Wave Life Sciences, Inc. (WVE) 2026 Q1 法說會逐字稿

Hello and welcome to WAVE Life Sciences' first-quarter 2026 earnings call.

大家好，歡迎參加 WAVE Life Sciences 2026 年第一季財報電話會議。

(Operator Instructions) Also, as a reminder, this conference call is being recorded today.

(接線員指示) 另外提醒各位，本次電話會議將於今日錄音。

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

現在我將把電話交給企業事務與投資人關係副總裁 Kate Rausch。

Thank you, operator. Good morning to everyone on the call.

謝謝，接線員。各位與會者早安。

Earlier this morning, we issued a press release outlining our first-quarter 2026 earnings update.

今天稍早，我們發布新聞稿，說明 2026 年第一季財務業績更新。

Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Erik Ingelsson, Chief Scientific Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer.

今天與我一同發表準備講稿的還有：總裁暨執行長 Paul Bolno 博士；科學長 Erik Ingelsson 博士；醫務長 Chris Wright 博士；以及財務長 Kyle Moran。

The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

今天早上發布的新聞稿可於我們網站 www.wavelifesciences.com 的「投資人」專區查閱。

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.

在開始之前，我想提醒各位，本次電話會議的討論將包含前瞻性陳述。這些陳述受到多項風險與不確定性影響，可能導致我們的實際結果與前瞻性陳述所描述者有重大差異。

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

可能導致實際結果不同的因素，已在今日發布的新聞稿及我們向美國證券交易委員會（SEC）提交的文件中討論。我們不承擔因任何原因更新或修訂任何前瞻性陳述的義務。

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

現在我想把電話交給 Paul。

Thanks, Kate. Good morning to everyone joining us on today's call.

謝謝，Kate。各位今天加入電話會議的朋友早安。

Coming into the year, we outlined our key priorities for 2026: accelerating development of WVE-007, our INHBE GalNAc-siRNA program for obesity, and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD and followed by WVE-008 for PNPLA3 liver disease.

在今年年初，我們闡述了 2026 年的關鍵優先事項：加速推進 WVE-007（我們針對肥胖的 INHBE GalNAc-siRNA 計畫）的開發，並快速推進由 WVE-006（用於 AATD）領軍、以及後續 WVE-008（用於 PNPLA3 肝病）的 RNA 編輯產品組合。

Today, I'm pleased to share an update on the significant progress we've made towards these goals. We are rapidly advancing 007, which has the potential to be transformational in the treatment of cardiometabolic diseases, including obesity.

今天，我很高興分享我們朝這些目標所取得的重大進展更新。我們正快速推進 007；它有潛力在包含肥胖在內的心臟代謝疾病治療上帶來變革。

Using our best-in-class chemistry, 007 continues to demonstrate a highly differentiated profile. Clinical data, even in a Phase I population, continues to demonstrate improvement in body composition, with fat loss -- importantly, visceral fat loss -- and muscle preservation, impressive durability with potential for once- or twice-a-year dosing and a clean safety profile.

憑藉我們同級最佳的化學技術，007 持續展現高度差異化的特性。臨床數據即使是在第一期受試者族群中，也持續顯示身體組成改善，包括脂肪減少——更重要的是內臟脂肪減少——以及肌肉保留；並具備令人印象深刻的持久性，可能達到每年一次或兩次給藥，以及乾淨的安全性概況。

We're accelerating 007 to the next stages of development, where we have the opportunity to unlock its full potential across multiple treatment settings, beginning with our Phase 2a trial in participants with higher BMI; and with and without diabetes. We are preparing to initiate our Phase 2a trial this quarter, as the FDA has recently accepted the multi-dose portion of INLIGHT.

我們正加速推進 007 進入下一階段開發，在那裡我們有機會於多種治療情境中釋放其全部潛力；首先從我們在 BMI 較高受試者中的第 2a 期試驗開始，並涵蓋有糖尿病與無糖尿病族群。我們正準備於本季啟動第 2a 期試驗，因為 FDA 近期已接受 INLIGHT 的多劑量部分。

Closely following the initiation of our Phase 2a trial in higher-BMI participants, we plan to initiate studies evaluating 007 in combination with incretins and maintenance, post-cessation of incretin treatment.

在針對較高 BMI 受試者的第 2a 期試驗啟動後不久，我們計畫啟動研究，評估 007 與腸泌素（incretins）合併使用，以及在停止腸泌素治療後的維持治療。

In RNA editing, we continue to lead the field with 006. Clinical data from our ongoing RestorAATion-2 trial has already demonstrated the potential for 006 to provide a much-needed novel therapeutic option to individuals living with AATD, including generating over 20 micromolar of AAT protein during an acute phase response.

在 RNA 編輯方面，我們持續以 006 領先該領域。我們正在進行的 RestorAATion-2 試驗之臨床數據，已顯示 006 有潛力為 AATD 患者提供迫切需要的新型治療選項，包括在急性期反應期間產生超過 20 微莫耳的 AAT 蛋白。

It's important to note that these acute phase responses are the drivers of lung damage in AATD. We look forward to highlighting these data during the ATS conference and hosting an investor webcast to share our monthly 400-milligram multiple dose, as well as single-dose 600-milligram data.

需要強調的是，這些急性期反應正是 AATD 肺部損傷的驅動因素。我們期待在 ATS 會議期間重點呈現這些數據，並舉辦投資人網路直播，分享我們每月 400 毫克多劑量數據，以及單次 600 毫克劑量數據。

Having already achieved therapeutically relevant AAT restoration with our interim data, we are on track to receive regulatory feedback on a potential accelerated approval pathway in mid-2026.

在我們的期中數據已達成具治療意義的 AAT 恢復之後，我們正按計畫於 2026 年年中取得監管機關對潛在加速核准途徑的回饋。

We're also building on our success in RNA editing to advance our next candidate, WVE-008, towards the clinic this year, which has the potential to address the 9 million individuals living with PNPLA3 liver disease.

我們也在 RNA 編輯的成功基礎上，推進下一個候選藥物 WVE-008 於今年邁向臨床，該藥物有潛力服務約 900 萬名 PNPLA3 肝病患者。

Beyond our lead RNAi and RNA-editing programs, we are continuing to push the boundaries of innovation through our bifunctional modality that allows us to both silence and/or edit to treat diseases with a single construct in a single dose.

除了我們領先的 RNAi 與 RNA 編輯計畫之外，我們也透過雙功能（bifunctional）治療模式持續突破創新邊界；該模式使我們能以單一構築體、單次給藥，同時達成沉默（silence）與／或編輯（edit）以治療疾病。

We're also advancing a growing pipeline of new hepatic and extra-hepatic candidates. With the substantial progress we've made, we believe we are well-positioned and well-capitalized to advance our pipeline of transformational therapies for patients.

我們也在推進一個持續擴增的肝臟與肝外新候選藥物管線。憑藉我們已取得的重大進展，我們相信公司已具備良好定位且資本充足，可推進我們的變革性療法管線以造福病患。

Now, I'd like to turn the call over to Erik, who will discuss how we are leveraging our proprietary chemistry and human genetic insights to advance WVE-006 for AATD and WVE-007 for obesity. Erik?

接下來，我想把電話交給 Erik，他將說明我們如何運用專有化學技術與人類遺傳學洞見，推進用於 AATD 的 WVE-006 與用於肥胖的 WVE-007。Erik？

Thank you, Paul. Thank you to everyone joining us on the call today.

謝謝你，Paul。也謝謝今天加入電話會議的各位。

I'll start with WVE-006, our gamma RNA-editing oligonucleotide or AIMer for alpha-1 antitrypsin deficiency. AATD is a uniquely compelling disease for RNA editing. It's a monogenic disorder caused by a single well-characterized genetic variant in the SERPINA1 gene, which leads to misfolded alpha-1 antitrypsin, or AAT, protein turned Z-AAT.

我先從 WVE-006 開始介紹，這是我們用於 α-1 抗胰蛋白酶缺乏症的 γ RNA 編輯寡核苷酸（oligonucleotide），或稱 AIMer。AATD 是一個特別適合 RNA 編輯的疾病。它是一種單基因疾病，由 SERPINA1 基因中單一且已充分特徵化的遺傳變異所致，導致 α-1 抗胰蛋白酶（AAT）蛋白錯誤摺疊，形成所謂的 Z-AAT。

Healthy circulating AAT, termed M-AAT, protects the lungs during inflammatory or infectious events. AATD is sometimes referred to as genetic COPD for a reason. Without dynamic production of functional AAT, patients are at risk of lung damage and ultimately developing emphysema and bronchiectasis, which is characterized by chronic cough, recurrent infections, and shortness of breath.

健康循環中的 AAT（稱為 M-AAT）可在發炎或感染事件期間保護肺部。AATD 有時被稱為遺傳性 COPD，是有其原因的。若無法動態產生具功能性的 AAT，患者將面臨肺部損傷風險，最終可能發展為肺氣腫與支氣管擴張症，其特徵為慢性咳嗽、反覆感染與呼吸急促。

In parallel, Z-AAT accumulates in hepatocytes and causes progressive liver injury and risk of liver disease. By correcting the mutant transcript in the liver, RNA editing addresses the root cause of both the lung and liver manifestations of the disease.

同時，Z-AAT 會在肝細胞中累積，造成進行性肝損傷並增加肝病風險。透過在肝臟中校正突變轉錄本，RNA 編輯可針對疾病的根本原因，同時處理肺部與肝臟的臨床表現。

Approximately 200,000 individuals in the US and Europe live with homozygous PiZZ AATD. It's a devastating disease, impacting the ability of patients to work, play with their children, or even walk to the mailbox.

在美國與歐洲，約有 20 萬名個體罹患同型合子 PiZZ AATD。這是一種毀滅性的疾病，影響患者工作、陪孩子玩耍，甚至走到信箱的能力。

Currently, the only approved treatment for AATD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there is no restoration of dynamic response, leaving patients at risk, if AAT protein fall too low during an acute phase reaction, as a result of infectious or inflammatory events.

目前，AATD 唯一獲核准的治療是每週一次的靜脈注射（IV）血漿來源增補療法，但存在多項限制。由於採固定排程劑量，無法恢復動態反應；當感染或發炎事件引發急性期反應時，若 AAT 蛋白降得過低，患者仍將面臨風險。

IV therapy is time-consuming and often requires in-patient visits. IV therapy does nothing to lower Z-AAT to address development of liver disease in these patients.

靜脈注射治療耗時，且往往需要到院就診。此外，靜脈注射治療無法降低 Z-AAT，因此無法處理這些患者肝病發展的問題。

RNA editing is designed to restore heterozygous M-AAT-like phenotype, including AAT production, that rises to meet the demand during acute phase responses.

RNA 編輯的設計目標是恢復類似雜合子 M-AAT 的表型，包括 AAT 產生量可在急性期反應期間上升，以滿足需求。

This is a particularly important distinction between RNA editing and the current augmentation standard of care that we continue to hear echoed in our conversations with physicians and patients, as there is uncertainty that there is adequate lung protection, when patients experience infections between infusions.

這是 RNA 編輯與目前增補療法標準照護之間一項特別重要的差異；我們在與醫師與患者的對話中也持續聽到同樣的回饋，因為當患者在兩次輸注之間發生感染時，是否能獲得足夠的肺部保護仍存在不確定性。

Such acute exacerbations, the sudden worsening of a patient's respiratory symptoms that often require urgent treatment, occurs roughly twice per year on average, even on weekly augmentation therapy.

此類急性惡化——亦即患者呼吸道症狀突然加劇、往往需要緊急治療——平均每年約發生兩次，即使在每週接受增強治療的情況下亦然。

006 is a highly specific and efficient GalNAc ADAR. Unlike DNA-editing therapies in development, RNA editing does not modify DNA. 006 does not require delivery with lipid nanoparticles or LNPs that may be associated with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response.

006 是一種高度特異且高效率的 GalNAc ADAR。不同於正在開發中的 DNA 編輯療法，RNA 編輯不會改變 DNA。006 不需要以脂質奈米粒（lipid nanoparticles，LNPs）遞送；LNPs 可能與全身性及肝臟發炎相關，並可能誘發肝細胞壓力與啟動肝臟急性期反應。

006 also avoids the irreversible collateral bystander edits and indels which are associated with DNA editing.

006 亦可避免與 DNA 編輯相關、不可逆的旁觀者（bystander）非目標編輯以及插入/缺失（indels）。

With 006, our goal is to recapitulate the MZ-like phenotype, as it's well established that heterozygous PiMZ individuals have significantly lower risk of both lung and liver disease. MZ individuals maintain basal AAT levels above the protective threshold of 11 micromolar; while type M-AAT, above 50% of total AAT; and, most importantly, they retain the ability to mount a dynamic AAT response during an acute infection.

透過 006，我們的目標是重現類 MZ 的表型，因為異型合子 PiMZ 個體的肺部與肝臟疾病風險顯著較低，這點已被充分證實。MZ 個體可將基礎 AAT 水準維持在 11 微莫耳的保護性閾值之上；同時，M 型 AAT 佔總 AAT 的 50% 以上；而且最重要的是，他們仍保有在急性感染期間啟動動態 AAT 反應的能力。

That combination -- protected basal levels, a meaningful proportion of authentic M-AAT, and a preserved acute phase response -- is the bar we set for 006 and that we cleared in the interim read-out of our RestorAATion-2 trial in the fall.

這樣的組合——受保護的基礎水準、具意義比例的真實 M-AAT，以及保留的急性期反應——就是我們為 006 設定的門檻，而我們在秋季 RestorAATion-2 試驗的期中讀出中已達成該門檻。

We demonstrated that 200-milligram bi-weekly dosing of 006 can restore endogenous M-AAT protein to therapeutically meaningful levels and reduce mutant Z-AAT, correspondingly. This will lead to improved liver health and potentially even higher M-AAT production, over time, in line with what we have observed pre-clinically and, ultimately, lead to improved lung and liver outcomes in AAT.

我們證明，每兩週一次 200 毫克劑量的 006 可將內源性 M-AAT 蛋白恢復至具治療意義的水準，並相應降低突變型 Z-AAT。這將改善肝臟健康，並且隨時間推移，可能帶來更高的 M-AAT 產量，與我們在臨床前觀察一致；最終可改善 AAT 相關的肺部與肝臟結局。

Crucially, we have shown that 006 re-establishes the body's physiological response to inflammatory stress, something that is not possible with IV augmentation. Now, with upcoming data from our 400-milligram multi-dose cohort, we look to continue to recapitulate the MZ-like phenotype but at a more convenient monthly dosing interval.

關鍵的是，我們已顯示 006 能重新建立身體對發炎壓力的生理性反應，這是靜脈注射（IV）增強治療無法做到的。接下來，隨著 400 毫克多次給藥隊列的數據即將出爐，我們希望在更便利的每月給藥間隔下，持續重現類 MZ 的表型。

Moving on to our INHBE GalNAc-siRNA program for obesity, WVE-007, individuals living with obesity face markedly higher risk of a range of diseases such as MASH, type 2 diabetes, and cardiovascular disease. Excess body fat -- in particular, visceral fat -- is a key driver behind this elevated risk of disease.

接著談我們用於肥胖的 INHBE GalNAc-siRNA 計畫 WVE-007：肥胖族群面臨多種疾病（如 MASH、第二型糖尿病與心血管疾病）顯著更高的風險。過多體脂——尤其是內臟脂肪——是造成此疾病風險升高的關鍵驅動因素。

Current standard-of-care therapies reduce body weight through both fat and muscle loss; and carry high discontinuation rates, limiting potential for long-term health benefits. An ideal obesity therapy would, instead, selectively reduce harmful visceral fat -- the fat surrounding one's organ that is most strongly linked to MASH, type 2 diabetes, and cardiovascular disease --while also lowering subcutaneous fat and liver steatosis; and critically preserving skeletal muscle.

目前的標準治療會透過脂肪與肌肉同時流失來降低體重；且停藥率高，限制了長期健康效益的潛力。理想的肥胖療法應改為選擇性降低有害的內臟脂肪——也就是包覆器官、與 MASH、第二型糖尿病及心血管疾病關聯最強的脂肪——同時降低皮下脂肪與肝臟脂肪變性；並且關鍵地保留骨骼肌。

Muscle preservation matters. Why? Because muscle sustains basal metabolic rate, glucose disposal, and insulin sensitivity. Also, it prevents weight regain; mostly, from fat, which occurs in a majority of individuals that discontinue incretin therapies.

保留肌肉很重要。為什麼？因為肌肉維持基礎代謝率、葡萄糖清除與胰島素敏感性。此外，它也能防止體重反彈；而在停止腸泌素（incretin）療法的大多數人身上，反彈主要來自脂肪。

Remember, as much as up to 70% of individuals discontinue incretins within a year.

請記得，多達 70% 的人會在一年內停止使用腸泌素類藥物。

Preserving muscle while decreasing total, and, in particular, visceral fat, is the ideal profile for an obesity medicine. It's well established that, already, a 5% to 10% reduction in visceral fat mass associated with direct health outcomes are reducing risk of multiple preventable metabolic diseases and preserving patient function and quality of life.

在降低總脂肪、尤其是內臟脂肪的同時保留肌肉，是肥胖藥物的理想特徵。眾所周知，即使僅將內臟脂肪量降低 5% 至 10%，也與直接健康結局相關：可降低多種可預防代謝性疾病的風險，並維持患者功能與生活品質。

All these benefits can be delivered by 007's mechanism of action. Rather than acting on appetite, it silences inhibin E and lowers serum Activin E, a liver-derived hepatokine that signals adipocytes to put the brakes on lipolysis.

上述所有效益都可由 007 的作用機制帶來。它不是透過影響食慾，而是沉默 inhibin E 並降低血清 Activin E；Activin E 是肝臟來源的肝激素（hepatokine），會向脂肪細胞發出訊號，讓脂解（lipolysis）踩煞車。

Removing those brakes drives fat loss without calorie restriction and without the muscle loss seen with incretin-based therapies.

解除這些煞車可在不限制熱量攝取的情況下驅動脂肪流失，且不會出現腸泌素類療法所見的肌肉流失。

This approach is also strongly grounded in human genetics, as carriers of heterozygous inhibin E's loss-of-function variants, nature's own knock-down experiment, exhibit a healthier overall metabolic profile, driven by lower visceral fat, as evidenced by lower waist-to-hip ratio and lower visceral adipose volume, as well as downstream effects with lower triglycerides, ApoB, and HbA1c, and higher HDL cholesterol.

此方法亦有強而有力的人類遺傳學基礎：帶有 inhibin E 失功能（loss-of-function）變異之異型合子攜帶者——也就是大自然自身的「敲低」實驗——呈現更健康的整體代謝特徵，其驅動因素為較低的內臟脂肪；證據包括較低的腰臀比與較低的內臟脂肪體積，以及下游效應如較低的三酸甘油酯、ApoB 與 HbA1c，並有較高的 HDL 膽固醇。

These carriers also have favorable associations with liver traits, such as ALT, a measure of liver damage; and cT1, a measure of liver inflammation and fibrosis; and, importantly, lower risk of developing type 2 diabetes and coronary heart disease.

這些攜帶者在肝臟相關性狀上也呈現有利關聯，例如 ALT（肝損傷指標）較佳；cT1（肝臟發炎與纖維化指標）較佳；且重要的是，罹患第二型糖尿病與冠狀動脈心臟病的風險更低。

As we've said on prior calls, targets supported by human genetics carry a 2 times to 4 times higher probability of success in drug development. Inbibin E is a textbook example of this opportunity.

如同我們在先前電話會議中所說，具有人類遺傳學支持的標的，在藥物開發中的成功機率高出 2 至 4 倍。Inbibin E 是此機會的教科書式例子。

We chose to target the Activin E ligand through inhibin E, silencing over its receptor, ALK7, for, several reasons. Turning off protein production in hepatocytes, the upstream source with a GaINAc-siRNA is the most efficient and durable way to impact this pathway.

我們選擇透過 inhibin E 來鎖定 Activin E 配體，而非鎖定其受體 ALK7，原因有數點。使用 GalNAc-siRNA 在肝細胞中關閉蛋白質生成（作為上游來源），是影響此路徑最有效且最持久的方法。

Also, suppressing Activin E, rather than disabling a receptor that induces signals via multiple ligands across different tissues, is a more selective approach, with lower risk of unintended consequences. This selectivity is especially important for long-term safety and for clinical translation.

此外，抑制 Activin E，而非使一個可在不同組織中透過多種配體傳遞訊號的受體失能，是更具選擇性的策略，且非預期後果的風險更低。此選擇性對長期安全性與臨床轉譯尤其重要。

007's unique ability to durably suppress inhibin E is driven by our proprietary chemistry and SpiNA siRNA design.

007 能夠持久抑制 inhibin E 的獨特能力，來自我們的專有化學與 SpiNA siRNA 設計。

While RNAi is a well-established therapeutic modality and there are extensive human genetic data supporting inhibin E as a target, we believe our proprietary chemistry distinguishes us from others attempting a similar approach.

雖然 RNAi 是成熟的治療模式，且有大量人類遺傳學資料支持 inhibin E 作為標的，我們相信我們的專有化學使我們有別於其他嘗試類似方法的團隊。

007 is highly differentiated by Wave's proprietary SpiNA design, including backbone stereochemistry and PN chemistry, which enhances interactions with Ago2, stabilizes the loaded RISC complex, and improves liver exposure. This contributes to dramatically improved potency and durability, when compared with industry-standard siRNA science.

007 透過 Wave 的專有 SpiNA 設計（包括骨架立體化學與 PN 化學）而具高度差異化；該設計可增強與 Ago2 的交互作用、穩定已載入的 RISC 複合體，並改善肝臟暴露。與業界標準 siRNA 技術相比，這帶來顯著提升的效力與持久性。

Our interim Phase 1 INLIGHT data sets from lower BMI -- otherwise, healthy individuals -- confirm that this proprietary chemistry and the underlying human genetics are already translating, with preservation of lean mass and clinically meaningful reductions in total fat, visceral fat, and waist circumference, after just a single dose.

我們在較低 BMI、其他方面健康的受試者中取得的 INLIGHT 第 1 期期中數據，證實此專有化學與其背後的人類遺傳學已開始轉化為臨床效果：僅一次給藥後，即可保留瘦體重，並在總脂肪、內臟脂肪與腰圍方面達到具臨床意義的下降。

As Chris will discuss further in a moment, we're rapidly advancing 007 into patients with higher BMI and comorbidities in the Phase 2a portion of INLIGHT, where a scientific rationale predicts a larger effect.

如同 Chris 稍後將進一步說明，我們正快速推進 007 進入 INLIGHT 第 2a 期部分，納入 BMI 較高且有共病的患者；在此族群中，科學理據預期效果會更大。

Activin E binds ALK7 on all adipocytes. Visceral fat, being the more metabolically active and better perfused, mobilizes first, exactly what we have observed in Phase 1.

Activin E 會與所有脂肪細胞上的 ALK7 結合。內臟脂肪因代謝更活躍且灌流更佳，會優先被動員，這正是我們在第 1 期所觀察到的。

Together, this means that we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher-BMI participants with more excess fat to lose.

綜合而言，這表示我們預期 007 所帶來的內臟脂肪與總脂肪流失，在 BMI 較高、可減脂肪量更多的參與者中將更為明顯。

To review our clinical progress with 007 and our RNA-editing programs in further detail, I'd now like to turn the call over to Chris.

為了更深入回顧 007 以及我們 RNA 編輯計畫的臨床進展，我現在想把電話會議交給 Chris。

Thanks, Erik.

謝謝你，Erik。

I'll begin by discussing our recent data and plans to accelerate development of WVE-007.

我將先談我們近期的數據，以及加速推進 WVE-007 開發的計畫。

In March, we shared interim data from the Phase 1 portion of our ongoing INLIGHT clinical program, a placebo-controlled, single-ascending dose study designed to measure safety, tolerability, and PK/PD.

在3月，我們分享了正在進行中的 INLIGHT 臨床計畫第一期（Phase 1）部分的期中數據；該研究為安慰劑對照、單次遞增劑量（SAD）試驗，旨在評估安全性、耐受性以及 PK/PD。

Participants were healthy individuals living with overweight or class 1 obesity, with an average BMI of 32, a population with less fat and lower BMI than those included in Phase 2 and Phase 3 obesity studies.

受試者為健康的過重或第一級肥胖者，平均 BMI 為 32；相較於第二期與第三期肥胖研究納入的族群，該族群脂肪量較少、BMI 較低。

The safety and tolerability profile of WVE-007 remains encouraging. We continued to observe robust, highly statistically significant, dose-dependent, and durable Activin E reductions through at least seven months.

WVE-007 的安全性與耐受性概況仍令人鼓舞。我們持續觀察到 Activin E 下降幅度強勁、具高度統計顯著性、呈劑量依賴性且具持久性，並至少可維持至七個月。

This combination of tolerability and durability supports a convenient dosing interval of once or twice a year that may allow for enhanced patient adherence, more persistent fat loss, and better health outcomes.

此一耐受性與持久性的組合，支持每年一次或兩次的便利給藥間隔，可能有助於提升病患依從性、帶來更持續的減脂效果，並改善健康結局。

Having reached six months of follow-up in our 240-milligram cohort, we observed further improvements in body composition, following a single subcutaneous dose. This included placebo-adjusted visceral fat reductions of 14.3%, well above the established threshold, to deliver improved cardiovascular outcomes.

在 240 毫克劑量組完成六個月追蹤後，我們在單次皮下注射後觀察到身體組成的進一步改善。其中包括經安慰劑校正後的內臟脂肪下降 14.3%，明顯高於既定門檻，可望帶來更佳的心血管結局。

Total fat reductions were 5.3%. Lean mass was stable.

總脂肪下降 5.3%。瘦體重維持穩定。

There were also improvements across clinical measures, including a clinically meaningful 3.3% reduction in waist circumference. These results are particularly encouraging, given this is a Phase 1 study of, otherwise, healthy participants with an average BMI of 32 and no dietary or exercise restrictions.

多項臨床指標亦有所改善，包括腰圍具臨床意義地下降 3.3%。鑑於這是一項第一期研究，受試者除平均 BMI 為 32 外皆屬健康，且未限制飲食或運動，這些結果尤其令人振奮。

As Erik just spoke to, reducing fat -- particularly, harmful visceral fat -- while also preserving muscle is critically important for the treatment of obesity, including overall functional improvement and cardiometabolic health benefits.

正如 Erik 剛才所提，減少脂肪——尤其是有害的內臟脂肪——同時保留肌肉，對於肥胖治療至關重要，包含整體功能改善與心代謝健康效益。

The current standard of care pushes the limits on high-percentage weight reductions. But it comes at a cost of substantial muscle loss.

目前的標準治療在高比例體重下降方面已逼近極限。但其代價是顯著的肌肉流失。

To provide context for our results at this early development stage, we calculated the visceral fat-to-muscle ratio, or VMR, which is a measure of body composition that integrates harmful visceral fat and beneficial lean mass into a single index.

為了在此早期開發階段提供結果的背景脈絡，我們計算了內臟脂肪對肌肉比（visceral fat-to-muscle ratio, VMR）。VMR 是一項身體組成指標，將有害的內臟脂肪與有益的瘦體重整合為單一指數。

Lower VMR is associated with decreased risk of MASH, type 2 diabetes, and cardiometabolic disorders. We believe VMR has the potential to serve as a novel composite biomarker, as compared to BMI alone, that more holistically captures the body composition improvements driven by inhibin E knockdown and that may better predict long-term clinical benefits.

較低的 VMR 與 MASH、第二型糖尿病及心代謝疾病風險降低相關。我們相信，相較於僅使用 BMI，VMR 有潛力作為一項新的複合生物標誌物，更全面反映由 inhibin E 敲低所驅動的身體組成改善，並可能更能預測長期臨床效益。

With a single dose of 007 in our Phase 1 population, we've already observed a 16.5% improvement or greater reduction in VMR, which was more than the 12.2% achieved with weekly semaglutide in BELIEVE and approached the 18.8%, observed with bimagrumab.

在我們第一期族群中，單次給予 007 後，我們已觀察到 VMR 改善 16.5%（或更高的下降幅度）；此結果高於 BELIEVE 研究中每週使用司美格魯肽（semaglutide）所達到的 12.2%，並接近 bimagrumab 觀察到的 18.8%。

What makes this comparison particularly exciting is that our INLIGHT participants had substantially lower BMI, visceral fat, and total fat compared to Phase 2 or Phase 3 obesity studies.

此比較之所以特別令人興奮，是因為我們的 INLIGHT 受試者相較於第二期或第三期肥胖研究，BMI、內臟脂肪與總脂肪皆顯著較低。

Clinical experience highlights the importance of baseline adiposity. Early Phase 1 studies in leaner subjects show modest fat reductions, while studies of individuals with higher baseline obesity demonstrate large, clinically meaningful losses in total and visceral fat mass.

臨床經驗凸顯基線脂肪量的重要性。在較瘦受試者的早期第一期研究中，脂肪下降幅度通常較溫和；而在基線肥胖程度較高的個體研究中，則可見總脂肪與內臟脂肪量出現大幅且具臨床意義的下降。

Early follow-up from our 400-milligram cohort, which included a substantially higher proportion of individuals with lower levels of visceral fat, also confirmed that higher baseline visceral fat leads to greater visceral fat reductions, overall.

我們 400 毫克劑量組的早期追蹤（其中包含相當高比例內臟脂肪較低的個體）亦證實：基線內臟脂肪越高，整體而言內臟脂肪下降幅度越大。

Collectively, these data emphasize the impact of baseline body composition on therapeutic effect and support the potential to deliver even more pronounced improvements in body composition than the phase 2a portion of INLIGHT, given participants' higher excess fat at baseline and 007's mechanism of targeted lipolysis.

綜合而言，這些數據強調基線身體組成對治療效果的影響，並支持在 INLIGHT 的第二期 a（phase 2a）部分中，鑑於受試者基線超額脂肪較高，以及 007 具靶向脂解機制，可能帶來比目前更顯著的身體組成改善。

Following the FDA's recent acceptance of our protocol amendment, we remain on track to initiate the phase 2a multiple dose portion of INLIGHT this quarter. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across two dose levels, 240 milligrams and 400 milligrams; and two study populations, with and without type 2 diabetes, for a total of four cohorts of 40 patients each.

在 FDA 近期接受我們的試驗方案修訂後，我們仍按計畫於本季啟動 INLIGHT 的第二期 a 多次給藥部分。這項全球性安慰劑對照試驗將納入 BMI 較高（35 至 50）且合併共病的受試者，涵蓋兩個劑量層級（240 毫克與 400 毫克）以及兩個研究族群（有與無第二型糖尿病），共四個隊列，每隊列 40 名病患。

Assessments in this multi-dose portion are similar to those in the SAD portion, with additional inclusion of body composition measures by MRI, liver fat content measured by MRI-PDFF, HbA1c, lipid levels, CRP, and muscle function.

此多次給藥部分的評估與 SAD 部分相似，並額外納入以 MRI 量測的身體組成、以 MRI-PDFF 量測的肝脂含量、HbA1c、血脂數值、CRP，以及肌肉功能。

The design and study population enables enhanced evaluation not only of improved body composition and weight loss but also informs additional opportunities for 007 in MASH, type 2 diabetes, and cardiovascular disease.

此試驗設計與研究族群不僅可加強評估身體組成改善與體重下降，也可為 007 在 MASH、第二型糖尿病與心血管疾病方面的其他機會提供資訊。

Participants will be given two doses of 007 at day 1 and day 85; and followed for 12 months, with the first main assessment occurring at day 85.

受試者將於第 1 天與第 85 天接受兩次 007 給藥；並追蹤 12 個月，首次主要評估點為第 85 天。

As Paul discussed earlier, we are also planning to initiate trials evaluating 007 in combination with incretins and as maintenance, post-incretins, this year. We believe that 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle, and favorable safety profile are aptly suited to combination and maintenance approaches.

如 Paul 先前所述，我們也計畫於今年啟動試驗，評估 007 與腸泌素（incretins）合併使用，以及在腸泌素治療後作為維持治療的應用。我們相信，007 的正交作用機制、在保留肌肉的同時降低脂肪的能力，以及良好的安全性概況，非常適合用於合併與維持策略。

Our pre-clinical data provides compelling support for both use cases. Planning is well underway for studies addressing incretin combination and post-incretin maintenance. These will initiate this year.

我們的臨床前數據為這兩種使用情境提供了有力支持。針對腸泌素合併與腸泌素後維持的研究規劃正在積極推進。這些研究將於今年啟動。

We also expect to share additional data from the Phase 1 portion of INLIGHT this year, including data from our 600-milligram cohort, which will further inform the durability of 007.

我們也預期於今年分享 INLIGHT 第一部分的更多數據，包括 600 毫克劑量組的數據，將進一步釐清 007 的持久性。

Turning to our ongoing RestorAATion-2 clinical trial of WVE-006 for AATD, we continue to advance this study, while engaging with key opinion leaders and patient organizations who are eager to be involved.

接著談到我們正在進行的 RestorAATion-2 臨床試驗：該試驗評估 WVE-006 用於 AATD。我們持續推進此研究，同時與關鍵意見領袖及病友組織互動，他們也熱切希望參與其中。

As we speak to key opinion leaders, there are several aspects of our data that excite them:

在與關鍵意見領袖交流時，我們的數據有幾個面向令他們感到振奮：

One, restoring a dynamic AAT response to address acute lung infections.

第一，恢復動態的 AAT 反應，以因應急性肺部感染。

Two, decreasing harmful Z-AAT to address liver disease.

第二，降低有害的 Z-AAT，以處理肝臟疾病。

Three, offering a safe, well-tolerated, infrequent non-intravenous treatment for patients that avoids permanent genetic modifications.

第三，為病患提供安全、耐受性良好、給藥頻率低且非靜脈注射的治療，同時避免永久性的基因改造。

We look forward to presenting an expanded dataset during ATS on May 18, which includes data from the 400-milligram monthly cohort, as well as the 600-milligram single-dose cohort.

我們期待於 5 月 18 日的 ATS 會議上發表擴增後的資料集，其中包含 400 毫克每月給藥隊列的數據，以及 600 毫克單次給藥隊列的數據。

Continuing to recapitulate our prior interim results with a less frequent dose would strengthen the overall profile of 006 as a differentiated patient-friendly therapy for AATD. In addition, we plan to share from the 600-milligram multi-dose cohort in the second half of this year.

若能以較低的給藥頻率持續重現先前的期中結果，將可強化 006 作為具差異化、以病患為中心之 AATD 治療的整體定位。此外，我們也計畫於今年下半年分享 600 毫克多次給藥隊列的數據。

Now, turning to our second RNA-editing clinical candidate, WVE-008, for homozygous PNPLA3 I148M liver disease, this PNPLA3 variant is a well-established driver of MASH pathology, yet there are no approved medicines that directly address this biology.

現在，轉向我們第二個 RNA 編輯臨床候選藥物 WVE-008，用於同型合子 PNPLA3 I148M 肝病。此 PNPLA3 變異已被充分證實是 MASH 病理的重要驅動因子，但目前尚無任何已核准藥物可直接針對此生物機制。

There are an estimated 9 million homozygous PNPLA3 I148M carriers across the US and Europe, who are at a ninefold higher risk of dying from their liver disease compared to non-carriers.

據估計，美國與歐洲約有 900 萬名同型合子 PNPLA3 I148M 帶因者；相較於非帶因者，他們因肝病死亡的風險高出 9 倍。

With 008, we aim to correct the I148M variant using our leading RNA-editing capability, which is expected to restore PNPLA3 activity and lipid metabolism, reversing steatosis and fibrosis and improving liver health.

透過 008，我們目標是運用領先的 RNA 編輯能力校正 I148M 變異，預期可恢復 PNPLA3 活性與脂質代謝，逆轉脂肪變性與纖維化，並改善肝臟健康。

In our upcoming first-in-human study of 008, we plan to leverage previously genotyped populations to efficiently identify homozygous I148M carriers, evaluate target engagement with circulating biomarkers, and assess early signs of efficacy using non-invasive imaging.

在我們即將展開的 008 首次人體試驗中，我們計畫運用既有的基因分型族群，以有效率地辨識 I148M 純合子攜帶者，透過循環生物標記評估標的結合（target engagement），並使用非侵入性影像評估早期療效訊號。

We remain on track for a CTA submission in 2026.

我們仍按計畫於 2026 年提交 CTA。

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

接下來，我把電話交給 Kyle，請他更新我們的財務狀況。Kyle？

Thanks, Chris.

謝謝你，Chris。

Our revenue for the first quarter of 2026 was $38.2 million compared to $9.2 million in prior-year quarter. The year-over-year increase primarily relates to recognizing the full amount of revenue associated with WVE-006 as a result of regaining full rights to that program, along with the progression of work in our ongoing GSK collaboration.

我們 2026 年第一季營收為 3,820 萬美元，較去年同期的 920 萬美元增加。年增主要與我們在重新取得 WVE-006 計畫完整權利後，認列與 WVE-006 相關的全部營收，以及我們與 GSK 持續合作中工作進展所帶動的認列有關。

Research and development expenses were $47.4 million in the first quarter of 2026, as compared to $40.6 million in the same period of 2025. The increase primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase 2a portion of INLIGHT and continued progress across our RNA-editing pipeline.

2026 年第一季研發費用為 4,740 萬美元，較 2025 年同期的 4,060 萬美元增加。增加主要反映我們持續投資推進臨床計畫，包括為 INLIGHT 的第 2a 期部分做準備，以及我們 RNA 編輯產品線的持續進展。

Our G&A expenses were $22.1 million in the first quarter of 2026, as compared to $18.4 million in the prior-year quarter. This increase primarily reflects costs associated with supporting our expanding pipeline and preparing for the next stages of development.

2026 年第一季一般及行政（G&A）費用為 2,210 萬美元，較去年同期的 1,840 萬美元增加。此增加主要反映為支援我們擴大的產品線並為下一階段開發做準備所產生的成本。

As a result, our net loss was $26.1 million for the first quarter of 2026, as compared to a net loss of $46.9 million in the prior-year quarter.

因此，我們 2026 年第一季淨損為 2,610 萬美元，較去年同期淨損 4,690 萬美元縮小。

We ended the first quarter with $544.6 million in cash and cash equivalents, which we expect will be sufficient to fund operations into the third quarter of 2028.

第一季期末我們持有現金及約當現金 5.446 億美元，我們預期足以支應營運至 2028 年第三季。

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

我現在把電話交回 Paul，請他做結語。

Thank you, Kyle.

謝謝你，Kyle。

As we look ahead, we believe we are well-positioned and well-capitalized to continue delivering on our clinical development plans.

展望未來，我們相信公司具備良好定位且資本充足，能持續落實我們的臨床開發計畫。

We are rapidly advancing multiple studies of 007 across treatment settings, which are strategically designed to unlock its full potential in obesity and other cardiometabolic diseases.

我們正快速推進 007 在不同治療情境下的多項研究，這些研究在策略上旨在釋放其在肥胖及其他心代謝疾病中的全部潛力。

We're delivering new 006 data in May that will continue to inform its potential to provide a differentiated treatment option to individuals living with AATD.

我們將於 5 月公布新的 006 數據，將持續協助評估其為 AATD 患者提供差異化治療選項的潛力。

We are progressing 008 towards the clinic for the 9 million individuals living with liver disease.

我們正推進 008 進入臨床，服務約 900 萬名肝病患者。

With our proprietary chemistry translating in the clinic and an emerging pipeline of next-generation candidates, we are committed to translating powerful human genetic insights into potentially transformational RNA medicines for people who need them.

憑藉我們專有化學技術在臨床上的轉譯成果，以及逐步成形的下一代候選產品線，我們致力於將強而有力的人類遺傳學洞見轉化為可能具變革性的 RNA 藥物，造福有需求的患者。

We look forward to keeping you updated on our progress.

我們期待持續向各位更新我們的進展。

With that, I will turn it over to the operator for Q&A. Operator?

接下來，我把電話交給接線員進行問答。接線員？

We will now move into our Q&A session.

我們現在進入問答環節。

Joe Schwartz, Leerink Partners.

Joe Schwartz，Leerink Partners。

Hi, team. Congrats on all the progress.

嗨，各位團隊成員。恭喜取得這麼多進展。

It seems like a treatment approach targeting inhibin E biology could be somewhat sensitive to baseline patient characteristics. I was wondering, how are you thinking about optimizing for that in future trial design? Are there any screening or enrichment strategies you could implement to enhance signal detection?

看起來，針對 inhibin E 生物學的治療策略可能對患者基線特徵有一定敏感性。我想請教，你們在未來試驗設計上打算如何最佳化這一點？是否有任何篩選或富集策略可以採用，以提升訊號偵測能力？

Yeah. Joe, we appreciate the question.

是的。Joe，我們很感謝這個問題。

I think, first and foremost, in any obesity study, as you point out, is -- particularly, as Chris mentioned on the study, a mechanism that's driven on lipolysis -- is excess fat; the requirement to have not just large BMI but have fat to lose in order to have a reduction in fat, which is typical in most Phase 1 to Phase 2 transitions.

我想，首先也是最重要的是，在任何肥胖研究中，如你所指出的——特別是如 Chris 在研究中提到的，這是一個由脂解（lipolysis）驅動的機制——關鍵在於脂肪過量；也就是必須不僅 BMI 高，還要有脂肪可減，才能看到脂肪下降，這在多數從第 1 期到第 2 期的轉換中都很典型。

If we look at the BELIEVE study, we actually have an update:

如果我們看 BELIEVE 研究，我們其實有一個更新：

Those who look at the 8-K today on the corporate deck, on slide 24, the realization that, as you shift patients from a low-BMI, low-fat setting to a higher-BMI, high-fat setting -- meaning, the shift that you see from where our study started, which is where the BELIEVE patients ended, to where the BELIEVE patients started, both on semaglutide and bimagrumab -- there's an elevation not just in visceral fat but, on the left panel of that slide, an increase in total fat.

今天若你查看 8-K 與公司簡報資料，在第 24 張投影片可以看到：當你把患者從低 BMI、低脂肪的情境轉移到較高 BMI、較高脂肪的情境——也就是你看到我們研究起始位置（BELIEVE 患者結束的位置）與 BELIEVE 患者起始位置之間的轉移，且兩組皆使用 semaglutide 與 bimagrumab——可以看到不僅內臟脂肪上升，而且在該投影片左側圖表中，總脂肪也增加。

And so, when we see those changes, we do expect, as you said, to see that reduction. Now, what can we do to actually assure that, as we enroll patients in that study, that the patients exhibit the phenotype; meaning, in an obese study are not just large in BMI but large in visceral fat and in total fat?

因此，當我們看到這些變化時，正如你所說，我們確實預期會看到脂肪下降。那麼，我們能做些什麼來確保在該研究收案時，患者呈現我們要的表型；也就是在肥胖研究中，患者不只是 BMI 大，還要內臟脂肪與總脂肪都高？

I think, there, we've seen pretty consistently that, if you use other metrics like waist circumference, allowing comorbidities, those patients do tend to fall into that range.

我想在這方面，我們相當一致地看到，如果使用其他指標，例如腰圍，並允許合併症納入，這些患者通常會落在那個範圍內。

One other opportunity we have to assure this, as the study's enrolling, is we are, as Chris mentioned, doing baseline MRI imaging on these patients, as we start. We will have the opportunity to look at baseline images to ensure that patients are collecting in that region.

另外一個可用來確保這點的機會是：如 Chris 所提到的，研究開始時我們會對這些患者做基線 MRI 影像檢查。我們將有機會檢視基線影像，以確保患者確實集中在那個區間。

Very helpful. Thanks for the insight.

非常有幫助。謝謝你的見解。

Thank you.

謝謝。

Steve Seedhouse, Cantor.

Steve Seedhouse，Cantor。

Great. Good morning. Thanks so much.

很好。早安。非常感謝。

Wanted to ask about the regulatory interactions in AATD and just get your thoughts on -- if the FDA -- or, really, just the discussions you've had; if the FDA is looking for specific M-AAT levels, if that's part of their thinking here or if, like, the degree of M-AAT increase that would support approval or accelerated approval is going to be more of a review issue.

我想問一下 AATD 的法規互動，並請你們分享看法——如果 FDA——或者更廣泛地說，就你們已進行的討論而言；FDA 是否在尋找特定的 M-AAT 水準，這是否是他們在此議題上的考量之一？或者說，支持核准或加速核准所需的 M-AAT 增幅程度，會更偏向審查時的判斷議題？

And then, I'm also curious if you know, yet, if the primary analysis in a pivotal study here is going to be more of like a responder analysis on a certain threshold or if it's more of like a mean change in M-AAT or total AAT in the entire population.

另外我也好奇，你們是否已經知道，在此的關鍵性試驗中，主要分析會比較像是針對某個門檻做反應者（responder）分析，還是更像是看整體族群的 M-AAT 或總 AAT 的平均變化？

Yeah. No. Thanks, Steven. I'll start and then turn, it over to Chris for further comments.

是的。不。謝謝你，Steven。我先回答，然後再請 Chris 補充更多評論。

I think, one, is, obviously, we don't comment on individual interactions. But we will have feedback, as we get to mid-year, so it's safe to assume we're preparing and engaging in those conversations.

我想第一點是，很明顯地，我們不會評論個別的互動細節。但我們會在年中取得回饋，因此可以合理推定我們正在準備並參與這些對話。

I think, in general, it's about the dynamic response, right? It is this shift from -- based, actually, on comments that the FDA has made, actually, publicly -- specifically, as it relates to AATD at patient meetings -- they did refer to AATD as an ideal example of the plausible mechanism pathway; meaning, there's the opportunity that we can see that editing translates these patients from a ZZ phenotype to an MZ phenotype.

我想整體而言，重點在於動態反應，對吧？這是從——其實是基於 FDA 曾公開發表的評論——特別是與 AATD 相關、在患者會議上提到的——他們確實把 AATD 稱為「可行機制途徑」的理想例子；也就是說，我們有機會看到編輯（editing）能把這些患者從 ZZ 表型轉換為 MZ 表型。

I think that, as we move past this just threshold concept of, what does it take to be an MZ patient, well, greater than 11. We need to step back and remember that, actually, the 11 micromolar, as people discuss that threshold level increasing, is one of protein replacement therapy; this idea with a consumptive protein that you need to put more in in order to have that, when it gets depleted during an acute event, be there.

我想，當我們不再只停留在「門檻」這個概念——也就是成為 MZ 患者需要什麼，例如大於 11——我們需要退一步記得，大家討論的 11 微莫耳（micromolar）門檻上升，其實是源自蛋白替代療法；也就是這種「會被消耗的蛋白」概念，你需要補進更多，才能在急性事件期間被耗竭時仍然存在。

I think the context of not just [WAVE] but, as we've seen, [BEAM], as well, seeing that, when you do edit, you see this restoring of this dynamic response and what is the ability of that dynamic response to actually protect patients, I think those are the best examples of the plausible mechanism; meaning, if you're at that greater-than-11 micromolar -- and over 50% of that being M protein -- then you're in the position that, when you have a proportionate CRP or inflammatory response, you can mount that proportionate response in both total protein and in M protein.

我認為脈絡不只是[WAVE]，而且如我們所見也包括[BEAM]；也就是說，當你進行編輯時，你會看到這種動態反應被恢復，而這種動態反應實際上保護病人的能力是什麼，我認為這些是最能說明合理機制的例子；意思是，如果你處在大於11微莫耳的水準——且其中超過50%為M蛋白——那麼當你出現相稱的CRP或發炎反應時，你就能在總蛋白與M蛋白兩方面都建立起相稱的反應。

That's exactly what we saw. We saw -- actually, if you model the CRP exposure that we saw, we saw an MZ-level response, both in total protein exceeding 20 micromolar and over 10 micromolar of M protein in that individual.

這正是我們所看到的。我們看到——實際上，如果你把我們看到的CRP暴露量做模型化，我們看到的是MZ等位型層級的反應，在該個體中，總蛋白超過20微莫耳，且M蛋白超過10微莫耳。

That dynamic response is what's required; being, demonstrating the total, both on threshold and percent M, we think is important. Those will be the nature of the conversations that we'll be having with the agency.

所需要的就是那種動態反應；也就是說，同時在門檻值與M百分比上證明總量，我們認為很重要。這些將會是我們與主管機關進行對話的內容。

I'm sorry. The last -- you asked a second question?

不好意思。最後——你問了第二個問題？

That was about, I think, responders versus (multiple speakers) --

那是關於，我想，是反應者相較於(多位講者)——

Yeah.

對。

-- and the like. I think those are exactly the types of questions that we'll be engaging with the FDA on -- behind the pivotal studies; more on that, as we have those discussions.

——等等。我認為這些正是我們會在關鍵性研究之後與FDA深入討論的問題——等我們完成那些討論後會再提供更多資訊。

Yeah. (multiple speakers) -- thank you.

對。（多位講者）——謝謝。

Yeah. It's important to note. Remember that these patients are coming in with zero M protein.

對。這點很重要。請記得，這些病人進來時M蛋白是零。

The idea that this is all de novo-functional from editing to mount those responses is crucial. I think the agency's been receptive.

這個概念——也就是這一切都是由編輯所帶來的全新（de novo）功能性，從而建立那些反應——至關重要。我認為主管機關一直很願意接受這個觀點。

Cheng Li, OppCo.

Cheng Li，OppCo。

Hi. Thanks for taking the questions. Congrats on the updates.

嗨。謝謝讓我提問。恭喜你們的最新進展。

I'm just curious about the 007, like, future clinical path, recognizing the body composition is an important feature for this mechanism. Also, you mentioned several measures, including BMR.

我只是好奇007未來的臨床路徑，考量到身體組成是這個機制的一個重要特徵。另外，你提到幾項衡量指標，包括BMR。

I'm just curious about which one you think can be incorporated into the clinical trial to support registration that you think has the best chance? Thank you so much.

我想請教，你認為哪一項最能納入臨床試驗以支持註冊、且成功機率最高？非常感謝。

I think, as Chris mentioned, we're going to have a number of endpoints in this study that independently help us build the cardiometabolic profile.

我認為，如Chris提到的，我們會在這項研究中設定多個終點，這些終點各自能幫助我們建立心代謝（cardiometabolic）特徵。

Obviously, we'll have body composition measures on DEXA, looking at total fat, visceral fat. We'll have MRI imaging, as well; and, importantly, MRI-PDFF to look at liver fat. I think that's going to be interesting, as these patients would be expected to have increases.

很明顯地，我們會用DEXA做身體組成測量，觀察總脂肪、內臟脂肪。我們也會做MRI影像；而且很重要的是，會用MRI-PDFF來看肝脂肪。我認為這會很有意思，因為預期這些病人的數值會上升。

In addition to that, as we think about just why, when you have -- I think about Phase 1 studies, where you exclude comorbidities of why you end up seeing this lower level of both total fat but, importantly, visceral fat (inaudible).

除此之外，當我們思考為什麼——我想到第一期研究，在那裡你會排除共病——為什麼最後會看到總脂肪較低，但更重要的是內臟脂肪也較低(聽不清楚)。

Viscreal fat is harmful fat. It's responsible for a number of these other cardiometabolic risk factors, including diabetes and cardiovascular disease.

內臟脂肪是有害脂肪。它與許多其他心代謝風險因子有關，包括糖尿病與心血管疾病。

One of the opportunities we have in removing the cardiometabolic -- sorry, the comorbidities, in addition to allowing patients with and without diabetes, is we're going to have the ability to see what's played out in human genetics with reduction in inhibin E, which is reductions in HbA1c.

我們在移除心代謝——抱歉，是移除共病——方面的一個機會是，除了允許納入有與沒有糖尿病的病人之外，我們也將有能力觀察在人類遺傳學中已呈現的結果：抑制素E（inhibin E）降低所帶來的HbA1c下降。

Well, that's a registrational endpoint in the treatment of diabetes. We'll be able to look at ratios of triglycerides and HDL in terms of insulin sensitivity. We'll be able to look at other measures, like CRP, from an inflammatory standpoint.

而HbA1c下降是糖尿病治療中的一個註冊性終點。我們也能看三酸甘油脂與HDL的比值，以評估胰島素敏感性。我們也能從發炎角度看其他指標，例如CRP。

It really is important, as we think about this study as being able to open up, one, how do we think about the treatment of obesity and what's really important. We are seeing a big shift, particularly in the last quarter, on, finally, discussions about body composition being what should be targeted for these patients, with an ability to tie that to an impactful measurements that'll be in the appropriate Phase 2a.

當我們思考這項研究時，這真的很重要，因為它能開啟兩件事：第一，我們如何看待肥胖治療、以及什麼才是真正重要的。我們看到一個很大的轉變，特別是在上一季，終於開始討論身體組成才是這些病人應該被鎖定的目標，並且能把它連結到具有影響力的量測指標，而這些會納入適當的2a期研究。

As Chris said, we'll have a 160 patient study across doses, across disease states, that really will let us fully exploit the mechanism -- and shortly thereafter. Again, accreting the data to where I do think there's a substantial opportunity for inhibin E, which is in the maintenance setting.

如Chris所說，我們會有一項160位病人的研究，涵蓋不同劑量、不同疾病狀態，這將真正讓我們充分發揮這個機制——而且在不久之後。同樣地，隨著資料逐步累積，我確實認為抑制素E在維持治療（maintenance）情境中有相當大的機會。

This idea that 70% of people can't stay on incretins, if we think about the therapy for obesity with incretins being like the treatment of hypertension, we're seeing patients who need a life-long treatment to stay in this range of body composition that they achieve.

這個概念是：70%的人無法持續使用腸泌素（incretins）。如果我們把以腸泌素作為肥胖治療類比成高血壓治療，我們看到的是病人需要終身治療，才能維持在他們所達到的身體組成範圍內。

I think we're also going to have the opportunity, as we think about the Phase 1 studies -- plural -- that we will be initiating -- the concept of being able to have and lock in a maintenance setting an infrequent way of treating patients and preserving and locking in the benefits from a cardiometabolic outcome position that's been achieved with other weight loss therapies.

我也認為，當我們思考第一期研究——複數——也就是我們將要啟動的研究時，我們有機會去驗證這個概念：在維持治療情境中，以不頻繁的方式治療病人，並保留、鎖定其他減重療法所達成的心代謝結局上的效益。

I think the totality of data that we'll be generating to unlock the full mechanism in inhibin E is both in this Phase 2a study and the multi-dose; but, also, in the subsequent studies that we'll be initiating.

我認為，為了釋放抑制素E完整機制，我們將產生的整體資料，既來自這項2a期研究與多劑量研究，也來自後續我們將啟動的研究。

Thank you so much.

非常感謝。

Thank you.

謝謝。

Samantha Semenkow, Citi.

Samantha Semenkow，花旗（Citi）。

Hi. Good morning. Thanks very much for taking the question. Just one for me on AATD.

嗨。早安。非常感謝讓我提問。我只有一個關於AATD的問題。

I think your explanation around the dynamic nature of the mechanism makes a lot of sense. I just wonder, from a competitive landscape, we're seeing the DNA base editors get up to a mean of about 16 micromolar, at total, in M-AAT. We've seen at least one patient from another competitor go up to 20.

我認為你對機制動態特性的解釋很有道理。我只是想知道，從競爭格局來看，我們看到DNA鹼基編輯（DNA base editors）在M-AAT的總量平均可達約16微莫耳。我們也看到至少有一位來自其他競爭者的病人達到20。

Do you think, optically, you need to achieve some threshold in order to entice both patients and physicians to use an RNA-editing approach? Or have you done any market research around this?

你認為在「觀感上」，是否需要達到某個門檻，才能吸引病人與醫師使用RNA編輯的方法？或者你們是否做過任何市場調查？

Just curious your thoughts there; and what the actual profile could end up being; and how competitive that would be. Thank you.

只是想聽聽你對此的看法；以及最終實際的產品特徵可能會是什麼；以及那會有多具競爭力。謝謝。

No. Thank you. This is where we've spent a lot of time with clinicians as, again, in preparation, as we think about ATS coming. I think there's a lot of enthusiasm from this community on RNA editing.

不。謝謝。這正是我們花了很多時間與臨床醫師交流的地方；同樣地，當我們思考ATS即將到來、並做準備時。我認為這個社群對RNA編輯有很高的熱情。

I say that for a couple reasons. One, teh idea of being able to -- we'll talk about these thresholds and numbers in a minute -- but I think the most important thing is that, if we think about the ability to be able to infrequently redose patients, it's important because, over time, the liver does regenerate.

我這麼說有幾個原因。第一，能夠——我們等一下會談這些門檻與數字——但我認為最重要的是，如果我們思考能夠不頻繁地對病人再次給藥，這很重要，因為隨著時間推移，肝臟確實會再生。

The idea that, as these cells that are on a pathway to dying and becoming fibrotic are actually now rescued and saved because you're able to, through editing, deplete Z protein, take those toxic aggregates out of the liver, restore liver health -- those cells are now ripe to be able to be dosed and have, actually, correction and actually become productive in their responses in producing healthy M protein.

這個想法是：當這些正走向死亡並發生纖維化的細胞，因為你能夠透過編輯去耗竭Z蛋白、把那些有毒的聚集體從肝臟中清除、恢復肝臟健康，而實際上被救回並存活下來——那麼這些細胞就已經具備條件可以接受給藥，並且真正得到矯正，進而在產生健康的M蛋白方面展現出有效且具生產力的反應。

As we talk to clinicians, that notion of re-infrequent repeat dosing is actually viewed as actually favorable, as opposed to the risks and potential outcomes from permanent DNA mutations.

當我們與臨床醫師交流時，這種不頻繁的重複給藥概念實際上被視為更有利，相較之下，永久性DNA突變所帶來的風險與潛在結果更令人擔憂。

I think the other thing that, as we think about patients who have liver disease -- and ZZ patients, where they are on the spectrum, will have liver disease -- is the notion of not using LNPs.

我認為另一點是，當我們思考肝病患者——以及ZZ患者（他們在疾病譜系中的位置）都會有肝病——時，就是不使用LNP的概念。

We have to remember that LNPs activate IL-6 and the CRP immune response; and, in and of themselves, are immunogenic. If we think about that as being causing and inducing an acute phase response, it could also elevate alpha-1 antitrypsin in a protective response to that.

我們必須記得，LNP會活化IL-6與CRP的免疫反應；而且其本身就具有免疫原性。如果我們認為這會造成並誘發急性期反應，它也可能在保護性反應中提高α-1抗胰蛋白酶的水平。

The notion that, in patients with liver disease, we want to avoid things that are going to irritate the liver is also important, as we think about the totality of the therapeutic modality that clinicians are thinking about in terms of their treatment of patients.

在肝病患者中，我們也希望避免任何會刺激肝臟的因素；當我們從臨床醫師在治療患者時所考量的整體治療方式來看，這一點同樣重要。

Now, while all of that is wonderful, at the same time, what we want to see is the ability to actually drive the correction. And so, as we think about the production of M protein and what RNA editing is designed to do, it's highly specific.

現在，雖然這一切都很棒，但同時我們想看到的是，真正能夠推動矯正的能力。因此，當我們思考M蛋白的產生以及RNA編輯的設計目的時，它具有高度特異性。

When we talk about protein -- and, oftentimes, these things get conflated with numbers -- when we say M protein numbers or M protein percentage, we are talking about purely the actual isoform of AATD. This is the native M-AAT protein.

當我們談到蛋白——而且很多時候這些概念會與數字混為一談——當我們說M蛋白數值或M蛋白百分比時，我們談的是AATD的實際同工型本身。這是天然的M-AAT蛋白。

As the prior question suggested, that's something we're discussing as part of our regulatory interactions, which is that we make only the native M-AAT protein. We don't create bystanders. We don't create indels.

如同前一個問題所暗示的，這也是我們在與監管單位互動時討論的一部分：我們只產生天然的M-AAT蛋白。我們不會產生旁觀者（bystander）。我們不會產生插入/缺失（indels）。

But, importantly, those bystander-edited proteins have different ranges of function so we can be assured that the protein we're creating behaves like the native natural protein.

但重要的是，那些被旁觀者編輯的蛋白具有不同的功能範圍，因此我們可以確信我們所產生的蛋白，其行為表現與天然自然蛋白一致。

As we shift back to the beginning of your question, which is, what's going to be important, as we think about this, I think, where we've also seen clinicians -- is not being able to make that switch to thinking about it.

回到你問題的起點，也就是在我們思考這件事時什麼會是重要的，我認為我們也看到臨床醫師——在思維上還無法完成那個轉換。

Actually, at ATS, it's going to be interesting because it will be Wave on presenting on editing. And then, there will be the updates on protein replacement therapy.

其實在ATS上會很有意思，因為將由Wave來發表關於編輯的內容。接著，還會有蛋白替代療法的最新進展。

It's really this shift from having to say, well, more is more to baseline because that is a protein replacement narrative. That's -- you have to put more protein in because the patient can't actually produce more. And so, therefore, it's a race to put more protein in that gets depleted.

這真的是一個轉變：從必須說「越多越好、要高於基線」，因為那是蛋白替代的敘事。也就是——你必須補進更多蛋白，因為患者其實無法自己產生更多。因此，這就變成一場把會被消耗掉的蛋白盡可能補進去的競賽。

We'll have the opportunity to continue to say, with editing, you can now create that dynamic response. As we said, we can create a dynamic response that's proportionate to a CRP response, up to 20, when the patient needed 20; and could have easily generated more, if the patients needed more.

我們將有機會持續強調：透過編輯，你現在可以創造那種動態反應。如我們所說，我們可以創造一種與CRP反應成比例的動態反應，最高可到20，當患者需要20時就能達到20；而且如果患者需要更多，也完全可以產生更多。

I think, if we think about the range of both total and M protein, we are very much convinced that we can create the baseline levels that serve as the biomarker to demonstrate that these patients are able to go out; live a healthy, functional, normal life; and have the appropriate responses to these acute phase events, as they happen.

我認為，如果我們思考總蛋白與M蛋白的範圍，我們非常確信能夠建立作為生物標誌的基線水平，以證明這些患者能夠走出去、過上健康、有功能、正常的生活；並且在急性期事件發生時，能有適當的反應。

I think one of the most interesting things, when we went back and looked at that initial patient, wasn't just the spike the patient had that got up to 20. But it was the realization -- and if you ever went back to those slides that are there on this dynamic response -- that, over the multi-dose, these patients had small elevations in CRP.

我認為最有趣的一件事是，當我們回頭看那位最初的患者時，不只是患者那次飆升到20的尖峰。而是我們意識到——如果你回去看那些關於這種動態反應的投影片——在多次給藥期間，這些患者的CRP有小幅上升。

What was really compelling is, every time they had those adjustments, they were generating an increased response to total protein that met that. I think, by restoring this dynamic response, that's ultimately how you prevent the chronic injury that happens for the 1 times to 3 times a year that these patients need it.

真正令人信服的是，每一次他們出現那些調整時，他們都會產生增加的總蛋白反應來匹配需求。我認為，透過恢復這種動態反應，最終你就能預防那些每年1到3次、患者需要它時所發生的慢性損傷。

Great. Thanks very much.

很好。非常感謝。

Thank you.

謝謝。

Alex Stranahan, Bank of America.

美國銀行的Alex Stranahan。

Hey, guys. Thanks for taking our questions.

嗨，各位。謝謝你們回答我們的問題。

Just a couple of quick ones on the Phase 2a portion of INLIGHT. Could you walk us through how you're thinking about the dose selection, given the Phase 1 portion is still ongoing? Will GLP-1 use be allowed in this population for enrollment? Or is this maybe a population you'll reserve for future studies?

關於INLIGHT的2a期部分，我有幾個簡短問題。鑑於1期部分仍在進行中，你們能否說明一下你們如何思考劑量選擇？在這個族群的入組中，是否允許使用GLP-1？還是這可能會是你們保留給未來研究的族群？

In terms of cadence of data from the Phase 2a, is your plan to share regular interim updates like the Phase 1, maybe, say, at the first three-month assessment, following the first dose? Thanks.

就2a期數據的發布節奏而言，你們是否計畫像1期那樣定期分享期中更新，例如在首次給藥後的第一個三個月評估時點？謝謝。

Thanks. I'll take the last question and hand it over to Chris.

謝謝。我先回答最後一個問題，然後交給Chris。

But, in terms of the cadence of data, at this point, yes, it's possible that we could deliver the initial, as you pointed out, three-month time point. We'll give a more concrete update on milestone cadence when the study initiates and as that study launches.

不過，就數據發布節奏而言，目前是的，我們有可能在你提到的三個月時點提供初步數據。當研究啟動並推進時，我們會就里程碑節奏提供更具體的更新。

But, yes, there's the possibility of data, as we think about it, this year.

但，是的，從我們的角度來看，今年有可能會有數據。

Chris, you want to take the first question?

Chris，你要回答第一個問題嗎？

Sure. In terms of the doses chosen, this is really based on -- it is ongoing but we clearly have interesting data on 240, as well as 400.

當然。就所選劑量而言，這確實是基於——雖然仍在進行中，但我們已經在240以及400上看到明確且有意思的數據。

And oso, based on the data that we've seen in terms of the level of knockdown, PK/PD modeling, and the degree of efficacy that we saw even at 240, we felt that we could move forward in the multi-dose with the 240 and 400; and that these should be the range of doses that are expected to be efficacious, also based on the modeling.

另外，根據我們看到的敲低幅度、PK/PD建模，以及即便在240劑量下也觀察到的療效程度，我們認為可以在多次給藥中推進240與400；而且根據建模，這些應該是預期具有療效的劑量範圍。

It all falls together; modeling from pre-clinical. It all falls together, from that perspective. That's how those two initial doses were chosen.

這一切都能相互吻合；包括來自臨床前的建模。從這個角度看，一切都能對得上。這就是最初選擇這兩個劑量的原因。

In terms of incretin, in this particular study, amendment, it's a monotherapy amendment. We're not allowing incretins. However, we're in the throes of a combination study design, which would include incretins. We'll provide more information on that, shortly, as well.

至於腸泌素（incretin），在這項特定研究的修訂中，這是一個單藥治療（monotherapy）的修訂。我們不允許使用腸泌素。不過，我們正在積極推進一項聯合用藥研究設計，其中會納入腸泌素。我們也會在不久後提供更多相關資訊。

Just to follow up on the last point: As Chris mentioned, we do see substantial reductions in the two dose cohorts that we're taking forward, with very tight ranges between patients.

補充上一點：如Chris所提到，我們確實在將要推進的兩個劑量隊列中看到顯著的下降，而且患者之間的範圍非常集中。

I think a lot of what we're going to learn is not just getting more efficacy from that but the impact of time, durability, and which dose is going to allow for the most less frequent interval, while not losing an efficacy signal.

我認為我們將學到的很多，不只是如何從中獲得更高的療效，還包括時間的影響、持久性，以及哪一個劑量能在不喪失療效訊號的情況下，讓給藥間隔最不頻繁。

Yun Zhong, Wedbush.

Yun Zhong，Wedbush。

Hi. Good morning. Thank you very much for taking the questions.

嗨。早安。非常感謝讓我提問。

The question is on the Phase 2a portion of the obesity study. On the second dose, do you have any expectation on the potential impact on gene and protein expression? In terms of a clinical outcome, would you expect the benefit to be on durability or the magnitude of fat reduction or both?

問題是關於肥胖症研究的第2a期部分。在第二次給藥方面，您是否預期會對基因與蛋白質表達產生任何潛在影響？就臨床結果而言，您預期效益會體現在持久性、脂肪減少幅度，或兩者皆是？

You're changing the patient, based on characteristics. I just wonder, will you be able to tell whether that's -- and any potential better outcome will be from repeat dosing or from the more higher BMI or both?

你們是依據特徵在改變受試者族群。我只是想知道，你們是否能判斷那是——以及任何潛在較佳結果——究竟來自重複給藥、較高的BMI，或兩者皆是？

Will you be able to tell the difference, please?

請問你們能分辨其中差異嗎？

Yeah. (multiple speakers) Chris, do you want to start or no?

是的。（多位講者）Chris，你要先開始嗎，還是不用？

I can just say, the way that it's designed; and what we know about the pharmacokinetics and pharmacodynamics, we expect a very substantial knock-down with the two doses that would be very persistent, over time.

我可以先說，就其設計方式以及我們對藥物動力學與藥效學的了解，我們預期兩次給藥會帶來非常顯著的下調效果，而且會隨時間維持得很持久。

We think that that's a great approach to identify the right doses and understand the duration better; and to optimize our likelihood of efficacy.

我們認為這是辨識正確劑量、並更好理解作用持續時間的絕佳方法；也能最佳化我們達到療效的可能性。

To that point -- and you also mentioned it -- the patient characteristics are different. And so the dose response could also be slightly different in people that have higher levels of obesity or higher BMIs.

就這點而言——你也提到了——病人的特徵不同。因此，在肥胖程度更高或BMI更高的人身上，劑量反應也可能略有不同。

And so it's important to look at a number of doses in that context, as well.

因此，在那樣的背景下檢視多個劑量也很重要。

But we should see stronger results there, as we outlined earlier, in the sense that this is a drug that increases fat metabolism. And so the more you have to metabolize, the bigger the effect should be.

但我們應該會看到更強的結果，如同我們先前概述的，因為這是一種能提升脂肪代謝的藥物。因此，你需要代謝的脂肪越多，效果就應該越大。

To just add one more thing, as well: Like, the design here, the zero and 3 months dosing, is, really, to accelerate the Phase 2a trial. It's not because we do think we need to give the doses that frequent.

另外再補充一點：這裡的設計——在第0個月與第3個月給藥——其實是為了加速第2a期試驗。並不是因為我們認為需要如此頻繁地給藥。

All of our PK modeling indicates that it's once a year or, at most, twice a year. It's a way to accelerate and facilitate data read-outs fast.

我們所有的PK建模都顯示一年一次，或最多一年兩次。這是一種加速並促進更快讀出數據的方法。

To that point, if you look at our 240, out past seven months, we're still seeing suppression of Activin E. Again, with 400, we expect that to be larger.

就這點而言，如果你看我們240的數據，超過七個月後，我們仍看到Activin E受到抑制。同樣地，使用400時，我們預期抑制幅度會更大。

You also bring up an interesting question on just -- I heard you mention genetics. I think we have to go back to the genetics and realize that Activin E is the biomarker. Hence, we're able to look at the impact of the reduction on the actual protein biomarker, over time.

你也提出了一個有趣的問題——我聽到你提到遺傳學。我認為我們必須回到遺傳學並認知到Activin E就是生物標誌物。因此，我們能夠隨時間觀察其降低對實際蛋白質生物標誌物的影響。

When one looks at that interaction -- there were the discussions that had come up a while ago about diabetes, non-diabetes. I think the data that had been shared, to date, doesn't demonstrate that these patients should be different in disposition, whether they had diabetes or not.

當我們看那個交互作用——之前曾有一段時間討論過糖尿病、非糖尿病。我認為截至目前分享的數據並未顯示這些病人在處置上會因是否有糖尿病而不同。

Actually, the data that was run in a -- God, I think it was an over 300-patient observational study from Alnylam -- clearly showed that Activin E correlated with high BMI, insulin sensitivity, and truncal fat in non-diabetic patients.

事實上，在一項——天啊，我想是Alnylam做的、超過300名病人的觀察性研究——清楚顯示在非糖尿病病人中，Activin E與高BMI、胰島素敏感性以及軀幹脂肪相關。

I think the implication here is, really, that, if you can dial back a protein that drives lipolysis, then you're going to see that impact. Now, we're going be able to be in a position where we're goin g to look at that in different settings.

我認為這裡的意涵是：如果你能把一個驅動脂解的蛋白質往下調，那你就會看到其影響。接下來，我們將能在不同情境下去檢視這一點。

We'll have it in the non-diabetic setting, the diabetic setting. We'll look at how that plays a role, particularly on endpoints like hemoglobin-A1c.

我們會在非糖尿病情境、糖尿病情境中都有資料。我們也會觀察它如何發揮作用，特別是在像糖化血色素A1c這類終點上。

If we think about the implications for broader cardiometabolic disease beyond obesity, we'll be able to look at what happens with insulin sensitivity; what happens with hemoglobin-A1C for diabetes; and other measurements in lipids and inflammatory markers, as we think about cardiovascular disease.

如果我們思考肥胖以外、更廣泛的心臟代謝疾病意涵，我們將能觀察胰島素敏感性會發生什麼變化；糖尿病的糖化血色素A1C會如何；以及在我們思考心血管疾病時，脂質與發炎指標等其他量測的變化。

I think the study is really stepping back and letting us look at the broad range of cardiometabolic diseases in those different patient settings.

我認為這項研究其實是退一步，讓我們能在不同病人情境中，檢視廣泛範圍的心臟代謝疾病。

Salim Syed, Mizuho.

Salim Syed，Mizuho。

Hey. Congrats on the progress, guys.

嘿。恭喜各位取得進展。

Paul, Chris, maybe one for us on the data coming out on 006 at ATS. Is it possible to just give us high-level of what people should expect here or look out for?

Paul、Chris，想請教一下關於006在ATS即將公布的數據。能否用高層次的方式告訴我們，大家應該期待或特別留意什麼？

Obviously, the data that was presented in September of last year -- the 200-single and 200-multi -- there wasn't much of a dose response or, even, going to the 400-milligram-single.

顯然，去年9月發表的數據——200單次與200多次——並沒有太多劑量反應，甚至提高到400毫克單次也一樣。

You guys continue progress here with the 400-multi. and then, we'll be getting 600-single; and then, in the second half of this year, 600-multi.

你們持續推進400多次；接著我們會看到600單次；然後在今年下半年會有600多次。

Is there any reason, here, people should be expecting some threshold effect, as you break through to the higher doses? Do we get more efficacy (multiple speakers) --

在這裡是否有任何理由讓大家預期，當你們突破到更高劑量時會出現某種閾值效應？我們會看到更高的療效嗎（多位講者）——

Yeah. I think (multiple speakers) --

是的。我想（多位講者）——

-- out of 006?

——在006上？

Well, no, it's a great question. I think, if we went back to September, there's actually a dose response, if we think about M protein. It went from zero to, like, 44% to 65% M.

嗯，不，這是個很好的問題。我認為如果回到9月，其實是有劑量反應的，若我們看M蛋白的話。它從0到大約44%再到65%的M。

I think, if we think about the context of where patients start and how that builds, over time, I think editing can continue to grow.

我認為，如果把病人起始狀態以及隨時間累積的情況放在一起看，編輯效果可能會持續增加。

I think, with the question of, is more going to drive more in the absence of an acute phase response, that's really the distinction that we're separating, which is, once you've hit a point where you can catalytically edit the transcripts that are necessary, it's really a function of time.

至於「在沒有急性期反應的情況下，更多劑量是否會帶來更多效果」這個問題，這正是我們要區分的重點：一旦你達到能夠以催化方式編輯所需轉錄本的程度，接下來基本上就是時間的函數。

You deplete Z protein. The Z protein continues to come down and clear up in the liver. The cells get better. You should, over time, as we've seen with MZ patients who actually don't have liver disease over their lifespan, they can actually generate more protein.

你會耗竭Z蛋白。Z蛋白會持續下降，並在肝臟中被清除。細胞狀況會變好。隨著時間推移，你應該會看到——正如我們在MZ病人身上所見，那些人在一生中其實不會出現肝病——他們確實能產生更多蛋白質。

I think that notion of correction, over time, is important. But I think our guidance is -- we were able to mount a response that could generate a lot of protein, 20 micromolar, if you had the right event.

我認為這種隨時間推移的校正概念很重要。但我認為我們的指引是——如果發生了正確的事件，我們能夠引發一個反應，產生大量蛋白質，達到20微莫耳。

It's not substrate-limited to the effect that people will say, is the enzyme exhausted? There is substrate limitation in the context that, if you're not having an acute phase response and the body's not producing or needing to produce protein, that it would not produce more.

它並不是受限於底物，以至於有人會說：酵素是不是耗盡了？在某種意義上確實存在底物限制：如果沒有急性期反應，而身體沒有在產生或需要產生蛋白質，那它就不會產生更多。

I think that's been the example we've seen and others have seen. I think what we're able to do is look at this without the conflation of LNP irritation, which can also create a a conflation or a signal of inflammation.

我認為這一直是我們以及其他人所看到的例子。我認為我們能做的是在不把 LNP 刺激混為一談的情況下來看待這件事，因為 LNP 刺激也可能造成混淆或引發發炎訊號。

In a signal where we have GalNAc so you can go directly to the target site, we do see that, when you have these elevations of acute phase responses, you can meet those dynamics.

在我們有 GalNAc、因此可以直接到達靶點部位的訊號中，我們確實看到，當急性期反應出現這些升高時，你可以符合那些動態變化。

I think, stepping back, if we could see that we could produce this -- the same levels -- meaning, you could create stable levels of greater-than-11 micromolar -- we were 13 -- edited protein that's M -- that's above, again, the MZ threshold; again, above 50% M protein -- and be in a position where you can protect patients from a dynamic response but now no longer have to deliver biweekly injections to get there but demonstrate we could do it monthly or less frequently, I think that puts us in a very good position in terms of the regulatory context and, ultimately, most importantly, to treat patients with alpha-1 antitrypsin deficiency.

我認為，退一步來看，如果我們能看到我們可以產生這個——相同的水準——也就是說，你可以建立穩定的、超過 11 微莫耳的水準——我們是 13——經編輯的蛋白 M——這又高於 MZ 閾值；同樣，高於 50% 的 M 蛋白——並且能在保護病人免於動態反應的同時，不再需要每兩週注射一次才能達到，而是證明我們可以每月或更低頻率做到，我認為這在法規監管脈絡下讓我們處於非常有利的位置，並且最終、最重要的是，用於治療 α-1 抗胰蛋白酶缺乏症患者。

Roger Song, Jefferies.

Roger Song，Jefferies。

Great. Thanks for taking the question.

很好。謝謝讓我提問。

Also, on the inhibin E, understanding you will have a poster at the ADA, just curious what incremental data we should expect to see.

另外，關於 inhibin E，我了解你們會在 ADA 上展示海報，只是好奇我們應該期待看到哪些增量數據。

And then, regarding the FDA interaction, have you had any discussion around -- the 5% is coming to the total body weight reduction versus we can look at a total fat or, even, a visceral fat reduction threshold moving away from the overall body weight, given the novel mechanism?

然後，關於與 FDA 的互動，你們是否有討論過——這個 5% 是以總體重減少來計算，還是考慮在這個新機制下，改以總脂肪量、甚至內臟脂肪減少的門檻來取代整體體重？

Thank you.

謝謝。

No. Thank you, Roger.

沒有。謝謝你，Roger。

To your first question, yes, we will have a poster in ADA. As it relates to new data cadence, we haven't provided any updates, other than, 2026, we'll be providing continued updates on 007.

針對你的第一個問題，是的，我們會在 ADA 有一張海報。至於新的數據發布節奏，我們除了提到 2026 年會持續更新 007 之外，尚未提供其他更新。

To your second question, as it relates to regulatory thresholds and 007, I think it is important that there is a broader range of discussions beyond a flat 5% change in total body weight.

針對你的第二個問題，就 007 的法規門檻而言，我認為重要的是，討論範圍應該更廣，而不只是總體重固定 5% 的變化。

Nonetheless, it's why I think slide 24 in the new corporate deck is important because I think the notion of -- I know people were trying to think about, with visceral fat it's a kilogram and a half; and If you lose it. Everybody's trying to figure out where body weight reduction comes from.

不過，這也是為什麼我認為新版公司簡報的第 24 頁很重要，因為我覺得這個概念——我知道大家一直在想，內臟脂肪大概是一公斤半；如果你把它減掉。每個人都在試著弄清楚體重減少是從哪裡來的。

But, If you look at the parallel side of what happens to total fat in that population, you've got about 48 kilos of total subcutaneous body fat that gets reduced that ultimately delivers weight loss. I don't think we're needing to necessarily have a different conversation around how, in a Phase 2, 3 obesity study in patients with excess fat, you can deliver on that 5% threshold.

但是，如果你看那個族群的總脂肪變化的對照面，你有大約 48 公斤的總皮下體脂會被減少，最終帶來體重下降。我不認為我們一定需要就「在第二、三期肥胖試驗中，針對脂肪過多的患者，如何達成 5% 門檻」去展開不同的對話。

Nonetheless, I think there's a very robust conversation that we're preparing for with the agency where I think there's a lot of alignment, particularly in this administration; thinking about the impact of harmful visceral fat.

儘管如此，我認為我們正在為與主管機關進行一場非常扎實的討論做準備，而且我認為有很多共識，特別是在本屆政府；在思考有害內臟脂肪的影響。

There's two decades of literature on elevations of visceral fat driving MASH; driving cardiovascular disease; driving diabetes, quantitatively; meaning, a 10% change in visceral fat changes outcomes that are clinically.

有二十年的文獻指出，內臟脂肪升高會推動 MASH；推動心血管疾病；推動糖尿病，而且是量化的；也就是說，內臟脂肪改變 10% 會改變具有臨床意義的結局。

What do payers pay for? They pay for outcomes. And so, as we think about the endpoints of visceral fat reduction as actually being the driver of what makes patients unhealthy, that focus on being able to reduce visceral fat is important.

付款方付費買什麼？他們付費買的是結果。因此，當我們把內臟脂肪降低的終點視為造成病人不健康的驅動因素時，聚焦於能夠降低內臟脂肪就很重要。

As Chris pointed out, there's not a lot of complicated mathematics to take BMR and look at the impact of visceral fat and lean mass preservation. There's literature around that so this is not a new metric of identifying how you can change body composition in a positive way.

如 Chris 所指出的，將 BMR 納入並觀察內臟脂肪與瘦體重保留的影響，並不需要很複雜的數學。相關文獻已經存在，所以這不是一個用來辨識如何正向改變身體組成的新指標。

Very much, we do plan to have a conversation with the agency that specifically focuses on looking at other metrics like BMR and visceral fat as an endpoint, not just to the exclusion of the 5%.

我們確實計畫與主管機關進行一場對話，特別聚焦於把 BMR 和內臟脂肪等其他指標作為終點，而不只是排除 5% 這個指標。

But even, in addition to that, being able to build in the real impact of improving body composition, which is what's required for the treatment of obesity, is important.

但除此之外，能夠把改善身體組成的真實影響納入其中也很重要，而這正是治療肥胖所需要的。

I think we just all need to remember that obesity is a cardiometabolic disease. And so, ultimately, a lot of the endpoints that we're measuring, hemoglobin A1C, insulin sensitivity, (inaudible) driven off of visceral fat reduction, are going to be important.

我認為我們都需要記得，肥胖是一種心臟代謝疾病。因此，最終我們正在衡量的許多終點——糖化血色素 A1C、胰島素敏感性、（聽不清）等——都是由內臟脂肪降低所驅動，將會很重要。

Yes. It will be very much a topic of conversation this year, as we think about the (inaudible).

是的。當我們思考今年的（聽不清）時，這將會是非常重要的討論主題。

Bill Maughan, Clear Street.

Bill Maughan，Clear Street。

Good morning and thanks.

早安，謝謝。

I wanted to just mix things up and actually ask about your exon-skipper program. While obviously not as massive a market as obesity, it is a fairly near-term opportunity and a potential significant revenue driver, yet there seems to be a bit of a lack of emphasis, just around discussions around WAVE on the exon-skipper.

我想換個話題，實際上想問你們的 exon-skipper（外顯子跳躍）計畫。雖然顯然市場規模不如肥胖那麼大，但這是相對近期的機會，也可能是重要的營收驅動因素；然而在關於 WAVE 的討論中，對 exon-skipper 似乎有點缺乏著墨。

I just wanted to get your most recent thoughts on how big that could be, commercially; and whether or not there's potential for that to surprise a bit and get a little more credit than it's being given, currently. Thanks.

我想了解你們最新的看法：在商業化上它可能有多大；以及是否有可能帶來一些驚喜，並獲得比目前更多的認可。謝謝。

Yeah. No. Thank you for the question.

是的。不。謝謝你的提問。

As we think about [DMD], we had delivered a differentiated approach with the clinical data update we gave. As we said, we were in the process of delivering and putting together -- that study is continuing to get to the monthly dosing regimen, which we believe would be, again, differentiated and required for an NDA filing.

當我們思考 [DMD] 時，我們透過所提供的臨床數據更新，提出了一個具差異化的方法。如我們所說，我們正在推進並整合——該研究仍在持續，以達到每月給藥的方案；我們相信這將再次具差異化，且是提交 NDA 申請所需要的。

That work continues to remain on track.

這項工作仍按計畫推進。

I think, as you also point out, as we think about the opportunities of allocation of capital, in terms of building out to commercialization, we have said that we do plan to engage in strategic partnering discussions, as it relates to that transitioning and commercialization.

我想，正如你也指出的，當我們考量資本配置的機會、以及建立商業化能力時，我們已表示確實計畫就轉換與商業化，展開策略性合作夥伴的討論。

We continue to look for several things, evolving.

我們持續在尋找幾件正在演變的事情。

One, the evolution of the commercial landscape, as we look at the product dispositions that are out there into the regulatory environment. I think, over the course of this year, there's going to be a lot of opportunities for us to make those assessments in commercial landscape, the regulatory landscape, as we can continue to deliver on that pathway.

第一，商業環境的演變，當我們觀察市場上產品的定位以及法規環境。我認為在今年的過程中，我們會有很多機會去評估商業環境與法規環境，同時持續推進那條路徑。

Ben Burnett, Wells Fargo.

Ben Burnett，Wells Fargo。

I think we can go to the next question.

我想我們可以進入下一個問題。

Danielle Brill, Truist Securities.

Danielle Brill，Truist Securities。

(technical difficulty)

（技術問題）

[Cassie Ewan], RBC.

[Cassie Ewan]，RBC。

Thanks so much for taking our question. Good morning, team. This is Cassie, in for [Luca]. Congrats on all the progress.

非常感謝讓我們提問。早安，各位團隊成員。我是 Cassie，代替[Luca]。恭喜各項進展。

A quick one on the competitive landscape for obesity: Your competitor is moving into combination approaches relatively earlier on in development. Could we take that as them maybe signaling that monotherapy, alone, has inherent limitations in obesity treatment for INHBE?

關於肥胖競爭格局的一個快問：你們的競爭對手在研發相對早期就轉向聯合療法。我們是否可以將此解讀為，他們可能在暗示單藥治療本身在 INHBE 的肥胖治療上存在固有限制？

Paul, you already gave some color on this but do you believe there's a ceiling to what INHBE science alone can achieve? Are you concerned that waiting till Phase 2 or later to explore combinations may put you in a competitive disadvantage versus competitors already testing combo strategies?

Paul，你先前已經對此提供了一些說明，但你是否認為單靠 INHBE 科學本身所能達成的效果存在上限？你是否擔心等到第二期或更後期才去探索聯合用藥，可能會讓你在競爭上落後於已經在測試聯合策略的競爭對手？

Sorry for the long question but any color, appreciated. Thanks.

抱歉問題有點長，但若能提供任何補充說明將不勝感激。謝謝。

No. I think (multiple speakers) --

不。我認為(多位講者) --

No. We can get all that.

不。我們都能做到。

I think it's a wonderful question.

我覺得這是一個很棒的問題。

'Cause I do think, already, if we look at where we were, relative to just our Phase I population, with our single-dose data, we're competing with visceral fat reductions that were in multi-dose of others, right, including combinations.

因為我確實認為，就目前而言，如果我們回頭看我們在第一期受試者族群、以單次給藥數據所呈現的結果，我們在內臟脂肪降低方面，已經能與其他人的多次給藥結果競爭，對吧，包括聯合用藥。

If we think about what we have that's differentiated -- and I think Erik shared that during his update on the call -- our chemistry is giving us a high degree of potency and durability. If we think about the inhibin E target itself, it requires not just potent reduction but requires stable suppression.

如果我們思考我們的差異化之處——我想 Erik 在電話會議更新時也分享過——我們的化學設計帶來了高度的效力與持久性。如果我們思考 inhibin E 這個標的本身，它不僅需要強力降低，還需要穩定的抑制。

And so this notion of being able to keep that target low, despite any desire of the body to upregulate it, is a key differentiator. We saw that in pre-clinical data that differentiated us from our competitors, where they had to do repeat dosing of a GalNAc-siRNA to drive weight loss.

因此，能夠讓該標的維持在低水平、即便身體有任何想要上調它的傾向，這一點是關鍵的差異化因素。我們在臨床前數據中看到了這點，並使我們與競爭對手區隔開來；他們必須重複給藥 GalNAc-siRNA 才能推動體重下降。

Remember, these were obese mice. The mice that we're all talking about in these studies were mice that would be much more representative of your Phase 2, 3 high-BMI mice.

請記得，這些是肥胖小鼠。我們在這些研究中談到的小鼠，會更能代表你們第二、三期中高 BMI 的小鼠模型。

What did we see? We saw that, if we could give a single dose and suppress Activin E, we could see weight loss in that model driven off of fat reduction -- visceral fat reduction, subcutaneous fat reduction.

我們看到了什麼？我們看到，如果能給予單次劑量並抑制 Activin E，就能在該模型中看到由脂肪降低所驅動的體重下降——內臟脂肪降低、皮下脂肪降低。

I think we're seeing strong clinical translation on potency and durability distinction from our competitors, such that, absolutely, I think, we will see continued fat loss, substantially, with muscle preservation in this high-BMI setting.

我認為我們正看到在效力與持久性方面，相較競爭對手有很強的臨床轉譯差異；因此，我絕對相信，在這個高 BMI 的情境下，我們將會看到持續且顯著的脂肪下降，同時保留肌肉量。

I don't think that there's necessarily this ceiling effect as much as it is the treatment effect in the appropriate population. As we said a number of times last year, it was always going be about treating the patients with the right disease setting; meaning, the Phase 2, 3 population in obesity -- high fat -- with the right dose over the right amount of time.

我不認為一定存在所謂的上限效應；更重要的是在適當族群中的治療效果。正如我們去年多次提到的，關鍵一直在於治療具有正確疾病情境的病人；也就是肥胖——高脂肪——的第二、三期族群，在正確的時間長度內使用正確的劑量。

I think we're set up to see that. Nonetheless, I think the power, as you point out, in combinations is very real. If we stay in the monotherapy, we do believe that that's goin gto be a segmented marketplace. We think about the opportunity for -- I think there's nearly 30 million people in the US who are at risk of lean mass reduction, who need weight loss.

我認為我們已經具備看到這些結果的條件。儘管如此，正如你指出的，聯合用藥的威力確實非常真實。如果我們維持在單藥治療，我們確實相信那會是一個分眾的市場。我們思考這個機會——我想美國大約有接近 3,000 萬人需要減重，但同時有瘦體重下降的風險。

And so, as we think about segmentation, I think there is a substantial population monotherapy that's going to need fat reduction without the risk of lean mass loss. Combination, nonetheless, is a very interesting place to be.

因此，當我們思考分眾時，我認為會有相當大的族群需要單藥治療：需要降低脂肪、但不希望承擔瘦體重流失的風險。不過，聯合用藥仍然是一個非常有趣的方向。

I don't think we're losing our lead there, as Chris alluded to. We're actually accelerating the combination studies. And so, already, at a monotherapy piece, we have a distinction from our competitors. Again, we believe that, in combination, we should see a more robust effect by being able to add inhibin E onto existing incretin therapies.

我不認為我們在那方面正在失去領先，正如 Chris 所暗示的。我們其實正在加速聯合用藥研究。因此，即使在單藥部分，我們已經與競爭對手有所區隔。同樣地，我們相信在聯合用藥中，透過把 inhibin E 加到既有的腸泌素（incretin）療法上，我們應該會看到更強勁的效果。

The opportunities there are twofold. I know, on one hand, we tend to think about giving more and trying to drive even more weight loss or, importantly, fat loss, which comes from inhibin E.

那裡的機會有兩個面向。我知道一方面，我們往往會想到給更多、並試圖推動更大的體重下降，或更重要的是脂肪下降，而這是來自 inhibin E。

I think we've got another distinction, which is the ability, frankly, not to have to push incretins to the edge of tolerability but being able to think about, actually, in this environment -- particularly, as we watch that space evolve -- being able to actually have to give less incretin therapy, in combination, to exert a maximal effect.

我認為我們還有另一個差異化點：坦白說，不必把腸泌素推到耐受性的極限；反而能在這個環境下——特別是當我們觀察該領域的演進——在聯合用藥時實際上可以用更少的腸泌素療法，就能發揮最大效果。

And so I think there's a big piece on titration where inhibin E can add to that combination strategy to ultimately drive profound visceral fat loss -- subcutaneous fat loss -- along and coincidentally with incretins.

因此我認為在劑量滴定上有很大一塊空間，inhibin E 可以加入這個聯合策略，最終與腸泌素並行且同步地推動顯著的內臟脂肪下降——以及皮下脂肪下降。

Ultimately, where we have generated data uniquely -- I think, for WAVE, with inhibin E, I think this maintenance setting is actually a wonderful place to be.

最終，就我們已經獨特地產生數據的地方——我認為對 WAVE 而言，搭配 inhibin E，我覺得這個維持治療（maintenance）的情境其實是個非常好的切入點。

We were just on calls recently where there's a lot of thought going into what does the evolving treatment landscape look like in a world where, like, antihypertensives, obesity treatment, is now going into a place where you have patients who have BMI reduction and, frankly, now you have payers saying, now that you're no longer meet the BMI criteria, you might need to come off therapy.

我們最近剛參加一些電話會議，大家正在深入思考：在一個不斷演進的治療版圖中，會是什麼樣子——就像降壓藥一樣，肥胖治療現在正走向一個階段：病人的 BMI 已經下降，而坦白說，現在有支付方（payers）說，既然你不再符合 BMI 標準，你可能需要停用治療。

And so there's actually now discussions on the payer side of saying, actually, you're going to lose those benefits and actually build a maintenance setting.

因此，支付方現在其實也在討論：實際上，你會失去那些效益，並且需要建立一個維持治療的情境。

As that maintenance concept evolves to what does a lifelong therapy look like that preserves outcomes, I think this maintenance opportunity is pretty substantial for us; that, if people invest, payers invest in getting to that healthy, stable outcome, how do you sustain that in a way that's going be tolerable; is not going to help drive additional complication side effects, tolerability effects.

隨著維持治療的概念演進到「如何以終身治療來維持療效成果」，我認為這個維持治療的機會對我們相當可觀；也就是說，如果人們投資、支付方投資讓病人達到健康且穩定的結果，那要如何以可耐受的方式維持它；不會去推動額外的併發症副作用、耐受性方面的影響。

The potential for, now, a once- to twice-a-year maintenance therapy is consequential.

因此，現在一年一次到一年兩次的維持治療潛力，是很有影響力的。

I think all three settings are set up for us to be uniquely differentiated. As we said, all three studies are pulled into this year and being accelerated. We'll be generating human data in the right population in all three of these settings.

我認為這三個情境都讓我們具備獨特的差異化優勢。正如我們所說，三項研究都已拉到今年並加速進行。我們將在這三個情境中、於正確的族群產生人體數據。

Maybe just add one more thing: Since this is new biology, as well, I think it's important to really try to understand the potential across a lot of ways. We have so many ways of winning this year.

也許再補充一點：由於這也是新的生物學機制，我認為非常重要的是，真的要用多種方式去理解其潛力。我們今年有很多種贏的方式。

Like, we're going to look at the 5% threshold for weight loss. We're looking at body composition, with a focus on fat loss. We're looking at potential cardiometabolic protection across lipids, HbA1c, with diabetes; and fats in liver for MASH; and then, in addition, the combo and maintenance.

例如，我們會看體重下降 5% 的門檻。我們會看身體組成，重點放在脂肪下降。我們會看在血脂、HbA1c（含糖尿病）等方面的潛在心代謝保護；以及肝臟脂肪對 MASH 的影響；此外，還有聯合用藥與維持治療。

There are a lot of opportunities. We're accelerating. We're going to get all of that data and starting everything this year.

機會很多。我們正在加速。我們會取得所有這些數據，並在今年啟動所有工作。

Catherine Novack, JonesTrading.

Catherine Novack，JonesTrading。

Hi. Morning. Thanks for taking my question.

嗨。早安。謝謝讓我提問。

I just have one on the 006 multi-dose regimen. When knowing that successive dosing can push mean max AAT higher, how should we be thinking about mean max AAT achievable with monthly versus biweekly dosing that was used for multi-dose regimen in the prior read-out?

我只有一個關於 006 多次給藥方案的問題。既然我們知道連續給藥可能會把平均最高 AAT 推得更高，那麼對於每月給藥相較於先前讀出中多次給藥方案所使用的每兩週給藥，我們應該如何看待可達到的平均最高 AAT？

How should we think about the delta between the single-dose and the multi-dose when we're switching to monthly?

當我們改成每月給藥時，我們應該如何看待單次給藥與多次給藥之間的差異（delta）？

Yeah. I think, one -- I'll take the second part first 'cause I think that'll be interesting, right, as we look about the what's the difference in terms of the on rate, if we think about it between the 200, the 400 and the [600]. We'll have the opportunity to look at, what do those kinetics look like, as you point out; and then, the difference between biweekly dosing versus, again, monthly and then, the impact on those rates.

是的。我想，有一點——我先回答第二部分，因為我覺得那會很有意思，對吧，當我們看在 on rate（起效速率）方面的差異時，如果我們把它放在 200、400 和[600] 之間來思考。我們會有機會去看，如你所指出的，那些動力學（kinetics）長什麼樣；然後，再看每兩週給藥相較於同樣是每月給藥的差異，以及對那些速率的影響。

I think, again, our framing today is that, if we assume that we are getting at biweekly 200 to near steady-state in the sense that it's not substrate-limited but in the absence of an acute phase response, where you're producing more transcript, you're not going to necessarily get more without the benefit of time, right?

我想，同樣地，我們今天的框架是：如果我們假設每兩週 200 的給藥已接近穩態（steady-state），也就是說在不受底物限制（not substrate-limited）的情況下，但在沒有急性期反應（acute phase response）的前提下——也就是你不會產生更多轉錄本（transcript）——那麼你不一定能在沒有時間累積的情況下得到更多，對吧？

The ability of cells to clear out Z cells to get healthier producing M, that's going to be the chief driver of seeing those increases. And so we'll be able to look at what happens on the repeat dosing of monthly versus biweekly. But I think that's the big shift in the dosing regimen.

細胞清除 Z 細胞、讓細胞更健康以產生更多 M 的能力，將會是看到那些增加的主要驅動因素。因此我們將能夠觀察每月重複給藥相較於每兩週給藥會發生什麼。但我認為這就是給藥方案上的重大轉變。

I think 600 is -- as Chris alluded to earlier this year, 600-monthly would give a better sense of keeping the kinetics and the timing of those dosing intervals, coupled with dose, to get better. This is really to see, can we see that we get to that same steady-state, the ability to mount acute phase responses of as much protein as patients need that they can produce but do that in a monthly regimen.

我想 600——正如 Chris 今年稍早提到的——每月 600 會讓我們更好地理解：維持動力學與這些給藥間隔的時序，並結合劑量，如何帶來更好的結果。這其實是要看：我們是否能達到相同的穩態，以及在病人需要的情況下，能否啟動急性期反應、產生足夠的蛋白，但同時以每月一次的方案來做到。

I think that's going to be the driver for this next update.

我想這將會是下一次更新的驅動因素。

Whitney Ijem, Canaccord Genuity.

Whitney Ijem，Canaccord Genuity。

Excuse me. I think -- just to quickly follow up on the last question. I think you answered it.

不好意思。我想——只是快速追問上一個問題。我想你已經回答了。

But just to put a finer point on it: Is what you're saying that, given the timeframe of the next update, we shouldn't necessarily expect to see a dose response on either total or M protein at steady-state at ATS. in particular, but that dose response could come, over time; or, maybe, in the setting of an acute phase response, later?

但我想把問題說得更精準一些：你的意思是，在下一次更新的時間範圍內，我們不一定應該期待在 ATS 上，特別是在穩態時，無論是總量或 M 蛋白會看到劑量反應（dose response）；但這種劑量反應可能會隨著時間出現；或者，可能在之後出現急性期反應的情境下才會看到？

Is that the right way to think about it?

這樣理解對嗎？

I think the way to see it is, when we share the data, it's going to be that. We'll see what the driver is of more.

我想比較好的看法是：當我們分享數據時，會呈現那樣的情況。我們會看看「更多」是由什麼驅動的。

Again, I think our demonstration, to date, even looking at the early data, is we got to more, right? We got to 20 micromolar in the setting of an acute phase response, where you actually generate more substrate, more transcript to be edited.

同樣地，我想我們迄今的證明——即使看早期數據——是我們確實達到了更多，對吧？我們在急性期反應的情境下達到 20 微莫耳（micromolar），在那種情況下你實際上會產生更多底物、更多需要被編輯的轉錄本。

I think, at a certain point, there's going to be this concept of steady-state editing, where, as much transcript there is being edited, you can clear Z. I think that's going to be what we clearly wat to see -- is Z protein continuing to come down.

我想在某個時間點，會有「穩態編輯（steady-state editing）」這個概念：也就是有多少轉錄本被編輯，你就能清除多少 Z。 我想我們非常想清楚看到的是——Z 蛋白是否持續下降。

And then, there's a function of time. I think it's more than thinking about dose as time -- how much duration is there for the body, over time, to clear Z; get healthier hepatocytes that can produce more protein.

然後，還有時間的因素。我想與其把它想成劑量，不如把它想成時間——身體隨時間清除 Z 的持續時間有多長；讓肝細胞（hepatocytes）更健康，從而能產生更多蛋白。

I don't know if there's -- yeah. (inaudible - microphone inaccessible)

我不知道是否有——是的。（聽不清——麥克風無法收音）

Madison El-Saadi, B Riley.

Madison El-Saadi，B Riley。

Hi. Good morning. Thanks for taking our question.

嗨。早安。謝謝讓我們提問。

Just looking at the Phase 2a MAD design, it's certainly looking like a [CV] MAD versus a, say, pure obesity study. I'm curious if the FDA acceptance include any commentary on body comp as a co-primary? Or was it more of a protocol discussion?

就第 2a 期 MAD 設計來看，它看起來更像是偏向 [CV] 的 MAD，而不是例如一個純粹的肥胖研究。我想知道 FDA 的接受是否包含任何關於把身體組成（body comp）作為共同主要終點（co-primary）的評論？還是更多是針對試驗方案（protocol）的討論？

Relatedly, what's the magnitude of MRI-PDFF reduction of Phase 2a INLIGHT that management would view as supporting a standalone MASH development versus, say, a subsegment of the obesity program? Thanks.

相關地，管理層認為第 2a 期 INLIGHT 的 MRI-PDFF 降幅要達到什麼幅度，才足以支持獨立的 MASH 開發，而不是例如作為肥胖計畫中的某個子分群？謝謝。

Yeah. I think, to your first point, in general, I do think it's just important -- we can't say this enough -- that obesity is a cardiometabolic disease -- running a study that fully interrogates the cardiometabolic implications of a target that comes out of human genetics that is a cardiometabolic target.

是的。我想就你第一點而言，總體來說，我確實認為有一點很重要——我們再怎麼強調都不為過——肥胖是一種心臟代謝疾病（cardiometabolic disease）——進行一項研究，全面探究一個源自人類遺傳學、且屬於心臟代謝靶點的靶點，其心臟代謝意涵。

I think, being able to fully extrapolate all of the value of what does that mean for a patient beyond just -- as you said, a classic obesity, which is -- the classic studies are looking at weight loss at the expense, really, of muscle. Muscle drives the predominant early reduction in that body weight.

我想，能夠把這對病人的意義所帶來的所有價值完整外推，而不只是——如你所說——傳統的肥胖研究；傳統研究是在減重，但代價其實是肌肉。在體重早期下降中，肌肉是主要驅動因素。

Being able to shift the narrative to not just reduction of fat, that will be important in the treatment of obesity. But all of the other advantages that come to patients and, frankly, are recognized by, again, what payers pay for, which is the cardiometabolic improvements is what this study is designed to elucidate.

能夠把敘事轉向不只是減少脂肪，這對肥胖治療會很重要。但對病人而言的所有其他優勢，而且坦白說，也正是支付方（payers）願意付費所認可的——也就是心臟代謝改善——這項研究就是為了闡明這些而設計的。

Yes,. we'll be able to look at body composition. That's part of the endpoints, as we said, as part of an obesity study, in addition to body weight.

是的，我們將能夠看身體組成。正如我們所說，這是終點的一部分，作為一項肥胖研究的一部分，除了體重之外。

But all the other important metrics, as you point out, are critical for us because they are all part of the development paradigm here.

但如你所指出的，所有其他重要指標對我們都至關重要，因為它們都是這裡開發範式（development paradigm）的一部分。

The last piece is -- and we've seen this with others and competitors who've done monotherapy reduction of liver fat -- and they saw consequential reductions in liver fat that pretty much surpassed other MASH programs and reduction of, again, fat in the liver.

最後一點是——我們也在其他公司與競爭對手身上看到：他們做了單藥（monotherapy）降低肝脂肪——而且他們看到顯著的肝脂肪下降，基本上超過了其他 MASH 計畫，以及肝臟脂肪的下降。

Given our potency, durability; given that we wouldn't expect this mechanism to be differentiated, we should see, in terms of, like, reduction in liver fat because of what we're doing -- we would expect to see substantial reductions.

考量到我們的效力（potency）與持久性（durability）；也考量到我們不預期這個機制會是差異化的，我們應該會看到——就像——因為我們正在做的事情而帶來的肝脂肪下降；我們預期會看到相當可觀的下降。

That target engagement there, reduction of fat on imaging, would guide us to say that MASH would be a target to pursue independently.

在那裡的靶點結合（target engagement）、影像上脂肪的下降，將會引導我們認為 MASH 是一個值得獨立推進的靶適應症。

Maybe add one more thing and that is that these cardiometabolic risk factors and liver fat, they're very strongly correlated with obesity and visceral fat.

也許再補充一點：這些心臟代謝風險因子與肝脂肪，與肥胖及內臟脂肪（visceral fat）高度相關。

It's not so much that -- we're not requiring, it's not an inclusion criteria. It's more that we're removing the exclusion criteria from the Phase 1, which hampered us in terms of looking at those things.

並不是說——我們並不要求，它不是納入標準（inclusion criteria）。更多是我們把第 1 期的排除標準（exclusion criteria）移除，因為那些標準妨礙了我們去觀察這些事情。

Again, we, just, based on the normal distribution of liver fat and this obesity class, expect that there is liver fat that we can look at.

同樣地，我們只是基於肝脂肪在這個肥胖族群中的常態分布（normal distribution），預期會有肝脂肪可供我們觀察。

Michael King, Rodman & Renshaw.

Michael King，Rodman & Renshaw。

Hey, guys. This is on (technical difficulty), for Mike. Congrats on the updates. Thank you for taking our questions.

嘿，各位。這裡因為（技術問題），我是代 Mike 發言。恭喜更新進展。謝謝回答我們的問題。

Just a quick question on the DMD program. Novartis was just talking about the drugs they got from (inaudible) that they're using antibodies to deliver oligos to the muscle.

關於 DMD 計畫我有個簡短問題。Novartis 剛剛在談他們從（聽不清）取得的藥物，他們正在用抗體把寡核苷酸（oligos）遞送到肌肉。

Do you think you have the best tissue penetration you can get with N531? How are you thinking about the competitive dynamic, as you head toward the NDA filing?

您認為使用 N531 時，您已經達到可取得的最佳組織穿透性了嗎？在您邁向 NDA 申請之際，您如何看待競爭態勢的變化？

Yeah. I think, in general, it's a wonderful question 'cause, again, in the absence of conjugates, if you look at the muscle exposure, our muscle exposure was pretty extraordinary, even in comparison to muscle-targeted ligands.

是的。我認為，整體而言，這是一個很棒的問題，因為同樣地，在沒有共軛物的情況下，如果你看肌肉暴露量，我們的肌肉暴露量相當驚人，即使與以肌肉為標的的配體相比也是如此。

When we think about distribution to the tissue, without having to add that -- that was consequential, not limiting. We saw for the first time, actually, real measurements of muscle regeneration.

當我們思考分佈到組織時，不需要再額外加入那個——那是重要的，但並非限制因素。我們其實第一次看到真正的肌肉再生實測數據。

When we think about getting into stem cells and regenerating muscle and think about, more broadly, the platform implications for being able to treat disease in the muscle, both with splicing oligonucleotides, siRNA, and others, as we talk about extrahepatic, I think there was not a requirement, as we think, to have to create the complexity of that to get exposure.

當我們思考進入幹細胞並促進肌肉再生，並更廣泛地思考此平台在治療肌肉疾病上的意涵——無論是剪接寡核苷酸、siRNA 或其他，正如我們談到肝外（extrahepatic）時——我認為，就我們的理解而言，並不需要為了取得暴露量而去增加那種複雜性。

The landscape's something we continue to look at, as it evolves. But, in terms of being able to access the tissue and what would be required to do that, I think our platform delivers exquisitely to muscle.

我們會持續關注這個領域的發展與演變。但就能否進入該組織以及需要什麼條件而言，我認為我們的平台能非常精準地遞送至肌肉。

Ananda Ghosh, HC Wainwright & Co.

Ananda Ghosh，HC Wainwright & Co.

Hey. Hey, guys Good morning.

嗨。嗨，各位，早安。

When you look at the genetics of the Activin E and when you talk to the academic community, one aspect of the biology which they all stress about is that inhibin E probably works best in the negative energy balance, which you see when you add Activin E knock-down approach with GLP-1s; which, also, Arrowhead has already shown.

當你看 Activin E 的遺傳學，並與學術界交流時，他們都強調生物學上的一個面向：inhibin E 可能在負能量平衡時效果最好；這種情況會出現在把 Activin E 敲低策略與 GLP-1 類藥物併用時；而 Arrowhead 也已經展示過。

The question is, what happens when you take off the GLP-1s during the maintenance phase, when, probably, the patient energy balance either neutralizes or probably goes to a positive energy balance?

問題是，在維持期把 GLP-1 類藥物停掉之後會發生什麼事？那時病人的能量平衡可能會回到中性，或甚至轉為正能量平衡。

And then, what happens to those liberated free fatty acids? Do you actually think that you will see a stability in the weight gain?

接著，那些被釋放出來的游離脂肪酸會怎麼樣？您是否認為體重增加會維持穩定？

If you do see, where do those free fatty acids go which are liberated, when you don't have GLP-1s? In which tissues do they accumulate?

如果確實會，那些在沒有 GLP-1 的情況下被釋放的游離脂肪酸會去哪裡？它們會在什麼組織中累積？

In the -- probably, in the same -- well, we've got to lab, as they did in the first point, right, when we saw it go to muscle.

在——可能是在同一個——嗯，我們得回到實驗室，就像他們在第一點所做的那樣，對吧，因為我們看到它進到肌肉。

If you actually -- a beautiful experiment that we had run in this was the pre-clinical data where, when you stabilize these obese mice on GLP-1, exactly to your point, their caloric consumption declines dramatically. They lose weight. They hit their steady-state.

如果你真的——我們在這方面做過一個很漂亮的實驗：在臨床前數據中，正如你所說，當你用 GLP-1 讓這些肥胖小鼠達到穩定時，它們的熱量攝取會大幅下降。它們會減重。然後達到穩態。

Interestingly enough, I think it does speak to the mechanism of action when you pre-dose. The timing of that was critical, not after you dose before the cessation to get the on-ramp of Activin E suppression before turning off the GLP-1.

有趣的是，我認為這也反映了預先給藥時的作用機制。時機非常關鍵：不是在停藥前才給藥，而是要在關掉 GLP-1 之前，先讓 Activin E 抑制開始發揮作用、完成「上坡」過程。

When you stop the GLP-1, you actually saw caloric consumption increase in both arms of the study; the placebo arm and the inhibin E treatment arm.

當你停止 GLP-1 時，你其實會看到兩個研究組別的熱量攝取都上升：安慰劑組以及 inhibin E 治療組。

Again, the energy balance, while going up, wasn't changed. What you did do in advance of putting those excess calories on is actually turn off exactly what the body wants to do -- actually, what's really damaging in weight cycling with GLP-1s.

同樣地，能量平衡雖然上升，但並沒有改變。你事先做的，是在那些額外熱量轉化為體重之前，先關掉身體最想做的事情——也就是在使用 GLP-1 進行體重循環時最具傷害性的那件事。

It's a real problem in patients who chronically come on and off of them -- is that, when the weight's regained, it's regained as fat; fat disposition in a variety of tissues. That's unhealthy.

這對於長期反覆使用、又停用的病人來說是個真正的問題——因為當體重回升時，回升的是脂肪；脂肪會沉積在多種組織中。那是不健康的。

What we did see is, when you actually take the brakes off lipolysis, the body's now not able to store new fat so you don't see that re-accumulation of fat. What you do see is we see this slight, like, increase -- is much like, probably, what we saw in the slight increase in the monotherapy arm, which is, it goes to muscle.

我們確實看到的是，當你把脂解（lipolysis）的煞車放開後，身體就無法再儲存新的脂肪，因此你不會看到脂肪再度累積。你會看到的是一點點、像是增加——很可能就像我們在單藥組看到的輕微增加一樣，也就是：它進到肌肉。

You end up with the free fatty acids and cholesterol. It feeds muscle. Muscle can then actually build.

最後你會有游離脂肪酸與膽固醇。它會供應肌肉。肌肉接著就能實際增長。

And so we don't expect -- that'll be interesting to see whether or not that plays out; that people who have actually been losing muscle, over time, might gain some muscle back (inaudible) at the same time but not restore that as fat and, hence, stay at steady-state.

因此我們不預期——這會很有意思，看看是否會如我們所想地發生；也就是那些長期在流失肌肉的人，可能會在同一時間把一些肌肉長回來（聽不清），但不會把它恢復成脂肪，因而維持在穩態。

Again, as we said on the call, that study's going to initiate this year. We're going to be generating that human data to recapitulate what we saw in the animal model.

同樣地，正如我們在電話會議上所說，那項研究將在今年啟動。我們將產出人體數據，以重現我們在動物模型中看到的結果。

I do think, if we think about what the best human genetic evidence is for Activin E, it's maintenance. These are people who go live a lifetime without thinking about their caloric consumption and have low abdominal visceral fat; have an improved metabolic profile in terms of risks of diabetes and cardiovascular disease and lipid profile.

我確實認為，如果我們思考 Activin E 最佳的人體遺傳學證據是什麼，那就是「維持」。這些人一輩子生活時不需要刻意思考熱量攝取，卻有較低的腹部內臟脂肪；在糖尿病與心血管疾病風險，以及血脂概況方面，也有更佳的代謝表現。

And so it's actually the setting where there's the most human genetic data for. We're excited to run that human clinical trial.

因此，這其實是擁有最多人體遺傳學數據支持的情境。我們很期待進行那項人體臨床試驗。

Thank you. There are no further questions at this time.

謝謝。目前沒有其他問題。

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

我現在把電話會議交回給 Paul Bolno 作結語。

Thank you for joining our call this morning.

感謝各位今天早上參與我們的電話會議。

We look forward to speaking with many of you later today and during the ATS conference next month.

我們期待今天稍晚以及下個月的 ATS 會議期間，能與各位中的許多人交流。

Have a great day.

祝各位有美好的一天。