delivering the first 48-week FORWARD-53 clinical results of WVE-N531 for DMD that have put us on track for our first NDA filing. We've also demonstrated our consistent execution by advancing our obesity and AATD clinical trials towards multiple meaningful data inflection points this year.

正是我們獨特的平台使我們能夠組裝多模式管道、開創 RNA 編輯，並且最近將寡核苷酸推進到肥胖症等常見疾病。自第四季度更新以來的短短兩個月內，我們繼續保持了整個產品線的積極勢頭，發布了用於治療 DMD 的 WVE-N531 的首批 48 週 FORWARD-53 臨床結果，這讓我們有望提交第一份 NDA 申請。今年，我們也透過將肥胖症和 AATD 臨床試驗推進到多個有意義的數據拐點，證明了我們始終如一的執行力。

I'll begin with an update on these ongoing clinical studies and then review our recent positive results in DMD. Starting in obesity, we are continuing to make tremendous progress in our INLIGHT clinical trial with WVE-007, our GalNAc-siRNA INHBE candidate designed to deliver healthy, sustainable weight loss. Despite the rapid ascension of GLP-1s as standard of care, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability, including GI side effects and high discontinuation rates.

我將首先介紹這些正在進行的臨床研究的最新進展，然後回顧我們最近在 DMD 方面取得的積極成果。從肥胖症開始，我們在 INLIGHT 臨床試驗中繼續取得巨大進展，使用 WVE-007 進行試驗，這是我們的 GalNAc-siRNA INHBE 候選藥物，旨在實現健康、可持續的減肥。儘管 GLP-1 作為治療標準迅速崛起，但其使用往往受到頻繁給藥、肌肉質量損失、耐受性差（包括胃腸道副作用）和高停藥率的限制。

With an ability to deliver sustainable, healthy weight loss with preservation of muscle and without the common negative side effects increasingly associated with GLP-1s, WVE-007 would unlock the next frontier in obesity treatment for more than 1 billion people living with obesity globally.

WVE-007 能夠實現可持續、健康的減肥效果，同時保持肌肉質量，並且不會產生 GLP-1 日益常見的負面副作用，它將為全球超過 10 億肥胖患者開闢肥胖治療的新領域。

Leveraging human genetic insights, WVE-007 is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass with infrequent dosing of once or twice a year. Our preclinical data on 007 have corroborated the strong genetic evidence for the INHBE target. With just a single dose of WVE-007, we've demonstrated weight loss on par with semaglutide and importantly, without suppressing food intake or loss of muscle mass.

WVE-007 利用人類基因見解，旨在透過一種完全獨特的作用機制來推動減肥，該機制可在不影響肌肉質量的情況下誘導脂肪燃燒，每年只需服用一到兩次。我們關於 007 的臨床前數據證實了 INHBE 標靶的強有力的遺傳證據。只需一劑 WVE-007，我們就證明了其減肥效果與司美格魯肽相當，而且重要的是，它不會抑制食物攝取或肌肉質量損失。

We've also shown synergies with GLP-1s, including as an add-on for individuals requiring greater weight loss or who cannot tolerate high doses of GLP-1s. And notably, we demonstrated WVE-007's potential as an off-ramp to GLP-1s, enabling long-term healthy weight maintenance. This maintenance approach would avoid the weight regain that is common when discontinuing GLP-1s and the associated metabolic risk of weight cycling.

我們也展示了與 GLP-1 的協同作用，包括作為需要更大減肥效果或無法耐受高劑量 GLP-1 的個體的附加藥物。值得注意的是，我們證明了 WVE-007 作為 GLP-1 出口的潛力，從而實現長期健康的體重維持。這種維持方法可以避免停用 GLP-1 時常見的體重反彈以及相關的體重循環代謝風險。

We are advancing WVE-007 in the INLIGHT clinical trial in overweight and obese, but otherwise healthy adults with a BMI between 28 and 40. Today, we can share that we have completed dosing in the first two single-dose cohorts of the study and remain on track to deliver initial data from the trial in the second half of this year, which will include safety, tolerability and early changes in body weight as well as biomarkers reflective of healthy weight loss.

我們正在 INLIGHT 臨床試驗中推進 WVE-007 的研究，該試驗針對的是體重超重和肥胖但身體健康的成年人，其 BMI 在 28 至 40 之間。今天，我們可以分享，我們已經完成了該研究的前兩個單劑量組的給藥，並將繼續按計劃在今年下半年提供試驗的初步數據，其中包括安全性、耐受性和體重的早期變化以及反映健康減肥的生物標誌物。

Turning to WVE-006, our GalNAc RNA editing oligonucleotide or AIMer for alpha-1 antitrypsin deficiency. WVE-006 is designed to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. WVE-006 does not require IV administered LNPs or complex delivery vehicles like other treatments in development.

轉向 WVE-006，我們的 GalNAc RNA 編輯寡核苷酸或 AIMer，用於治療 alpha-1 抗胰蛋白酶缺乏症。WVE-006 旨在成為首個透過便捷的皮下給藥療法解決疾病根本原因的 AATD 治療方法。WVE-006 不需要像其他正在開發中的治療方法那樣透過靜脈注射 LNP 或複雜的輸送載體。

And by editing at the RNA level, WVE-006 differs from DNA editing technologies, which rely on hyperactive exogenously delivered artificial enzymes. Preclinical data has clearly demonstrated DNA-based editing results in irreversible collateral bystander edits and indels, and these known bystander edits must be taken into consideration when interpreting clinical results.

透過在 RNA 層級進行編輯，WVE-006 不同於依賴高活性外源遞送人工酵素的 DNA 編輯技術。臨床前數據已清楚地表明基於 DNA 的編輯會導致不可逆的旁觀者編輯和插入/缺失，在解釋臨床結果時必須考慮這些已知的旁觀者編輯。

As a quick reminder, our restoration clinical program began with dose escalation of WVE-006 in healthy volunteers. And earlier this year, we announced the completion of the multi-dosing in the final cohort at dose levels greater than any plan for AATD patients in our RestorAATion-2 study. In this ongoing RestorAATion-2 study, we are dosing individuals who have the homozygous PiZZ mutation.

簡單提醒一下，我們的復健臨床計畫始於在健康志願者中增加 WVE-006 的劑量。今年早些時候，我們宣佈在 RestorAATion-2 研究中完成了最後一批 AATD 患者的多劑量給藥，其劑量水平高於任何針對 AATD 患者的計劃。在正在進行的 RestorAATion-2 研究中，我們正在對具有純合子 PiZZ 突變的個體進行給藥。

We delivered a breakthrough in the field of RNA medicines last year with the first-ever clinical demonstration of RNA editing in humans. We observed a mean 6.9 micromolar of circulating M-AAT and 10.8 micromolar of total AAT two weeks after a single dose in the first two patients in the 200-milligram cohort. We also observed increases in AAT from baseline as early as day three and as late as day 57, highlighting WVE-006's impressive durability of effect.

去年，我們在 RNA 藥物領域取得了突破，首次在人體上進行了 RNA 編輯的臨床演示。我們觀察到，在 200 毫克組的前兩名患者中，單次給藥兩週後，循環 M-AAT 平均為 6.9 微摩爾，總 AAT 平均為 10.8 微摩爾。我們還觀察到 AAT 從基線開始在第 3 天和第 57 天才有所增加，突顯了 WVE-006 令人印象深刻的持久效果。

In both RestorAATion-2 and the completed RestorAATion-1 clinical trial of healthy volunteers, we reported that 006 was well tolerated with a favorable safety profile. Following our announcement last year, interest in our study remains very high. In the first quarter, we initiated multi-dosing in the first cohort of RestorAATion-2, where patients are receiving 200 milligrams of WVE-006 every other week. This dosing interval is consistent with our preclinical data, but I'll remind you that our proof of mechanism clinical data suggests the potential for monthly or less frequent dosing intervals.

在 RestorAATion-2 和已完成的健康志願者 RestorAATion-1 臨床試驗中，我們都報告 006 具有良好的耐受性和良好的安全性。自從我們去年宣布這項消息以來，人們對我們研究的興趣仍然很高。在第一季度，我們開始在 RestorAATion-2 的第一批患者中進行多次給藥，患者每隔一周接受 200 毫克 WVE-006 治療。此給藥間隔與我們的臨床前數據一致，但我要提醒您，我們的機制臨床數據證明表明有可能實現每月或更頻繁的給藥間隔。

Dosing is also underway in our second single-dose cohort at 400 milligrams. Looking ahead, we are on track to share comprehensive updates from RestorAATion-2 this year with data from the complete 200-milligram multi-dose and single-dose cohorts expected in the third quarter and data from the complete 400-milligram single-dose cohort expected in the fall. We believe this higher single-dose cohort, coupled with the multi-dose 200-milligram data will give us meaningful insights into extending the dose interval as our preclinical and clinical data support the potential for extended dosing intervals in subsequent cohorts.

我們的第二個單一劑量組 400 毫克的給藥也正在進行中。展望未來，我們預計今年將分享 RestorAATion-2 的全面更新，其中包括預計在第三季度發布的完整 200 毫克多劑量和單劑量隊列的數據，以及預計在秋季發布的完整 400 毫克單劑量隊列的數據。我們相信，這更高的單劑量組，加上多劑量 200 毫克數據，將為我們提供延長給藥間隔的有意義的見解，因為我們的臨床前和臨床數據支持在後續組中延長給藥間隔的潛力。

These data will also inform the therapeutic potential of WVE-006 and our pipeline of RNA editing programs. Behind 006, we are advancing a wholly owned discovery pipeline addressing both hepatic and extrahepatic targets. We unveiled three of these programs at our Research Day last year, which collectively provide the potential to address upwards of 10 million patients.

這些數據還將揭示 WVE-006 和我們的 RNA 編輯程序系列的治療潛力。在 006 背後，我們正在推進一條全資擁有的針對肝臟和肝外目標的發現管道。我們在去年的研究日上公佈了其中三個項目，它們總共有可能為超過 1000 萬名患者提供治療。

We are sharing preclinical data from these programs at multiple medical meetings in the second quarter and expect to share additional new preclinical data from our hepatic and extrahepatic RNA editing programs throughout the remainder of this year. We are on track to initiate clinical development of new programs in 2026. I'll now turn to WVE-N531 for DMD. Since March, we have been actively engaged with the DMD community, sharing our exciting FORWARD-53 clinical results. These data have supported WVE-N531 as a best-in-class and important new therapeutic option for boys with exon 53 amenable DMD.

我們將在第二季度的多個醫學會議上分享這些項目的臨床前數據，並預計在今年剩餘時間內分享我們肝臟和肝外 RNA 編輯計畫的更多新臨床前數據。我們計劃於 2026 年啟動新計畫的臨床開發。我現在將轉向 WVE-N531 進行 DMD。自三月以來，我們一直積極與 DMD 社群合作，分享我們令人興奮的 FORWARD-53 臨床結果。這些數據支持 WVE-N531 成為患有外顯子 53 易感 DMD 的男孩的最佳且重要的新治療選擇。

Following 48 weeks of treatment with WVE-N531, we observed a statistically significant and clinically meaningful improvement of 3.8 seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks. We also saw additional functional benefits observed in other outcome measures, including NSAA.

經過 48 週的 WVE-N531 治療，我們觀察到起床時間與自然病程相比有顯著的改善，即提高了 3.8 秒，具有統計學意義和臨床意義，這是 48 週內相對於任何已獲批准的肌營養不良蛋白恢復療法觀察到的最大效果。我們還看到了在其他結果測量中觀察到的額外功能益處，包括 NSAA。

With biopsies taken after 24 and 48 weeks of treatment, we were able to evaluate muscle health over time. We saw the first ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in CK and circulating inflammatory biomarkers.

透過在治療 24 週和 48 週後進行活檢，我們能夠評估一段時間內的肌肉健康狀況。我們首次看到了外顯子跳躍對肌肉健康的顯著改善，包括纖維化的統計顯著減少以及 CK 和循環發炎生物標記的減少。

In addition, we've also observed clinical evidence of myogenic stem cell or satellite cell uptake of WVE-N531 earlier in our trial. This is particularly notable as myogenic stem cells are the progenitor cells for new myoblasts, which would support the improvements in muscle health and muscle fiber maturation we observed at 48 weeks.

此外，我們在試驗早期也觀察到了成肌幹細胞或衛星細胞攝取 WVE-N531 的臨床證據。這一點尤其值得注意，因為成肌幹細胞是新成肌細胞的祖細胞，它將支持我們在 48 週觀察到的肌肉健康和肌纖維成熟的改善。

We are not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake. Dystrophin expression averaged 7.8% between the 24- and 48-week time points with 88% of boys above 5% average dystrophin.

我們不知道外顯子跳躍或基因療法的任何其他臨床數據能夠證明成肌幹細胞的吸收。在 24 週到 48 週的時間點之間，肌肉營養不良蛋白的表達平均為 7.8%，其中 88% 的男孩肌肉營養不良蛋白的平均表現量高於 5%。

WVE-N531 was safe and well tolerated with no serious adverse events. DMD is a devastating disease that impacts individuals early in life. Each year, there are approximately 20,000 new cases of DMD with up to 10% amenable to exon 53 skipping. There is an urgent need for more effective and safe therapeutic options for patients. Despite the limitations of currently marketed therapies, sales of exon skipping therapies were about $1.1 billion in 2024.

WVE-N531 安全且耐受性良好，沒有發生嚴重不良事件。DMD 是一種毀滅性疾病，會對早期患者造成影響。每年約有 20,000 例新的 DMD 病例，其中高達 10% 可透過外顯子 53 跳躍治療。患者迫切需要更有效、更安全的治療選擇。儘管目前市場上的療法有其局限性，但外顯子跳躍療法的銷售額在 2024 年仍將達到約 11 億美元。

Notably, up to half of exon 53, 51 and 45 patients remain untreated with exon skipping therapy, which, through our conversations with KOLs are due in a large part to the burden of weekly dosing and limited evidence of benefit. Our data with N531 strongly demonstrate its potential to be a best-in-class treatment for boys amenable to exon 53 skipping.

值得注意的是，多達一半的外顯子 53、51 和 45 患者仍未接受外顯子跳躍療法治療，透過與 KOL 的對話，我們了解到這在很大程度上是由於每週服藥的負擔和有限的益處證據。我們關於 N531 的數據有力地證明了它有可能成為適合外顯子 53 跳躍的男孩的最佳治療方法。

Following a positive and productive meeting with the CDER division of the FDA on our 24-week data and initial plans for our confirmatory trial, the FDA has confirmed to us that the accelerated approval pathway with dystrophin expression as a surrogate endpoint remains open. We are aligned with the agency on next steps for N531, and we intend to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In the interim, we plan to continue to engage the agency with our new 48-week data, particularly in light of our statistically significant and clinically meaningful time to rise data as well as other functional outcomes and our planned global confirmatory trial.

在與 FDA 的 CDER 部門就我們的 24 週數據和確認試驗的初步計劃進行了積極而富有成效的會議後，FDA 向我們確認，以肌營養不良蛋白表達作為替代終點的加速審批途徑仍然開放。我們與該機構就 N531 的後續步驟保持一致，並計劃在 2026 年提交 NDA，以加速批准每月給藥方案的 N531。在此期間，我們計劃繼續向該機構提供我們新的 48 週數據，特別是考慮到我們具有統計意義和臨床意義的上升時間數據以及其他功能結果和我們計劃的全球確認試驗。

To support a monthly dosing regimen at launch, all participants in the extension portion of FORWARD-53 are receiving monthly dosing, and we are expanding the trial to include additional boys who will be dosed monthly. Beyond N531, we are advancing an exon skipping franchise with candidates that leverage our best-in-class chemistry, and we anticipate filing CTAs for multiple candidates in 2026.

為了支持啟動時的每月給藥方案，FORWARD-53 擴展部分的所有參與者都將接受每月給藥，我們正在擴大試驗範圍，以包括更多將每月給藥的男孩。除了 N531 之外，我們正在利用利用我們一流化學技術的候選藥物推進外顯子跳躍特許經營權，我們預計將在 2026 年為多個候選藥物提交 CTA。

Finally, turning to WVE-003 for the treatment of Huntington's disease. There is an urgent unmet need in HD as the disease impacts more than 200,000 people in the US and Europe alone, and there are no disease-modifying therapies available. HD is a devastating autosomal dominant genetic disease that impacts multiple generations of family members and is sometimes compared to having Alzheimer's, Parkinson's and ALS all at once.

最後，轉向 WVE-003 治療亨廷頓舞蹈症。亨廷頓氏舞蹈症 (HD) 是一種迫切需要滿足的治療需求，因為這種疾病僅在美國和歐洲就影響了 20 多萬人，目前還沒有可以改善病情的療法。亨廷頓氏舞蹈症是一種破壞性的體染色體顯性遺傳疾病，會影響多代家庭成員，有時被比作同時患有阿茲海默症、帕金森氏症和 ALS。

Using our platform specificity of stereochemical control and best-in-class chemistry, we developed WVE-003 using a first-in-class allele-selective approach. By reducing mutant Huntington at the mRNA and protein level, WVE-003 addresses the underlying drivers of neurodegeneration. And by sparing wild-type protein, which is critical to the health of the central nervous system, WVE-003 is uniquely positioned to address the full spectrum of HD from early asymptomatic stages to the onset of symptoms and beyond.

利用我們平台的立體化學控制和一流化學特性，我們採用一流的等位基因選擇方法開發了 WVE-003。透過在 mRNA 和蛋白質層面減少突變亨廷頓舞蹈症，WVE-003 解決了神經退化性疾病的根本驅動因素。而且，透過保留對中樞神經系統健康至關重要的野生型蛋白質，WVE-003 具有獨特的優勢，可以解決亨廷頓氏舞蹈症從早期無症狀階段到症狀出現及以後的整個治療過程。

In our SELECT-HD trial, we demonstrated the impact of our novel chemistry and allele-selective approach as we observed potent and durable mutant Huntington reductions of up to an industry-leading 46% and preservation of wild-type Huntington with just three doses.

在我們的 SELECT-HD 試驗中，我們展示了我們的新型化學和等位基因選擇性方法的影響，因為我們觀察到僅用三個劑量就能有效且持久地減少突變型亨廷頓舞蹈症，最高可達業界領先的 46%，並且能夠保留野生型亨廷頓舞蹈症。

Importantly, we observed a statistically significant correlation between allele-selective mutant Huntington reductions and slowing of caudate atrophy, marking the first time this correlation has been observed in HD. This correlation is particularly notable as caudate is one of the primary areas where HD manifests in the brain, with atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about 2% to 4% per year.

重要的是，我們觀察到等位基因選擇性突變亨廷頓氏病減少和尾狀核萎縮減緩之間存在統計學上顯著的相關性，這是首次在亨廷頓氏症中觀察到這種相關性。這種相關性尤其值得注意，因為尾狀核是亨廷頓氏症在大腦中表現的主要區域之一，其萎縮在症狀出現前很多年就已開始，並以每年約 2% 至 4% 的速度持續穩定下降。

Analyses have also demonstrated that caudate loss correlates with clinical outcomes. At the beginning of the year, we shared our own internal analysis, which investigated natural history data sets, including Track and Predict-HD and observed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with the delay of onset of disability by more than 7.5 years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting rate of caudate atrophy as a primary endpoint for efficient clinical trials.

分析也顯示尾狀核丟失與臨床結果相關。今年年初，我們分享了自己的內部分析，調查了包括 Track 和 Predict-HD 在內的自然史資料集，並觀察到尾狀核萎縮率絕對降低僅 1% 就與殘疾發生時間延遲 7.5 年以上有關。這是一個驚人的數字，對健康和經濟結果具有重要意義，並提供了進一步的證據支持尾狀萎縮率作為有效臨床試驗的主要終點。

These data, along with the full clinical results from SELECT-HD were both part of our engagement with FDA last year that led to supportive initial feedback, and we are continuing to prepare for a global potentially registrational Phase II/III study of WVE-003 in adults with SNP3 and HD using caudate as a primary endpoint. And we remain on track to submit clinical trial applications, including an IND application for this Phase II/III study in the second half of this year. And we are actively engaged in discussions with prospective strategic partners.

這些數據以及 SELECT-HD 的完整臨床結果都是我們去年與 FDA 合作的一部分，並獲得了支持性的初步反饋，我們正在繼續準備一項全球性的、可能註冊的 II/III 期研究，該研究針對患有 SNP3 和 HD 的成年人，以尾狀核為主要終點。我們仍在按計劃提交臨床試驗申請，包括今年下半年針對該 II/III 期研究的 IND 申請。我們正在積極與潛在的策略夥伴進行討論。

With that, I'll turn the call over to Erik to share more detail on our INHBE program and the emerging wholly owned pipeline.

接下來，我將把電話轉給 Erik，讓他分享更多關於我們的 INHBE 計劃和新興全資管道的細節。

Thank you, Paul, and thank you to everyone joining us on the call today. I'll begin by discussing our INHBE program for obesity. As Paul shared earlier, there have been numerous efforts to develop therapies in the obesity space. So it's important to examine how our INHBE GalNAc-siRNA approach differs from current treatments such as GLP-1 agonists and other therapies in development.

謝謝你，保羅，也感謝今天參加我們電話會議的所有人。我將首先討論我們的肥胖症 INHBE 計劃。正如保羅之前所分享的，人們已經做了許多努力來開發肥胖症領域的治療方法。因此，研究我們的 INHBE GalNAc-siRNA 方法與 GLP-1 激動劑和其他正在開發的療法等當前治療方法有何不同非常重要。

Among the reasons that I'm very excited about this program is to target strong foundation in human genetics. Several large human genetic studies have found that carriers of heterozygous loss of function variants in the INHBE gene have favorable metabolic profiles, including reduced abdominal obesity and visceral fat, serum triglycerides, ApoB, fasting glucose, HbA1c and decreases in several measures of liver disease.

我對這個計畫感到非常興奮的原因之一是它旨在為人類遺傳學奠定堅實的基礎。多項大型人類遺傳學研究發現，INHBE 基因雜合功能喪失變異的攜帶者俱有良好的代謝特徵，包括腹部肥胖和內臟脂肪減少、血清三酸甘油酯、載脂蛋白 B (ApoB)、空腹血糖、糖化血紅蛋白 (HbA1c) 減少，以及肝病幾項指標下降。

Importantly, these carriers also have reduced risk of type 2 diabetes and coronary heart disease. So essentially, the outcome studies have already been conducted for this target using nature's experiments. This is particularly notable for the development of WVE-007 as targets supported by human genetics are on average associated with a 2 to 4 times higher probability of success in drug development.

重要的是，這些帶因者罹患第 2 型糖尿病和冠狀動脈心臟病的風險也降低了。因此，從本質上講，已經利用自然實驗針對這一目標進行了結果研究。這對於 WVE-007 的開發尤其值得注意，因為人類遺傳學支持的目標平均與藥物開發成功的機率高出 2 到 4 倍相關。

Importantly, in addition to evidence from human genetics and our convincing preclinical data, internal work has also demonstrated a strong correlation of circulating activin E levels with BMI in blood samples from humans, providing an additional confirmation of the importance of this mechanism in driving obesity. INHBE is a gene predominantly expressed in liver that produce the hepatokine activin. Activin E is then secreted from the liver and binds to receptor in adipose tissue called ALK7.

重要的是，除了來自人類遺傳學的證據和我們令人信服的臨床前數據之外，內部研究還證明了循環激活素 E 水平與人類血液樣本中的 BMI 之間存在很強的相關性，這進一步證實了這種機制在驅動肥胖方面的重要性。INHBE 是一種主要在肝臟中表現的基因，可產生肝因子激活素。然後，激活素 E 從肝臟分泌出來並與脂肪組織中的 ALK7 受體結合。

With easy access to energy dense food in modern society, liver INHBE mRNA is upregulated, resulting in higher circulating activin E levels, which promotes increased fat storage and abdominal obesity. We chose to target the ligand INHBE over the receptor, ALK7 for several reasons.

在現代社會中，高能量食物的獲取十分便捷，導致肝臟 INHBE mRNA 上調，導致循環中激活素 E 水平升高，進而促進脂肪儲存增加和腹部肥胖。我們選擇以配體 INHBE 而不是受體 ALK7 為目標有幾個原因。

First, using our best-in-class oligonucleotide chemistry to turn off protein production directly at the upstream source is the most efficient way to down regulate activity of this ligand receptor pair. And second, GalNAc conjugates allow for highly specific and efficient targeting the liver cells. INHBE silencing in the liver leads to lower circulating Activin E levels and less ALK7 activation in fat.

首先，使用我們一流的寡核苷酸化學技術直接從上游源關閉蛋白質生產是下調此配體受體對活性最有效的方法。其次，GalNAc 結合物可以高度特異性和高效地靶向肝細胞。肝臟中的 INHBE 沉默導致循環中 Activin E 水平降低和脂肪中 ALK7 活性降低。

This results in increased adipose light polysies, decreased abdominal obesity and ultimately, healthy weight loss and an improved cardiometabolic profile. We continue to make great progress in INLIGHT as we've already completed dosing in the first two cohorts, and we look forward to sharing data from the trial in the second half of this year. These data will include safety, tolerability and biomarkers reflective of healthy weight loss, and we'll also be looking at early changes in body weight.

這會導致脂肪輕度多發性硬化症增加、腹部肥胖減少，最終實現健康減肥並改善心臟代謝狀況。我們在 INLIGHT 方面繼續取得巨大進展，因為我們已經完成了前兩組的給藥，我們期待在今年下半年分享試驗數據。這些數據將包括安全性、耐受性和反映健康減肥的生物標記物，我們還將觀察體重的早期變化。

Recall that the current standard of care approaches such as GLP-1s are associated with substantial muscle loss, which can account for up to approximately 40% of total weight loss. WVE-007 leverages an orthogonal mechanism from GLP-1s, focusing on peripheral action directly on fat tissue rather than the centrally acting appetite regulation. Therefore, delivering a similar magnitude of pound-by-pound weight loss at a comparable time on treatment would suggest substantially larger effects on fat loss than the current standard of care.

回想一下，目前的標準治療方法（例如 GLP-1）與大量肌肉損失有關，這可佔總體重損失的約 40%。WVE-007 利用 GLP-1 的正交機制，專注於直接作用於脂肪組織的周邊作用，而非中樞作用的食慾調節。因此，如果在治療的相同時間內達到相同程度的減重效果，則比目前的標準治療對減脂的效果要大得多。

Combining this with the retention of skeletal muscle, which has a crucial role in glucose uptake, highlights the potential of this program to result in profound improvements of insulin sensitivity and lower risk for type 2 diabetes and cardiovascular disease. The upcoming data will provide us with valuable insights into WVE-007's potential to transform obesity treatment paradigm.

結合這一點以及在葡萄糖吸收中起著關鍵作用的骨骼肌的保留，凸顯了該計劃在顯著改善胰島素敏感性和降低 2 型糖尿病和心血管疾病風險方面的潛力。即將獲得的數據將為我們提供有關 WVE-007 改變肥胖治療模式的潛力的寶貴見解。

Now turning to our emerging pipeline. Our WVE-006 proof of mechanism data last year demonstrated that we could drive impressive potency and durability of effect in the clinic with an AIMer. Now with the advance of RNA editing in the clinic, we have the privilege of helping define how this new modality is applied.

現在轉向我們新興的管道。我們去年的 WVE-006 機制數據證明，我們可以透過 AIMer 在臨床中實現令人印象深刻的效力和持久的效果。現在，隨著 RNA 編輯在臨床上的進步，我們有幸協助定義如何應用這種新模式。

Behind WVE-006, we're continuing to advance a wholly owned discovery pipeline addressing both hepatic and extrahepatic targets. As with WVE-006, our pipeline programs are strongly supported by human genetics, offer novel ways to treat diseases in areas of high unmet need and feature readily accessible biomarkers and approaches to assess pharmacodynamics along with the established regulatory path.

在 WVE-006 背後，我們將繼續推進一條全資擁有的、針對肝臟和肝外目標的發現管道。與 WVE-006 一樣，我們的管道計畫受到人類遺傳學的大力支持，為治療高度未滿足需求領域的疾病提供了新方法，並具有易於獲取的生物標誌物和評估藥效學的方法以及既定的監管路徑。

We unveiled three of these programs at our Research Day last fall, which used GalNAc conjugation. These programs included our PNPLA3 RNA correction approach, aimed at addressing the 9 million I148M homozygous individuals in the US and Europe with a variety of liver diseases, and our LDLR upregulation and ApoB correction programs, which together would address approximately 1 million people living with heterozygous familial hypercholesterolemia in the US and Europe.

我們在去年秋天的研究日上公佈了其中三個使用 GalNAc 結合的項目。這些項目包括我們的 PNPLA3 RNA 校正方法，旨在解決美國和歐洲 900 萬患有各種肝病的 I148M 純合子個體的問題，以及我們的 LDLR 上調和 ApoB 校正項目，這些項目將共同解決美國和歐洲約 100 萬患有雜合子家族性高膽固醇血症的人的問題。

It should also be noted that the LDLR upregulation approach has an opportunity for a substantial indication expansion to individuals with statin intolerance or prior cardiovascular disease with uncontrolled LDL cholesterol. In addition to these programs, we also have shared preclinical data highlighting our ability to direct silencing and editing to high-priority extrahepatic tissues, including CNS, skeletal muscle, adipose, heart, pancreas and lungs.

還應注意的是，LDLR 上調方法有機會大幅擴展其適應症，使其適用於對他汀類藥物不耐受或先前患有心血管疾病且 LDL 膽固醇未控制的個體。除了這些項目之外，我們還分享了臨床前數據，強調了我們直接沉默和編輯高優先級肝外組織的能力，包括中樞神經系統、骨骼肌、脂肪、心臟、胰腺和肺臟。

One application of these capabilities that we shared at our Research Day last fall was our ability to apply our AIMers to support RNA editing across CNS tissues in Rett syndrome. In this devastating disease, the R168X mutation in the MECP2 gene on the X chromosome leads to a neurodevelopmental disorder in females. Our AIMers, which are designed to edit the R168X mutation degenerates full-length MECP2 protein with an R168W substitution showed substantial increases in protein expression throughout the CNS in a humanized mouse model.

我們在去年秋天的研究日上分享的這些能力的一個應用是，我們能夠應用我們的 AIMer 來支援雷特氏症中樞神經系統組織的 RNA 編輯。在這種毀滅性疾病中，X 染色體上的 MECP2 基因的 R168X 突變導致女性神經發育障礙。我們的 AIMers 旨在編輯 R168X 突變，透過 R168W 替換使全長 MECP2 蛋白退化，在人源化小鼠模型中，整個中樞神經系統的蛋白質表現顯著增加。

Further, next week is in an oral presentation at the ASGCT 28th Annual Meeting, we'll share additional preclinical data demonstrating proof of principle for AIMers in lung indications, including cystic fibrosis. In cystic fibrosis, the W1282X and the G542X nonsense mutations result in stop codons to prevent protein production. Without the protein, there is no way for current small molecule approaches that impact these individuals. The preclinical data we plan to share next week demonstrate that in CFTR W1282X, human bronchial epithelial cells, CFTR AIMers, increased expression of CFTR mRNA threefold and restored up to 50% of functional wild-type CFTR protein levels, which is well above the expected threshold to improve lung function.

此外，下週我們將在 ASGCT 第 28 屆年會上進行口頭報告，分享更多臨床前數據，為 AIMers 在肺部適應症（包括囊性纖維化）方面提供原理證明。在囊性纖維化中，W1282X 和 G542X 無義突變會導致終止密碼子阻止蛋白質的產生。如果沒有這種蛋白質，目前的小分子方法就無法影響這些人。我們計劃下週分享的臨床前數據表明，在 CFTR W1282X 中，人類支氣管上皮細胞 CFTR AIMers 的 CFTR mRNA 表達增加了三倍，並恢復了高達 50% 的功能性野生型 CFTR 蛋白水平，這遠高於改善肺功能的預期閾值。

We're actively engaged with the CF Foundation as our AIMers have the potential to edit and restore protein production, which would be incredibly meaningful for this segment of the CF community that currently have no treatment options.

我們積極與 CF 基金會合作，因為我們的 AIMers 有潛力編輯和恢復蛋白質的產生，這對於目前沒有治療選擇的 CF 群體來說意義重大。

As we look to the remainder of the year, we plan on sharing new preclinical data from our emerging pipeline in 2025, highlighting our path to initiating clinical development of additional wholly owned programs in 2026.

展望今年剩餘時間，我們計劃在 2025 年分享我們新興產品線的新臨床前數據，重點介紹我們在 2026 年啟動更多全資項目臨床開發的道路。

With that, I'd like to turn the call over to Kyle to provide an update on our financials. Kyle?

說到這裡，我想把電話轉給凱爾，讓他提供我們的財務狀況更新。凱爾？

Thanks, Erik. Our revenue for the first quarter of 2025 was $9.2 million as compared to $12.5 million in the prior year quarter. The year-over-year decrease was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $40.6 million for the first quarter of 2025 as compared to $33.4 million in the same period in 2024.

謝謝，埃里克。我們 2025 年第一季的營收為 920 萬美元，而去年同期的營收為 1,250 萬美元。年比下降的原因是，我們與葛蘭素史克的合作協議確認收入的時間不同。2025 年第一季的研發費用為 4,060 萬美元，而 2024 年同期為 3,340 萬美元。

This increase was primarily driven by spending for one of -- for our INHBE program, RNA editing programs as well as compensation-related expenses, including share-based compensation. Our G&A expenses were $18.4 million for the first quarter in 2025 as compared to $13.5 million in the prior year quarter, primarily related to share-based compensation as well as professional fees.

這一增長主要得益於我們的 INHBE 項目、RNA 編輯項目以及薪酬相關費用（包括基於股票的薪酬）的支出。2025 年第一季度，我們的 G&A 費用為 1,840 萬美元，而去年同期為 1,350 萬美元，主要與股權激勵以及專業費用有關。

As a result, our net loss was $46.9 million for the first quarter of 2025 as compared to a net loss of $31.6 million in the prior year quarter. We ended the first quarter of 2025 with $243.1 million in cash and cash equivalents compared to $302.1 million as of December 31, 2024.

因此，2025 年第一季我們的淨虧損為 4,690 萬美元，而去年同期的淨虧損為 3,160 萬美元。截至 2025 年第一季度，我們的現金和現金等價物為 2.431 億美元，而截至 2024 年 12 月 31 日為 3.021 億美元。

We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027. It is important to note that potential future milestones and other payments to Wave under our GSK collaboration are not included in our cash runway.

我們預計，我們目前的現金和現金等價物足以支持到 2027 年的營運。值得注意的是，我們與 GSK 合作下潛在的未來里程碑和向 Wave 支付的其他款項不包括在我們的現金流中。

I'll now turn the call back over to Paul for closing remarks.

現在我將把電話轉回給保羅，請他作最後發言。

Thank you, Kyle. Our consistent execution in the clinic has positioned us to deliver on multiple key milestones throughout 2025, including the first demonstration of healthy weight loss with INHBE and the first multi-dose data in RNA editing. We look forward to keeping you updated on our progress throughout the year as we continue to reimagine what's possible for patients.

謝謝你，凱爾。我們在臨床上的持續執行使我們能夠在 2025 年實現多個關鍵里程碑，包括首次展示 INHBE 的健康減肥效果以及 RNA 編輯中的第一個多劑量數據。我們期待著全年向您通報我們的進展，因為我們將繼續重新設想為患者帶來的可能性。

With that, I'll turn over the call to the operator for Q&A. Operator?

說完這些，我將把電話轉給接線生進行問答。操作員？

(Operator Instructions)

（操作員指示）

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

For the INHBE program, what's the trigger for data disclosure? Would you need to have completed dosing in all 5 SAT cohorts for the disclosure or once you have reached some other internal threshold? And I have a quick follow-up question.

對於 INHBE 計劃，資料揭露的觸發因素是什麼？您是否需要在所有 5 個 SAT 隊列中完成劑量才能進行揭露，或者一旦達到其他內部閾值？我有一個快速的後續問題。

Yeah. Thank you for the question, Joon. So the way the current study is running is, as we said on the call today, the first two cohorts are dosed. That's very important as it puts us on track for delivering data. The disclosure will be triggered, as you'd imagine, we'll be looking at time points, one month, three months, six months. And so we have an internal disclosure cutoff where we would do a cut of the data to disclose. As we said, target engagement weight loss and biomarkers. We haven't updated which one of those would be the time point for that disclosure.

是的。謝謝你的提問，Joon。因此，正如我們今天在電話會議上所說的那樣，目前研究的運作方式是，對前兩組患者進行劑量測定。這非常重要，因為它使我們的資料傳輸步入正軌。正如您所想像的，資訊揭露將會被觸發，我們將關注時間點，一個月、三個月、六個月。因此，我們有一個內部揭露截止點，我們會對需要揭露的資料進行篩選。正如我們所說，目標是減肥和生物標記。我們尚未更新其中哪一個是披露的時間點。

Got it. And then you have a few drugs slated for accelerated approval, including for DMD and Huntington's. Can you confirm that they are all under CDER and not CBER? And any risks to the accelerated approval process for you guys?

知道了。還有一些藥物計劃加速審批，包括用於治療杜氏肌肉營養不良症和亨廷頓氏病的藥物。您能否確認它們均受 CDER 而非 CBER 管轄？你們的加速審批流程是否有風險？

Yeah. I think to elevate and answer your first question, it is CDER, not CBER. I think when we talk about genetic medicines in a broad context, I think we have to recognize there are different divisions that still cover the concept of looking at genetically defined medicines. But we are a big small molecule, not a gene therapy or a protein biologic. What's also important to note is our conversations as we've exchanged the agency have not changed.

是的。我認為要提升並回答您的第一個問題，它是 CDER，而不是 CBER。我認為，當我們在廣泛的背景下談論基因藥物時，我們必須認識到，仍然存在不同的劃分來涵蓋基因定義藥物的概念。但我們是一個大的小分子，而不是基因療法或蛋白質生物製劑。同樣值得注意的是，我們與代理商交流時的對話並沒有改變。

So the cadence of communication remains consistent. The discussions that we have shared with you all publicly have been aligned around the accelerated approval pathway and nothing has suggested that there is a change to that. I think it's also important to step back and reflect that we've also taken a comprehensive approach to advancing our programs.

因此溝通的節奏保持一致。我們與大家公開分享的討論都是圍繞著加速審批途徑進行的，沒有任何跡象顯示這一點會改變。我認為回顧並反思我們也採取了全面的方法來推進我們的計劃也很重要。

If we think about DMD, this is not just a discussion on dystrophin. It's a conversation on dystrophin, muscle health and ultimately, as we've shared, statistically significant and clinically meaningful outcome benefits. And so the nature of the discussion that we'll have around the 48 weeks is really around utilizing the concordance of clinical data along with biomarker.

如果我們考慮 DMD，這不僅僅是關於肌肉營養不良蛋白的討論。這是關於肌肉營養不良蛋白、肌肉健康以及最終如我們所分享的具有統計意義和臨床意義的結果益處的討論。因此，我們將在 48 週內進行的討論的本質實際上是圍繞著利用臨床數據和生物標記的一致性。

Same thing is true in HD, where it's not just about industry-leading 46% reduction in mutant protein and wild-type sparing, it's the consistency of what we've seen in correlation of caudate, which is the key anatomical endpoint. And so I think the comprehensive nature of our data will continue to support our filings and dialogue with the agency.

同樣的情況也發生在亨廷頓氏舞蹈症中，它不僅僅是業界領先的突變蛋白減少 46% 和野生型保留，它還與我們在尾狀核相關性中看到的一致性，這是關鍵的解剖學終點。因此我認為我們數據的全面性將繼續支持我們向該機構提交文件和進行對話。

If I could squeeze one more in just on the Huntington's program, the recent data, very fresh data from Votoplam, the splice modulator. It seems to imply that the MRI of the caudate may not be as consistent per their data. Any thoughts there? And also, they include a Stage III, which I don't think you'll be including in your proposed Phase II/III, any thoughts based on that -- read-through from that data?

如果我可以在亨廷頓計劃中再擠進一個，最近的數據，來自 Votoplam（拼接調製器）的非常新鮮的數據。這似乎意味著尾狀核的 MRI 數據可能並不一致。有什麼想法嗎？此外，它們還包括第三階段，我認為您不會將其包括在提議的第二/第三階段中，基於此有什麼想法——從該數據中讀出來？

Yeah. No, I think I look at that data in the context of tominersen and other pan-silencing approaches that have looked at imaging over time. And it's difficult, and I can't comment on their MRI quality of their patients in Stage III and how those studies were run. What I can do is step back and say, when one looks at Track and Predict-HD at the quality of MRI imaging and the consistency with which you can see changes, actually, MRI has been highly consistent. And this isn't just around our own internal analyses. There have been analyses of ExCo, Sarah Tabrizi team, Jeff Long will publish soon his report from University of Iowa. And so MRI has been highly consistent.

是的。不，我認為我是在 tominersen 和其他泛沉默方法的背景下看待這些數據的，這些方法已經研究了一段時間內的成像。這很困難，我無法評論他們對 III 期患者的 MRI 品質以及這些研究是如何進行的。我可以做的是退一步說，當人們觀察 Track and Predict-HD 的 MRI 成像品質以及可以看到變化的一致性時，實際上，MRI 一直高度一致。這不僅涉及我們自己的內部分析。ExCo、Sarah Tabrizi 團隊已經進行了分析，愛荷華大學的 Jeff Long 很快就會發表他的報告。因此 MRI 一直具有高度一致性。

And so I think it is an opportunity for us to really reflect now on a number of pan-silencing approaches that take down the healthy protein and really look at this as an opportunity as allele-selective silencing on mutant reduction, not the least of which is we've had substantially more mutant Huntington lowering than any of the other programs. So again, the consistency with which we saw reduction of protein correlating with caudate is a very different program.

因此，我認為現在對我們來說是一個機會，讓我們真正反思一些消除健康蛋白質的全沉默方法，並真正將其視為等位基因選擇性沉默突變減少的機會，其中最重要的是，我們擁有的突變亨廷頓降低量比任何其他項目都要多。因此，我們再次看到與尾狀核相關的蛋白質減少的一致性是一個非常不同的程序。

Joseph Schwartz, Leerink Partners.

Leerink Partners 的 Joseph Schwartz。

Jenny on for Joe. Congrats on all the progress. For alpha-1, even with single dose data at the lowest dose that you've tested, you're getting to that previously established 11 micromolar threshold range for total AAT protein. First, do you think there are any additional benefits to getting above that threshold? And if so, at what point would there be no additional benefit? And second, can you talk a little bit more about the major pros and cons of RNA editing versus DNA editing in diseases like alpha-1? You pointed out bystander edits and reversibility as major points of differentiation in the past. But just wondering if you think there are other things that an alpha-1 patient might consider if they were to have multiple options in the future?

珍妮代替喬上場。恭喜你所取得的進步。對於 alpha-1，即使使用您測試過的最低劑量的單劑量數據，您也會達到先前設定的總 AAT 蛋白的 11 微摩爾閾值範圍。首先，您認為超過該門檻還有什麼額外的好處嗎？如果是這樣，那麼什麼時候不會有額外的好處？其次，您能否詳細談談 RNA 編輯與 DNA 編輯在治療 alpha-1 等疾病的主要優缺點？您指出旁觀者編輯和可逆性是過去的主要區別點。但只是想知道，如果 alpha-1 患者將來有多種選擇，他們是否還會考慮其他事情？

Yeah. No, thank you for the question. And I think if we step back and say, again, what's the target product profile, I mean, I think we've all talked about in the field of this concept of 11 micromolar being similar to what the MZ patient has. I think it doesn't mean that there aren't opportunities to continue to correct that protein over time, not just for thinking about lung, but ultimately, how do we continue to clear hepatic aggregates more quickly, meaning prevent more aggregating protein and therefore, drive that correction.

是的。不，謝謝你的提問。我認為，如果我們退一步再說一遍，目標產品概況是什麼，我的意思是，我認為我們都在這個概念領域討論過 11 微摩爾與 MZ 患者的情況相似。我認為這並不意味著沒有機會隨著時間的推移繼續糾正這種蛋白質，不僅僅是考慮肺部，而且最終，我們如何繼續更快地清除肝臟聚集物，這意味著防止更多的聚集蛋白質，從而推動這種糾正。

So I think it's incredibly exciting that we're already at that threshold with the lowest single dose. But I think what's really in front of us, and this is why the 200-milligram multi-dose is going to be an important inflection is really seeing how much higher we push that.

因此，我認為我們已經以最低單劑量達到了這一閾值，這非常令人興奮。但我認為我們真正面臨的是，這就是為什麼 200 毫克多劑量將成為一個重要的轉折點，真正看到我們將其推高到什麼程度。

And particularly, rather than just thinking about this in terms of total, and we -- I think it's an important point to continue to drive home. Is that really following the M protein levels is going to be critical in terms of seeing continued improvement. So moving from what we already saw, which was over 60% of the protein in total serum being 7 micromolar, being able to continue to push that M protein level even higher towards what could be a heterozygous level could still continue to improve the potential for clearing out the liver.

特別是，我們不要只從整體角度來考慮這個問題——我認為這是需要繼續強調的重要一點。追蹤 M 蛋白質水平對於持續改善是否真的至關重要。因此，從我們已經看到的情況來看，即總血清中超過 60% 的蛋白質為 7 微摩爾，能夠繼續將 M 蛋白水平推得更高，直至達到雜合水平，仍然可以繼續提高清除肝臟的潛力。

And I think what's important is we follow that and what we saw in the SERPINA1 models early on was that Z protein will fluctuate over time. It's important why we follow total just to see collectively get a sense of what's happening as a reservoir for what may be clearing out of the liver. And that's separate from the M protein, which is being produced and secreted and protecting lung.

我認為重要的是我們遵循這一點，我們早期在 SERPINA1 模型中看到的是 Z 蛋白會隨著時間而波動。我們追蹤整體情況很重要，只是為了集體了解作為肝臟清除庫所發生的情況。這與 M 蛋白是分開的，M 蛋白的產生和分泌是為了保護肺部。

So I think there's more opportunity ahead of us as we think about repeat dosing and higher doses to continue to drive that improvement towards nearly healthy. So it's incredible where we've started. Stepping back and thinking about DNA editing, as you asked versus RNA editing, I do think it's important to really note that distinguishable difference between what you get with bystander editing and indels, either knocking out the frame of proteins and not producing it or producing protein with a bystander edit, you create a misolding of that protein. That can result in several things.

因此，我認為，當我們考慮重複給藥和提高劑量以繼續推動這種改善直至接近健康時，我們面前還有更多機會。所以，我們的起點真是令人難以置信。退一步思考 DNA 編輯，正如您所問的與 RNA 編輯相比，我認為真正注意到旁觀者編輯和插入/缺失之間的明顯差異非常重要，要么敲除蛋白質框架而不產生蛋白質，要么通過旁觀者編輯產生蛋白質，從而造成該蛋白質的錯誤銷售。這可能會導致幾種結果。

One is obviously what's been talked about and what's been shared in some scientific poster presentations, which is those isoforms can have very different efficacy in terms of the neutrophil assay -- inhibition assay. So they can functionally behave as different proteins. I think it's also to note that this is a highly sensitive protein to mutations in terms of aggregation.

顯然，其中一個就是我們已經討論過的內容以及在一些科學海報展示中分享的內容，即這些亞型在中性粒細胞測定——抑制測量方面可能具有非常不同的功效。因此它們在功能上可以表現為不同的蛋白質。我認為還要注意的是，就聚集而言，這是一種對突變高度敏感的蛋白質。

So we don't know yet and it'd be interesting to see whether or not those isoforms of bystander edit proteins actually aggregate in the liver and therefore, trapped and aren't getting out. So I think it's going to be important to study the impact of these bystander edits over time and the potential impact to these patients over time. I think the second piece is also less of DNA versus RNA. It's implied in DNA editing because delivery is key and therefore, the use of lipid nanoparticles. This is true for both DNA and RNA editing constructs that use LNPs. But you can get sporadic changes in AFTLT elevations just based on the lipid nanoparticle alone, you can get accumulation of those particles and hepatic injury. And so if we think about long term for patients with hepatic insufficiency, IV loading of LNPs over time is probably not ideal for the liver.

因此我們還不知道，但有趣的是看看這些旁觀者編輯蛋白的異構體是否真的在肝臟中聚集，因此被困住而無法排出。因此，我認為研究這些旁觀者編輯隨時間產生的影響以及對這些患者的潛在影響非常重要。我認為第二部分也與 DNA 和 RNA 的關係較少。它隱含在 DNA 編輯中，因為傳遞是關鍵，因此使用脂質奈米粒子。對於使用 LNP 的 DNA 和 RNA 編輯構建體來說，這都是正確的。但僅基於脂質奈米顆粒，AFTLT 升高就會發生零星變化，這些顆粒會累積並造成肝損傷。因此，如果我們為肝功能不全患者的長期治療考慮，長期靜脈注射 LNP 可能對肝臟並不理想。

And so therefore, that really fed into our approach between starting the program, which was a GalNAc-conjugated drug that doesn't require LNPs and particularly to the specificity of not generating bystander isoforms for indels.

因此，這確實融入了我們啟動該計畫的方法，該計畫是一種不需要 LNP 的 GalNAc 結合藥物，特別是不會為插入/缺失生成旁觀者異構體的特殊性。

Eric Joseph, JPMorgan.

摩根大通的艾瑞克‧約瑟夫。

This is Ron, on for Eric. I wanted to ask about the scope of analysis you're going to look at for AAT expression in terms of protein concentration, its functionality, whether it's M or Z protein. And to what extent did the recent competitor disclosure serve? Does it serve as a road map for the type of endpoints you'd like to report? And then just another short one is specifically in the readout disclosure before, was the -- were the AAT levels measured through turbidity or through LC-MS?

我是羅恩，代替埃里克。我想問一下，就蛋白質濃度、功能以及它是 M 蛋白還是 Z 蛋白而言，您要分析的 AAT 表現範圍。最近的競爭對手披露有多大作用？它是否可以作為您想要報告的端點類型的路線圖？然後還有一個簡短的問題，具體來說是在先前的讀數披露中，AAT 水平是透過濁度還是透過 LC-MS 來測量的？

Great. I think our disclosures, which preceded that of others was an update on proof of mechanism. But I think it's the totality of data as we shared. It's total protein. It's importantly M protein and looking at that, which is edited protein. And then it's following that over duration of time. And so the next update because we'll have both single and multi-dose data for the complete cohort will be a totality of understanding the dynamics of what happens with single-dose intervals and that editing over time. And importantly, what happens with the repeat dosing.

偉大的。我認為，我們先於其他人披露了有關機制證明的更新資訊。但我認為這就是我們共享的全部數據。這是總蛋白質。重要的是 M 蛋白，它是經過編輯的蛋白質。然後它會隨著時間的推移而改變。因此，下一次更新將使我們對整個隊列的單劑量和多劑量數據有全面的了解，以了解單劑量間隔發生的動態以及隨時間推移的編輯情況。重要的是，重複服藥會發生什麼情況。

Every time we've seen repeat dosing with PN chemistry, we see that, that tends to lead to more drug retention, therefore, not just higher potential production of protein, but actually longer duration of activity. And so we'll be able to plot those kinetics over time. And I think it's important on the longitudinal side of the data to have the full disclosure. We've seen with others that there's actually potential with some of the -- even the DNA editors waning activity. So I think for us to have a complete data set that we can follow over time, I think it's going to give us a very good opportunity to follow not just the potency, but also the duration.

每次我們看到使用 PN 化學方法重複給藥時，我們都會看到，這往往會導致更多的藥物保留，因此，不僅可以提高蛋白質的潛在產量，而且實際上可以延長活性持續時間。這樣我們就能繪製出隨時間變化的動力學曲線。我認為從縱向來看，全面揭露數據非常重要。我們已經看到其他人確實有潛力——甚至 DNA 編輯活動也在減弱。因此，我認為，如果我們擁有一套可以隨時間推移進行追蹤的完整資料集，那麼我們將有很好的機會不僅追蹤效力，還可以追蹤持續時間。

We have had and we shared before, the elastase inhibition work. So again, the functionality of the protein. But again, in the absence and as we've shown that these proteins aren't bystander, it is pure wild type. We wouldn't expect that to be different and nonfunctional. We shared that early, but we would just share the elastase inhibition assay as part of that. We haven't shared data on the assay that we're using for the total AAT.

我們之前曾進行過並且分享過彈性蛋白酶抑制工作。再次強調，這是蛋白質的功能。但是，正如我們所表明的，在沒有的情況下，這些蛋白質不是旁觀者，而是純野生型。我們不希望它有所不同並且不起作用。我們很早就分享了這一點，但我們只會分享彈性蛋白酶抑制試驗作為其中的一部分。我們尚未分享用於總體 AAT 的分析數據。

Yun Zhong, Wedbush.

雲中，韋德布希。

A follow-up question on the AATD program reporting. Why do you divide the data set into two separate announcement, third quarter versus fall? And why don't you just combine data from both cohorts into a more comprehensive data set? Do you think it's important to provide maybe some piece of data as soon as it becomes available?

關於 AATD 計劃報告的後續問題。為什麼要將資料集分成兩個單獨的公告，第三季和秋季？為什麼不將兩個群體的數據合併成一個更全面的數據集呢？您是否認為在資料可用時立即提供某些資料很重要？

Yeah. It's a wonderful question that everybody always thinks about and holding back and waiting. I think what we can feel very confident on is the dosing is -- patients are fully enrolled, and we're going to deliver data on the multi-dose. And we have absolute specificity for the timing of that data set. It's a comprehensive data set. And we believe in totality, that's a very material data set. So when we have that conclusion of that, we'll share that data.

是的。這是一個非常奇妙的問題，每個人都在思考、等待。我認為我們可以非常有信心的是劑量——患者已經全部入組，我們將提供多劑量數據。我們對此資料集的時間有絕對的特異性。這是一套綜合的資料集。我們相信，總體而言，這是一個非常重要的數據集。因此，當我們得出結論時，我們就會分享這些數據。

Whether or not -- and as we're enrolling the 400, I can't say that's why there's -- I say fall. If that happens to move faster, it's not to say that we wouldn't be able to pull those in. But I think if wouldn't plan to hold one data set back for the other. And we do believe that, that 200 multi is highly informative as we think about not just going forward for alpha-1 antitrypsin, but it's also going to help us as we think about the other AIMers in the portfolio and understand for the first time, right, human modeling between a mouse to a nonhuman primate ultimately to a human repeat dose, it's highly informative across the AIMer platform as we advance other programs.

不管怎樣——由於我們正在招收 400 名學生，我不能說這就是原因——我說的是秋天。如果這種情況發生得更快，這並不意味著我們就無法將它們拉進來。但我認為，我不會計劃將一個資料集保留給另一個資料集。我們確實相信，當我們考慮不僅要推進 alpha-1 抗胰蛋白酶的發展時，200 種多種藥物具有很高的信息量，而且當我們考慮產品組合中的其他 AIMer 時，它也會有所幫助，並且首次了解到從小鼠到非人靈長類動物最終到人類重複劑量的人體建模，隨著我們推進其他項目，它在整個 AIMer 平台上具有很高的信息量。

So understanding that pharmacology is going to be important. And I will say the 400 is enrolling very well. So I think at this point, there is that opportunity to have that on the earlier side, but we'll provide updates in the future.

因此了解藥理學非常重要。我想說的是，400 人的入學情況非常好。所以我認為目前有機會儘早實現這一目標，但我們將在未來提供更新。

Okay. Then on the DMD program, and would you expect to include monthly dosing data into the NDA submission package?

好的。那麼在 DMD 計劃中，您是否希望將每月的劑量資料納入 NDA 提交包中？

Yeah. I mean that is the plan. And based on our discussions with the agency, the plan is to have monthly dosing in the label. So that -- those updates on the extension expansion would match the anticipated filing time line for that. We're also engaging the agency to discuss the 48-week clinical data and discussing the -- perhaps putting clinical data in the label as well.

是的。我的意思是這就是計劃。根據我們與該機構的討論，計劃在標籤上註明每月劑量。因此，有關延期擴展的更新將與預期的提交時間表相符。我們還與該機構合作討論 48 週的臨床數據，並討論——也許將臨床數據也放入標籤中。

So if we think about the comprehensive differentiation from other exon skipping therapies, the opportunity for monthly dosing, the opportunity for highest level of dystrophin that's been seen -- and again, I'm talking now about the commercial 53 patient population as we're going into that. The ability to show holistically change in improvement in muscle health, reduction in fibrosis and then clinical outcome measurements with safety that doesn't look different than standard of care is a real opportunity. We want to be able to capture that.

因此，如果我們考慮與其他外顯子跳躍療法的全面區別，每月給藥的機會，達到迄今為止最高水平的肌肉營養不良蛋白的機會——再次強調，我現在談論的是我們正在進入的商業 53 名患者群體。能夠全面展示肌肉健康改善、纖維化減少以及臨床結果測量的安全性，並且與標準護理並無二致，這是一個真正的機會。我們希望能夠捕捉到這一點。

Salim Syed, Mizuho.

薩利姆賽義德，瑞穗。

I guess a couple from us. One on INHBE. Paul, from your comments around like the one, three and six months, is it that you haven't decided yet which time point you want to cut at? Or are you looking at some sort of like -- and can you remind, do you have access to the blinded data here that can help inform your decision? Or you just haven't disclosed? It just wasn't clear there. And then one on -- go ahead, sorry. And then a follow-up on...

我想我們當中有幾個人。一個關於 INHBE。保羅，從你對一個月、三個月和六個月的評論來看，你是否還沒有決定要在哪個時間點削減？或者您正在考慮某種類似的——您能否提醒一下，您是否可以訪問此處的盲數據來幫助您做出決定？還是你只是還沒透露？只是那裡的情況不太清楚。然後再說一個——請繼續，抱歉。然後是後續…

I'll just take that one off just right away. So no, not observing data. We just haven't disclosed where those cutoffs are going to be. Those are just the time points that are involved in the study, but no, we haven't broken out when we're going to cut it, and we have a predefined opportunity to look.

我馬上就把那件脫掉。所以不，沒有觀察數據。我們只是還沒有透露這些截止點在哪裡。這些只是研究中涉及的時間點，但是，我們還沒有確定何時進行研究，我們有一個預先確定的機會來觀察。

I mean I think what's interesting is -- and I think sometimes people are on the late side of thinking about GLP-1s and weight loss. But just to put it in context, if you think about the one, three and six months in a placebo adjustment for GLP-1s, you've got about a 1%, 1.5% weight loss at one month about somewhere around 4% at three months and around 7% at six months.

我的意思是，我認為有趣的是——我認為有時人們對 GLP-1 和減肥的考慮有些太晚了。但僅從上下文來看，如果您考慮 GLP-1 安慰劑調整後的一、三和六個月，您會發現一個月時體重減輕約 1%、1.5%，三個月時體重減輕約 4%，六個月時體重減輕約 7%。

And so we've got a real opportunity, I think, to define what the kinetics of INHBE are going to look like and recognizing that a grand slam would be if we see similar to that where it's all fat and not muscle, recognizing 40% of that percentage body weight loss on GLP-1s is muscle. I think we've got a real opportunity within a relatively short time frame to substantially differentiate INHBE as a best-in-class healthy weight loss solution.

因此，我認為，我們有一個真正的機會來確定 INHBE 的動力學是什麼樣的，並且認識到，如果我們看到類似的情況，即全部是脂肪而不是肌肉，那將是一個大滿貫，認識到 GLP-1 減輕的體重百分比中有 40% 是肌肉。我認為，我們有一個真正的機會，可以在相對較短的時間內將 INHBE 大幅提升為一流的健康減肥解決方案。

Okay. Just to be clear, you're not looking at blinded data and you already have a predefined time cutoff, you just haven't disclosed it.

好的。需要明確的是，您沒有查看盲數據，並且您已經有了預先定義的時間截止，只是您還沒有披露它。

Correct. Correct.

正確的。正確的。

Okay. And then just on DMD, your comments around the initial plans for using dystrophin expression for accelerated approval, are those plans locked in? Like do you have it in writing from the agency that, that would be acceptable for an accelerated approval? Or is there any risk here that if we do get a new Cedar head that would like to change things or has a different view on accelerated approval for diseases like DMD, is there any risk there to that endpoint moving?

好的。然後就 DMD 而言，您對使用肌肉營養不良蛋白表達來加速批准的初步計劃的評論，這些計劃是否已經確定？例如，您是否有該機構的書面證明，可以接受加速批准？或者，如果我們確實有了一位新的 Cedar 負責人，他想改變現狀，或者對 DMD 等疾病的加速審批有不同的看法，那麼這個終點轉移是否存在風險？

Yeah. We have in that conversation, CDER and the division of CDER responsible for DMD commenting that dystrophin is a clinical surrogate endpoint. So that's the division. As of now, that's their statement that dystrophin is a clinical surrogate endpoint for accelerated approval. I think -- as we continue to go forward, I think we want to continue to bolster that support with our additional data like we have with TTR and other clinical endpoints to drive differentiation. But at this point, the agency comment on dystrophin has not changed.

是的。在那次談話中，CDER 和 CDER 負責 DMD 的部門評論說，肌肉營養不良蛋白是一個臨床替代終點。這就是分工。截至目前，他們的聲明是，肌肉營養不良蛋白是加速批准的臨床替代終點。我認為——隨著我們不斷前進，我們希望繼續利用我們的附加數據（例如我們對 TTR 和其他臨床終點的數據）來加強這種支持，以推動差異化。但目前為止，該機構對抗肌萎縮蛋白的評論尚未改變。

Okay. So just to be clear, their view is that's the endpoint right now, but it's not locked in, correct? I mean, if we do get a new CDER head who has a different view, there is potential for that to move, correct?

好的。所以要先明確的是，他們的觀點是，這是目前的終點，但還沒有鎖定，對嗎？我的意思是，如果我們確實找到了一位持有不同觀點的新 CDER 負責人，那麼就有可能改變這一局面，對嗎？

It's always and I think this is really important. When the agency establishes something as a clinical surrogate endpoint, that's important, right? Like that's a definition. There have been approvals locked in on that. And so the agency tends to be very consistent. I think what we want to provide is continued support to the agency, as we've seen with the TTR data that, again, there is a relationship between dystrophin and that endpoint.

我認為這始終非常重要。當機構將某個事物確立為臨床替代終點時，這很重要，對嗎？就像那是一個定義。對此已經獲得批准。因此該機構往往非常一致。我認為我們想要提供的是對該機構的持續支持，正如我們從 TTR 數據中看到的那樣，肌肉營養不良蛋白和該終點之間存在關聯。

I think what we're probably more apt to see is the agency pushing, which is why the confirmatory discussions are important, is really designing to say you still have to confirm that dystrophin is a clinical surrogate endpoint. So the pressure would come in very much on existing companies and completing the confirmatory studies within a timely standpoint to do that.

我認為我們更可能看到的是機構的推動，這就是確認性討論很重要的原因，實際上是在說你仍然必須確認肌營養不良蛋白是一個臨床替代終點。因此，現有公司面臨很大的壓力，需要及時完成確認性研究。

I think it's why our assumption going into this is you need a substantially enrolling confirmatory study to prove to the agency that you have the plans to commit and finish that study on the other side of that approval. But the agency, a new head could come in and revisit it. I think it's highly unlikely that they would overturn a precedent on a clinical surrogate endpoint, but more likely continue to hold companies to completing confirmatory studies to substantiate that.

我認為這就是為什麼我們的假設是，你需要進行大量的確認性研究，以向該機構證明你有計劃在獲得批准後承諾並完成這項研究。但該機構的新負責人可能會重新審視這個問題。我認為他們不太可能推翻臨床替代終點的先例，但更有可能繼續要求公司完成確認性研究來證實這一點。

And I think that's consistent with the carry and the head of the FDA saying, how do we accelerate new medicines. On one hand, you can accelerate new medicines and still -- and I think this is just an important notion. You can accelerate medicines and hold companies to completing, improving those endpoints. And I think we're very much committed to both of those.

我認為這與 FDA 負責人所說的「我們如何加速新藥研發」是一致的。一方面，你可以加速新藥的研發，而且──我認為這是一個重要的概念。您可以加速藥物研發並督促公司完成並改善這些終點。我認為我們對這兩點都非常重視。

And the current data we've generated is very much supportive that we can bring those 2 pieces together for once in DMD that we can see that dystrophin is creating healthier muscle, is creating clinical outcome measurement changes. And I think being able to put those pieces together, we can say that was of interest to the agency of being able to connect those dots. And we'll obviously have an upcoming discussion on the 48-week data that's going to be informative of how to build clinical endpoints to into the label.

我們目前獲得的數據非常有力地證明，我們可以在 DMD 中將這兩個部分結合在一起，我們可以看到肌肉營養不良蛋白正在產生更健康的肌肉，正在產生臨床結果測量變化。我認為，能夠將這些碎片拼湊在一起，我們可以說，能夠將這些點連接起來，對於機構來說，這是有意義的。顯然，我們將就 48 週數據進行討論，這些數據將為如何將臨床終點納入標籤提供資訊。

Catherine Novack, Jones Research.

凱瑟琳‧諾瓦克，瓊斯研究公司。

Just thinking about the enrollment for the monthly DMD cohorts, how many additional DMD patients do you expect that you'll need to ensure monthly dosing regimen at launch? And then following up on that, as you're enrolling in the study and working with these investigators, are you getting any indication that providers are maybe reassessing the risk-benefit profile of gene therapy in DMD?

僅考慮每月 DMD 隊列的招募情況，您預計需要多少額外的 DMD 患者才能確保在啟動時進行每月的給藥方案？然後繼續跟進，當您參與研究並與這些研究人員合作時，您是否得到任何跡象表明供應商可能正在重新評估 DMD 基因治療的風險效益狀況？

Yeah. I think for the last point, the short answer is yes. I mean, I think in general, I think there was a lot of questions and concerns. I think where the questions really come up, we have to remember that there are boys who are amenable to exon skipping and there are boys who are at risk and who aren't.

是的。我認為對於最後一點，簡短的回答是肯定的。我的意思是，我認為總的來說，存在著許多問題和擔憂。我認為，當問題真正出現時，我們必須記住，有些男孩適合進行外顯子跳躍，有些男孩有風險，有些則沒有。

And I think that's where we see some of the clinicians thinking about these different treatment opportunities of if they have a boy who's not amenable to exon skipping and amenable to gene therapy, we might see them go there. I think with the recent signals, I think what we are hearing is where there is an opportunity for exon skippers that could actually be beneficial that there'll be an error on the side of saying, we should go with that approach.

我認為，我們看到一些臨床醫生正在考慮這些不同的治療機會，如果他們有一個不適合外顯子跳躍但適合基因療法的男孩，我們可能會看到他們去那裡。我認為，根據最近的信號，我們聽到的是，外顯子跳躍實際上可能是一個有益的機會，但說我們應該採用這種方法卻是一個錯誤。

So we'll see how that ultimately translates into practice, but highly encouraged based on our discussions with clinicians. Enrollment -- sorry, going back to the enrollment side on the cohorts, one, as we said, we have the 11 boys in the study rolled over on to the monthly dosing on the extension portion of the study. And we would anticipate just for guidance on enrollment that, that expansion cohort would equilibrate such that we'll have the total number of patients we think about filing similar to those other exon skipping 53 programs that filed like...

因此，我們將看看這最終如何轉化為實踐，但根據我們與臨床醫生的討論，我們強烈鼓勵這樣做。招生 - 抱歉，回到隊列的招生方面，首先，正如我們所說，我們將研究中的 11 名男孩轉入研究擴展部分的每月劑量給藥。我們預計，僅就招生指導而言，擴展隊列將達到平衡，這樣我們考慮提交的患者總數將與其他提交的跳過 53 個外顯子的項目相似...

Okay. That's helpful. And then thinking about the AATD program, how are you interpreting your increase in serum Z protein versus being significant decrease in Z protein? What do you hypothesize is happening to the Z protein aggregates in the liver with DNA base editing versus RNA base editing?

好的。這很有幫助。然後考慮 AATD 計劃，您如何解釋血清 Z 蛋白的增加與 Z 蛋白的顯著減少？您認為 DNA 鹼基編輯與 RNA 鹼基編輯對肝臟中的 Z 蛋白聚集體有何影響？

Yeah, it's interesting, and I'm glad you asked the question. When we looked at all of our preclinical work, and that was really what drove us to really dig into the aggregates is when we saw that secondary increase in Z protein, the Z protein isn't being produced through M proteins, but produced through editing. Z protein is actually coming into serum by a byproduct of breaking up the aggregates in the liver, right? That's the reservoir that leads to that Z protein increases.

是的，這很有趣，我很高興你問了這個問題。當我們回顧所有臨床前工作時，真正促使我們深入研究聚集體的原因在於，我們看到 Z 蛋白的二次增加，Z 蛋白不是透過 M 蛋白產生的，而是透過編輯產生的。Z 蛋白實際上是透過肝臟分解聚集物的副產品進入血清的，對嗎？這就是導致 Z 蛋白增加的儲存器。

And so the fact that we are seeing that, which correlated very much to what we saw in our preclinical models is highly encouraging of both the lung and liver applications of our RNA editing format. I think it raises into questions in this kind of plateauing almost of protein without seeing those corresponding increases. And again, of whether or not with DNA editors, whether or not there's increased protein actually aggregation in the liver, whether or not there's actually any breakdown of that protein from the liver.

因此，我們所看到的情況與我們在臨床前模型中看到的情況非常相關，這對於我們的 RNA 編輯格式在肺部和肝臟中的應​​用非常令人鼓舞。我認為，這種蛋白質水平幾乎處於穩定狀態而沒有出現相應的增加，這引發了一些問題。再說一遍，無論是否有 DNA 編輯器，肝臟中蛋白質的聚集是否會增加，肝臟中蛋白質是否真的會分解。

And I think that's a great question that continue to be explored as these two technologies move forward in treating both lung and liver is what is happening to the Z protein that's aggregating in the liver. So we can be very clear, edited protein, M protein increasing, Z protein coming out of that reservoir. But I think it's interesting to continue to follow these over time.

我認為這是一個很好的問題，隨著這兩種技術在治療肺部和肝臟方面取得進展，這個問題將繼續被探索，那就是肝臟中聚集的 Z 蛋白發生了什麼。因此我們可以非常清楚，編輯蛋白質，M 蛋白質增加，Z 蛋白質從該儲存器中出來。但我認為隨著時間的推移繼續關注這些會很有趣。

Maybe just to add, this is also why we think it's important to focus on the M protein because it's just an easier benchmark to compare across different approaches.

也許只是補充一下，這也是我們認為關注 M 蛋白很重要的原因，因為它只是一個更容易比較不同方法的基準。

Steve Seedhouse from Cantor Fitzgerald.

來自 Cantor Fitzgerald 的 Steve Seedhouse。

This is Nick, on for Steve. Two for us. First, what does the distribution profile look like in lung tissue with your existing AIMers? And are there any novel modifications or conjugation methods you're using here to optimize PK? I have a follow-up.

我是尼克，代替史蒂夫。給我們兩個。首先，您現有的 AIMer 在肺組織中的分佈是什麼樣的呢？您是否使用了任何新穎的修改或結合方法來優化 PK？我有一個後續問題。

Yeah. I mean, one, I'll refer you definitely to -- and we're happy to -- the R&D Day deck was pretty comprehensive as we think about not just for AIMers, but also our siRNA formats where we saw incredible silencing and durability in CNS and muscle. So I think about the totality of the work that we've done on a platform context in driving distribution to a variety of cell types. You can think about editing liver, adipocytes and others.

是的。我的意思是，首先，我肯定會向您推薦——我們很高興——研發日平台非常全面，因為我們不僅考慮了 AIMers，還考慮了我們的 siRNA 格式，我們在其中看到了中樞神經系統和肌肉中令人難以置信的沉默和耐久性。因此，我考慮了我們在平台環境下為推動向各種細胞類型分發所做的全部工作。您可以考慮編輯肝臟、脂肪細胞和其他細胞。

And so -- and CNS and as Erik shared, lung as well. How we drive that can be through PN variants. And so these are modifications to the chemistry on the backbone separate from distinct GalNAc-like delivery. We also have activities delivering specifically to certain cell types in a way that would be similar to GalNAc, and we're excited to share those updates as we move into R&D Day later this year.

所以 — — 還有中樞神經系統，以及艾瑞克分享的肺部。我們可以透過 PN 變體來實現這一點。因此，這些是對主鏈化學性質的修改，與獨特的 GalNAc 類遞送不同。我們還有一些活動專門針對某些細胞類型，其方式類似於 GalNAc，我們很高興在今年稍後進入研發日時分享這些更新。

But I think the real opportunity is continuing to see we've optimized GalNAc delivery and showed that consistently. We've removed GalNAc and drove the editing and high efficiency levels to a variety of very important tissues, of which there's really strong genetic targets. And we'll continue to provide updates on that, both in medical meetings, as Erik shared at ASGTC and others and then into the fall at R&D day.

但我認為真正的機會是繼續看到我們已經優化了 GalNAc 交付並始終如一地展示這一點。我們已經去除了 GalNAc，並將編輯和高效率水平推向了各種非常重要的組織，其中有非常強大的遺傳靶點。我們將繼續提供有關這方面的最新信息，無論是在醫學會議上，還是在秋季研發日，正如 Erik 在 ASGTC 和其他會議上分享的那樣。

Maybe just to add as well that we don't need a conjugate for getting into lung. It's all about the chemistry optimization with the PN chemistry, et cetera.

也許還要補充一點，我們不需要結合物來進入肺部。這一切都與 PN 化學等的化學優化有關。

Got it. Makes sense. Okay. And for INHBE, Arrowhead has mentioned they intend to do quarterly dosing for their program. Just wanted to check your view on that, given you previously talked about Wave targeting in every six month or annual dosing interval. Are you still confident in that strategy for WVE-007? That will be it.

知道了。有道理。好的。對於 INHBE，Arrowhead 提到他們打算為其專案進行每季的劑量給藥。只是想確認一下您對此的看法，因為您之前談到每六個月或每年的給藥間隔進行 Wave 目標治療。您對 WVE-007 的策略還有信心嗎？就這樣吧。

Yeah. Thanks. Very confident in our strategy. And I think that goes back to the preclinical data that we've had versus the preclinical data of our peers. The data that we have suggests much greater potency and durability. We shared that in the NAR paper a couple of years ago that we have 30-fold the improvement in AGO2 loading over the best-in-class siRNA formats, and that's not just Arrowhead.

是的。謝謝。對我們的策略非常有信心。我認為這可以追溯到我們擁有的臨床前數據與同行的臨床前數據之間的對比。我們掌握的數據顯示其效力和持久性都更強。幾年前，我們在 NAR 論文中提到，與同類最佳的 siRNA 格式相比，我們的 AGO2 負荷量提高了 30 倍，而且這不僅僅是 Arrowhead 的情況。

And so as we think about this opportunity, what it really provides is depth of knockdown to that kind of amplitude potency, but most importantly, durability. So we have a differentiated siRNA format from the other siRNA companies, and we think this is a very attractive opportunity and place to apply it.

因此，當我們考慮這個機會時，它真正提供的是擊倒深度和那種振幅效力，但最重要的是持久性。因此，我們擁有與其他 siRNA 公司不同的 siRNA 格式，我們認為這是一個非常有吸引力的機會和應用場所。

Roger Song, Jefferies.

傑富瑞 (Jefferies) 的羅傑宋 (Roger Song)。

This is Shasha, on for Roger. I had a follow-up question for your INHBE program. I just wanted to know what you think would be a successful data readout and what benchmarks you're using for that as you consider that.

我是莎莎，代替羅傑。我對您的 INHBE 計劃有一個後續問題。我只是想知道您認為什麼樣的資料讀取是成功的，以及您在考慮這一點時使用了什麼基準。

Yeah. I mean, as we shared before, I mean, it's important to think about where the references are around the GLP-1 weight loss over these various time points. So if you're around 1%, 1.5%, one month, 4% at three months and somewhere around 5%, 6% as you go into the six month time frame.

是的。我的意思是，正如我們之前所分享的，重要的是要思考在這些不同時間點上 GLP-1 體重減輕的參考在哪裡。因此，如果一個月的利率在 1% 或 1.5% 左右，那麼三個月的利率在 4% 左右，六個月的利率在 5% 或 6% 左右。

Remembering that those percent body weight losses at those various time points, again, sometimes I know we tend to think about this weight loss as one category. But if you think about the movement and even the FDA guidance at the beginning of the year around what healthy weight loss looks like in terms of fat loss versus muscle, 40% of those numbers on body weight loss are driven off of muscle loss.

記住在不同時間點的體重減輕百分比，有時我知道我們傾向於將體重減輕視為一個類別。但是，如果你考慮今年年初的運動，甚至是 FDA 的指導，關於健康減肥在脂肪減少和肌肉減少方面的表現，你會發現，40% 的體重減輕數字是由肌肉減少引起的。

So a home run and more likely a grand slam as you see similar like we saw in the mouse weight loss, that is all fat. That would be incredible. I think the opportunity to still continue to see the fat loss component of that or more is also there. But everything in the animal model suggests a similar cadence.

因此，本壘打和大滿貫更有可能是相似的，就像我們在老鼠減肥中看到的一樣，那都是脂肪。那真是太不可思議了。我認為還有機會繼續看到其中的脂肪減少部分或更多。但動物模型中的一切都顯示了相似的節奏。

But I think it's important for us to think about the characterization of percent body weight loss and just how much of that GLP-1 loss is actual muscle and the fact that we don't see that. So I think the data preclinically are highly encouraging, and we'll be generating that data second half that will be encouraging in terms of the program's future.

但我認為，我們必須思考體重減輕百分比的特徵，以及 GLP-1 損失中有多少是實際的肌肉，而事實上我們並沒有看到這一點。因此，我認為臨床前的數據非常令人鼓舞，而且我們將在下半年產生這些數據，這對該計劃的未來將是令人鼓舞的。

Ryan Deschner, Raymond James.

瑞安‧德施納、雷蒙‧詹姆斯。

This is Anthony, on for Ryan. I wanted to ask what specific biomarkers are you planning to report for this readout from INLIGHT for WVE-003?

這是安東尼，代替瑞安。我想問一下，您計劃在 INLIGHT 的 WVE-003 讀數中報告哪些特定的生物標記？

Yeah. I mean the disclosed biomarkers in addition to, obviously, body weight will be Activin E. So that's the disclosed biomarker that we've reported. There are other exploratory endpoints that we are looking at that we haven't disclosed. But Activin E will be important.

是的。我的意思是，除了體重之外，公開的生物標記顯然還有激活素 E。這就是我們報告的公開生物標記。我們正在研究其他尚未披露的探索性終點。但 Activin E 很重要。

And that will give us a sense of -- as Erik shared, with elevation in BMI, you see an increase in active E. And so being able to follow those Activin E levels are going to give us a sense of target engagement. They're also going to inform as the last question, an ability to follow these patients out over time and look at the durability of effect. So Activin E will be an important biomarker to look at. And we will have additional biomarkers that we'll be evaluating in an exploratory fashion as part of the study.

這會讓我們感覺到——正如 Erik 所說，隨著 BMI 的升高，你會看到活性 E 的增加。因此，能夠追蹤這些激活素 E 水平將讓我們感覺到目標參與。他們還將告知最後一個問題，即是否有能力隨著時間的推移追蹤這些患者並觀察其效果的持久性。因此，Activin E 將是值得關注的重要生物標記。作為研究的一部分，我們將以探索性的方式評估更多的生物標記。

Ananda Ghosh, H.C. Wainwright & Company.

阿南達·戈什（Ananda Ghosh），H.C. Wainwright & Company。

Two questions from me. The first one is a lot of GLP-1 discussion revolves around the pleiotropic effects. I was wondering what does the fundamental biology talks about inhibin and the pleiotropic effects of weight loss in terms of the signaling pathway? The second question is, I wanted to understand your thoughts on the Fazirsiran and how does it differentiate with your program?

我有兩個問題。首先，許多關於 GLP-1 的討論都圍繞著多效性作用。我想知道基礎生物學從訊號路徑的角度如何談論抑制素和減肥的多效性效應？第二個問題是，我想了解您對 Fazirsiran 的看法以及它與您的計劃有何不同？

Can you just repeat the last portion of the question?

你能重複問題的最後一部分嗎？

Yeah. So the second one is with respect to Fazirsiran and your AATD program, differentiation in terms of what you have learned from the Fazirsiran data?

是的。那麼第二個問題是關於 Fazirsiran 和您的 AATD 計劃，您從 Fazirsiran 數據中了解到了什麼？

I'll take the first one on your pleiotropic effect, then we'll come back to the second one, just to think about whether or not we hear that one correctly. On the first side, if we think about the impact of INHBE biology, I think what's intriguing and we saw that based on our preclinical data, you see it on human genetics.

我會先討論多效性效應，然後我們再回到第二個問題，只是想思考我們是否聽對了。首先，如果我們考慮 INHBE 生物學的影響，我認為這很有趣，而且根據我們的臨床前數據，你可以在人類遺傳學上看到它。

And as Erik said, we even see it prospectively and looking with patients with elevated BMI is that Activin E is a hepatokine that's supportive of sustaining adipocytes. And so actually, the biology is very well correlated. In fact, the receptor for Activin E, so the INHBE, the receptor and the ligand both feature very prominently on the genetics.

正如艾瑞克所說，我們甚至前瞻性地看待這個問題，並觀察體重指數升高的患者，發現激活素 E 是一種支持維持脂肪細胞的肝因子。因此實際上，生物學具有很好的相關性。事實上，Activin E 的受體，即 INHBE，受體和配體在遺傳學上都具有非常突出的特徵。

So therefore, it's just important that the biology is -- there's a good concordance in biology between those that both the target ligand and the receptor. And so we saw that play out in the DIO mouse model across several opportunities, again, single dose against GLP-1s in combination with GLP-1s that showed it's orthogonal in terms of its mechanism of action and then ultimately in sustaining and maintenance of weight loss. So again, there's a good concordance between those 2 activities.

因此，重要的是生物學——目標配體和受體在生物學上有良好的一致性。因此，我們在 DIO 小鼠模型中看到了幾種機會，再次，單劑量對抗 GLP-1 與 GLP-1 的組合表明其在作用機制方面是正交的，並最終維持和保持體重減輕。所以，這兩項活動之間有著很好的一致性。

Yeah. Maybe just to add to this. So the ligand receptor pair is very specific in this case. So we don't expect any pleiotropy at all, a primary pleiotropy. Now obviously, we would expect downstream positive effects of targeting ALK7. So increasing lipolysis will lead to a lot of downstream positive metabolic effects, but that's not how it is.

是的。也許只是為了補充這一點。因此在這種情況下配體受體對非常特殊。所以我們根本不期望任何多效性，一種原發性多效性。現在顯然，我們期待針對 ALK7 產生下游正面影響。因此，增加脂肪分解將導致許多下游的積極代謝效應，但事實並非如此。

Yeah. And in terms of that, I mean, just to be really clear on minimizing any other pleiotropic effects outside is we're targeting the liver. What actually is there's a high degree of specificity of INHBE. And there's a lot of other activins. So sometimes people get confused. So maybe that's stepping back.

是的。就這一點而言，我的意思是，為了真正清楚地減少外界任何其他多效性影響，我們的目標是肝臟。事實上，INHBE 具有高度的特異性。還有很多其他的激活素。所以有時人們會感到困惑。所以這也許是一種倒退。

There are a variety of different activins in the family, hence, a good reason to target the ligand, not the receptor. The concordance of activin E is it is produced in the hepatocyte with its receptor on the adipocytes. So one, it's an ideal target for an siRNA in the liver. And then you put GalNAc on that. And again, you drive specificity to that single cell type anyway. So we're not worried about off-target effects of that particular activin receptor. Then you were asking -- just to make sure I have it because it was a little bit...

該家族中有多種不同的激活素，因此，有充分的理由針對配體而不是受體。激活素 E 的一致性在於它是在肝細胞中產生的，其受體在脂肪細胞上。因此，首先，它是肝臟中 siRNA 的理想標靶。然後你把 GalNAc 放在上面。無論如何，你都要針對該單細胞類型進行特異性驅動。因此我們並不擔心特定活化素受體的脫靶效應。然後你問——只是為了確保我有它，因為它有點......

Fazirsiran for AATD.

Fazirsiran 為 AATD 撰稿。

That's right, yes, for the AATD program.

是的，對於 AATD 計劃來說確實如此。

Yeah. So I mean, if we think about siRNA and the reason why we've got really potent durable siRNA is why we didn't take a GalNAc potent siRNA forward in alpha-1 antitrypsin deficiency is the recognition that actually potency is -- it could be potentially detrimental. It's a protein that you need. So therefore, it just turn off that protein. Ultimately -- while it may clear hepatic aggregates because you no longer are producing misfolded protein, you ultimately put patients on a course for IV protein replacement therapy, right? You prevent the protection of the lung. And so therefore, this is the benefit of multimodal platforms as we could step back and actually say, even though we could, it's not the best tool to do that job, editing is the best tool to do that job where you create a functional protein and therefore, restore function to protecting the lung, but also allow the removal of aggregates from the liver.

是的。所以我的意思是，如果我們考慮 siRNA，我們之所以能獲得真正強效持久的 siRNA，是因為我們沒有在 alpha-1 抗胰蛋白酶缺乏症中採用 GalNAc 強效 siRNA，因為我們認識到效力實際上 - 它可能具有潛在的危害。這是您需要的蛋白質。因此，它只是關閉了那種蛋白質。最終——雖然它可能會清除肝臟聚集物，因為您不再產生錯誤折疊的蛋白質，但您最終會讓患者接受靜脈注射蛋白質替代療法，對嗎？你妨礙了肺部的保護。因此，這就是多模式平台的優勢，我們可以退一步說，即使我們可以，它也不是完成這項工作的最佳工具，編輯才是完成這項工作的最佳工具，你可以創建功能性蛋白質，從而恢復保護肺的功能，同時也允許從肝臟中去除聚集物。

So again, the opportunity that we have with different tools is and despite a potentially best-in-class siRNA format, we wouldn't apply our siRNA format to that. But we do see in terms of differentiation of siRNAs, and we shared this again in that NAR paper, highly potent, highly durable siRNA format, not just in GalNAc in the liver, but in CNS and other tissues as well.

因此，我們再次強調，利用不同工具的機會是，儘管我們的 siRNA 格式可能是同類最佳的，但我們不會將我們的 siRNA 格式應用於此。但我們確實看到了 siRNA 的分化，並且我們在 NAR 論文中再次分享了這一點，高效、高持久的 siRNA 格式不僅存在於肝臟中的 GalNAc 中，還存在於中樞神經系統和其他組織中。

Luca Issi, RBC.

盧卡·伊西（Luca Issi），RBC。

This is Lisa, on for Luca. Maybe a couple here on A1AT. The A1AT program makes progress. Just wondering if you can share what you need to see before starting a Phase II. Is the bogey to achieve A1AT serum above 11? Or do you need to see something closer to 20 micromolar, which is more in the normal range? Any color here would be helpful.

我是麗莎，代替盧卡。也許 A1AT 上就有幾個。A1AT計劃取得進展。只是想知道您是否可以分享在開始第二階段之前您需要看到的內容。達到 A1AT 血清高於 11 的忌諱是什麼？或者您需要看到更接近 20 微摩爾的值，這更符合正常範圍？這裡的任何顏色都會有幫助。

Yeah. I mean I think the goal is that we'll complete this study, and that will obviously guide the framework and planning of the Phase II. I mean we're already at 11 micromolar, single lowest dose. So the opportunity we have with more doses and more frequency, it's really two things. One is pushing that dynamic range, as you said, between 11 and 20 and really saying not just in total, but where -- what dynamic range do we get to with an M edited protein.

是的。我的意思是，我認為我們的目標是完成這項研究，這顯然將指導第二階段的框架和規劃。我的意思是我們已經達到了 11 微摩爾的最低單次劑量。因此，我們有機會獲得更多劑量和更高的頻率，這實際上是兩件事。一個是推動動態範圍，正如你所說，在 11 到 20 之間，實際上說的不僅僅是總量，而是在哪裡——我們用 M 編輯蛋白質可以得到什麼動態範圍。

So that's one big opportunity. The second, and as many of you are aware, what you want to do in this Phase I/II study is really define not just a potency aspect, but durability. So we'll be able to do both understanding of dosing frequency and target product profile in terms of alpha-1 antitrypsin levels. And that will be determined at the end of the study as we plan forward into the Phase II.

所以這是一個很大的機會。第二，正如你們許多人所知，在 I/II 期研究中，你們真正想要做的不僅僅是定義效力方面，還要定義持久性。因此，我們將能夠根據 α-1 抗胰蛋白酶水平了解給藥頻率和目標產品概況。我們將在研究結束時確定這一結果，並計劃進入第二階段。

And Paul, maybe one on the regulatory path here. How are you thinking about a path to approval for A1AT? Will you potentially need to run a head-to-head study versus INHBE's long-acting augmentation therapy, should it be fully approved by the time you're ready to head to a pivotal study? Any color here on your thinking about regulatory would be helpful.

保羅 (Paul) 也許是這裡的監管途徑之一。您如何考慮 A1AT 的核准途徑？您可能需要與 INHBE 的長效增強療法進行頭對頭研究，當您準備進行關鍵研究時，它是否應該獲得完全批准？您對監管的任何思考都會有所幫助。

Yeah. I mean this is the wonderful aspect of being partnered that as the studies potentially could become more complex, although we do believe there's still a pathway for approval based on if you can -- if alpha-1 antitrypsin levels, right, in human levels and healthy protein is differentiated and still driving a therapeutic threshold for approval, then that should still support an accelerated pathway and a different approach than IV protein replacement. So editing versus protein replacement should be a potential pathway.

是的。我的意思是，這是合作的美妙之處，因為研究可能會變得更加複雜，儘管我們確實相信仍然有一條獲得批准的途徑，如果可以的話 - 如果 α-1 抗胰蛋白酶水平，對，在人體水平和健康蛋白質是不同的，並且仍然推動著治療批准的門檻，那麼這仍然應該支持途徑和不同於靜脈蛋白質替代的方法。因此，編輯而非蛋白質替換應該是一種潛在的途徑。

I think the opportunity that we've discussed too, and our partner will be thinking a lot about that is being able to drive continued ways of differentiating this program and as well as driving opportunities for expansion. If we think about AATD in total and why we're incredibly excited about the data we'll have this year and what it's going to inform going forward is there's a belief that there's a number of COPD patients who are technically being called nonresponders who may actually be alpha-1 antitrypsin patients.

我認為我們也討論過這個機會，我們的合作夥伴也會認真考慮這個機會，即能夠繼續推動該計劃的差異化，並推動擴張的機會。如果我們從總體上考慮 AATD，我們為什麼對今年獲得的數據感到無比興奮，以及它對未來有何啟示，那就是人們相信，有許多 COPD 患者在技術上被稱為無反應者，但實際上可能是 α-1 抗胰蛋白酶患者。

So I think the opportunity ahead to think about, again, as you're pointing out, respiratory endpoints, pathways in the regulatory environment, I think, still speak to the fact that there's a regulatory approach that's driven off of a numerical threshold in terms of its delivery. But not to be forgotten is the hepatic endpoints.

因此，我認為，正如您所指出的，未來的機會是思考呼吸終點、監管環境中的途徑，我認為，仍然說明存在一種監管方法，這種方法在交付方面是由數位閾值驅動的。但不要忘記肝臟終點。

And I think there is the opportunity to bifurcate into subsequent studies, those patients who have liver disease and how do you build liver and lung ultimately into a combined label. So not -- AATD patients aren't lung patients or liver patients, they're AATD patients, and they have both lung and liver disease.

我認為有機會在後續研究中對那些患有肝病的患者進行研究，以及如何最終將肝臟和肺部建構成一個聯合標籤。所以不是——AATD 患者不是肺癌患者或肝癌患者，而是 AATD 患者，他們同時患有肺癌和肝癌。

And so I think the opportunity ahead is really not to just think about it as a treatment for lung disease, but really a treatment of AATD. And I think our partner, and we are both excited about what that opportunity provides.

因此，我認為未來的機會實際上不僅僅是將其視為一種治療肺部疾病的方法，而是一種治療 AATD 的方法。我認為我們的合作夥伴和我們都對這個機會所帶來的一切感到興奮。

Madison, B. Riley.

麥迪遜，B. 萊利。

So with the 200 mg single dose, we've already seen that your own AATD conversion is over 60%. Do you believe or are you confident that the 200 mg multi-dose and/or the 400 mg single dose could push that conversion rate to over 80%? And any feedback -- site-specific feedback you're getting regarding enrollment? And then a follow-up.

因此，透過 200 毫克單劑量，我們已經看到您自己的 AATD 轉換率超過 60%。您是否相信或有信心 200 毫克多劑量和/或 400 毫克單劑量可以將轉換率提高到 80% 以上？還有什麼回饋嗎？您收到過關於招生的具體站點的回饋嗎？然後進行後續行動。

Yeah. I think on the last one, enrollment is going very well, particularly after we had our last data set. So our conversations with KOLs were achieving heterozygous levels after the lowest single dose is highly encouraging along with the profile.

是的。我認為最後一個方面，入學情況非常好，特別是在我們獲得最後一組資料集之後。因此，我們與 KOL 的對話表明，在最低單劑量之後達到雜合水平與概況一樣令人鼓舞。

I do think if we think about both the opportunity and actually why the 200-milligram multi-dose is so important is if you think about the total amount of drug under the 200-milligram dosing, there's a lot of -- we're going to get a lot of doses, a lot of medicine into the cells and a lot of opportunity to see how that ultimately pushes the upper bounds of editing.

我確實認為，如果我們同時考慮機會以及為什麼 200 毫克多劑量如此重要，那麼如果你考慮 200 毫克劑量下的藥物總量，就會有很多——我們將獲得很多劑量，將很多藥物注入細胞，並且有很多機會看看這最終如何突破編輯的上限。

The 400 mg is a single dose, right? So we're going to get a good sense of dose response between -- and see going forward, 200 mg versus 400 mg on a single-dose basis where we can flat out some of the pharmacokinetics. But the 200 mg multi-dose is going to be extraordinarily informative, and it's why we're excited for that data this year.

400 毫克是單劑量，對嗎？因此，我們將對劑量反應有一個很好的了解——並且觀察今後 200 毫克與 400 毫克單劑量之間的對比情況，我們可以在其中平衡一些藥物動力學。但 200 毫克的多劑量將會帶來極其豐富的信息，這就是我們今年對這些數據感到興奮的原因。

Got it. Understood. And then I also wanted to ask -- you've mentioned Rett syndrome today couple of times as a potential indication that would be appropriate for RNA editors. Have you discussed how you would get across the blood-brain barrier? Is this something related to your PN or your stereopure chemistry? Or would you need some type of shuttle vehicle?

知道了。明白了。然後我還想問一下——您今天幾次提到雷特氏症是適合 RNA 編輯的潛在指徵。你們討論過如何跨越血腦障壁嗎？這與您的 PN 或立體純化學有關嗎？或者您需要某種類型的穿梭車輛？

Yeah. So just to step back MECP2, I think we've got a variety of opportunities that we shared well beyond CF, MECP2, LDLR, ApoB, others, right? So we've shared a whole range. Importantly, MECP2 is important, to your point, as we're really defining what CNS editing looks like, both from an intrathecal standpoint. And as you mentioned, and we're going to have opportunities as we think about Research Day later this year to think about alternative approaches that we're doing for delivery. And so we've spent a lot of efforts in looking at how we deliver.

是的。因此，僅回顧 MECP2，我認為我們擁有多種共享機會，遠遠超越 CF、MECP2、LDLR、ApoB 等，對嗎？因此我們分享了整個範圍。重要的是，正如您所說，MECP2 非常重要，因為我們確實從鞘內的角度定義了 CNS 編輯是什麼樣子。正如您所提到的，當我們考慮今年稍後的研究日時，我們將有機會思考我們正在採取的替代交付方法。因此，我們花費了大量精力來研究如何實現這一目標。

And this is not just unique for AIMers, how we think about siRNAs, how we think about our AIMer technology, but being able to think about accessibility. So there's more to come as we think about the platform approaches, as we get into Research Day second half of this year. But we've spent a lot of time thinking about alternative ways of delivering across the blood-brain barrier.

這不僅對 AIMers 來說是獨一無二的，我們如何看待 siRNA，如何看待我們的 AIMer 技術，而且能夠考慮可訪問性。因此，隨著我們進入今年下半年的研究日，我們在考慮平台方法時還會有更多事情要做。但我們花了很多時間思考跨越血腦障壁的替代方法。

Got it. That's helpful. And then my last question is, have you said how many boys you would enroll in the expanded open-label cohort in the N531 trial? And then at what point you would reengage with the FDA?

知道了。這很有幫助。我的最後一個問題是，您是否說過在 N531 試驗的擴展開放標籤隊列中會招募多少名男孩？那麼你們什麼時候會重新與 FDA 合作？

Yeah. So the engagement around the 48-week data and our plan for confirmatory, we have, as we said earlier, the alignment on what's required for filing. To talk about numbers, we said the extension cohorts, that's the 11 boys continuing on monthly plus the additional expansion cohort that we would expect to be in line with other exon 53 files like Viltepso would all be supportive of the NDA filing in 2026. And that would be the next update is on that filing.

是的。因此，圍繞著 48 週數據和確認計劃的參與，正如我們之前所說，我們已經就提交所需的內容進行了協調。說到數字，我們說的是擴展隊列，即每月繼續的 11 名男孩加上額外的擴展隊列，我們預計這些隊列將與其他外顯子 53 文件（如 Viltepso）保持一致，所有這些都將支持 2026 年的 NDA 申請。這將是該文件的下一次更新。

That concludes our question-and-answer session. I would like to turn the conference over to Dr. Paul Bolno for closing comments.

我們的問答環節到此結束。我想將會議交給 Paul Bolno 博士來做最後總結。

Thank you for joining our call this morning. We look forward to connecting with many of you at upcoming conferences. Have a great day.

感謝您今天上午參加我們的電話會議。我們期待在即將召開的會議上與你們中的許多人建立聯繫。祝你有美好的一天。

Thank you. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

謝謝。會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。