WAVE Life Sciences Ltd (WVE) 2025 Q3 法說會逐字稿

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Hello, and welcome to Wave Life Sciences third quarter 2025 earnings call. (Operator Instructions) Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

大家好，歡迎參加 Wave Life Sciences 2025 年第三季財報電話會議。（操作說明）另外提醒一下，本次會議將在今天進行錄音。現在我將把電話轉交給企業事務和投資者關係副總裁凱特·勞施。

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our third quarter 2025 earnings update. Joining me today with prepared remarks is Dr. Paul Bolno, President and Chief Executive Officer; and Kyle Moran, Chief Financial Officer. Dr. Chris Wright, Chief Medical Officer; Dr. Erik Ingelsson, Chief Scientific Officer; and Dr. Chandra Vargeese, Chief Technology Officer, will be available for questions following the prepared remarks. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

謝謝接線員，也祝福所有通話中的朋友們早安。今天早些時候，我們發布了一份新聞稿，概述了我們 2025 年第三季的收益更新。今天與我一起發表準備好的演講的有總裁兼執行長保羅·博爾諾博士和財務長凱爾·莫蘭。首席醫療官克里斯·賴特博士、首席科學官埃里克·英格爾松博士和首席技術官錢德拉·瓦爾吉斯博士將在準備好的演講結束後回答問題。今天早上發布的新聞稿可在我們網站 www.wavelifesciences.com 的投資者關係版塊查閱。

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

在會議開始前，我想提醒各位，本次電話會議的討論內容將包含前瞻性陳述。這些聲明受到多種風險和不確定因素的影響，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。可能導致我們實際結果與預期結果不同的因素已在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進行了討論。我們不承擔因任何原因更新或修改任何前瞻性聲明的義務。現在我想把電話交給保羅。

Thanks, Kate, and good morning to everyone joining us on today's call. I would like to first thank those of you who are able to join us for our 2025 Research Day on October 29, where we shared the first ever demonstration of activin E reductions in a clinical trial. Notably, with a single dose of WVE-007, our INHBE GalNAc siRNA, we were excited to show highly significant and durable human activin E reductions that exceeded levels needed in preclinical models to drive meaningful weight loss and prevent rebound weight gain following cessation of the GLP-1.

謝謝凱特，也祝今天參加電話會議的各位早安。首先，我要感謝各位能夠參加我們 2025 年 10 月 29 日的研究日活動，在活動中，我們首次展示了在臨床試驗中激活素 E 減少的情況。值得注意的是，我們很高興地發現，僅使用一劑 WVE-007（我們的 INHBE GalNAc siRNA），就能顯著且持久地降低人類激活素 E 水平，其降低幅度超過了臨床前模型中驅動有意義的體重減輕和防止停止 GLP-1 治療後體重反彈所需的水平。

In addition, we provided an in-depth overview of our recent progress in RNAi and RNA editing and how we are building on the successful clinical translation of our WVE-007 and WVE-006 programs to advance our pipeline, including our new RNA editing clinical candidate, WVE-008 for the treatment of the up to 9 million homozygous individuals living with PNPLA3 I148M liver disease in the US and Europe.

此外，我們還深入概述了我們在 RNAi 和 RNA 編輯方面的最新進展，以及我們如何利用 WVE-007 和 WVE-006 項目的成功臨床轉化來推進我們的研發管線，包括我們新的 RNA 編輯臨床候選藥物 WVE-008，用於治療美國和歐洲多達 900 萬患有 PNPLA3 I148M 的純合子患者。

We also unveiled how we're harnessing the power of both siRNA and RNA editing to advance an innovative new bifunctional single oligonucleotide construct that is designed to silence one target while simultaneously editing or upregulating another distinct target. All of these clinical and preclinical advancements are made possible by our unique and proprietary chemistry and platform innovations. Just last week, we had the privilege of sharing data on WVE-007 at Obesity Week, where we received significant attention from the patient community, key opinion leaders and companies with deep understanding of and strategic interest in the obesity space. There was a clear recognition for the need for non-incretin treatment approaches and overwhelmingly positive engagement on 007's potential to induce fat loss, preserve lean mass and improve cardiometabolic health, all without the negative GLP-1 class effects and with the convenience of once to twice a year dosing.

我們還揭示了我們如何利用 siRNA 和 RNA 編輯的力量來推進一種創新的新型雙功能單寡核苷酸構建體，該構建體旨在沉默一個靶標，同時編輯或上調另一個不同的靶標。所有這些臨床和臨床前進展都得益於我們獨特且專有的化學和平台創新。就在上週，我們有幸在肥胖週上分享了 WVE-007 的數據，並受到了患者群體、關鍵意見領袖以及對肥胖領域有深刻了解和戰略興趣的公司的廣泛關注。人們清楚地認識到需要非腸促胰島素治療方法，並且對 007 誘導脂肪減少、保持瘦體重和改善心血管代謝健康的潛力給予了壓倒性的積極評價，所有這些都沒有 GLP-1 類藥物的負面作用，而且每年只需服用一到兩次，非常方便。

There is particular excitement in 007's potential as a maintenance therapy, which would allow patients to transition off chronic incretin therapies while at the same time preventing rebound weight gain, preserving lean mass and sustaining cardiometabolic health. Reflecting on the rapid progress we've made advancing 007 in our INLIGHT clinical trial, we have now enrolled over 70 participants and are well-positioned to deliver data on over 100 participants from the clinical trial sites in Europe and the US in the first half of 2026. We began testing WVE-007 in INLIGHT at our lowest subtherapeutic dose cohort of 75 milligrams in 8 participants. Then for the subsequent cohorts, 240 milligrams, 400 milligrams and 600 milligrams, which are in the potential therapeutic range, we have expanded to 32 participants.

007 作為維持療法的潛力尤其令人興奮，它可以讓患者在停止長期腸促胰素療法的同時，防止體重反彈增加，保持瘦體重，並維持心血管代謝健康。回顧我們在 INLIGHT 臨床試驗中推進 007 所取得的快速進展，我們現在已經招募了 70 多名參與者，並已做好充分準備，在 2026 年上半年提供來自歐洲和美國臨床試驗點的 100 多名參與者的數據。我們在 INLIGHT 中開始測試 WVE-007，最低亞治療劑量組為 75 毫克，共有 8 名參與者。然後，對於後續的劑量組，即 240 毫克、400 毫克和 600 毫克（這些劑量在潛在的治療範圍內），我們擴大到 32 名參與者。

WVE-007 was generally safe and well tolerated, and our independent data monitoring committee has approved further escalation to a next higher dose in Cohort 5.

WVE-007 總體上安全且耐受性良好，我們的獨立資料監測委員會已批准在第 5 組隊列中進一步增加劑量。

At Research Day, we shared highly significant dose-dependent and durable activin E reductions 1 month post single dose of 007 in the first 3 cohorts of INLIGHT, including a 56% reduction for the 75-milligram cohort, 75% reduction for the 240-milligram cohort and an 85% reduction for the 400-milligram cohort compared to baseline. In addition, we had the opportunity to evaluate our lowest dose cohort out to 6 months. And throughout the 6-month follow-up period, we continue to see sustained reduction, supporting 007's potential for once or twice yearly dosing. The durability and potency we've observed thus far is particularly encouraging as we expect consistent and robust activin E reduction over time is necessary to achieve meaningful weight loss. As we shared at Research Day, Wave's unique Pena design and proprietary chemistry enabled the achievement of the potent and durable suppression needed for the INHBE target.

在研究日上，我們分享了 INLIGHT 前 3 個隊列在單次注射 007 後 1 個月內，激活素 E 顯著降低，且具有劑量依賴性和持久性，其中 75 毫克組降低了 56%，240 毫克組降低了 75%，400 毫克組降低了 85%（與基線相比）。此外，我們還有機會對最低劑量組進行為期 6 個月的評估。在 6 個月的追蹤期內，我們持續觀察到病情有所好轉，這支持了 007 每年只需給藥一次或兩次的潛力。到目前為止，我們觀察到的持久性和效力尤其令人鼓舞，因為我們預計，隨著時間的推移，持續而強勁的激活素 E 減少是實現有意義的減肥所必需的。正如我們在研究日上分享的那樣，Wave 獨特的 Pena 設計和專有化學技術實現了 INHBE 目標所需的強效持久抑制。

In our DIO mouse model, we demonstrated that weight loss in the same range as semaglutide occurred when activin E was durably reduced by greater than 70% from baseline. The knockdown we've observed in the 240 and 400-milligram cohorts already exceed these levels.

在我們的 DIO 小鼠模型中，我們證明，當激活素 E 從基線水平持續降低 70% 以上時，體重減輕的幅度與司美格魯肽相當。我們在 240 毫克和 400 毫克劑量組中觀察到的擊倒效應已經超過了這些水平。

In our preclinical studies, we have shown extensive data supporting 007's unique mechanism of action to drive weight loss in monotherapy as well as maintenance in combination settings. Specifically, we shared data that support 007's ability to double weight loss when added to semaglutide and prevent rebound weight gain following cessation of GLP-1 in DIO mice. Furthermore, we've shown that INHBE reduction led to adipocyte shrinkage, fewer pro-inflammatory macrophages, less fibrosis and improved insulin sensitivity in adipose tissues, highlighting mechanisms that could explain the risk reduction for type 2 diabetes and coronary artery disease observed in human genetic data. With robust and durable target engagement in the clinic and comprehensive preclinical data that support both the mechanism of action and impact of our proprietary chemistry, we're incredibly excited to build on this positive momentum. We plan to deliver multiple near-term updates that assess blood-based biomarkers of metabolic health, body composition and weight loss across multiple cohorts.

在我們的臨床前研究中，我們已經展示了大量數據，支持 007 獨特的作用機制，既能促進單藥治療中的減肥，也能在聯合治療中維持體重。具體來說，我們分享的數據支持 007 在與索瑪魯肽一起添加時能夠使體重減輕一倍，並防止 DIO 小鼠在停止 GLP-1 後出現體重反彈。此外，我們已經證明，INHBE 減少會導致脂肪細胞縮小、促炎巨噬細胞減少、纖維化減少以及脂肪組織胰島素敏感性提高，這突出了可以解釋在人類遺傳數據中觀察到的 2 型糖尿病和冠狀動脈疾病風險降低的機制。憑藉著在臨床上穩健持久的標靶作用以及支持我們專有化學作用機制和影響的全面臨床前數據，我們非常高興能夠在此積極勢頭的基礎上繼續發展。我們計劃在近期發布多項更新，評估多個隊列中基於血液的代謝健康、身體組成和體重減輕的生物標記。

Beginning this quarter, we'll have the first opportunity to assess the early impact of INHBE reduction at 3 months in the 240-milligram cohort. And importantly, in the first quarter of 2026, we'll be able to assess 6-month follow-up data from the 240-milligram cohort as well as 3-month follow-up data from the 400-milligram cohort. In RNA editing, we continue to lead the field with WVE-006, our GalNAc RNA editing oligonucleotide for AATD. WVE-006 has the potential 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 investigational treatments in development.

從本季度開始，我們將首次有機會評估 240 毫克劑量組中 INHBE 減少 3 個月後的早期影響。更重要的是，在 2026 年第一季度，我們將能夠評估 240 毫克組的 6 個月追蹤數據以及 400 毫克組的 3 個月追蹤數據。在 RNA 編輯領域，我們憑藉 WVE-006（一種用於 AATD 的 GalNAc RNA 編輯寡核苷酸）繼續引領該領域。WVE-006 有可能成為第一個透過方便的皮下給藥方式治療 AATD 並解決該疾病根本原因的療法。WVE-006 不需要像其他正在研發的試驗性療法那樣透過靜脈注射 LNP 或複雜的遞送載體。

This profile supports treating individuals living with AATD, including those living with lung or liver manifestations of the disease or both. Since the approval of weekly IV augmentation therapies to help manage lung disease, the field has focused on keeping serum AAT levels above a minimum threshold of 11 micromolar, in part because ZZ individuals do not produce any M-AAT and have limited ability to increase serum AAT levels during an acute phase response or exacerbation.

此方案支持治療患有 AATD 的個體，包括患有肺部或肝臟疾病或兩者兼有的個體。自從每週靜脈注射增強療法被批准用於幫助控制肺部疾病以來，該領域一直致力於將血清 AAT 水平保持在 11 微摩爾的最低閾值以上，部分原因是 ZZ 型個體不產生任何 M-AAT，並且在急性期反應或病情加重期間提高血清 AAT 水平的能力有限。

However, with RNA editing, our goal is to restore the MZ phenotype by achieving 3 criteria: keeping basal protein levels at or above 11 micromolar, driving 50% or greater circulating M-AAT with corresponding decreases in Z-AAT protein and most importantly, restoring the physiological response of serum AAT protein to acute inflammatory events. In September, we delivered data from our RestorAATion-2 trial demonstrating that we have already achieved these goals with 006. We observed AAT levels of up to almost 13 micromolar. We showed 64% of AAT was wild-type M-AAT with a corresponding 60% decrease in mutant Z-AAT protein. And these effects were highly consistent and durable across individuals, supporting infrequent dosing of monthly or less.

然而，透過 RNA 編輯，我們的目標是透過實現 3 個標準來恢復 MZ 表型：保持基礎蛋白水平在 11 微摩爾或以上，驅動 50% 或以上的循環 M-AAT 蛋白，同時相應降低 Z-AAT 蛋白，最重要的是，恢復血清 AAT 蛋白對急性發炎事件的生理反應。9 月，我們公佈了 RestorAATion-2 試驗的數據，證明我們已經透過 006 實現了這些目標。我們觀察到 AAT 水平高達近 13 微摩爾。我們發現 64% 的 AAT 為野生型 M-AAT，突變型 Z-AAT 蛋白則相應減少了 60%。而且這些效果在不同個體間具有高度一致性和持久性，支持每月或更少的不頻繁給藥。

Most notably, we are able to restore a ZZ participants ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar, just 2 weeks after a single dose of 006. Encouragingly, the magnitude and 4-week duration of this response were also proportional to the levels you'd anticipate in an MZ patient based on natural history.

最值得注意的是，我們能夠在單次注射 006 後僅 2 週，使 ZZ 參與者對急性發炎事件的反應能力恢復到總 AAT 水平大於 20 微摩爾。令人鼓舞的是，這種反應的強度和 4 週持續時間也與根據自然病程預期 MZ 患者的水平成正比。

Following our September data, we've had multiple interactions with key opinion leaders in the field who expressed their excitement about these data. In particular, the ability of WVE-006 to restore physiologic AAT production represents a major paradigm shift from weekly IV augmentation therapies. As we look ahead to the remainder of our RestorAATion-2 trial, we are highly encouraged by our initial results progressing rapidly and excited to advance a potentially transformational new medicine to individuals living with AATD. Dosing is ongoing in the 400-milligram multi-dose cohort, and we remain on track to deliver data in the first quarter of 2026. We've also initiated the single-dose portion of our third and final 600-milligram cohort, and we look forward to delivering single and multi-dose data from the 600-milligram cohort in 2026.

繼我們9月份的數據之後，我們與該領域的關鍵意見領袖進行了多次交流，他們對這些數據感到興奮。尤其值得一提的是，WVE-006 能夠恢復生理性 AAT 生成，這代表著與每週一次的靜脈注射增強療法相比，是一個重大的範式轉移。展望 RestorAATion-2 試驗的剩餘部分，我們對初步結果的快速進展感到非常鼓舞，並很高興能為患有 AATD 的人們推進這種可能具有變革意義的新藥。400 毫克多劑量組的給藥工作仍在進行中，我們仍有望在 2026 年第一季提供數據。我們也啟動了第三組也是最後一組 600 毫克劑量組的單劑量部分，並期待在 2026 年提供 600 毫克劑量組的單劑量和多劑量數據。

Building on our success with 006, we are advancing WVE-008, a GalNAc-conjugated RNA editing program for PNPLA3 I148M liver disease as our next RNA editing clinical candidate. Like 006 and 007, PNPLA3 is a compelling target with strong human genetic evidence and a clear translational path to early clinical proof of concept. There are an estimated 9 million homozygous I148M carriers with liver disease across the US and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. The PNPLA3 I148M variant is a well-established driver of steatosis, inflammation, ballooning and fibrosis, and yet there are no approved medicines that directly address this biology.

繼 006 的成功之後，我們正在推進 WVE-008，這是一個針對 PNPLA3 I148M 肝病的 GalNAc 偶聯 RNA 編輯程序，作為我們的下一個 RNA 編輯臨床候選藥物。與 006 和 007 一樣，PNPLA3 是一個引人注目的靶點，具有強大的人類遺傳學證據，並且有明確的轉化路徑可以實現早期臨床概念驗證。據估計，美國和歐洲有 900 萬 I148M 純合子帶因者患有肝病，與非帶原者相比，他們死於肝病的風險高出九倍。PNPLA3 I148M 變異體是脂肪變性、發炎、氣球樣變性和纖維化的公認驅動因素，然而目前還沒有核准的藥物能夠直接針對這種生物學特性。

Emerging preclinical and clinical data indicate that simply knocking down PNPLA3 is not the right solution as loss of PNPLA3 function can worsen the very features we're trying to treat. By contrast, with 008, we aim to correct I148M using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reverse steatosis as well as improve inflammation, ballooning and fibrosis.

新興的臨床前和臨床數據表明，僅僅抑制 PNPLA3 並不是正確的解決方案，因為 PNPLA3 功能的喪失可能會加劇我們試圖治療的症狀。相較之下，對於 008，我們旨在利用我們領先的 RNA 編輯能力來糾正 I148M，預計這將恢復 PNPLA3 活性和脂質動員，逆轉脂肪變性，並改善發炎、氣球樣變性和纖維化。

We've shared preclinical data that corroborate this approach. We've demonstrated that O08 restores functional PNPLA3 and decreases lipid accumulation. And importantly, we showed that we were able to achieve robust editing with no bystander edits or off-target signals and achieve high deliver tissue exposure, which supports infrequent dosing. Clinical planning is underway for our first-in-human study, where we will leverage previously genotype populations to efficiently identify homozygous I148M carriers, and we are on track for a CTA submission in 2026.

我們已分享了證實這種方法的臨床前數據。我們已經證明 O08 可以恢復功能性 PNPLA3 並減少脂質累積。更重要的是，我們證明了我們能夠實現穩健的編輯，沒有旁觀者編輯或脫靶信號，並實現高組織暴露，這支持了不頻繁給藥。我們正在進行首次人體研究的臨床規劃，我們將利用先前對人群進行基因分型，以有效地識別純合 I148M 攜帶者，並且我們正按計劃於 2026 年提交 CTA 申請。

Turning to DMD and HD clinical programs. Earlier this year, we shared data from FORWARD-53 in DMD, which supported WVE-N531 as a potentially best-in-class and important new therapeutic option for individuals with exon 53 amenable DMD. 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 observed the first ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in creatinine kinase and circulating inflammatory biomarkers. Moreover, we saw additional clinical evidence of myogenic stem cell or satellite cell uptake in N531 earlier in our trial, which supports the improvements in muscle health and muscle fiber maturation we observed at 48 weeks.

轉向DMD和HD臨床項目。今年早些時候，我們分享了 FORWARD-53 在 DMD 中的數據，這些數據支持 WVE-N531 成為針對外顯子 53 適用 DMD 患者的潛在最佳且重要的全新治療選擇。我們觀察到，與自然病程相比，起身時間有統計學意義和臨床意義的改善，改善了 3.8 秒，這是在 48 週時觀察到的相對於任何已批准的肌肉營養不良蛋白恢復療法的最大效果。我們也首次觀察到外顯子跳躍對肌肉健康有顯著改善作用，包括纖維化程度顯著降低，肌酸激酶和循環發炎生物標記水平下降。此外，我們在試驗早期就觀察到 N531 中肌源性幹細胞或衛星細胞的吸收，這進一步證實了我們在 48 週時觀察到的肌肉健康和肌肉纖維成熟的改善。

WVE-N531 is also differentiated by supporting preclinical evidence, demonstrating even greater access to heart and diaphragms as compared to skeletal muscle. We remain on track to submit an IND in 2026 for accelerated approval of N531 with a monthly dosing regimen.

WVE-N531 也透過臨床前證據得到證實，顯示其與骨骼肌相比，更容易進入心臟和橫膈膜，從而展現出差異化優勢。我們仍按計劃於 2026 年提交 N531 的 IND 申請，以期獲得加速批准，該藥物採用每月一次的給藥方案。

In HD, we are continuing to prepare for a global potentially registrational Phase II/III study of WVE-003 in adults with STP3 and HD using caudate volume as a primary endpoint, and we are actively engaged in discussions with prospective strategic partners. Developed using our platform's specificity of stereochemical control and best-in-class chemistry, we designed 003 to be the first allele-selective approach in HD. By reducing mutant Huntington at the mRNA and protein level, 003 addresses the underlying drivers of neurodegeneration. And by sparing wild-type Huntington protein, which is critical to central nervous system health, 003 is uniquely positioned to address the full spectrum of HD from early asymptomatic stage through the onset of symptoms and beyond. In SELECT-HD, we demonstrated potent and durable mutant Huntington reductions of up to an industry-leading 46% and preservation of wild-type Huntington with just 3 doses.

在 HD 領域，我們正在繼續準備一項針對患有 STP3 和 HD 的成年人的 WVE-003 的全球潛在註冊 II/III 期研究，該研究以尾狀核體積為主要終點，並且我們正在積極與潛在的戰略合作夥伴進行討論。利用我們平台立體化學控制的特異性和一流的化學技術，我們設計了 003，使其成為亨廷頓氏舞蹈症中第一個等位基因選擇性方法。003 透過降低 mRNA 和蛋白質層面的突變亨廷頓蛋白，解決了神經退化性疾病的根本驅動因素。003 保留了對中樞神經系統健康至關重要的野生型亨廷頓蛋白，因此它具有獨特的優勢，能夠解決亨廷頓舞蹈症從早期無症狀階段到症狀出現及以後的所有問題。在 SELECT-HD 中，我們證明了只需 3 劑即可有效且持久地減少突變型亨廷頓舞蹈症，減少幅度高達 46%，在業界遙遙領先，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. As a reminder, our own internal analysis of natural history data sets, including Track and Predict-HD, showed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a 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 the rate of caudate atrophy as a primary endpoint for an efficient clinical trial. These analyses, along with the complete clinical results from our SELECT-HD trial were both part of our engagement with FDA that led to supportive feedback. We remain on track to submit an IND application for this Phase II/III study in the second half of this year.

重要的是，我們觀察到等位基因選擇性突變亨廷頓減少與尾狀核萎縮減緩之間存在統計學上的顯著相關性，這是首次在亨廷頓舞蹈症中觀察到這種相關性。提醒一下，我們自己對自然歷史資料集（包括 Track 和 Predict-HD）的內部分析表明，尾狀核萎縮率絕對降低 1% 與殘疾發生時間延遲 7.5 年以上相關。這是一個驚人的數字，對健康和經濟結果具有重要意義，並進一步證實了尾狀核萎縮率作為有效臨床試驗的主要終點。這些分析以及我們 SELECT-HD 試驗的完整臨床結果，都是我們與 FDA 溝通的一部分，並獲得了支持性回饋。我們仍按計劃於今年下半年提交該 II/III 期研究的 IND 申請。

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

接下來，我想把電話交給凱爾，讓他為大家介紹我們的財務狀況。凱爾？

Thanks, Paul. Our revenue for the third quarter of 2025 was $7.6 million compared to negative $7.7 million in the prior year quarter. The year-over-year increase was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $45.9 million in the third quarter of 2025 as compared to $41.2 million in the same period of 2024. This increase was primarily driven by our rapidly advancing INHBE program and RNA editing programs as well as compensation-related expenses, including share-based compensation.

謝謝你，保羅。2025 年第三季度，我們的營收為 760 萬美元，而去年同期則虧損 770 萬美元。年比成長是由於我們與葛蘭素史克 (GSK) 的合作協議中確認的收入時間所致。2025 年第三季的研發費用為 4,590 萬美元，而 2024 年同期為 4,120 萬美元。這一增長主要得益於我們快速推進的 INHBE 項目和 RNA 編輯項目，以及與薪酬相關的支出，包括股權激勵。

Our G&A expenses were $18.1 million for the third quarter of 2025 as compared to $15 million in the prior year quarter. The increase was primarily related to share-based compensation and other external expenses. As a result, our net loss was $53.9 million for the third quarter of 2025 as compared to a net loss of $61.8 million in the prior year quarter.

2025 年第三季度，我們的一般及行政費用為 1,810 萬美元，而去年同期為 1,500 萬美元。此次成長主要與股權激勵和其他外部支出有關。因此，2025 年第三季我們的淨虧損為 5,390 萬美元，而去年同期淨虧損為 6,180 萬美元。

We ended the third quarter of 2025 with $196.2 million in cash and cash equivalents compared to $302.1 million as of December 31, 2024. Subsequent to quarter-end, an additional $72.1 million in ATM proceeds and committed GSK milestones extended our expected cash runway into Q2 2027. By contrast, it is important to note that potential future milestones and other payments to us under our GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

截至 2025 年第三季末，我們持有現金及現金等價物 1.962 億美元，而截至 2024 年 12 月 31 日，這一數字為 3.021 億美元。季度末之後，ATM 收益和承諾的 GSK 里程碑付款又增加了 7,210 萬美元，使我們的預期現金儲備能夠維持到 2027 年第二季。相較之下，值得注意的是，根據我們與葛蘭素史克 (GSK) 的合作，未來可能出現的里程碑事件和其他款項並未計入我們的現金儲備。現在我將把電話交還給保羅，請他作總結發言。

Thank you, Kyle. We are incredibly encouraged by the progress we've made across our pipeline. In the past 2 months alone, we've rapidly advanced INLIGHT and delivered robust and durable activin E reductions, and we have achieved the key treatment goals for 006 in RestorAATion-2. Looking ahead, we have a tremendous opportunity to build on our strong momentum as we continue to reimagine what's possible for patients. We look forward to keeping you updated on our progress.

謝謝你，凱爾。我們對所有產品線的進展感到無比鼓舞。僅在過去兩個月裡，我們就迅速推進了 INLIGHT 的發展，實現了強勁而持久的激活素 E 減少，並且實現了 RestorAATion-2 中 006 的關鍵治療目標。展望未來，我們擁有巨大的機會，可以鞏固我們強勁的發展勢頭，繼續重新構想患者能夠獲得的各種可能性。我們會持續向您報告最新進展。

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

接下來，我將把問答環節交給接線員。操作員？

Thank you. We will now move on to our Q&A session. (Operator Instructions)

謝謝。接下來我們將進入問答環節。（操作說明）

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

Great. Thanks for the updates and for taking our questions. And it's really great to see a nice dose response of activin E knockdown and weight loss in the DIO model. Have you looked into what happens to all the fat that's mobilized post activin E knockdown? Specifically, have you checked the liver fat deposits or looked at lipid panels for any LDL or triglycerides in these mice? And I have a quick follow-up on Huntington's.

偉大的。感謝您提供最新資訊並解答我們的問題。很高興看到在 DIO 模型中，激活素 E 敲低和體重減輕之間有良好的劑量反應。你有沒有研究過激活素 E 被抑制後，所有被動員起來的脂肪會發生什麼變化？具體來說，您是否檢查過這些小鼠的肝臟脂肪沉積情況，或查看它們的脂質譜，看看是否有低密度脂蛋白或三酸甘油酯？我還有一個關於亨丁頓舞蹈症的後續問題。

Yes. Thank you, Joon. And yes, one, it was wonderful to see dose responses, as you pointed out, in the DIO mouse, -- it's even better when we got to see dose responses in humans, which is obviously incredibly encouraging. To the point that you're making on fat, I mean, I think we can comment on -- positively on multiple approaches. One, to your point, preclinically, we haven't observed any changes in increased lipids and deposits in the liver.

是的。謝謝你，俊。是的，正如你所指出的，在 DIO 小鼠身上看到劑量反應真是太棒了——而當我們在人類身上看到劑量反應時，那就更好了，這顯然令人非常鼓舞。關於你提到的脂肪問題，我的意思是，我認為我們可以對多種方法進行正面評價。第一，正如您所說，在臨床前研究中，我們尚未觀察到肝臟中脂質和沈積增加的任何變化。

That's both in the DIO studies we've done, but also in our preclinical toxicology studies. So, nothing to suggest that, that stat is finding its way to other tissues. I also point back to the clinical genetics, which show these patients actually have a decreased risk of NASH and liver disease. And then most importantly, as we look at the clinical study progressing, as we said on the last update that we're up to 600 milligrams with an FDA review so that we could start in the US at 600.

這一點在我們進行的 DIO 研究以及我們的臨床前毒理學研究中都有體現。所以，沒有任何跡象表明，這項統計數據正在傳播到其他組織。我還指出臨床遺傳學研究表明，這些患者患 NASH 和肝病的風險實際上有所降低。最重要的是，隨著臨床研究的進展，正如我們在上次更新中所說，我們已經達到了 600 毫克的劑量，並且正在接受 FDA 的審查，這樣我們就可以在美國以 600 毫克的劑量開始使用。

And they got to review all the safety data that preceded that. And so, at that point, again, encouraging, not just from a preclinical and mouse perspective, but also from a human perspective. And while we get this question, I mean, I think what we have to think about is lipolysis breaks up these free fatty acids and they're used as energy, energy and muscle, energy and heart. And so, these are positive findings that have been seen in other heart failure activities. So, nothing that we would -- that would suggest any concerns from our standpoint.

他們得以審查之前的所有安全資料。因此，從臨床前和動物實驗的角度來看，這令人鼓舞，而且從人類的角度來看也是如此。既然有人問了這個問題，我的意思是，我認為我們必須思考的是，脂肪分解會將這些遊離脂肪酸分解，它們會被用作能量，為肌肉、心臟提供能量。因此，這些是在其他心臟衰竭研究中也觀察到的正面結果。所以，從我們的角度來看，沒有什麼事情會顯示我們有任何擔憂。

And on Huntington's, have you had a pre-IND meeting with the FDA? And any changes to their comments on the use of MRI as a reasonable surrogate for Huntington's? And any thoughts regarding recent backtracking by the FDA according to some of the companies that you -- in your peer group?

關於亨丁頓舞蹈症，您是否與FDA進行IND前會議？對於使用核磁共振成像作為亨廷頓氏症合理替代指標的觀點，他們的評論是否有所改變？對於您——以及您所在行業中的一些公司——所反映的FDA最近政策的倒退，您有什麼看法？

Thank you.

謝謝。

Yes. No, and we appreciate the question. I know there's a lot of discussions about HD recently. And yes, I mean, I think we have -- and we've shared this, have alignment with the FDA on the use of MRI as an imaging endpoint in connection with all of the other clinical data we're measuring. But it's important to note that we're running this as a placebo-controlled study as we're using that imaging endpoint as a primary endpoint.

是的。不，我們感謝您的提問。我知道最近有很多關於高清的討論。是的，我的意思是，我認為我們已經——並且我們已經分享了這一點——與 FDA 就使用 MRI 作為成像終點以及我們正在測量的所有其他臨床數據達成了一致。但要注意的是，我們採用安慰劑對照研究方法，因為我們將此影像學終點作為主要終點。

I think there is a lot of consternation over the agency's perceived changes of opinion. And to date, we haven't observed that or found that. I think it is important when we think about caudate. And I reflect on this relative to some of the discussions that are ongoing relating to utility of natural history studies in clinical trials. And I think it's important to note that when we use Track and Predict-HD as the natural history studies for comparison and supporting use of MRI imaging data, those 2 studies include MRI as a prominent feature.

我認為，人們對該機構態度的轉變感到非常不安。到目前為止，我們還沒有觀察到或發現這種情況。我認為這一點在我們思考尾狀核時很重要。我將這一點與目前正在進行的關於自然史研究在臨床試驗中的應用價值的討論連結起來思考。我認為值得注意的是，當我們使用 Track 和 Predict-HD 作為自然史研究進行比較和支持 MRI 成像數據的使用時，這兩項研究都將 MRI 作為一項突出特徵。

And I do think -- the recognition is we just reminded people on the call today, and we've shared a number of times that a 1% change in caudate atrophy can translate to a 7.5-year delay in clinical disability really does set the stage that small meaningful changes in caudate can change clinical outcome measurements. And I think what's important there, if we think about other studies that have been done that haven't looked at propensity matching of caudate volume to patient sizes in natural history, some natural history roll don't include MRI imaging. Actually, if you have a larger caudate at the beginning of that study, that could actually be attributable to a delay in clinical disability on CHDURS and other clinical outcome measurements. So, I think it is important that while there's a lot of discussion about the agency, we feel very confident in both what's driving our decision on the utility of MRI imaging caudate, but also making sure we run a well-powered, well-designed clinical trial to determine that.

而且我認為——正如我們今天在電話會議上提醒大家的，我們也多次提到，尾狀核萎縮 1% 可以轉化為臨床殘疾延遲 7.5 年，這確實表明尾狀核的微小而有意義的變化可以改變臨床結果測量。我認為重要的是，如果我們考慮其他一些研究，這些研究沒有考察自然病程中尾狀核體積與患者體型的傾向性匹配，一些自然病程研究甚至沒有包括 MRI 成像。事實上，如果在研究開始時尾狀核較大，這實際上可能導致 CHDURS 和其他臨床結果測量中臨床殘疾的延遲出現。所以，我認為重要的是，雖然關於該機構有很多討論，但我們對推動我們做出關於 MRI 成像尾狀核效用的決策的因素非常有信心，同時也確保我們開展一項有充分效力、設計良好的臨床試驗來確定這一點。

Paul, just a quick follow-up. How variable is the caudate volume within the same Huntington's stage, like Stage 2 and Stage 3 and et cetera. Within the same stage, are there variabilities in the caudate volume? And how much?

保羅，還有一個後續問題。在同一亨廷頓病階段內，尾狀核體積的變化有多大，例如第 2 期和第 3 期等等。在同一發育階段，尾狀核的體積是否有差異？多少錢？

There can be -- I think what we've seen is very steady changes in caudate. And actually, with the shift in the staging criteria now, actually caudate is becoming a core component of that staging criteria. And so actually, you can assess stages and what patients have -- what change in caudate at each particular stage. And I think that's why it's helpful as we think about other studies that are done and trying to benchmark their size of caudate volume relative to that. We could assess that in looking at those data sets externally.

尾狀核可能會發生——我認為我們看到的是尾狀核非常穩定的變化。事實上，隨著分期標準的轉變，尾狀核正在成為分期標準的核心組成部分。因此，實際上，你可以評估各個階段以及患者在每個特定階段尾狀核的變化。我認為這就是為什麼當我們考慮其他已完成的研究並試圖將它們的尾狀核體積大小與此進行比較時，它是有幫助的。我們可以透過查看外部資料集來評估這一點。

And I think if you had to bias a study towards larger caudate, let's say, so that they would be accessible, that could be attributable to actually delaying and slowing clinical progression, not related to potential medicines. I mean I think what's critical about the data we've generated to date is we've seen the most substantial reductions in mutant Huntington.

我認為，如果你必須讓一項研究偏向較大的尾狀核，以便更容易進行手術，那麼這可能實際上會延緩和減緩臨床進展，而與潛在的藥物無關。我的意思是，我認為我們迄今為止產生的數據的關鍵在於，我們已經看到了亨廷頓氏症突變體的最大程度減少。

I think looking at target engagement, coupled with changes in anatomical findings is important. We actually -- people remember, but at the HSG meeting back in October, even the oral small molecules showed a lower reduction in mutant Huntington. I mean, I think we looked at the data presented by Novartis on PTC, I mean they had less than 20% target engagement and actually had ventricular enlargement and brain volume reduction. So, I think looking at target engagement relative to outcomes is going to be critical. And I think we remain -- have high conviction on an allele-specific approach to mutant huntingtin lowering.

我認為觀察靶點參與情況，並結合解剖學發現的變化，是非常重要的。實際上——人們還記得，在 10 月的 HSG 會議上，即使是口服小分子藥物也顯示出對突變型亨廷頓舞蹈症的抑製作用較小。我的意思是，我們看過諾華公司公佈的關於PTC的數據，他們的標靶結合率不到20%，而且實際上出現了腦室擴大和腦容量減少的情況。所以，我認為考察目標受眾的參與度與最終結果之間的關係至關重要。而且我認為我們仍然對針對突變亨廷頓蛋白降低的等位基因特異性方法抱有高度信心。

And I think post all of this have been actively engaged with our potential partners in terms of accelerating the study.

我認為，在這一切之後，我們一直在積極與潛在合作夥伴接洽，以加快研究進程。

Cheng Li, Oppenheimer.

程莉，奧本海默。

Hey, thanks for taking the question and congrats on the progress. I have a question on the obesity we poster. It just seems like some gene expression changes actually happen pretty early, but some maybe happen later. So, I'm just wondering, by the time you report initial data in the fourth quarter, what kind of changes in those biomarkers related to metabolism, inflammation and fibrosis you would like to see and maybe which biomarkers are more important? And I have a quick follow-up.

嘿，謝謝你回答這個問題，也祝賀你的進展。我對我們發布的肥胖症海報有個問題。似乎有些基因表現變化發生得比較早，有些則發生得比較晚。所以，我想知道，到你們在第四季度公佈初步數據時，你們希望看到與代謝、發炎和纖維化相關的生物標記物發生哪些變化，以及哪些生物標記物更為重要？我還有一個後續問題。

Thank you.

謝謝。

Yes. I'll let Erik add his thoughts to this. But there is an induction over time. I think what we do see is the rapid engagement of both the target and suppression of protein happens fairly rapidly and is sustained. And as you point out, that change over time drives lipolysis as we saw in the DIO models.

是的。我請艾瑞克補充他的想法。但隨著時間的推移，會發生歸納歸因。我認為我們看到的是，標靶的快速結合和蛋白質的抑制都發生得相當迅速，而且是持續的。正如你所指出的，隨著時間的推移，這種變化會驅動脂肪分解，正如我們在 DIO 模型中看到的那樣。

And then along that way, are going to be able to track various biomarkers of metabolic health that correspond with that. I don't know, Erik, if you want to add to that.

然後，透過這種方式，我們將能夠追蹤與此相對應的各種代謝健康生物標記。艾瑞克，我不知道你是否想補充什麼。

No, I think that's a good summary. There is a trajectory. I think maybe worth just pointing out that on the obesity week poster, those are from liver biopsies. And obviously, these are healthy individuals living with obesity and -- so there will not be any liver biopsies. But we -- as we have reported, we are able to look at some circulating biomarkers, but we haven't shared exactly what we're going to look at.

不，我覺得這個總結很好。這其中存在一條發展軌跡。我覺得有必要指出，肥胖週海報上的那些圖片來自肝臟切片。顯然，這些都是患有肥胖症的健康個體，因此不會進行肝臟活檢。但是，正如我們之前報導的那樣，我們能夠觀察一些循環生物標誌物，但我們還沒有透露我們將要觀察的具體內容。

And just wondering, based on your like preclinical study, when do you think the weight loss can plateau with 007?

我只是想問一下，根據你們的臨床前研究，你們認為使用 007 減肥產品，減肥效果什麼時候會達到平台期？

Thank you.

謝謝。

Yes. I think one of the encouraging findings is even out of that study where -- and everybody has that image in their head of the INHBE fat loss, which is weight loss, but all driven off of fat, similar to semaglutide's total body weight reduction. It doesn't appear at that point that we necessarily start to plateau versus the GLP-1 as it relates to fat loss. So, I think that's going to be -- while we talk about the early changes in kinetics, I think the opportunity is really to establish that floor. I mean I think people often talk about basically greater than a year on the GLP-1s plateauing.

是的。我認為這項研究中最令人鼓舞的發現之一是——每個人腦海中都有一個畫面，即 INHBE 脂肪減少，也就是體重減輕，但所有減重都是由脂肪驅動的，類似於司美格魯肽的全身減重。就減脂而言，似乎我們與 GLP-1 相比，並不會就此進入平台期。所以，我認為——雖然我們談論的是動力學的早期變化，但我認為真正的機會在於確立這個底線。我的意思是，我認為人們經常談到 GLP-1 水平在一年多後趨於穩定。

But I think what's nice is we haven't seen that point yet. So, I think we'll have an opportunity to continue to see what that curve looks like for INHBE over time, and the study is designed to assess that.

但我認為令人欣慰的是，我們還沒有看到那一天。所以，我認為我們將有機會繼續觀察 INHBE 隨時間推移的曲線變化情況，而這項研究正是為了評估這一點而設計的。

Salim Syed, Mizuho Securities.

Salim Syed，瑞穗證券。

Great. Congrats on the progress, Paul and team. Just a couple from us. One on alpha-1 antitrypsin. Paul, just curious to get your thoughts around some of the DNA editor ATD programs that we've seen some recent preclinical data on some discussion there, obviously, being able to reduce 20 micromolar plus M-AAT, and just how does that framework you thinking all do you need to be in that sort of range for outside the acute phase response? And then the second question is just on DMD.

偉大的。祝賀保羅和團隊的進展。我們兩個就說這兩點吧。一是α1-抗胰蛋白酶。Paul，我很好奇你對我們最近看到的一些DNA編輯ATD計畫的一些看法，我們有一些臨床前數據和討論，顯然，能夠降低20微摩爾以上的M-AAT，你認為在急性期反應之外，你需要達到怎樣的水平？第二個問題是關於DMD的。

I noticed in the press release, there's no more reference to the additional exon skipping program, CTAs for 2026. I'm wondering if that was removed, it's no longer the plan.

我注意到新聞稿中不再提及額外的外顯子跳躍計劃和 2026 年的臨床試驗申請。我想知道是不是已經取消了，不再是之前的計畫了。

Thank you.

謝謝。

Yes. To start with the first one. I mean, I think as we've learned in trying to benchmark preclinical to clinical data, recognizing a lot of that's driven in the sort of A1 mouse model, that's high copy number. I think the absolute translation if we were to compare those data, let's say, DNA editing to DNA editing at beam, I think we've seen the corresponding changes that there's so much opportunity to edit transcript. But for that, that I don't necessarily think there's going to be substantially more editing than necessarily what we're seeing across potential other editors on the DNA editing side.

是的。先從第一個開始。我的意思是，我認為正如我們在嘗試將臨床前數據與臨床數據進行基準比較時所了解到的那樣，許多數據都是由 A1 小鼠模型（即高拷貝數模型）所驅動的。我認為，如果我們要對這些數據進行絕對的比較，比如說，DNA 編輯與束流 DNA 編輯，我認為我們已經看到了相應的變化，那就是有很多機會可以編輯轉錄本。但就此而言，我不認為DNA編輯方面會有比我們目前在其他潛在編輯器中看到的更多的編輯。

I think what the opportunity is, is whether or not that changes the off-target potential, and we've seen that across a number of DNA editing constructs, both in AATD and not in AAT that off-target rates are consequential and can be detrimental. I think we see bystander edits that create apparent proteins, and that's challenging. And so, I think people are trying to work and address that. And with hepatic turnover, the potential to see that change.

我認為機會在於，這是否會改變脫靶效應，我們已經看到，在AATD和非AAT中，許多DNA編輯構建體的脫靶率都是有後果的，而且可能是有害的。我認為我們看到旁觀者編輯產生了明顯的蛋白質，這很有挑戰性。所以，我認為人們正在努力解決這個問題。隨著肝臟代謝的進行，這種變化是有可能發生的。

So, I think all of that is to say, I think we need to see how those others translate, not from what data they're posting preclinically to differentiate and distinguish, let's say, them from being on the DNA editing side, but really how they ultimately translate into human clinical data. I mean I think at the end of the day; the most important feature is really can you get to MZ phenotype levels. And as we've seen, it's not about getting higher. I think the real misnomer in this space is applying the recombinant protein strategy, which is pour more protein into the body because it gets utilized as soon as there's an acute event. I think we have to all remember that alpha-1 antitrypsin is a chronic disease of acute exacerbations.

所以，我認為所有這些都表明，我們需要看看其他研究是如何轉化的，不是從他們發布的臨床前數據來區分和辨別他們是否屬於 DNA 編輯領域，而是真正看看他們最終是如何轉化為人類臨床數據的。我的意思是，我認為歸根結底，最重要的特徵是能否達到 MZ 表型水平。正如我們所看到的，關鍵不在於爬得更高。我認為這個領域真正的誤稱是應用重組蛋白策略，即向體內注入更多蛋白質，因為一旦發生急性事件，這些蛋白質就會被立即利用。我認為我們都必須記住，α-1抗胰蛋白酶缺乏症是一種慢性疾病，常有急性發作。

And I think if we think about it in that context, it always comes down to what is the requirement to have enough protein so that you have this event, you don't deplete everything. I mean, theoretically, you could argue that maybe 11 micromolar was a questionable threshold for replacement because by the time you have an acute event, there's no protein left to actually protect your lung. And we've had a KOL recently remind us that his biggest fear is a patient who between infusions has an acute event, can't get infused and is now left exposed to the insult in the lung.

我認為，如果我們從這個角度來考慮，最終都會歸結為：需要多少蛋白質才能進行這項活動，才能避免蛋白質耗盡。我的意思是，理論上講，你可以說 11 微摩爾可能是一個值得懷疑的替代閾值，因為到發生急性事件時，已經沒有蛋白質可以真正保護你的肺了。最近一位 KOL 提醒我們，他最擔心的是病人在兩次輸液之間發生急性事件，無法輸液，導致肺部暴露在損傷之下。

We have to reframe that whole narrative as we think about the paradigm shift for RNA editing, which is about rising to meet the need of what's required during those periods of acute inflammation. And as we've shown, we can achieve over 20 micromolar of protein during the acute exacerbation. So, I don't think this is a competition of like us because we're in RNA editing being limited to how we respond. We respond extraordinarily well. We respond with infrequent sub-Q administration.

當我們思考 RNA 編輯的典範轉移時，我們必須重新建構整個敘事，這關乎如何滿足急性發炎期間的需求。正如我們所展示的，在急性加重期，我們可以達到超過 20 微摩爾的蛋白質濃度。所以，我不認為這是一場競爭，因為我們在RNA編輯領域受到限制，只能被動地應對。我們的反應非常出色。我們採用不頻繁的皮下注射方式進行治療。

We have no by edits. We have no off target editing, no indels. And so, I think long-term, for treating a chronic disease, I think RNA editing and particularly our approach to RNA editing with our AMR designs, I think really meet the therapeutic need of patients with these diseases.

我們沒有透過編輯進行任何修改。我們沒有脫靶編輯，也沒有插入缺失。因此，我認為從長遠來看，對於治療慢性疾病，RNA 編輯，特別是我們採用 AMR 設計進行 RNA 編輯的方法，我認為真正滿足了這些疾病患者的治療需求。

To your second question, I think on other exons, I don't think there's a fundamental change. We're ready to progress. I think what we want to see is the continued progress that we're making on exon 53 and where we're allocating capital to make sure that we progress on 53 and then continue to move other programs forward behind that. So, it's less about a formal change and more saying that as we reflect on guidance, I think the key is advancing exon 53, drive that forward and be prudent on the acceleration of other exons. I think as we look forward to '26, and we're going to share a lot more on this during the year, we are highly encouraged about the progress we're making in obesity space and with reflection that we're seeing from a number of parties, the work that we're doing on potential maintenance where we can wash patients off of GLP-1s and support them on a once to twice a year sub-Q therapy that actually prevents rebound weight gain, drives metabolic health and really becomes, I think, the standard for maintenance has us thinking about 2026 in a really positive way about studies that will continue to drive and support that.

關於你的第二個問題，我認為在其他外顯子方面，應該沒有根本性的改變。我們已準備好繼續前進。我認為我們希望看到的是我們在外顯子 53 方面取得的持續進展，以及我們如何分配資金以確保我們在 53 號外顯子方面取得進展，然後繼續推進其他項目。所以，與其說是正式的改變，不如說是在反思指導原則時，我認為關鍵在於推進第 53 號外顯子，推動它向前發展，並謹慎地加速其他外顯子的推進。展望2026年，我們將在今年分享更多相關資訊。我們對在肥胖領域取得的進展感到非常鼓舞，並且從各方反饋來看，我們正在進行的維持治療方面的工作，旨在幫助患者停止使用GLP-1，並支持他們每年進行一到兩次皮下注射治療，這種治療能夠有效防止體重反彈，促進代謝健康，並真正成為維持治療的標準。這些都讓我們對2026年充滿信心，期待相關研究能繼續推動和支持這個目標的實現。

And we just have to think about the totality of where we're allocating capital, hence, why collaborations are important to us. So yes.

我們必須考慮資本分配的整體方向，因此，合作對我們很重要。是的。

Steve Seedhouse, Cantor.

史蒂夫·西德豪斯，領唱。

Yeah, good morning. Thanks for taking the question and congrats on all the recent progress. I wanted to ask in the AATD study, obviously, that is ongoing, and you have that one really profound example of the acute phase response. Are you able to maybe gather more examples of that by protocolizing AAT assessment if people get sick this winter or if they get their flu shots. Just curious if there's anything you can do in the study to supplement that finding.

早安.感謝您回答這個問題，並祝賀您最近的所有進展。我想問的是，在 AATD 研究中，顯然這項研究仍在進行中，而 AATD 正是急性期反應的一個非常深刻的例子。如果人們今年冬天生病或接種流感疫苗，您是否可以透過制定 AAT 評估規程來收集更多此類案例？我只是好奇，在研究中，您是否可以做些什麼來補充這項發現。

It's an interesting question, Steve. It's one of the things that we obviously can identify. So, I think corresponding as we saw there, CRP levels with changes in AAT levels give us a way to be able to not miss those opportunities for assessment. We're not changing the protocol design on a prospective basis. But to your point, as we come into the winter season, the opportunities that we have to be able to capture those events.

史蒂夫，這個問題很有趣。這是我們顯然可以識別出的事情之一。所以，我認為正如我們所看到的，CRP 水平與 AAT 水平的變化相對應，這使我們能夠不錯過這些評估機會。我們不會從長遠角度改變協議設計。但正如您所說，隨著冬季的到來，我們有機會捕捉這些事件。

are there. I think what's highly encouraging is at a basal level, we recognize that we believe we are at an MZ phenotype editing capability. So, these patients, to your point, should be responding as such, and we'll be able to identify them.

就在那裡。我認為最令人鼓舞的是，從基礎層面來說，我們已經意識到我們具備了MZ表型編輯能力。所以，正如您所說，這些患者應該會有這樣的反應，我們將能夠識別他們。

And then just in INLIGHT, I was curious if you could clarify or just guide us what proportion of that study enrolled in the US versus ex-US? And even if it's sort of relevant, would you expect any difference in the patient demographics or something that would affect the results?

另外，關於 INLIGHT 研究，我很好奇您能否澄清或指導我們一下，該研究中美國參與者與美國以外參與者的比例是多少？即使它與研究結果有一定關聯，您認為患者的人口統計特徵或其他方面會有什麼差異，從而影響研究結果嗎？

Yes, I'll let Chris join in. So obviously, the study started ex-US, and we provided the update during the last update that we now had the FDA IND acceptance to begin and begin at the highest dose, so at 600. So proportionately, obviously, in the early setting, it's proportionately ex US with the opportunity to come here. I wouldn't expect any changes.

是的，我會讓克里斯加入。顯然，這項研究是在美國以外開始的，我們在上次更新中提供了最新消息，我們現在已經獲得了 FDA IND 的批准，可以開始研究，並且將從最高劑量開始，即 600 毫克。所以，從比例上看，很明顯，在早期階段，來自美國以外地區的人有機會來到這裡。我預計不會有任何變化。

Chris?

克里斯？

No, that's right. So as Paul said, we're just starting up in the US now. So, we're going to be recruiting patients there going forward. And we haven't really changed our inclusion criteria based on region.

沒錯。正如保羅所說，我們現在才剛開始在美國發展。所以，接下來我們將在那裡招募患者。我們並沒有真正根據地區改變納入標準。

So, we'd expect that all the subjects here would meet those criteria just like the ones in the ex-US

因此，我們預期這裡的所有受試者都將符合這些標準，就像前美國受試者一樣。

I think it's important so that as we are able to, in the future, start analyzing data, I mean, there's the ability to look at the dose cohorts, but also to substantially power the ability to look at activity reduction related to body composition changes and other, which would allow us to work across cohorts as well as we get to the later data points. So, to Chris' point, it is important that we have cohesiveness amongst these patients so that we can do better analysis across the study.

我認為這一點很重要，這樣，將來我們就可以開始分析數據，我的意思是，我們不僅可以查看劑量組，還可以大幅提升我們查看與身體組成變化和其他因素相關的活動減少的能力，這將使我們能夠跨組進行研究，並獲取後續的數據點。所以，正如克里斯所說，重要的是這些患者之間要有凝聚力，這樣我們才能更好地進行研究分析。

Madison El-saadi, B. Riley Securities.

Madison El-saadi，B. Riley Securities。

Hi, good morning, everyone. Thanks for taking our question. A couple from us. On the single AATD patient that experienced the acute phase response, curious if there's any additional insights or observations from that patient that you could comment on? And then secondly, I actually wanted to ask about your bifunctional single nucleotide construct. Curious if you've optimized this construct to avoid any type of intermolecular interference and if you're seeing any off-target end, basically where you're at in the optimization phase.

大家早安。感謝您回答我們的問題。我們中的一對夫婦。關於唯一一位出現急性期反應的 AATD 患者，您是否有其他見解或觀察結果可以分享？其次，我其實想問關於您的雙功能單核苷酸構建體的問題。我很好奇您是否已經優化了這種結構以避免任何類型的分子間幹擾，以及您是否觀察到任何脫靶效應，基本上，您目前處於優化階段的哪個階段。

Thank you.

謝謝。

Yes. I mean I think to the first one, there's no new insights other than, obviously, patient recovered, and we saw like very good corresponding relationship between that CRP exacerbation and down. I think it's important to this point, that is the disease. The disease of these infrequent, but they happen. There are these acute exacerbations.

是的。我的意思是，對於第一個問題，除了患者康復之外，沒有其他新的見解，而且我們看到了 CRP 升高和下降之間非常好的對應關係。我認為重要的是，到目前為止，這就是這種疾病。這些疾病雖然不常見，但確實會發生。會出現急性加重的情況。

And so that response rate is what you expect to see in an MZ patient who is protected. But I think they responded exactly as you would anticipate an MZ patient response to occur. I'll look to Chandra just to confirm, but I mean, we did the work. We've shared some of those recent updates. And I think that was the piece that had me most excited about the fact that these bifunctional approaches to SI and editing could provide really compelling ways to treat diseases.

因此，這種反應率正是您在受到保護的 MZ 患者身上所期望看到的。但我認為他們的反應完全符合預期，就像MZ患者的反應一樣。我會向 Chandra 確認一下，但我的意思是，我們已經完成了這項工作。我們已經分享了其中一些最新的進展。我認為最讓我興奮的是，這些針對 SI 和編輯的雙功能方法可以為治療疾病提供真正引人注目的方法。

I mean, as we shared the opportunity to think about things like the combinations and actually watching, PCSK9 reductions coupled with LDLR upregulation is a fascinating approach long-term to effectively treat cardiovascular disease and lipodystrophies. And so I think the opportunity is seeing each of those behave, and I think that was Chandra's compelling data on knockdown wasn't blocked by editing and editing wasn't blocked by knockdown shows that there wasn't steric hindrance across, and I don't -- we haven't seen any -- because AIMers are specific to the enzyme that they're working on in Dels or bystander edits, but I'll let Chandra. We haven't seen anything to that effect.

我的意思是，當我們有機會思考諸如組合之類的事情，並且實際觀察時，PCSK9 減少與 LDLR 上調相結合是一種長期有效治療心血管疾病和脂肪營養不良的迷人方法。所以我認為機會在於觀察它們各自的行為，我認為 Chandra 令人信服的數據表明，敲低不會被編輯阻止，編輯也不會被敲低阻止，這表明不存在空間位阻，而且——我們還沒有看到任何——因為 AIMers 是針對 Dels 或旁觀者編輯中它們所作用的酶的，但我還是讓 Chandra 來解釋吧。我們還沒有看到任何類似情況發生。

Yes. So, this is -- the platform provides us an opportunity to be highly specific for both enzymes. So that's the design principles, taking into consideration how our SpiNA react with our Ago2 highly specific and see specific knockdown and adding to that the AIMer that is also highly specific recruiting ADAR. And we found -- using our platform, we found a way to combine these 2 properties to give us exactly what we observed with single entity, but with one construct.

是的。所以，這個平台為我們提供了一個能夠高度特異性地針對這兩種酵素的機會。所以這就是設計原則，考慮到我們的 SpiNA 如何與我們的 Ago2 高度特異性地反應，並看到特異性的擊倒，再加上同樣高度特異性地招募 ADAR 的 AIMer。我們發現──利用我們的平台，我們找到了一種方法，將這兩個屬性結合起來，用一個構造就能得到我們用單一實體觀察到的完全相同的結果。

So, the best way to think about it is the uniqueness and specificity of each endogenous enzyme is able to observe its own unique endogenous function. So, the enzymes are highly specific for their approach.

因此，最好的理解方式是，每種內源性酵素的獨特性和特異性使其能夠發揮自身獨特的內源性功能。因此，這些酵素對其作用方式具有高度特異性。

[Bill Mohan, Clear Street.]

[比爾莫漢，《清晰街》]

Good morning and thanks. I was hoping you could comment on the recent data from Sarepta's exon skippers that failed to confirm benefit in the confirmatory studies. Obviously, this highlights the unmet need in the space. But at the same time, do you expect any difficulties in maybe a changing FDA attitude towards dystrophin expression as a proper accelerated approval endpoint?

早安，謝謝。我希望您能對Sarepta公司最近公佈的外顯子跳躍療法的數據發表評論，這些數據在驗證性研究中未能證實其療效。顯然，這凸顯了該領域尚未滿足的需求。但同時，您是否認為FDA對肌肉營養不良蛋白表現作為加速審批終點的態度可能會改變，帶來一些困難？

Yes. I think it's critical as we shared data very early on, on looking at consistent dystrophin expression across patients. If you remember, one of the key highlights, both 6-month and the 48-week data that we shared was not just an amplitude of how much protein. I think there's been a lot of discussions about mean protein levels. I think the narrative that was important for us to make sure people start pushing is how well distributed was that across patients?

是的。我認為這一點至關重要，因為我們很早就分享了數據，觀察患者間肌肉營養不良蛋白表現的一致性。如果你還記得的話，我們分享的 6 個月和 48 週數據中的關鍵亮點不僅僅是蛋白質含量的幅度。我認為關於平均蛋白質水平已經有很多討論了。我認為對我們來說，需要確保人們開始關注的重要一點是，這種做法在患者群體中的普及程度如何？

Because if patients don't have adequate amounts of protein level, then it shouldn't be unexpected if they don't continue to show benefit because they don't have adequate levels of protection. So, the highly consistent distribution we were seeing was important. I think what was most important to us was the fact that we actually did see that translate to statistically significant clinical meaningful improvements in time to rise. We saw those corresponding changes in muscle fibrosis. And I think that is really what was important and driving for us, and we're going to have the opportunity by the time we file in '26 to continue to follow those patients who are on the open-label extension study and additional patients being treated monthly to continue to see those clinical improvements.

因為如果患者體內蛋白質含量不足，那麼他們因為缺乏足夠的保護而無法繼續獲益也就不足為奇了。因此，我們看到的這種高度一致的分佈非常重要。我認為對我們來說最重要的是，我們確實看到了這轉化為具有統計意義的、臨床上有意義的起身時間改善。我們在肌肉纖維化中觀察到了相應的變化。我認為這才是真正重要且驅動我們前進的動力，到 2026 年提交申請時，我們將有機會繼續追蹤那些參與開放標籤擴展研究的患者以及每月接受治療的其他患者，以繼續觀察這些臨床改善情況。

So, I think while we haven't seen any correspond from the FDA changing on dystrophin, I think we do recognize the importance of seeing clinical meaningful responses and being an important part of our decision.

所以，雖然我們還沒有看到 FDA 對肌肉營養不良蛋白做出任何改變，但我認為我們確實認識到看到具有臨床意義的反應的重要性，而這是我們決策的重要組成部分。

And it might be a little early for this question. I know there's a lot of clinical derisking left in your INHBE program. But do you have a view on the pricing dynamic in the obesity market where there seems to be this sort of a sustained pricing pressure that we probably wouldn't expect to go away for a while.

現在問這個問題可能有點早。我知道你們的 INHBE 計畫還有很多臨床風險降低的工作要做。但您對肥胖症市場的定價動態有何看法？目前似乎存在一種持續的價格壓力，我們預計這種壓力在一段時間內不會消失。

No. And I think that's the unique opportunity that we have with INHBE and particularly the modality we're using to drive activin E reduction. So, we continue to see strong durability looking again beyond 6 months. So, we're through that at the lowest subtherapeutic dose. So again, highly supportive of once to twice a year sub-Q dosing.

不。我認為這是我們利用 INHBE，特別是我們用來驅動激活素 E 減少的這種模式所擁有的獨特機會。因此，我們繼續看到其強大的耐久性，即使超過 6 個月也是如此。所以，我們已經完成了最低亞治療劑量的測試。因此，我再次強烈支持每年一到兩次皮下注射給藥。

And if we think about the global greater than 1 billion people living with obesity, many of whom don't have access to GLP-1s. If we think about the markets more broadly, the ability to expand where we don't have to -- manufacturing, let's say, is not as big a challenge as with the protein therapies. The ability to really drive accessibility, we think, is a unique feature. And I think if we imagine a world where patients are even currently being able to transition to a once-a-year maintenance therapy where they still get the benefits in cardiovascular outcomes as we've seen with human clinical genetics and sustained weight loss. I think there's a really unique opportunity to think about the true global landscape for obesity.

如果我們考慮到全球超過 10 億人患有肥胖症，其中許多人無法獲得 GLP-1 類藥物。如果我們更廣泛地考慮市場，就會發現，在不必擴張的領域（例如製造業）擴張的能力，並不像蛋白質療法那樣具有挑戰性。我們認為，真正推動無障礙設計的能力是一項獨特的功能。我認為，如果我們設想這樣一個世界：患者現在甚至能夠過渡到每年一次的維持治療，他們仍然可以獲得心血管方面的益處，就像我們在人類臨床遺傳學和持續減肥方面看到的那樣。我認為這是一個非常難得的機會，讓我們認真思考全球肥胖問題的真實面貌。

And I think actually a GalNAc siRNA approach with our chemistry that drives durability is highly disruptive as we think about the evolving obesity landscape, which is really dominated by similar increase.

我認為，我們採用 GalNAc siRNA 方法，結合我們能夠增強持久性的化學特性，對於不斷發展的肥胖格局而言，具有極大的顛覆性，因為肥胖格局實際上以類似的增長為主。

I mean a shift from once a week to once a month still doesn't really radically change the environment and the landscape. And so, what does is the ability to do this with a once or twice a year drug. I think the other piece that's becoming more and more apparent to us coming out of the week is who's being treated. And as we think about the evolution of patients who -- and think about this with Medicare and other things picking up reimbursement, patients who really can't have sustained loss of lean muscle mass, loss of bone, loss of muscle as they continue to age and have to treat these diseases, the opportunity really to bring a medicine that drives fat loss, healthy outcomes, but retains lean muscle mass, I think, is both therapeutically relevant, but also as we think about the cost of transition.

我的意思是，從每週一次改為每月一次，並不會從根本上改變環境和格局。因此，關鍵在於能否用一年服用一到兩次的藥物來達到這個目的。我認為，經過這一週的觀察，我們越來越清楚地看到，究竟是誰在接受治療。當我們思考患者的演變——考慮到醫療保險和其他機構的報銷——隨著年齡的增長，患者確實無法承受持續的瘦肌肉量、骨骼和肌肉流失，並且不得不治療這些疾病，因此，開發一種能夠促進脂肪減少、帶來健康結果，同時又能保持瘦肌肉量的藥物的機會，我認為，這不僅具有治療意義，而且在我們考慮過渡成本時也具有重要意義。

Roger Song, Jefferies.

Roger Song，傑富瑞集團。

Great, thanks for the update and thank your question and great to see you at the Obesity Week as well. So also, a couple of questions related to obesity inhibitor program. Just interested in learning a little bit more about the kinetics of the weight loss. I know you have the DIO model. And then -- so any reason you have to guide 6 months versus earlier or longer for the substantial weight loss similar to semaglutide?

太好了，謝謝你的最新消息，也謝謝你的提問，很高興在肥胖週上見到你。另外，還有幾個與肥胖抑制劑計劃相關的問題。我只是對了解減肥動力學方面的內容比較感興趣。我知道你用的是DIO型號。那麼－您認為6個月的療程比更短或更長時間的療程更能達到類似索瑪魯肽的顯著減重效果有什麼原因嗎？

And maybe any insight from the human genetics can give us a little bit more color around that? And then also related to the dose response, yes, in the DIO, you see the dose response for the weight loss. Just curious about your human dose. How should we think about you step up from 240 to 400 and 600, what's the range of the corresponding dose to preclinical? And then if that possible, you can dose even higher than 600, is that necessary?

或許人類遺傳學的一些見解能讓我們對此有更深入的了解？還有一點與劑量反應有關，是的，在 DIO 中，你可以看到體重減輕的劑量反應。只是好奇你們的人體劑量是多少。我們應該如何看待您從 240 劑量逐步增加到 400 和 600 劑量的情況？相應的臨床前劑量範圍是多少？如果可能的話，劑量甚至可以超過 600，有必要嗎？

Thank you.

謝謝。

Yes. Thank you. And I'll have Erik chime in on the other side because I think he'll have some valuable thoughts about kinetics, too. But I think most importantly, we do look to the modeling of our models. The DIO models translated well for GLP-1.

是的。謝謝。我也會請艾瑞克在另一邊發表意見，因為我認為他對動力學也有一些寶貴的見解。但我認為最重要的是，我們確實要關注模型的建模。DIO模型對GLP-1的轉換效果很好。

So, it's been great to see that corresponding positive control as we look to not just weight loss. And I think it's important to think about it as fat loss, so healthy weight loss. So, if we think about those kinetics, we achieved in the DIO mouse model up to similar levels of total body weight reduction of GLP-1s, but it's all fat. And so, there is a rate of kinetics on that curve that does appear to take more time. So that's something in that early time point as we think about these first 3 months into the 6 months, we're going to learn about the kinetics of INHBE reduction together.

所以，看到相應的積極對照，我們不僅關注減肥，這真是太好了。我認為重要的是要把它看作是減脂，也就是健康的減肥方式。所以，如果我們考慮這些動力學，我們在 DIO 小鼠模型中實現了與 GLP-1 類似的總體重減少水平，但全部都是脂肪。因此，該曲線上的動力學速率似乎需要更長的時間。所以，在最初的3個月到6個月的時間點上，我們將一起了解INHBE還原的動力學。

We know we potently lower it, and we're going to get to see what transpires during that window of time and whether or not the mouse model is reflective of that curve or is it similar both. I think what we feel more confident about is you get to 6 months and longer, the ability to see that continue to transition.

我們知道我們可以有效地降低它，我們將觀察在此期間會發生什麼，以及小鼠模型是否反映了該曲線，或者兩者是否相似。我認為我們更有信心的是，如果能堅持 6 個月甚至更長時間，就能看到這種轉變繼續發生。

And I think the opportunity there is then whether or not that plateauing is what's seen because it does look like you can continue to drive fat loss beyond that point of where you have GLP-1 weight loss. So, I think the ability to kind of follow this over time, much like we all did with the GLP-1s is going to be critical as we understand what that journey looks like. The human clinical genetics gives us kind of a benchmark of what happens with a protective loss of function from birth. So, what happens when you have that. In a lot of ways, it both supports what we've seen in the DIO mouse model in the human study, but it's also really supportive of what we see with these revised maintenance therapies where you kind of have this weight loss and create a set point and then drive that forward.

我認為機會在於，無論是否出現了平台期，因為看起來你仍然可以在 GLP-1 減肥達到瓶頸期之後繼續推動脂肪減少。所以，我認為能夠像我們之前對 GLP-1 一樣，隨著時間的推移追蹤這個過程，對於我們了解這個過程的進展至關重要。人類臨床遺傳學為我們提供了一個基準，讓我們了解從出生起保護性功能喪失會發生什麼。那麼，當你擁有這種情況時會發生什麼事？在許多方面，它既支持了我們在 DIO 小鼠模型中看到的人體研究結果，也確實支持了我們在這些改進的維持療法中看到的結果，即透過減輕體重並建立一個設定點，然後推動它向前發展。

So, I think it's highly encouraging as we look at those genetics, both on initiation of weight loss, but also as we think about the potential future for maintenance therapy, which is incredibly exciting. So, I think that in totality, and Erik, I'd love your opinion on that. As it relates to dose, Roger, I think the ability that we do see this dose responsiveness in the animal models, I think we're going to get an opportunity to evolve that as we said on both -- Chris said on the past call at Research Day and as we reiterated on this call, we are approved to go higher than 600, whether or not we need to is a different story. But I think the ability to continue to drive a dose responsiveness of not just the totality of fat loss, but whether or not the kinetics happen faster in a dose responsive way is something we'll be able to study in humans over the course of the study. But with that, Erik, I don't know if you want to add on a couple of points.

所以，我認為，當我們研究這些基因時，無論是在減肥的啟動方面，還是在考慮維持治療的未來潛力方面，這都非常令人鼓舞，也令人無比興奮。所以，總的來說，我認為…艾瑞克，我很想聽聽你的看法。關於劑量方面，羅傑，我認為我們在動物模型中觀察到的這種劑量反應性，將使我們有機會進一步發展，正如我們在之前的研究中提到的——克里斯在上次研究日電話會議上說的，以及我們在這次電話會議上重申的，我們獲準使用高於 600 的劑量，但我們是否需要這樣做則是另一回事。但我認為，我們不僅要研究脂肪減少總量的劑量反應性，還要研究其動力學是否以劑量反應的方式更快發生，這是我們將在研究過程中在人體上研究的內​​容。但是，艾瑞克，我不知道你是否想補充幾點。

Yes. I think you summarized it very nicely, but just, I guess, to double-click on a few things. So, from the human genetics, then obviously, we know that if you have a germline loss of function variant from birth, then you have a substantially better cardiometabolic profile and lower type 2 diabetes risk and cardiovascular risk. So that's 50%, right? And then we know from our in vivo models that if you can achieve more than 70% activin E reduction, we see that translate in the mouse models to weight loss and a better -- all driven from fat and especially as Paul pointed out, this double effect from semaglutide, the prevention of weight regain, cessation of GLP-1s, all of those effects.

是的。我覺得你總結得很好，不過，我想，可能還需要雙擊一些內容。因此，從人類遺傳學的角度來看，顯然我們知道，如果你從出生起就攜帶種系功能缺失變異，那麼你的心血管代謝狀況就會明顯更好，罹患第 2 型糖尿病和心血管疾病的風險也會更低。所以是50%，對吧？然後，我們從體內模型中得知，如果能使激活素 E 減少 70% 以上，我們在小鼠模型中就能看到體重減輕和更好的——所有這些都是由脂肪驅動的，特別是正如 Paul 指出的那樣，司美格魯肽的這種雙重作用，防止體重反彈，停止 GLP-1 的產生，所有這些作用。

And we do observe that kinetics looks a bit slower than semaglutide. So that's why we're anchoring on the 6-month time point. But again, this is a novel mechanism we're learning together on the kinetics of this. But we're -- just to remind everyone, we're already in that range now in the 240 and the 400 mg cohort. We're in that range where we would expect this to translate to better cardiometabolic health and weight loss from fat loss.

我們觀察到，其動力學似乎比索瑪魯肽慢一些。所以這就是為什麼我們將時間節點定為 6 個月的原因。但再次強調，這是一種全新的機制，我們正在共同學習其動力學。但是——提醒大家一下，我們現在已經達到了 240 毫克和 400 毫克劑量組的水平。我們目前所處的劑量範圍，預計會轉化為更好的心血管代謝健康和透過減脂實現的體重減輕。

Joseph Schwartz, Leerink Partners.

Joseph Schwartz，Leerink Partners。

This is Jenny on for Joe. For obesity, assuming you have positive early data, how do you envision the next steps in development beyond the INLIGHT study? What could these studies look like? And will you be able to do these on your own? Or would you consider strategic partnerships for this program?

這裡是Jenny，替Joe問問題。關於肥胖症，假設你們已經獲得了積極的早期數據，你們如何設想在INLIGHT研究之後，下一步的研發方向是什麼？這些研究可能會是什麼樣的呢？你能獨立完成這些事嗎？或者您是否考慮為該專案尋求策略合作夥伴關係？

And would the GSK collaboration affect your ability to pursue anything if there are opportunities?

如果出現機會，與葛蘭素史克（GSK）的合作是否會影響您追求其他目標的能力？

Thank you.

謝謝。

Thank you. I'll start with that last one because I think it's an important one to get out of the way. There is no inhibition for us to do anything related to INHBE with GSK. So INHBE is a wholly owned Wave program, and we have full control over that, not just clinically but commercially. So, it is a Wave asset.

謝謝。我先從最後一個問題開始，因為我認為這個問題很重要，必須先解決它。我們沒有任何顧慮可以與葛蘭素史克 (GSK) 進行任何與 INHBE 相關的業務。因此，INHBE 是 Wave 的全資項目，我們對其擁有完全的控制權，不僅在臨床方面，而且在商業方面。所以，它是一種Wave資產。

So, move past that one. As we think about the opportunities ahead, I think one of the things coming out of obesity, we enhanced our meetings with a number of KOLs who are incredibly excited about the profile, both not just the driver of fat loss without lean muscle mass loss and that profile as a monotherapy, particularly for a substantial number of patients with it. We're learning more and more, there is concern about anhedonia over time, hair loss, lean muscle mass, loss meaning muscle and bone and the ability to drive healthy weight loss with an infrequent injection and accessibility, I think, was highly encouraging. So, I think that, coupled with a huge amount of excitement for what maintenance could look like and a number of interested parties saying, how could we think about these things in conjunction, give us a number of opportunities as we think forward around what the right strategy is for running these studies.

所以，就此翻篇吧。當我們思考未來的機會時，我認為肥胖症帶來的一個好處是，我們加強了與許多關鍵意見領袖的會面，他們對該產品的特性感到非常興奮，它不僅能在不損失瘦肌肉量的情況下減少脂肪，而且作為一種單一療法，尤其對相當一部分患者來說，也具有很大的潛力。我們了解到，隨著時間的推移，人們越來越擔心快感缺失、脫髮、瘦肌肉量減少（肌肉和骨骼流失），以及透過不頻繁注射和易於獲取的方式實現健康減肥的能力，我認為這非常令人鼓舞。所以，我認為，再加上大家對維護工作的未來充滿熱情，以及許多感興趣的人士提出“我們如何才能將這些事情結合起來考慮”，這為我們提供了許多機會，讓我們能夠展望未來，思考開展這些研究的正確策略。

Irrespective of partnering, we're committed to driving these studies forward. We think that there is a huge need for this in these therapies as we've seen with really the innovation coming in this space from more less frequent administration of incretins and other forms of incretins as opposed to really treating the underlying healthy fat loss and preservation of lean mass. So, with that, I think we're working on planning for running studies in obese patient populations and maintenance that we could drive and we'll give more updates as we think about these studies in 2026 that don't necessarily have us waiting to the completion of INLIGHT. I think INLIGHT is a study that we can envision ongoing as providing ample safety coverage. We're seeing that now with durability.

無論是否合作，我們都致力於推動這些研究。我們認為，這些療法中存在著巨大的需求，正如我們所看到的，該領域的創新來自於減少腸促胰島素和其他形式的腸促胰島素的給藥頻率，而不是真正治療潛在的健康脂肪減少和保持瘦體重。因此，我認為我們正在努力規劃針對肥胖患者群體進行的研究和維持治療，我們可以推動這些研究，隨著我們對 2026 年這些研究的思考，我們將提供更多更新，這些研究不一定需要等到 INLIGHT 研究完成。我認為 INLIGHT 是一項我們可以設想持續進行的研究，它能提供充足的安全保障。我們現在在耐用性方面也看到了這一點。

But we don't have to look at these things in cession that INLIGHT needs to complete before we accelerate studies in obese patients and potentially, as we said, in maintenance. So, we're actively underway in that. We see that as a huge need, and we're working very quickly with a number of KOLs in the field to accelerate the studies.

但我們不必將 INLIGHT 需要完成的這些事情視為理所當然，然後才能加快對肥胖患者以及可能如我們所說，對維持治療的研究。所以，我們正在積極推進這項工作。我們認為這是一個巨大的需求，我們正在與該領域的許多關鍵意見領袖迅速合作，以加快研究進程。

Thanks that's really helpful.

謝謝，這真的很有幫助。

Yeah.

是的。

Yun Zhong, Wedbush Securities.

雲忠，韋德布希證券公司。

Good morning. So first question on DMD program. I wanted to check if you have had any interactions with the FDA on your 48-week data and any additional clarity that you are able to provide in terms of how much monthly dosing data you will need to or you will be able to include in the package, please? And I have a follow-up question, please.

早安.那麼，關於DMD項目，第一個問題是什麼？我想確認一下您是否就您提交的48週數據與FDA有過任何溝通，以及您能否就您需要或能夠包含在資料包中的每月給藥數據提供任何進一步的說明？我還有一個後續問題。

Yes. I mean, as we provided, we've had updates with the agency that we've discussed our plans as we think about filing. One, and as you point out, key was generating data, not just OLE data on a monthly basis, but ensuring that we have de novo patients that are treated on a monthly regimen with which we can study. We have, as we said on prior calls, enough patients, we believe, based on the existing approvals on both new patients as well as the existing patients to support that filing. And we'll continue to stay engaged with the agency as we advance those discussions towards that filing to avoid surprises.

是的。我的意思是，正如我們所提供的，我們已經與相關機構進行了溝通，討論了我們的計劃，並考慮提交申請。第一，正如你所指出的，關鍵在於產生數據，不僅是每月的 OLE 數據，還要確保我們有接受每月治療方案的新發患者，以便我們進行研究。正如我們在先前的電話會議中所說，我們相信，根據目前對新患者和現有患者的批准情況，我們有足夠的患者來支持該申請。我們將繼續與該機構保持溝通，並推進相關討論，直至提交申請，以避免意外情況。

Then on the Huntington's disease program, it's very encouraging to see or hear the FDA is open to accelerated approval pathway. But you commented on the capital allocation. So, I just wanted to ask, would you be able -- would you be open to moving the program independently even without a partner? Or would you prefer to have a partner before taking the next step?

在亨廷頓舞蹈症計畫方面，令人非常鼓舞的是，看到或聽到 FDA 對加速審批途徑持開放態度。但你對資金配置發表了評論。所以，我只是想問一下，您是否能夠——您是否願意在沒有合作夥伴的情況下獨立推進這個專案？還是你希望在採取下一步行動之前先找到伴侶？

Thank you very much.

非常感謝。

No, thank you. And I think we've been consistent on this point. So, within HD, I think why we have conviction and why we have aligned with the agency is we're running a well-powered placebo-controlled study, and that's -- the design is advancing. I think what we're also having in conversations with potential strategic partners for the discussion is assuring that we're aligned on what that trial needs to look like to make sure it does meet the criteria, not just for the accelerated approval, but potentially in design the full approval of that study continues to progress. So, we don't have to go back.

不，謝謝。我認為我們在這一點上一直保持一致。所以，在HD領域，我認為我們之所以有信心並與該機構保持一致，是因為我們正在進行一項有充分力量的安慰劑對照研究，而且——設計正在推進。我認為，我們在與潛在戰略合作夥伴的討論中也在確保我們對試驗需要是什麼樣子達成一致，以確保它不僅符合加速批准的標準，而且在設計上也可能符合該研究的全面批准，從而繼續推進。所以，我們不必回去。

And so, as we get that alignment, that study, we would prefer to progress alongside another collaborator.

因此，在達成共識並完成研究後，我們更願意與另一位合作者共同推進。

Samantha Semenkow, Citi.

Samantha Semenkow，花旗銀行。

This is Ben on for Sam. Going back to obesity, you shared in the R&D slides, the placebo-adjusted benchmark based on semaglutide was approximately minus 2.5%. Are you expecting you'll see that in the upcoming data this quarter for the 240-milligram 3-month data? Or is it possible we'll need more time to reach that benchmark, just given what you kind of had described earlier about the kinetics?

這是本替薩姆報道。回到肥胖症的問題，您在研發幻燈片中分享了基於索瑪魯肽的安慰劑調整基準約為 -2.5%。您是否預期會在本季度即將公佈的 240 毫克劑量 3 個月的數據中看到這一點？或者，鑑於您先前對動力學的描述，我們是否可能需要更多時間才能達到該基準？

Yes. And I think that's what we were -- I mean, if we go back to that slide on Research Day, it was really important that we're anchoring on is the 6-month data to that point. So that curve continues, remember about 4.4% out at the 5-month time point with fat loss for semaglutide. And I think that was key for us is we have the benchmark of fat loss following the GLP-1s over time. And I think what we're -- as we said before, what we're going to learn together is what happens on those rates of fat loss at the early time points.

是的。我認為這就是我們當時的想法——我的意思是，如果我們回到研究日的那張投影片，我們真正關注的是當時的6個月數據。所以這條曲線還在繼續，記住，在 5 個月的時間點，使用司美格魯肽治療後，脂肪減少約 4.4%。我認為關鍵在於，我們有了使用 GLP-1 一段時間後脂肪減少的基準。我認為，正如我們之前所說，我們將共同學習的是，在早期階段脂肪減少的速度會發生什麼變化。

We now have benchmarks, as you said, of what we're benchmarking with GLP-1s. But I think it's really important as it relates to kind of a set point and what is a target range of fat loss to really get 6 months further than in the initial 6 months simply because, as we said, anchoring on preclinical data, there does appear to be a rate of kinetics that looks apparently different. And I think it's important for us to assess that in humans. So, it's why we're not guiding to a specific target number of fat loss in this first 3-month data set, but rather looking at continued engagement and reductions of activity, durability of activity, which is going to be critical and other biomarkers of metabolic health as well as body composition. So, we're going to have a number of features.

正如您所說，我們現在有了基準，可以用來衡量我們使用 GLP-1 進行基準測試的內容。但我認為這非常重要，因為它關係到設定一個目標點，以及減脂的目標範圍，以便真正比最初的 6 個月多堅持 6 個月，因為正如我們所說，基於臨床前數據，似乎確實存在一個動力學速率看起來​​明顯不同的情況。我認為評估這一點對人類來說很重要。因此，在前 3 個月的資料集中，我們沒有設定具體的減脂目標，而是專注於持續參與和活動減少、活動的持久性（這將至關重要）以及其他代謝健康生物標記和身體組成。所以，我們將推出一系列功能。

We're measuring body weight, so it will be important to not miss but it really is important to look at that kinetics over time.

我們正在測量體重，所以準確無誤很重要，但更重要的是觀察體重隨時間變化的動態變化。

And if I may ask a follow-up question. What is other consideration for initiating the Cohort 5 given the IV MZ approved escalation?

我可以問一個後續問題嗎？考慮到 IV MZ 已獲批准升級治療，啟動第 5 組還有哪些考慮因素？

Yes. I mean the only thing now is given how -- I mean, we are at 85% reduction at the 400-milligram cohort and now have a 600-milligram cohort. So, some of that is how much more utility we're going to get from going higher, and we'll have some of that biomarker data to assess. From a safety perspective, we can continue to go up substantially higher. But at the end of the day, it's still about understanding not again, leaving activin E in the efficacy on the table, what's going to drive durability, but also realizing what's going to be, frankly, necessary.

是的。我的意思是，現在唯一的問題是——我的意思是，400毫克劑量組的減少率達到了85%，現在又增加了600毫克劑量組。所以，其中一部分原因是，如果我們提高標準，就能獲得更多的效用，而我們將有一些生物標記數據來評估這一點。從安全角度來看，我們可以繼續大幅提高價格。但歸根究底，關鍵還是在於理解，不要再讓激活素 E 的功效被忽視，要了解什麼才能持久有效，同時也要意識到，坦白說，什麼是必要的。

And again, that's why we're highly encouraged and already planning what are the next subsequent Phase II studies start to look like as it relates to studying this in obese patients as well as men. So, we have the coverage beyond what we think we need currently, and it's why we are confident about the subsequent studies.

再次強調，正因如此，我們備受鼓舞，並且已經在計劃接下來的 II 期研究將如何開展，以研究肥胖患者和男性患者的相關情況。因此，我們目前的覆蓋範圍已經超過了我們認為需要的範圍，這也是我們對後續研究充滿信心的原因。

Luca Issi, RBC Capital Markets.

伊西 (Luca Issi)，加拿大皇家銀行資本市場部。

Hi, Tim. Thanks so much for taking our question. This is Cassie on for Luca. Congrats on all the progress. And we have another one on INHBE, and this is circling back on the ex-US versus US You have a single site now in Moldova listed on clinicaltrial.gov.

嗨，提姆。非常感謝您回答我們的問題。這是卡西替盧卡上場。祝賀你們取得的所有進展。我們還有關於 INHBE 的另一件事，這又回到了前美國與美國的問題。目前在 clinicaltrial.gov 上列出了摩爾多瓦的一個試驗點。

But you did mention that you have activated other sites, including the US at 600-milligram. So, can we assume that the second quarter 2026 update in the 600-milligram cohort is when we will start seeing data from the US patients? Or is that update still going to be data from the Moldova patients?

但你確實提到過，你已經啟動了其他網站，包括美國，劑量為 600 毫克。那麼，我們可以假設在 2026 年第二季 600 毫克劑量組的更新中，我們將開始看到來自美國患者的數據嗎？或者，這次更新的數據仍然會來自摩爾多瓦的患者？

Yes. No, look, we appreciate the question. One, it's on -- just to make sure because at one point you mentioned, just to make sure that it's not confusing this is obesity, this is 007. And it's beyond Moldova. We have sites in U.K., Moldova, Europe, and the update was moving beyond Europe to starting in the US

是的。不，我們很感謝你的提問。第一，它開啟了——只是為了確保——因為你曾經提到過，只是為了確保不會混淆，這是肥胖，這是 007。而且它遠在摩爾多瓦以外。我們在英國、摩爾多瓦和歐洲設有站點，此次更新的範圍將從歐洲擴展到美國。

So, there's a number of sites that will be generating patients. As we provided on the call, the real shift is from Europe to the US And as we said, the US is coming online at the 600-milligram cohort. That's what we shared at Research Day because one, the agency didn't have us restart at a lower dose.

因此，有很多網站都會產生患者。正如我們在電話會議上提到的，真正的轉變是從歐洲到美國。而且正如我們所說，美國正在逐步推出 600 毫克劑量組。這就是我們在研究日上分享的內容，因為首先，該機構並沒有讓我們以較低的劑量重新開始。

We could start at the subsequent cohort, which is 600. So, I think it's obvious from that, that we would expect that you wouldn't have US patients not at 600. So, the US contribution would come at 600.

我們可以從下一批學生開始，這群學生有 600 人。所以，我認為很明顯，我們預計不會有美國患者不在 600 名之列。因此，美國的貢獻將是 600。

Our last question comes from Leonaise Jones. Please go ahead and ask your question.

最後一個問題來自 Leonaise Jones。請繼續提問。

Hello, thank you so much for taking our questions. Just looking at your preclinical DIO mouse data you showed at Obesity Week, do you think the reduction in macrophages is simply due to reduction in adipocyte size? Or do you think there are other anti-inflammatory mechanisms involved?

您好，非常感謝您回答我們的問題。僅從您在肥胖週上展示的臨床前 DIO 小鼠數據來看，您認為巨噬細胞的減少僅僅是由於脂肪細胞體積減少所致嗎？或者您認為還有其他抗發炎機制？

Yes, I'll let Erik add, but it's not just reduction in that its shift to macrophage phenotype from an anti-inflammatory phenotype to anti-inflammatory. But Erik, I don't know if you want to add anything.

是的，我會讓艾瑞克補充，但這不僅僅是減少，而是巨噬細胞表型從抗發炎表型轉變為抗發炎表型。但是艾瑞克，我不知道你是否還有什麼要補充的。

Yes. I mean exactly. So, it's a shift from less pro-inflammatory to more larger proportion anti-inflammatory, as Paul said. We also do see with the RNA-Seq data that we also see supportive evidence of that as well. There is less inflammatory -- inflammation in both the subcutaneous and visual fat.

是的。沒錯。所以，正如保羅所說，這是從較少促發炎成分轉變為較大比例抗發炎成分的過程。我們從 RNA-Seq 數據也看到了支持這一觀點的證據。發炎減輕－皮下脂肪和皮下脂肪的發炎均減輕。

So, I think something is going on. It is probably partly driven by adipocyte size, but there could be additional mechanisms that are all related to the lipolysis.

所以，我覺得一定有什麼事發生了。這可能部分是由脂肪細胞大小驅動的，但也可能存在其他與脂肪分解相關的機制。

And just a quick follow-up on DMD. Do you have any sense of the FDA's opinion on muscle content adjusted dystrophin versus unadjusted?

最後再簡單跟進DMD的情況。您了解美國食品藥物管理局 (FDA) 對肌肉含量調整後的肌肉營養不良蛋白與未調整的肌肉營養不良蛋白的看法嗎？

I think all of the conversations to date across a number of programs have been really exciting. I do think as we look at the new programs that have come in, looking at actually the production of dystrophin in muscle is important, realizing the high propensity for fat and making sure to look at that. So, there's been nothing from our standpoint that seems to change the agency's opinion on that.

我認為迄今為止，各個節目中的所有對話都非常精彩。我認為，當我們審視新推出的方案時，關注肌肉中肌肉營養不良蛋白的產生非常重要，要意識到脂肪的高易感性，並確保關注這一點。所以，從我們的角度來看，似乎沒有任何跡象表明該機構對此事的看法會改變。

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Barno for closing remarks.

謝謝。目前沒有其他問題了。現在我將把電話轉回給保羅·巴諾，請他作總結發言。

Thank you for joining our call this morning, and we appreciate your continued support. Have a great day.

感謝您今天早上參加我們的電話會議，我們非常感謝您一直以來的支持。祝你有美好的一天。