WAVE Life Sciences Ltd (WVE) 2024 Q2 法說會逐字稿

Good morning, and welcome to the Wave Life Sciences second quarter 2024 financial results conference call. (Operator Instructions) As a reminder, this call is being recorded and webcast. I'll now 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 2024 年第二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 Wave's second quarter 2024 financial results. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Anne-Marie Li-Kwai-Cheung, Chief Development Officer; and Kyle Moran, Chief Financial Officer. Erik Ingelsson, Chief Scientific Officer; Chandra Vargeese, Chief Technology Officer; and Ginnie Yang, SVP of Translational Medicine, will also be available for questions following the call.

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 Wave 2024 年第二季度的財務業績。今天與我一起發表事先準備好的演講的是總裁兼執行長 Paul Bolno 博士； Anne-Marie Li-Kwai-Cheung，首席開發長；和財務長凱爾莫蘭。Erik Ingelsson，首席科學官； Chandra Vargeese，技術長；轉化醫學高級副總裁 Ginnie Yang 也將在電話會議後回答問題。

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.

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。

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 statement for any reason.

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。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不同的因素。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。

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

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. We have made incredible progress throughout the first half of this year, both in demonstrating the continued translation of our unique novel platform in the clinic and advancing our high-impact RNA medicines pipeline across modalities.

謝謝，凱特。早安，感謝大家參加今天的電話會議。今年上半年，我們取得了令人難以置信的進展，無論是在臨床上展示我們獨特的新型平台的持續轉化，還是在跨模式推進我們的高影響力 RNA 藥物管道方面。

A highlight of the second quarter was the positive results from the SELECT-HD clinical trial for WVE-003 for Huntington's disease. And I'll begin today with some remarks on this program and progress we've made since we announced them.

第二季的一大亮點是針對亨廷頓舞蹈症的 WVE-003 的 SELECT-HD 臨床試驗的正面結果。今天我將首先對這個計劃以及我們宣布這些計劃以來所取得的進展發表一些評論。

The clinical data, which we announced in June, serve as a testament to our best-in-class chemistry capabilities where our proprietary PN and stereochemistry enabled WVE-003 to achieve potent and durable mutant protein lowering while attaining exquisite specificity with wild-type preservation. This also led to a statistically significant correlation between mutant huntingtin lowering and slowing of caudate atrophy, a potential clinical endpoint for accelerated approval.

我們在 6 月宣布的臨床數據證明了我們一流的化學能力，我們專有的 PN 和立體化學使 WVE-003 能夠實現有效且持久的突變蛋白降低，同時透過野生型保存獲得精緻的特異性。這也導致突變亨廷頓蛋白降低和尾狀核萎縮減慢之間存在統計學上顯著的相關性，尾狀核萎縮是加速批准的潛在臨床終點。

HD is a devastating disease affecting more than 200,000 patients across all stages of disease in the US and Europe. HD is compared to having Alzheimer's disease, Parkinson's disease and ALS combined. Patients are faced with extremely limited treatment options, and there are no disease-modifying therapies currently available.

HD 是一種毀滅性的疾病，影響美國和歐洲超過 20 萬名各個疾病階段的患者。HD 與阿茲海默症、帕金森氏症和肌萎縮性側索硬化症的總和比較。患者面臨著極其有限的治療選擇，目前沒有可用的疾病緩解療法。

WVE-003 was designed to selectively knock down the mutant huntingtin protein while preserving the healthy wild-type huntingtin protein, which is critical to the health and function of neurons. With the first ever clinical demonstration of allele-selective silencing in patients, WVE-003 is uniquely positioned to address the larger presymptomatic patient population in addition to symptomatic HD patients.

WVE-003 旨在選擇性敲除突變亨廷頓蛋白，同時保留健康的野生型亨廷頓蛋白，這對神經元的健康和功能至關重要。隨著首次在患者中進行等位基因選擇性沉默的臨床演示，WVE-003 具有獨特的定位，可以解決除有症狀的 HD 患者之外的更大的症狀前患者群體。

Since announcing our SELECT-HD results, we have submitted our opt-in package to our partner, Takeda. If Takeda exercised its option right, our HD programs, including potential additional stint, shift to a 50-50 R&D and profit split. Takeda pays an opt-in payment, and Wave is eligible for development and commercial milestone payments.

自從宣布 SELECT-HD 結果以來，我們已向我們的合作夥伴 Takeda 提交了我們的選擇加入包。如果武田行使其選擇權，我們的 HD 計劃（包括潛在的額外期限）將轉向 50-50 的研發和利潤分配。武田支付選擇加入付款，而 Wave 有資格獲得開發和商業里程碑付款。

Our team has also initiated engagement with regulators on a clinical development path for WVE-003 that could support accelerated approval. We look forward to providing an update on regulatory feedback as well as an update on Takeda's decision by the end of the year.

我們的團隊也開始與監管機構就 WVE-003 的臨床開發路徑進行接觸，以支持加速批准。我們期待在年底前提供監管反饋的最新資訊以及武田決定的最新資訊。

Turning to DMD, our next expected clinical data update. With WVE-N531, our exon-skipping candidate for patients amenable to exon 53 skipping, we are looking to achieve dystrophin expression greater than 5% with consistency across patients, which would provide a meaningful best-in-class new option.

轉向 DMD，我們的下一個預期臨床數據更新。透過WVE-N531（我們的外顯子跳躍候選藥物，適用於易於外顯子53 跳躍的患者），我們希望實現肌營養不良蛋白表達大於5%，並且在患者之間保持一致，這將提供一個有意義的同類最佳新選擇。

As we look at the current treatment paradigm and therapies in development for DMD, there remains a significant scientific gap in the functional benefits of micro or mini dystrophin as well as durability. And when paired with unknown safety risks associated with AAV gene therapies, there is an urgent need to deliver better therapeutic option to patients.

當我們審視目前 DMD 的治療模式和正在開發的療法時，我們發現，微型或微型肌營養不良蛋白的功能益處以及耐久性方面仍然存在重大科學差距。當與 AAV 基因療法相關的未知安全風險相結合時，迫切需要為患者提供更好的治療選擇。

As a reminder, in our Part A study of N531 following just three doses administered every other week, we achieved industry-leading exon skipping and unprecedented muscle concentrations. Importantly, the tissue concentration levels are approximately 20 times higher than the top levels reported by exon-skipping technologies leveraging muscle delivery conjugate in DMD patients.

提醒一下，在我們對 N531 的 A 部分研究中，每隔一周僅注射三劑後，我們就實現了行業領先的外顯子跳躍和前所未有的肌肉濃度。重要的是，組織濃度水平大約比 DMD 患者中利用肌肉輸送綴合物的外顯子跳躍技術報告的最高水平高出 20 倍。

Despite low and inconsistent dystrophin data, exon-skipping therapeutics are standard of care for DMD and recorded approximately $1 billion in sales last year, primarily in the US for therapeutics that addressed approximately 29% of the population. Positive data with N531 would unlock the totality of our exon-skipping programs which would enable us to address up to 40% of the population, representing an opportunity to provide differentiated therapeutic portfolio to patients.

儘管肌肉營養不良蛋白數據較低且不一致，但外顯子跳躍療法仍是 DMD 的標準治療方法，去年銷售額約為 10 億美元，主要是在美國，針對約 29% 人口的治療方法。N531 的積極數據將解鎖我們的外顯子跳躍計劃的全部內容，這將使我們能夠覆蓋高達 40% 的人群，這代表著一個為患者提供差異化治療組合的機會。

Moving to RNA editing, WVE-006, our first-in-class GalNAc RNA editing candidate for AATD aims to correct the AATD causing mutation to increase circulating levels of wild-type or M-AAT protein and reduce mutant Z-AAT protein aggregation in the liver, thereby treating patients with lung manifestations, liver manifestations or both. There are an estimated 200,000 homozygous Pi*ZZ patients in the US and Europe. Treatment today is limited to weekly IV augmentation therapy for lung disease, while no therapies address AATD liver disease.

轉向 RNA 編輯 WVE-006，我們針對 AATD 的一流 GalNAc RNA 編輯候選藥物旨在糾正導致突變的 AATD，以增加野生型或 M-AAT 蛋白的循環水平，並減少突變型 Z-AAT 蛋白的聚集。 ，從而治療有肺部表現、肝臟表現或兩者兼具的患者。美國和歐洲估計有 20 萬名純合 Pi*ZZ 患者。目前的治療僅限於每週針對肺部疾病進行靜脈強化治療，而沒有針對 AATD 肝病的治療方法。

SiRNA treatments in development are confined to treating only liver disease and could exacerbate lung injury. By editing RNA, WVE-006 differs from DNA-editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels. WVE-006 contained a GalNAc conjugate, a highly specific and elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market.

正在開發的 siRNA 療法僅限於治療肝臟疾病，並可能加劇肺損傷。透過編輯 RNA，WVE-006 與 DNA 編輯技術不同，DNA 編輯技術依賴過度活躍的外源性人工酶，這些酶可能導致不可逆的旁觀者編輯和插入缺失。WVE-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。

GalNAc enables the ease and convenience of subcutaneous dosing, effective and selective delivery to hepatocyte as well as a high degree of confidence of preclinical to clinical translation since the entire dose delivered is reliably sent to the target organ, unlike lipid nanoparticles.

GalNAc 能夠輕鬆便捷地進行皮下給藥，有效且選擇性地遞送至肝細胞，並且使臨床前轉化為臨床轉化具有高度可信度，因為與脂質奈米顆粒不同，遞送的整個劑量均可靠地發送至靶器官。

In preclinical studies, our proprietary chemistry has enabled WVE-006 to effectively recruit endogenous ADAR enzymes and achieve potent and durable editing. We've shown AAT protein levels that exceed the threshold for both MZ and healthy MM populations and have confirmed this functionality with neutrophil elastase inhibition assay. Additionally, WVE-006 decreased lobular inflammation, reduced liver aggregates and prevented increases in mitosis indicating improved hepatocyte survival, in preclinical models.

在臨床前研究中，我們的專有化學使 WVE-006 能夠有效招募內源 ADAR 酶並實現有效且持久的編輯。我們發現 AAT 蛋白水平超過了 MZ 和健康 MM 群體的閾值，並透過中性粒細胞彈性蛋白酶抑制測定證實了這一功能。此外，在臨床前模型中，WVE-006 減少小葉炎症，減少肝臟聚集並防止有絲分裂增加，顯示肝細胞存活率增加。

Dosing in our RestorAATion-2 trial initiated in third quarter and we expect to deliver proof of mechanism data in the fourth quarter of this year. These data would not only meaningfully derisk our AATD program but would also serve as proof of concept for our growing pipeline of wholly-owned editing candidates, which are designed to either correct or upregulate mRNA in both rare and prevalent diseases.

我們的 RestorAATion-2 試驗於第三季啟動，我們預計將在今年第四季提供機制資料證明。這些數據不僅會有意義地消除我們的 AATD 計劃的風險，而且還可以作為我們不斷增長的全資編輯候選產品管道的概念證明，這些候選產品旨在糾正或上調罕見和流行疾病中的 mRNA。

WVE-006 is part of our ongoing collaboration with GSK and development and commercialization responsibilities transferred to GSK at their sole cost after we complete our RestorAATion-2 study. Under the collaboration, there are $525 million in total milestones related to WVE-006 and Wave is eligible for double-digit tiered royalties as a percentage of net sales up to the high teens.

WVE-006 是我們與 GSK 持續合作的一部分，在我們完成 RestorAATion-2 研究後，開發和商業化責任將轉移給 GSK，費用由 GSK 自行承擔。根據此次合作，與 WVE-006 相關的總里程碑價值為 5.25 億美元，Wave 有資格獲得兩位數的分層特許權使用費（佔淨銷售額的百分比，最高可達十位數）。

I'll next give an update on our GalNAc siRNA inhibiting program, which is now called WVE-007. Obesity is a public health epidemic impacting approximately 175 million adults in the US and Europe. Increasingly, it is being recognized that reduction of weight and fat mass are linked to improved health outcomes, including reduced risk of many diseases.

接下來我將介紹我們的 GalNAc siRNA 抑製程序（現在稱為 WVE-007）的最新情況。肥胖是一種公共衛生流行病，影響美國和歐洲約 1.75 億成年人。人們越來越認識到，體重和脂肪量的減少與健康狀況的改善有關，包括降低許多疾病的風險。

With WVE-007, we are advancing a completely novel approach to weight loss. Enabled by our best-in-class siRNA technology, we believe this molecule has the potential to unlock the next frontier to obesity treatment and address millions impacted by the disease.

透過 WVE-007，我們正在推進一種全新的減肥方法。在我們一流的 siRNA 技術的支持下，我們相信該分子有潛力開啟肥胖治療的下一個前沿領域，並解決數百萬人受疾病影響的問題。

This program is supported by human genetics. INHBE loss-of-function heterozygous carriers have a favorable cardiometabolic profile, including reduced abdominal obesity and reduced odds of type 2 diabetes and coronary artery disease. One can think of this target as the PCSK9 of obesity. INHBE mRNA is expressed in the liver with its corresponding receptor on adipocytes, which control fat storage.

該計劃得到了人類遺傳學的支持。INHBE 功能喪失雜合子攜帶者俱有良好的心臟代謝特徵，包括減少腹部肥胖以及降低 2 型糖尿病和冠狀動脈疾病的幾率。人們可以將此目標視為肥胖症的 PCSK9。INHBE mRNA 在肝臟中表達，脂肪細胞上有相應的受體，控制脂肪儲存。

We designed WVE-007 to silence the INHBE gene transcript, thereby recapitulating the cardiometabolic protection of carriers of INHBE loss-of-function mutations. While GLP-1s have become the current standard of care for weight loss, their impact is often limited by frequent dosing, loss of muscle mass or tolerability and high discontinuation rates.

我們設計了 WVE-007 來沉默 INHBE 基因轉錄本，從而重現 INHBE 功能喪失突變攜帶者的心臟代謝保護作用。雖然 GLP-1 已成為目前減重治療的標準，但其影響往往受到頻繁給藥、肌肉質量或耐受性損失以及高停藥率的限制。

We see three key areas of opportunity to address obesity with WVE-007 as a frontline monotherapy in combination with GLP-1s for further improvement of weight loss or to reduce the doses of GLP-1s or as a maintenance therapy following cessation of GLP-1s.

我們看到了解決肥胖問題的三個關鍵領域，將 WVE-007 作為與 GLP-1 聯合的一線單一療法，以進一步改善體重減輕或減少 GLP-1 的劑量，或作為停止 GLP-1 後的維持治療。

First, our INHBE siRNA, we have demonstrated highly potent and durable silencing with an ED50 of less than 1 milligram per kilogram, supporting dosing intervals of just once or twice a year. Preclinically, our INHBE siRNA also led to weight loss similar to semaglutide and reduction in fat mass with a preferential effect on visceral fat, all with no loss of muscle mass.

首先，我們的 INHBE siRNA 已證明具有高效且持久的沉默作用，ED50 低於 1 毫克每公斤，支持每年一次或兩次的給藥間隔。臨床前，我們的 INHBE siRNA 也導致與索馬魯肽類似的體重減輕和脂肪量減少，並優先影響內臟脂肪，所有這些都沒有損失肌肉質量。

As a reminder, the mechanism of INHBE silencing is distinct from GLP-1s, opening an exciting opportunity for use in combination following weight loss induction. New results from an ongoing study underscored the potential for this use. Specifically, when administered in combination with semaglutide, a single dose of our INHBE GalNAc siRNA doubled the weight loss observed with semaglutide alone and this effect was sustained throughout the duration of the study.

提醒一下，INHBE 沉默的機制與 GLP-1 不同，這為減肥誘導後的聯合使用提供了令人興奮的機會。一項正在進行的研究的新結果強調了這種用途的潛力。具體來說，當與索馬魯肽聯合給藥時，單劑量的 INHBE GalNAc siRNA 使單獨使用索馬魯肽觀察到的體重減輕加倍，並且這種效果在整個研究期間持續存在。

As we described previously, treatment with our INHBE siRNA upon cessation of semaglutide also curtailed expected rebound weight gain. We are very excited about the broad potential of this program in obesity and look forward to sharing more data at our Annual R&D Day.

正如我們之前所描述的，在停止索馬魯肽後使用我們的 INHBE siRNA 治療也減少了預期的體重反彈。我們對該計畫在肥胖方面的廣泛潛力感到非常興奮，並期待在我們的年度研發日分享更多數據。

Looking ahead, we believe we can demonstrate clinical proof of concepts with just a single dose of our INHBE siRNA in a study of healthy overweight volunteers. We remain on track to file a CTA for WVE-007 as early as the end of year and initiate a clinical trial in the first quarter of next year.

展望未來，我們相信我們可以在健康超重志願者的研究中僅用單劑量的 INHBE siRNA 來證明概念的臨床證明。我們仍有望在年底前提交 WVE-007 的 CTA，並在明年第一季啟動臨床試驗。

We have a vast opportunity ahead of us to deliver differentiated therapies to millions of patients in areas of high unmet need. We are poised to deliver on multiple important catalysts in the second half of the year, which would unlock and derisk additional programs. Additionally, at our annual R&D Day this fall, we expect to give an update on our emerging pipeline, including our wholly-owned RNA editing programs.

我們面臨著巨大的機會，可以為需求高度未滿足的地區的數百萬名患者提供差異化治療。我們準備在今年下半年推出多個重要的催化劑，這將釋放額外的計劃並消除風險。此外，在今年秋天的年度研發日上，我們預計將更新我們的新興產品線，包括我們全資擁有的 RNA 編輯專案。

Now to discuss our clinical programs in more detail, I'll turn the call over to Anne-Marie. Anne-Marie?

現在，為了更詳細地討論我們的臨床計劃，我將把電話轉給安妮瑪麗。安妮瑪麗？

Thank you, Paul. It's certainly been a busy year thus far, and I'm excited to share an update on our clinical programs. I'll begin with HD and our recent clinical results. Our SELECT-HD clinical trial was designed to demonstrate safety and tolerability, PK and mutant huntingtin silencing over 30%, with healthy wild-type huntingtin preservation with multiple doses of WVE-003.

謝謝你，保羅。到目前為止，這無疑是忙碌的一年，我很高興分享我們臨床計畫的最新情況。我將從 HD 和我們最近的臨床結果開始。我們的 SELECT-HD 臨床試驗旨在證明安全性和耐受性、PK 和突變型亨廷頓蛋白沉默超過 30%，並以多劑量的 WVE-003 保存健康的野生型亨廷頓蛋白。

In this multi-dose cohort, where we tested 30 milligrams dosed intrathecally every eight weeks, we saw excellent translation of our preclinical modeling with potent and durable mutant huntingtin

在這個多劑量隊列中，我們測試了每八週鞘內注射 30 毫克的劑量，我們看到了我們的臨床前模型與有效且持久的突變亨廷頓蛋白的出色轉化

reductions of up to 46% plus preservation of wild-type huntingtin.

減少高達 46%，並保留野生型亨廷頓蛋白。

Multi-dosing was generally safe and well tolerated with mild-to-moderate adverse events and no serious adverse events. Further, this cohort showed a statistically significant correlation between mutant huntingtin reductions and slowing of caudate atrophy, a known imaging biomarker that is predictive of clinical outcomes. This was also the first ever demonstration of such a correlation in the clinic, reinforcing the potential benefit of allele-selective mutant huntingtin lowering.

多次給藥通常是安全的，耐受性良好，有輕度至中度不良事件，且沒有嚴重不良事件。此外，此群組顯示突變亨廷頓蛋白減少和尾狀核萎縮減慢之間存在統計學上顯著的相關性，尾狀核萎縮是一種已知的成像生物標記物，可以預測臨床結果。這也是臨床上首次證明這種相關性，增強了等位基因選擇性突變亨廷頓蛋白降低的潛在益處。

Since sharing this data, we have been connecting with KOLs and patient groups who are excited about the mutant huntingtin knockdown and most of all, the first potential therapeutic option that preserves healthy wild-type huntingtin. We'll be sharing these previously announced results with a broader HD community at the Annual Meeting of the European Huntington's Disease Network, or EHDN, taking place on September 12 to 14 in Strasbourg, France.

自從分享這些數據以來，我們一直在與 KOL 和患者團體建立聯繫，他們對突變亨廷頓蛋白的敲低感到興奮，最重要的是，這是第一個保留健康野生型亨廷頓蛋白的潛在治療選擇。我們將在 9 月 12 日至 14 日在法國斯特拉斯堡舉行的歐洲亨廷頓病網絡 (EHDN) 年會上與更廣泛的 HD 社區分享這些先前公佈的結果。

One thing that's been clear to me in my conversations with HD patients' families and physicians who have experienced challenges with large and long placebo-controlled studies, there was a pressing need for novel biomarkers to enable a more efficient path to registration.

在我與 HD 患者家屬和醫生的交談中，我清楚地意識到，迫切需要新型生物標記物來實現更有效的註冊途徑，這些患者都經歷過大規模且長期的安慰劑對照研究的挑戰。

For accelerated approval, we know regulators are looking for biomarkers with biological relevance for the disease in question. Caudate is one of the primary areas where HD manifests in the brain. At the point of clinical diagnosis, patients have a marked brain atrophy compared to controls, typically having lost more than 40% of their caudate at the time of first symptom onset and clinical diagnosis.

為了加速批准，我們知道監管機構正在尋找與相關疾病具有生物學相關性的生物標記。尾狀核是 HD 在大腦中表現的主要區域之一。在臨床診斷時，與對照組相比，患者有明顯的腦萎縮，在首次症狀出現和臨床診斷時，通常已失去 40% 以上的尾狀核。

Since loss of caudate manifests many years before diagnosis and continues to be lost at a rate of about 2% to 4% a year, there are clear correlations between caudate loss and clinical outcomes giving it the potential to be used to design a clinical development path to accelerated approval.

由於尾狀核丟失在診斷前很多年就已顯現，並且繼續以每年約2% 至4% 的速度丟失，因此尾狀核丟失與臨床結果之間存在明顯的相關性，使其有可能用於設計臨床開發路徑以加快審批速度。

Just last month, we attended the Critical Path Institute Critical Risk meeting where the consortium and FDA engaged on the urgency for disease-modifying therapies in Huntington's disease and ways to enable more efficient trial designs, including the use of endpoints reasonably likely to predict clinical outcomes.

就在上個月，我們參加了關鍵路徑研究所的關鍵風險會議，該聯盟和 FDA 討論了亨廷頓病疾病修飾療法的緊迫性以及實現更有效試驗設計的方法，包括使用合理可能預測臨床結果的終點。

Given our focus on caudate atrophy, we are pleased to announce that we have joined the Huntington Disease Image Harmonization Consortium and are working in conjunction with CHDI and IXICO to advance the data sets needed to support establishment of caudate atrophy as an endpoint reasonably likely to predict clinical outcomes.

鑑於我們對尾狀核萎縮的關注，我們很高興地宣布，我們已加入亨廷頓病影像協調聯盟，並與 CHDI 和 IXICO 合作，推進支持建立尾狀核萎縮作為合理預測終點所需的數據集臨床結果。

In tandem, we've engaged regulators on our clinical development pathway, including the potential for accelerated approval and expect feedback by year-end. The SELECT-HD trial is now complete, and all future steps will be informed by this regulatory feedback. In addition, as Paul mentioned, we've submitted our opt-in package to Takeda. We would like to sincerely thank the patients' families and sites who participated in SELECT-HD. None of this research would be possible without them.

同時，我們已經與監管機構就我們的臨床開發途徑進行了接觸，包括加速批准的潛力，並期望在年底前得到回饋。SELECT-HD 試驗現已完成，未來的所有步驟都將根據此監管回饋進行通知。此外，正如保羅所提到的，我們已向武田提交了我們的選擇加入包。我們衷心感謝參與 SELECT-HD 的患者家屬和站點。沒有他們，所有這些研究都是不可能的。

Turning to DMD, we are advancing our open-label FORWARD-53 trial of WVE-N531 for boys with exon 53 amenable DMD. We are on track to deliver a 24-week dystrophin data later this quarter. The preclinical and clinical data we've observed thus far with WVE-N531 bolster our confidence and excitement to deliver potential transformative new therapeutic option for patients.

至於 DMD，我們正在推進 WVE-N531 的開放標籤 FORWARD-53 試驗，該試驗針對外顯子 53 適合 DMD 的男孩。我們預計在本季度稍後提供 24 週肌肉營養不良蛋白數據。迄今為止，我們觀察到的 WVE-N531 臨床前和臨床數據增強了我們為患者提供潛在的變革性新治療選擇的信心和興奮。

In part A of our clinical trial, N531 demonstrated industry-leading mean 53% exon skipping, which was driven by muscle tissue concentrations of 42,000 nanograms per gram which is far above what other exon-skipping companies have reported. Also in part A, we observed clinical evidence of myogenic stem cell or satellite cell uptake of N531. This is particularly notable as myogenic stem cells are the progenitor cells for new myoblasts, and 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.

在我們臨床試驗的A 部分中，N531 表現出行業領先的平均外顯子跳躍率為53%，這是由每克42,000 納克的肌肉組織濃度驅動的，這遠高於其他外顯子跳躍公司報告的水平。同樣在 A 部分中，我們觀察到肌源幹細胞或衛星細胞攝取 N531 的臨床證據。這是特別值得注意的，因為肌源性幹細胞是新成肌細胞的祖細胞，我們不知道任何其他外顯子跳躍者或基因治療的臨床數據能夠證明肌源性幹細胞的攝取。

Preclinically, we've shown N531 concentrations in the heart and diaphragm exceed that of skeletal muscle, which could speak to the promise of addressing what remains a huge unmet need in DMD, respiratory and cardiac function. As a reminder, in addition to having a safe and tolerable profile, we are focused on what we believe will be the key for success for next-generation exon skippers.

臨床前，我們已經證明 N531 在心臟和橫膈膜中的濃度超過了骨骼肌的濃度，這有望解決 DMD、呼吸和心臟功能方面尚未滿足的巨大需求。提醒一下，除了擁有安全和可容忍的特徵之外，我們還關注我們認為下一代外顯子船長成功的關鍵。

Firstly, of course, is increasing the quantity of dystrophin available to provide a better light dystrophin profile of greater than 5%, which would exceed the current standard of care. Secondly, delivering high-quality functional dystrophin through exon skipping. Dystrophin produced through exon skipping includes important regions that are absent from mini or microdystrophin. Lastly, consistency of response. We know prior therapies have provided highly variable and inadequate response at the patient level.

首先，當然是增加可用的肌肉營養不良蛋白數量，以提供超過 5% 的更好的輕度肌肉營養不良蛋白分佈，這將超出當前的護理標準。其次，透過外顯子跳躍提供高品質的功能性肌肉營養不良蛋白。透過外顯子跳躍產生的肌肉營養不良蛋白包括迷你或微肌營養不良蛋白所缺乏的重要區域。最後，響應的一致性。我們知道，先前的療法在患者層面上提供了高度可變且不充分的反應。

Despite there being approved therapies in the market, when we speak to KOLs and patients, we hear a need for more and better treatment options -- about the treatment options available. Coupled with extending dosing in tools to once or twice a month, N531 could provide meaningful benefit to patients and their families currently needing weekly infusion. We are well poised to provide a meaningful new therapeutic option for the treatment of DMD.

儘管市場上有經過批准的治療方法，但當我們與 KOL 和患者交談時，我們聽到需要更多、更好的治療選擇——關於可用的治療選擇。再加上工具中的給藥劑量延長至每月一次或兩次，N531 可以為目前需要每週輸注的患者及其家人帶來有意義的益處。我們已準備好為 DMD 的治療提供有意義的新治療選擇。

If positive, dystrophin data would support our plans to file for accelerated approval of N531 in the US and would accelerate our clinical development plans to build a multi-exon DMD franchise beyond exon 53. We've generated data on compounds that would all together address up to 40% of the DMD patients. And importantly, these programs continue to demonstrate skipping and protein restoration in preclinical studies that's on a par with or exceeds N531.

如果呈陽性，肌肉營養不良蛋白數據將支持我們在美國申請加速批准 N531 的計劃，並將加速我們的臨床開發計劃，以建立外顯子 53 以外的多外顯子 DMD 專營權。我們已經產生了有關化合物的數據，這些數據總共可以治療多達 40% 的 DMD 患者。重要的是，這些項目在臨床前研究中繼續證明了跳躍和蛋白質恢復與 N531 相當或超過 N531。

With WVE-006, we are rapidly advancing our RestorAATion clinical program for AATD, the first RNA editing program in the clinic. This clinical program is comprised of RestorAATion-1, a dose escalation study in healthy volunteers, and RestorAATion-2, a Phase 1b/2a open-label study with single and multiple ascending dose portions that's designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of WVE-006 in patients with AATD who have the homozygous Pi*ZZ mutation. RestorAATion-1 continues to dose escalate and pharmacokinetic data are translating as expected for a GalNAc-conjugated oligonucleotide.

借助 WVE-006，我們正在快速推進針對 AATD 的 RestorAATion 臨床計劃，這是臨床上的第一個 RNA 編輯計劃。該臨床計劃包括RestorAATion-1（一項在健康志願者中進行的劑量遞增研究）和RestorAATion-2（一項1b/2a 期開放標籤研究，具有單次和多次遞增劑量部分，旨在評估安全性、耐受性、藥效學和WVE-006 在具有純合子 Pi*ZZ 突變的 AATD 患者中的藥物動力學。RestorAATion-1 繼續劑量遞增，藥物動力學數據正按照 GalNAc 綴合寡核苷酸的預期進行轉化。

Utilizing our pharmacokinetic data from healthy volunteers as well as our robust preclinical data, we identified the dose level expected to engage target. In the third quarter of 2024, we commenced dosing in AATD patients in the first single dose cohort in RestorAATion-2. Throughout dose cohorts, we will be taking multiple assessments to measure the potential presence of wild-type healthy M-AAT protein in the serum.

利用健康志願者的藥物動力學數據以及可靠的臨床前數據，我們確定了預期達到目標的劑量水平。2024 年第三季度，我們開始在 RestorAATion-2 的第一個單劑量隊列中對 AATD 患者進行給藥。在整個劑量組中，我們將進行多次評估來測量血清中野生型健康 M-AAT 蛋白的潛在存在。

As a reminder, ZZ patients do not produce any M-AAT protein. So detection of M-AAT protein would be the first ever clinical demonstration of RNA editing in humans. The trial is progressing, and we expect to announce a proof of mechanism in the fourth quarter of 2024.

提醒一下，ZZ 患者不會產生任何 M-AAT 蛋白。因此，M-AAT 蛋白的檢測將是人類 RNA 編輯的首次臨床演示。試驗正在進行中，我們預計將在 2024 年第四季宣布機制證明。

Beyond that, we have the flexibility to adjust both dose level and frequency in RestorAATion-2 as we look ahead to delivering a medicine that can bring AATD ZZ patients to a healthier MZ phenotype with total serum AAT protein levels above the anticipated therapeutic threshold of 11 micromolar.

除此之外，我們還可以靈活調整RestorAATion-2 的劑量水平和頻率，因為我們期待提供一種藥物，可以使AATD ZZ 患者達到更健康的MZ 表型，使總血清AAT 蛋白水平高於預期治療閾值11微摩爾。

With that, I'd like to turn our call to our CFO, Kyle Moran, to provide an update on our financials.

說到這裡，我想致電我們的財務長凱爾·莫蘭（Kyle Moran），請他提供有關我們財務狀況的最新資訊。

Thanks, Anne-Marie. We recognized collaboration revenue of $19.7 million in the second quarter of 2024 as compared to $22.1 million in the prior year quarter. This slight decrease in revenue reflects typical variations in recognition of collaboration revenue.

謝謝，安妮瑪麗。我們確認 2024 年第二季的協作收入為 1,970 萬美元，而去年同期為 2,210 萬美元。收入的小幅下降反映了協作收入確認的典型變化。

Research and development expenses were $40.4 million in the second quarter of 2024 as compared to $33.3 million in the prior year quarter. This increase was primarily driven by spending in our INHBE program along with AATD and DMD programs and early-stage pipeline initiatives.

2024 年第二季的研發費用為 4,040 萬美元，而去年同期為 3,330 萬美元。這一增長主要是由我們的 INHBE 計劃以及 AATD 和 DMD 計劃以及早期管道計劃的支出所推動的。

Our G&A expenses were $14.3 million for the second quarter of 2024 as compared to $12.3 million in the prior year quarter. As a result, our net loss was $32.9 million for the second quarter as compared to $21.1 million in the prior year quarter. We ended the second quarter with $154 million in cash and cash equivalents.

2024 年第二季我們的一般管理費用為 1,430 萬美元，去年同期為 1,230 萬美元。因此，我們第二季的淨虧損為 3,290 萬美元，而去年同期淨虧損為 2,110 萬美元。第二季結束時，我們擁有 1.54 億美元的現金和現金等價物。

We expect that our current cash and cash equivalents will be sufficient to fund operations into the fourth quarter of 2025. It is important to note that we do not include any future milestones or opt-in payments under our GSK or Takeda collaboration in our cash runway, but we do have the potential to receive meaningful near-term milestone payments this year and beyond.

我們預計目前的現金和現金等價物將足以為 2025 年第四季的營運提供資金。值得注意的是，我們的現金跑道中不包括任何未來里程碑或選擇加入葛蘭素史克或武田合作的付款，但我們確實有可能在今年及以後收到有意義的近期里程碑付款。

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做總結發言。

Thank you, Kyle. It is an incredibly exciting time for Wave as we are poised to sustainably translate new human genetic insights into breakthrough medicines. With ongoing validation of our platform and several important program milestones ahead, our confidence and conviction in the promise of our pipeline has never been stronger.

謝謝你，凱爾。對於 Wave 來說，這是一個令人難以置信的令人興奮的時刻，因為我們準備將新的人類遺傳見解可持續轉化為突破性藥物。隨著我們平台的持續驗證和未來幾個重要的計劃里程碑，我們對管道承諾的信心和信念從未如此堅定。

In this half of 2024, we expect to provide updates across each of our clinical programs, including dystrophin data this quarter as well as advance our obesity program into clinical development with the submission of the CTA. We are also planning an R&D day this fall to share new preclinical data on our wholly-owned portfolio, including our WVE-007 INHBE program. We look forward to keeping you updated on our progress along the way.

2024 年下半年，我們預計將提供每個臨床項目的最新信息，包括本季度的肌肉營養不良蛋白數據，並透過提交 CTA 將我們的肥胖計畫推進臨床開發。我們還計劃在今年秋天舉辦研發日，分享我們全資投資組合的新臨床前數據，包括我們的 WVE-007 INHBE 計畫。我們期待著向您通報我們一路走來的最新進展。

In closing, I would like to thank our teams that are working tirelessly to advance our programs, deliver our clinical results and are preparing to initiate new clinical studies. Additionally, I would like to express our deepest gratitude to the patients and families participating in our studies and all who inspire us at Wave.

最後，我要感謝我們的團隊，他們不懈地努力推進我們的項目，提供我們的臨床結果，並準備啟動新的臨床研究。此外，我也要向參與我們研究的病人和家屬以及所有在 Wave 激勵我們的人表示最深切的感謝。

And with that, I'll turn it over to the operator for Q&A. Operator?

然後，我會將其轉交給操作員進行問答。操作員？

(Operator Instructions)

（操作員說明）

Joon Lee, Truist.

李俊，真理主義者。

Congrats on the progress and looking forward to a lot of data readouts in the next five months. Glad to hear that you have submitted the opt-in package to Takeda with decision by year-end. Regarding the conversations with regulators, is Takeda involved in those conversations? Or is it just between you and the FDA? And what has been the feedback so far on the possibility of using imaging as a surrogate biomarker? Thank you. And I have a quick follow-up.

恭喜您的進展，並期待在接下來的五個月內獲得大量數據。很高興得知您已向武田提交了選擇加入方案，並在年底前做出決定。關於與監管機構的對話，武田是否參與了這些對話？或者這只是您和 FDA 之間的事？到目前為止，關於使用成像作為替代生物標記的可能性的反饋是什麼？謝謝。我有一個快速的跟進。

Thank you, Joon. Obviously, we don't comment on specific regulatory interactions point in time. But yes, Takeda is involved in our interactions.

謝謝你，瓊。顯然，我們不會對具體的監管互動時間點發表評論。但是，是的，武田參與了我們的互動。

Great. And on DMD, just looking at the approved antisense oligos in DMD, about 42% exon skipping for the 53 from Viltepso lead to around 4.8% dystrophin. So would you say the bar for N531 is around 5%. Is there some internal bar for efficacy you'd like to see in the forthcoming data? Thank you.

偉大的。對於 DMD，僅查看 DMD 中批准的反義寡核苷酸，Viltepso 的 53 號外顯子跳躍約 42%，導致約 4.8% 的肌肉營養不良蛋白。所以你會說 N531 的門檻是 5% 左右嗎？您希望在即將發布的數據中看到一些內部功效標準嗎？謝謝。

Yeah. Thank you for the question, Joon. I mean as we think about dystrophin expression and our guidance to 5% or more, right, greater than 5%, I think we look at this as the 42% you were citing from Viltepso was after six months of dosing. So what's encouraging to us is the 53% that we were seeing after three doses at six weeks.

是的。謝謝你的提問，瓊。我的意思是，當我們考慮肌肉營養不良蛋白表達以及我們對5% 或更多（對，大於5%）的指導時，我認為我們將這一點視為您引用的Viltepso 的42% 是在給藥六個月後。因此，令我們感到鼓舞的是，在六週內注射三劑後，我們看到了 53% 的患者出現這種情況。

So again, getting the machinery of dystrophin production going earlier with a protein that has a high rated stability. I think if we think about that conversion where you said that 42% to 4.8%, it's also important as we looked at those data sets from the clinic out of six months that really that 4.8% was being driven by two outliers.

再次強調，利用具有高穩定性的蛋白質，使抗肌營養不良蛋白的生產機制更早啟動。我認為，如果我們考慮一下您所說的42% 到4.8% 的轉換，這一點也很重要，因為我們查看了六個月內診所的資料集，實際上4.8% 是由兩個異常值驅動的。

So as Anne-Marie mentioned, the consistency of response, which we saw early is something we'll be looking for in this study. And if you remove those outliers, it is actually somewhere around 3%, just slightly above 3% dystrophin. So again, the production that we see of high quality, high quantity, so greater than 5% and consistency we think will drive a differentiated profile.

正如安妮瑪麗所提到的，我們早期看到的反應的一致性是我們在這項研究中要尋找的東西。如果去掉這些異常值，實際上約為 3%，略高於 3% 的肌肉營養不良蛋白。再說一遍，我們看到的高品質、高數量的生產，因此大於 5% 的生產以及我們認為的一致性將推動差異化形象。

I do think as Anne-Marie -- getting back to your first question, I was reflecting on a lot of the work that's happening over the course of this year in clinical surrogate endpoints, both through the HD Risk Consortium work that's being done to evaluate the CHD Track-HD data. And I do think it is highly encouraging, the work that's being done on caudate imaging. I don't know Anne-Marie, if there's any additional insights you want to reflect on back on the first question.

我確實認為，作為 Anne-Marie，回到你的第一個問題，我正在反思今年在臨床替代終點方面所做的大量工作，包括透過 HD 風險聯盟正在進行的評估工作CHD Track-HD 數據。我確實認為尾狀核子造影方面正在進行的工作非常令人鼓舞。我不知道安妮瑪麗，您對第一個問題是否有任何其他見解想要反思。

Yes. I think FDA is highly engaged with the community in general and with the HD Risk Consortium in particular. And as I mentioned in the recent meeting we had, they're absolutely aligned in the intent of trying to find more efficient ways to bring therapies to people with HD and also supporting endpoints reasonably likely to predict clinical outcome.

是的。我認為 FDA 與整個社區，特別是 HD 風險聯盟高度互動。正如我在最近的會議中提到的，他們的意圖完全一致，即試圖找到更有效的方法為 HD 患者提供治療，並支持合理可能預測臨床結果的終點。

And I think that's why it's really important that we've entered into the consortium -- the imaging consortium to start placing and providing the data set that will be necessary to establish caudate atrophy as an endpoint reasonably likely to predict a clinical outcome. So it's all very encouraging.

我認為這就是為什麼我們加入成像聯盟非常重要，該聯盟開始放置和提供將尾狀核萎縮確定為合理可能預測臨床結果的終點所必需的數據集。所以這一切都非常令人鼓舞。

Great. Thank you and I'm looking forward to the R&D event in the fall.

偉大的。謝謝您，我期待秋季的研發活動。

Thank you.

謝謝。

Salim Syed, Mizuho.

薩利姆賽義德，瑞穗。

Good morning, guys, and congrats on the progress. Paul, I wanted to follow up a little bit on the Takeda stuff that we're going to get this year. So could you just clarify for us, is this -- are you anticipating that the feedback we're going to get to the Street, is it going to be one event or two events? In other words, are we supposed to expect the regulatory feedback as one event and the Takeda decision as another event? Are these two things linked?

早安，夥伴們，恭喜你們的進展。保羅，我想跟進一下我們今年將獲得的武田產品。那麼您能否為我們澄清一下，您是否預期我們將得到華爾街的回饋，這將是一個事件還是兩個事件？換句話說，我們是否應該將監管回饋視為一個事件，而將武田的決定視為另一個事件？這兩件事有連結嗎？

And then also just what is the disclosure format, if you can just clarify for us, are we just going to get that some time as it happens? Or are you going to wait for the quarterly -- the next quarterly call? And then just lastly, just related to that, as you're considering financing the company, just given DMD is a third quarter event and the feedback from the regulatory body in Takeda could be potentially a 4Q event, would you wait for that to occur? Or would you be willing to finance on DMD given your runway is now at 4Q '25? Thank you.

然後，披露格式是什麼，如果您能為我們澄清一下，我們是否會在事情發生時得到它？或者你要等待季度電話會議——下一個季度電話會議嗎？最後，與此相關的是，當您正在考慮為公司融資時，考慮到 DMD 是第三季度的事件，而武田監管機構的反饋可能是第四季度的事件，您會等待這種情況發生嗎？或者考慮到您的跑道現在是 25 年第 4 季度，您願意為 DMD 提供資金嗎？謝謝。

Thank you, Salim. And I'll take these in reverse order. So as it relates to when and where potential financings occur. Again, besides just the Takeda opt-in, there's also continued milestones through the GSK collaboration, which we announced even in the first quarter. We received a $12 million payment for work that was happening under the research collaboration.

謝謝你，薩利姆。我將以相反的順序處理這些內容。因為它關係到潛在融資發生的時間和地點。同樣，除了武田選擇加入之外，我們甚至在第一季就宣布了與葛蘭素史克合作的持續里程碑。我們收到了 1200 萬美元的研究合作付款。

So we do anticipate some big milestones through 2024 and 2025. As it relates to your first question in terms of disclosure, it's important to think about these as two independent events. The Takeda opt-in decision is not predicated on regulatory feedback, it is based on the data from the prior study. So as we said on the call, the submission of the package was driven off of the data that met the threshold for us to submit that package.

因此，我們確實預期 2024 年和 2025 年會出現一些重大里程碑。由於它與您在披露方面的第一個問題有關，因此將它們視為兩個獨立事件很重要。武田的選擇決定並非基於監管回饋，而是基於先前研究的數據。正如我們在電話中所說，包的提交是由滿足我們提交該包的閾值的數據驅動的。

Now those two pieces that are happening simultaneously towards the end of the year, there are interactions of what's happening across both of those, the regulatory feedback and the ongoing discussion with Takeda. So we do view those as while the two separate distinct opportunities to provide feedback.

現在，這兩件事在年底同時發生，監管反饋和與武田正在進行的討論這兩件事之間存在著相互作用。因此，我們確實將這視為提供回饋的兩個不同的機會。

Obviously, any time we cross the material threshold and an opt-in decision that shifts the nature of the program into not just a cash infusion, but also importantly, a shift in the HD program to a 50-50 profit split and a 50-50 R&D split is material. And so those updates would happen as they occur. And again, the timeline for these takes us to by the end of the year. So these two events pretty introduce distinctly as two separate events.

顯然，任何時候我們跨越物質門檻和選擇加入的決定，該計劃的性質不僅轉變為現金注入，而且重要的是，將 HD 計劃轉變為 50-50 的利潤分成和 50-50 的利潤分配。分拆很重要。因此，這些更新會在發生時發生。同樣，這些的時間表將我們帶到今年年底。因此，這兩個事件非常明顯地被介紹為兩個獨立的事件。

Got it. Thanks so much, Paul.

知道了。非常感謝，保羅。

Thank you, Salim.

謝謝你，薩利姆。

Luca Issi, RBC.

盧卡·伊西，加拿大皇家銀行。

Great. Thanks so much for taking our questions. This is Lisa on for Luca. First on the Takeda opt-in, just wondering, should Takeda ultimately choose not to opt in, just wondering what are your options for the program if that happens? And secondly, on INHBE, given the target can potentially reduce fat and maintain muscle, wondering if you are thinking about any ways to assess muscle preservation in the clinic? Any color there would be helpful. Thank you so much.

偉大的。非常感謝您回答我們的問題。這是盧卡的麗莎。首先關於武田選擇加入，只是想知道武田最終是否應該選擇不選擇加入，只是想知道如果發生這種情況，您對該計劃有何選擇？其次，在 INHBE 上，鑑於該目標有可能減少脂肪並保持肌肉，想知道您是否正在考慮在臨床上評估肌肉保存的任何方法？任何顏色都會有幫助。太感謝了。

Sure. Thank you, Lisa. So for your first question, if Takeda makes the decision not to opt in, I mean, obviously, we're not waiting for that decision. So one of the benefits of a full data disclosure, which we've had is inbound interest and questions from other strategics asking whether or not Takeda is planning on opting in on these data sets, and whether or not we'd be interested in having conversations.

當然。謝謝你，麗莎。因此，對於你的第一個問題，如果武田決定不選擇加入，我的意思是，顯然我們不會等待這個決定。因此，我們所擁有的完整資料揭露的好處之一是來自其他策略的入站興趣和問題，詢問武田是否計劃選擇使用這些資料集，以及我們是否有興趣擁有對話。

Obviously, Takeda is a wonderful partner, and we're engaged with them. But at the same time, given that these data sets are publicly disclosed, we are allowed to have discussions with others relative to the HD space and these data, and we were going to put ourselves in the best position to assure that this program should alignment with regulators around the path to accelerated registration be aligned but this has a supportive path to continue to go to patients.

顯然，武田是一位出色的合作夥伴，我們正在與他們合作。但與此同時，鑑於這些數據集是公開披露的，我們可以與其他人就高清空間和這些數據進行討論，並且我們將把自己置於最佳位置，以確保該計劃應該保持一致與監管機構圍繞加速註冊的路徑保持一致，但這有一條繼續惠及患者的支持路徑。

In addition, we've also had discussions from folks who want to potentially fund the asset to step in financially in the Takeda decisions. So we are in parallel to the ongoing discussions with Takeda, making sure that we put the program in the best light that's put forward to assure that there is a disease-modifying treatment for patients if the FDA aligns with us on a path to accelerated registration.

此外，我們也與那些希望為該資產提供資金以在財務上介入武田決策的人士進行了討論。因此，我們正在與武田進行持續的討論，確保我們以最好的方式提出該計劃，以確保如果 FDA 與我們在加速註冊的道路上保持一致，則可以確保為患者提供疾病緩解治療。

As it relates to the profile for INHBE, which we're incredibly excited about, given where we think it differentiates itself from the existing standard of care and obesity to your point on both fat loss and being able to spare muscle.

因為它與 INHBE 的簡介有關，我們對此感到非常興奮，因為我們認為它與現有的護理和肥胖標準不同，符合您在減脂和節省肌肉方面的觀點。

And the fact that we can design not just what we saw the DIO mouse model, but a clinical study in healthy overweight volunteers to recapitulate that phenotype. Yes, we will be embedding in the study the opportunity to look at both fat and muscle. I don't know, Erik, if you want to add anything additionally or Anne-Marie on in terms of the clinical trial design that we plan to.

事實上，我們不僅可以設計我們所看到的 DIO 小鼠模型，還可以在健康超重志願者中進行臨床研究，以重現該表型。是的，我們將在研究中嵌入觀察脂肪和肌肉的機會。我不知道，艾瑞克，您是否想在我們計劃的臨床試驗設計方面添加任何額外內容或安妮瑪麗。

Not really. Again, we -- as Paul said we see in the human genetic data, we see muscle sparing. We see profound effects on the fat distribution, and we replicate that in our preclinical studies. We haven't shared yet the design of the first clinical study. It will be in healthy overweight volunteers and we will measure different measures of fat distribution and muscle, but we haven't shared the details of that yet.

並不真地。再說一次，正如保羅所說，我們在人類基因數據中看到，我們看到了肌肉的保留。我們看到了對脂肪分佈的深遠影響，並在臨床前研究中複製了這一點。我們還沒有分享第一個臨床研究的設計。它將在健康的超重志願者中進行，我們將測量脂肪分佈和肌肉的不同指標，但我們尚未分享相關細節。

I mean interestingly enough, just for those who aren't aware, we know that as we go into new spaces of looking at ways to determine that, there are tests that are very good, whether that's DEXA, MRI, the SomaSignal test. So there are ways for us to embed in the clinical trial, ability to really differentiate and distinguish the profile of the program, but we'd obviously give more updates on that as we get closer to the regulatory filing and the beginning of the clinical trial.

我的意思是，有趣的是，對於那些不知道的人來說，我們知道，當我們進入尋找確定方法的新領域時，有一些非常好的測試，無論是 DEXA、MRI 還是 SomaSignal 測試。因此，我們有多種方法可以嵌入臨床試驗，能夠真正區分和區分該項目的概況，但隨著我們接近監管備案和臨床試驗的開始，我們顯然會提供更多更新。

Steve Seedhouse, Raymond James.

史蒂夫席德豪斯，雷蒙德詹姆斯。

Hi. Thank you for your question. This is Nick on for Steve. Just wanted to clarify for the RestorAATion-2 update in Q4, do you plan to show changes in AAT protein concentration? Or do you plan to only show the proportion of corrected M-AAT versus Z-AAT? And as a quick follow-up, will the initial readout include data from the multi-ascending dose cohorts or only single-ascending dose cohorts? Thank you.

你好。謝謝你的提問。這是尼克替史蒂夫發言。只是想澄清第四季度的 RestorAATion-2 更新，您是否打算顯示 AAT 蛋白濃度的變化？還是您打算僅顯示校正後的 M-AAT 與 Z-AAT 的比例？作為快速跟進，初始讀數將包括來自多劑量遞增隊列的數據還是僅包含單次遞增劑量隊列的數據？謝謝。

Yeah. So the initial proof of mechanism data is not tied to either a single or multi-dose threshold, that's tied to exactly the first part of your question of profile. And so we'll be evaluating and assessing as part of that total protein, M protein in combination.

是的。因此，機制資料的初始證明並不與單劑量或多劑量閾值相關，而是與您的概況問題的第一部分完全相關。因此，我們將評估和評估總蛋白 M 蛋白的組合。

And the key driver of that is, to your point, to really be able to assess for the first time in humans, the principle of RNA editing. And therefore, the translation from what we've seen in the SERPINA1 model and how that's translating now into humans. But we will be assessing both M-AAT protein in total.

就您而言，其關鍵驅動因素是真正能夠首次在人類中評估 RNA 編輯的原理。因此，我們在 SERPINA1 模型中看到的翻譯以及現在如何翻譯到人類身上。但我們將對兩種 M-AAT 蛋白進行整體評估。

Thank you.

謝謝。

Joseph Schwartz, Leerink Partners.

約瑟夫‧施瓦茨，Leerink Partners。

Hi. This is Lili, thanks for the opportunity, on for Joe. I was just wondering if you could give us a little more insight into the data that's been generated so far to support caudate atrophy and what will be needed to establish that biomarker as reasonably likely to predict benefit? And can you tell us kind of what you're expecting? How soon you might see meaningful changes in this biomarker? And if the proposed study design might include some interim analogies? Thank you.

你好。我是莉莉，謝謝你給喬的機會。我只是想知道您是否能讓我們更深入地了解迄今為止產生的支持尾狀核萎縮的數據，以及需要什麼才能建立合理可能預測益處的生物標記？您能告訴我們您的期望嗎？您多久才能看到該生物標記發生有意義的變化？建議的研究設計是否可能包括一些臨時類比？謝謝。

So thank you for the question. And I'll start, and then I'll turn it over to Anne-Marie, but there is a lot of data emerging over time, and Anne-Marie can speak to that both on the consortium that we're engaged with and looking at the large data sets coming off of Track-HD to assess MRI changes on caudate.

謝謝你的提問。我將開始，然後將其交給安妮瑪麗，但隨著時間的推移，會出現大量數據，安妮瑪麗可以在我們參與的聯盟中談論這些數據，並尋找利用來自Track-HD 的大數據集來評估尾狀核的MRI 變化。

We do think in going forward, as we've shared before, that we do think there's the possibility to image that within 12 to 18 months. Obviously, the design of that study has to be agreed to with regulators. But the benefit of this is that there are the ability with imaging to see that over reasonably short periods of time with much smaller patient population than what has been done before in HD with large clinical outcome studies. Anne-Marie, I think do you want to reflect on the caudate atrophy and some of the imaging data coming?

我們確實認為，正如我們之前所分享的那樣，我們確實認為有可能在 12 到 18 個月內實現這一目標。顯然，該研究的設計必須得到監管機構的同意。但這樣做的好處是，與先前在 HD 中進行的大型臨床結果研究相比，影像技術能夠在相當短的時間內以少得多的患者群體觀察到這種情況。安妮瑪麗，我想你想反思一下尾狀核萎縮和一些即將到來的影像資料嗎？

Yes. Happy to. So there are -- it's one way in which we're very lucky in the HD environment is that there's some -- a lot of natural history data available that's being collected prospectively by the community. And that includes databases called Track and Predict-HD, and this means there are rich data sets available that would allow us to establish the predictive relationship between caudate change and clinical outcomes. And then one of the first things that you need to establish an endpoint that's reasonably likely to predict a clinical outcome.

是的。很高興。因此，我們在高清環境中非常幸運的一種方式是，社區正在前瞻性地收集一些可用的自然歷史數據。其中包括名為 Track 和 Predict-HD 的資料庫，這意味著有豐富的資料集可供使用，使我們能夠建立尾狀核變化和臨床結果之間的預測關係。然後，您需要做的第一件事就是建立一個合理可能預測臨床結果的終點。

So the consortium that we mentioned, the Huntington's Disease Image Harmonization Consortium, that's run by IXICO and CHDI that made these scans available and harmonized them in a way that they would meet the standard required for a regulatory submission so that we can show FDA this predictive value between the caudate atrophy and the outcome.

因此，我們提到的亨廷頓病圖像協調聯盟，由 IXICO 和 CHDI 運營，提供這些掃描並以符合監管提交要求的標準的方式協調它們，以便我們可以向 FDA 展示這種預測尾狀核萎縮和結果之間的值。

So that's the first part of it. The second part of it is that you have to show that your drug is able to have an impact on caudate atrophy. And obviously, in our SELECT-HD study, we've already seen the first signs of that. So I think taken together, this is a strong package. We're excited to be engaging with regulators on this package.

這是第一部分。第二部分是你必須證明你的藥物能夠對尾狀核萎縮產生影響。顯然，在我們的 SELECT-HD 研究中，我們已經看到了最初的跡象。所以我認為綜合起來，這是一個強大的一攬子計劃。我們很高興能夠與監管機構就這項方案進行合作。

So I think, just to follow up. I mean, I think the profile is extraordinarily important. Initially, as Anne-Marie said, showing a high impact on the target, addressing questions that have been involved with HD around wild-type sparing, so knocking down the target substantially, showing that we preserve wild type, showing that the concentration and the knockdown of protein correlates with caudate atrophy.

所以我想，只是跟進。我的意思是，我認為個人資料非常重要。最初，正如 Anne-Marie 所說，顯示出對目標的高度影響，解決了與 HD 相關的野生型保留問題，因此大幅降低了目標，表明我們保留了野生型，表明濃度和蛋白質的敲低與尾狀核萎縮相關。

And then as Anne-Marie said, now having the imaging tools available to assess that relative to clinical outcome measurement, I think really sets up a dynamic for the first time, I think, for the HD community with disease modification to engage in this conversation around the potential accelerated registration pathway.

然後，正如 Anne-Marie 所說，現在有了成像工具來評估相對於臨床結果測量的情況，我認為，我認為，確實第一次為具有疾病修飾的 HD 社區參與這一對話奠定了基礎圍繞潛在的加速註冊途徑。

Tiago Fauth, Wells Fargo.

蒂亞戈·福斯，富國銀行。

Great. Thank you so much for taking the question. I had one just on the AATD. Just wondering if you can discuss more of your expectations about the translatability of the dose finding studies in animal models into humans, there's some questions mostly from the mutations of those animal models and the novelty of the approach.

偉大的。非常感謝您提出這個問題。我剛剛參加了 AATD。只是想知道您是否可以更多地討論您對動物模型中的劑量發現研究可轉化為人類的期望，有一些問題主要來自這些動物模型的突變和方法的新穎性。

So what gives you confidence that those dose levels you're taking forward are actually likely to be at a therapeutic relevant range in humans? More details on that would be appreciated.

那麼，是什麼讓您確信您所採用的劑量水平實際上可能處於人類治療相關範圍內？如果有更多詳細信息，我們將不勝感激。

No. It's a wonderful question, and we put a lot of time into the modeling work going into -- from the SERPINA1 study to our non-human primate studies to our humans. And I think that's really where we're able to take advantage of and I think benefit GalNac conjugation and the translative pharmacology that we've seen in the liver surface area between mouse, non-human primates and humans.

不。這是一個很好的問題，我們投入了大量時間進行建模工作——從 SERPINA1 研究到非人靈長類動物研究再到人類研究。我認為這確實是我們能夠利用的地方，我認為有益於 GalNac 結合以及我們在小鼠、非人靈長類動物和人類之間的肝臟表面區域中看到的翻譯藥理學。

So as we think about exposures, as we think about concentrations in those species, and we look at PK modeling of where is drug going, I think we're able to say that there is, again, a very well-established pathway in pharmacology.

因此，當我們考慮暴露情況時，當我們考慮這些物種的濃度時，當我們研究藥物去往何處的 PK 模型時，我認為我們可以說，藥理學中存在一條非常完善的途徑。

I think what's exciting as we think about the field of RNA editing and particularly RestorAATion-1 is even in the healthy volunteers while you don't get TD assessment, that PK is translating very nicely. So I think that gives us a lot of confidence on the early modeling where we've got TD in the preclinical experiment but can translate that PK modeling across species, again, mouse to non-human primates to humans.

我認為令人興奮的是，當我們考慮 RNA 編輯領域，特別是 RestorAATion-1 時，即使在健康志願者中，即使沒有進行 TD 評估，PK 也能很好地轉化。所以我認為這給了我們對早期模型很大的信心，我們在臨床前實驗中得到了 TD，但可以將 PK 模型轉化為跨物種，同樣，從小鼠到非人靈長類動物再到人類。

I think the piece of why we say this proof of mechanism data is so critical is it will give us and affirm for us as we relate back to that modeling in the PD prediction. And then that's why we have set up multiple cohorts, which is not just about dose finding, but the ability to really now assess also dose frequency. And so we do think the advantage of having GalNac does give us that predictability that we are seeing in the translation.

我認為我們之所以說這種機制數據證明如此重要，是因為當我們與 PD 預測中的模型相關時，它會給我們並肯定我們的觀點。這就是為什麼我們建立了多個隊列，這不僅僅是關於劑量發現，而且是現在真正評估劑量頻率的能力。因此，我們確實認為 GalNac 的優勢確實給了我們在翻譯中看到的可預測性。

Got it. Perhaps just one quick follow-up there. Because again, there's mix expectations from investors on what's the actual bar given the perceived to be competitive AATD landscape. So at your optimal dose, is crossing the 11 micromolar range enough? Do you need to get to an MM phenotype? Oe how are you guys thinking about the product profile? Thank you.

知道了。也許只是一個快速的後續行動。因為，考慮到 AATD 的競爭格局，投資人對實際門檻有不同的預期。那麼，在最佳劑量下，跨越 11 微摩爾範圍就足夠了嗎？您需要獲得 MM 表型嗎？Oe 你們覺得產品簡介怎麼樣？謝謝。

Yeah. I mean -- and great question, and obviously, we spend a lot of time thinking about that as we enter the clinic and why we see an advantage across the entire profile of the therapeutic, meaning GalNAc subcu conjugation, durable and frequent dosing, and to the last point, high potent editing.

是的。我的意思是——這是一個很好的問題，顯然，當我們進入診所時，我們花了很多時間思考這個問題，以及為什麼我們在整個治療方案中看到了優勢，這意味著GalNAc subcu 結合、持久和頻繁的給藥，以及最後一點，高效編輯。

So really three really important ingredients for a chronic therapy. As you mentioned, 11 micromolar is a threshold that we think about the conversion of ZZ patients to an MV patient, and that's really one of the features of editing, that really reflects while we're talking there about micromolar, about a fold improvement over baseline, and we saw that as a sevenfold improvement from where patients started -- from where Mike started to where we got them to.

因此，對於慢性治療來說，這確實是三個非常重要的成分。正如您所提到的，11 微摩爾是我們考慮將ZZ 患者轉變為MV 患者的閾值，這確實是編輯的功能之一，它真正反映了我們在談論微摩爾時的情況，即相對於MV 患者的倍數改善。

That threshold took us -- surpassing that threshold of an MV even into the MM healthy phenotype. So our preclinical data really demonstrated the fact that the full editing. And that's really one of the best ways to look at it going forward because while you always see where that micromolar threshold is, it's that really ability to turn and push that threshold above where those patients are.

這個閾值使我們超越了 MV 的閾值，甚至進入了 MM 健康表型。所以我們的臨床前數據確實證明了完全編輯的事實。這確實是看待未來的最佳方法之一，因為雖然你總是看到微摩爾閾值在哪裡，但它確實有能力將該閾值轉變並推至患者所在的位置之上。

So we're going to get a sense of that. Obviously, the proof of mechanism is the first step on that journey. But through the study, both single, multiple cohorts, that's where we're going to be able to continue to establish what that upper limit looks like. But again, as you pointed out, our preclinical data supports that we can surpass an 11 micromolar threshold, which gives us a lot of confidence given the totality of the profile that this really could be a best-in-class therapeutic and first-in-class for RNA editing for the treatment of alpha-1 antitrypsin deficiency.

所以我們將對此有所了解。顯然，機制證明是這趟旅程的第一步。但透過這項研究，無論是單一隊列還是多個隊列，我們將能夠繼續確定上限。但正如您所指出的，我們的臨床前數據支持我們可以超越 11 微摩爾閾值，考慮到整體情況，這給了我們很大的信心，這確實可能是一流的治療方法和首創用於治療α- 1 抗胰蛋白酶缺乏症的RNA 編輯類。

Understood. Thank you very much for taking the questions.

明白了。非常感謝您接受提問。

Thank you.

謝謝。

Joon Lee, Truist.

李俊，真理主義者。

Hey, guys. Thanks for taking our follow-up question. We recently conducted a Carewell call discussing the data that's been generated in the Huntington space? Can you PTC, UniQure and Roche? And regarding the safety signal of hydrocephalus seen with Tominersen and AMT-130, there are sort of two petting or maybe complementary theories.

嘿，夥計們。感謝您提出我們的後續問題。我們最近進行了 Carewell 電話會議，討論了亨廷頓空間中產生的數據？PTC、UniQure 和 Roche 可以嗎？關於 Tominersen 和 AMT-130 所觀察到的腦積水的安全訊號，有兩種理論或可能是互補的理論。

One is hydrocephalus due to defective cilia due to nonspecific knockdown of wild-type huntingtin leading to defective CSF flow. And the other is what you described as pseudoatrophy due to reduced inflammation within the caudate and the basal ganglia driving that sort of pseudoatrophy and having concerns of hydrocephalus. Would love to hear your thoughts on these theories and what your evidence -- what sort of evidence you have in your preclinical models and whatnot to support one versus the other? Thank you.

一種是由於野生型亨廷頓蛋白的非特異性敲低導致腦脊髓液流動缺陷而導致的纖毛缺陷所引起的腦積水。另一個是你所描述的假性萎縮，因為尾狀核和基底核內的發炎減少導致了這種假性萎縮並擔心腦積水。很想聽聽您對這些理論的想法以及您的證據——您的臨床前模型中有哪些證據以及支持其中一種理論和另一種理論的證據？謝謝。

Yeah. No. I mean I think those are dualing theories that have been out there since the tominersen experience. And I think they spoke to why we looked at imaging at the point where we did. And the key driver was the (inaudible). So sure, we weren't seeing hydrocephalus.

是的。不。我的意思是，我認為這些是自托米納森經歷以來就一直存在的雙重理論。我認為他們談到了我們為什麼要在此時關注成像。關鍵的驅動因素是（聽不清楚）。可以肯定的是，我們沒有看到腦積水。

So I think it was really important to note that we didn't see hydrocephalus on the study. I think, to the point on that theory, and I think it was one that was prevailing, was the cilia that are responsible for the movement of CSF flow are structurally comprised of healthy Huntington protein.

因此，我認為值得注意的是，我們在研究中沒有發現腦積水。我認為，就這個理論而言，我認為這是一個流行的理論，負責腦脊髓液流動的纖毛在結構上由健康的亨廷頓蛋白組成。

And so I think it was really a driver, and this goes back to the early starting point of when we decided to go into the Huntington's disease space, wasn't to make a lower dose, more so more potent and durable version of tominersen, it was really to reflect on the underlying biology of suppression of the mutant protein, while sparing wild type.

所以我認為這確實是一個驅動因素，這可以追溯到我們決定進入亨廷頓氏病領域的早期起點，不是製造劑量更低、更有效、更持久的托米納森版本，這實際上是為了反思抑制突變蛋白的潛在生物學，同時保留野生型。

So the ability to demonstrate that, the ability then to be able to assess whether or not the absence of hydrocephalus and some of those other signals were there. Again, we didn't see that. I think they're highly encouraging. So it was really a fundamental driver both in what we saw in the existing study and we drove forward. I don't know, Anne-Marie, if there's anything you want to add to that.

因此，能夠證明這一點，然後能夠評估是否存在腦積水和其他一些訊號。再說一次，我們沒有看到這一點。我認為他們非常鼓舞人心。因此，這確實是我們在現有研究中所看到的以及我們繼續前進的基本驅動力。我不知道，安妮瑪麗，你是否還有什麼要補充的。

Tominersen also reported that they are targeting young generations and because they think that they've got a better benefit risk in a younger age group with a lower disease burden. And it's also known that as people age, CSF flow becomes slower and less functional. So that might also point towards the theory around cilia.

托米納森也報告說，他們的目標是年輕一代，因為他們認為，在疾病負擔較低的年輕族群中，他們可以獲得更好的受益風險。眾所周知，隨著人們年齡的增長，腦脊髓液流動變得緩慢且功能減弱。因此，這也可能指向有關纖毛的理論。

(multiple speakers)

（多個發言者）

Thank you, Joon.

謝謝你，瓊。

Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Dr. Paul Bolno with any closing remarks.

謝謝。目前我在隊列中沒有顯示任何其他問題。我現在想將電話轉回保羅·博爾諾博士並發表結束語。

Wonderful. Thank you for joining our call this morning. We hope you all take some time to enjoy the remainder of your summer, and we look forward to keeping you updated on our progress. Have a great day.

精彩的。感謝您今天早上加入我們的電話會議。我們希望大家能抽出一些時間來享受剩下的夏天，我們期待著向您通報我們的最新進展。祝你有美好的一天。

This concludes today's program. Thank you all for participating. You may now disconnect.

今天的節目到此結束。感謝大家的參與。您現在可以斷開連線。