WAVE Life Sciences Ltd (WVE) 2024 Q4 法說會逐字稿

Good morning and welcome to the Wave Life Sciences fourth quarter and full year 2024 earnings conference call. I'll now turn the call over to Kate Rausch, Vice President of Investor Relations and Corporate Affairs. Please go ahead.

早安，歡迎參加 Wave Life Sciences 2024 年第四季和全年財報電話會議。現在我將把電話轉給投資者關係和公司事務副總裁 Kate Rausch。請繼續。

Thank you, operator and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our fourth quarter and full year 2024, financial results in recent business highlights, including progress updates for obesity and AAPD clinical trials.

謝謝接線員，祝電話中的各位早安。今天早些時候，我們發布了一份新聞稿，概述了我們 2024 年第四季度和全年的財務業績以及最近的業務亮點，包括肥胖症和 AAPD 臨床試驗的進展更新。

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

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

Before we begin, I'd 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.

在我們開始之前，我想提醒您，本次電話會議中的討論將包括前瞻性陳述。這些聲明受到多種風險和不確定性的影響，可能導致我們的實際結果與這些前瞻性聲明中所述的結果有重大差異。

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

今天的新聞稿和我們提交給美國證券交易委員會的文件中討論了可能導致實際結果不同的因素，我們不承擔因任何原因更新或修改任何前瞻性聲明的義務。

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

現在我想把電話轉給保羅。

Thanks, Kate, good morning, and thank you all for joining us on today's call. Over the past decade, we have been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. And 2024 was an incredibly important year for Wave in realizing this vision. We announced positive data supporting our AATD, DMD and HD clinical programs.

謝謝，凱特，早安，謝謝大家參加今天的電話會議。在過去的十年裡，我們一直堅持不懈地致力於釋放 RNA 藥物改變人類健康的廣泛潛力。2024年對於Wave實現這個願景來說是極為重要的一年。我們公佈了支持我們的 AATD、DMD 和 HD 臨床計畫的積極數據。

Derisked an entirely new modality in the clinic with RNA editing and expanded our pipeline with novel, high impact programs that have potential to address millions of patients. We've carried this strong momentum into 2025 with the advancement of WVE-007 our gal neck, siRNA for obesity, to the clinic, and our consistent execution has kept us on track to deliver on key milestones for each program this year, I'll start today by discussing the progress we've made advancing WVE-007 for obesity.

利用 RNA 編輯降低了臨床中一種全新治療方式的風險，並透過有可能惠及數百萬患者的新穎、高影響力的計畫擴展了我們的產品線。我們將這一強勁勢頭帶入了 2025 年，將我們的女性頸部肥胖症 siRNA WVE-007 推進到臨床，並且我們始終如一的執行使我們在今年能夠實現每個項目的關鍵里程碑，今天我將首先討論我們在推進 WVE-007 治療肥胖症方面所取得的進展。

I'd first like to acknowledge that today, March 4, is world of obesity day and this year, the community is highlighting ways to take action to reduce the burden of obesity and related chronic illnesses.

首先我要承認，今天，3 月 4 日，是世界肥胖日，今年，社會正在強調採取行動減輕肥胖和相關慢性疾病的負擔的方法。

At Wave, we are engaged with individuals living with obesity as well as clinicians, so we can do our part to combat disease stigma and deliver healthier futures for this community. In these conversations, the opportunity for healthy, sustainable weight loss with our inhibitory silencing approach is resonating, enabled by our best in class, siRNA technology, we believe WVE-007 has the potential to lead the next frontier in obesity treatment for more than 1 billion people living with obesity globally, while GLP ones are rapidly becoming standard of care among weight loss therapeutics, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability and high discontinuation rates.

在 Wave，我們與肥胖患者以及臨床醫生合作，以便我們能夠盡自己的一份力量來對抗疾病恥辱並為這個社區帶來更健康的未來。在這些對話中，我們利用抑制沉默方法實現健康、可持續減肥的機會引起了共鳴，透過我們一流的 siRNA 技術，我們相信 WVE-007 有可能引領全球超過 10 億肥胖人士的肥胖治療的下一個前沿，而 GLP 藥物正在迅速成為減肥療法中的標準治療方法，它們的使用通常受到治療耐受性、肌肉停藥、耐受性差的高低性。

We believe WVE-007 is uniquely positioned to provide a best in class approach that addresses these limitations, it is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass with doses just once or twice a year.

我們相信 WVE-007 具有獨特的優勢，能夠提供一流的方法來解決這些限制，它旨在透過一種完全獨特的作用機制來推動減肥，這種機制可以促進脂肪燃燒，而不會影響肌肉質量，每年只需服用一兩次。

Our preclinical data on 07 have not only demonstrated its potential as front line treatment options, but have shown synergies with GLP ones, including as an add on for individuals requiring greater weight loss who cannot tolerate higher doses of GLP ones.

我們關於 07 的臨床前數據不僅證明了其作為一線治療選擇的潛力，而且還顯示出與 GLP 藥物的協同作用，包括作為需要更大減肥效果但無法耐受更高劑量 GLP 藥物的個人的補充。

We are also excited about WVE-007 potential as an off ramp to GLP one, enabling long term healthy weight maintenance with just once for twice yearly dosing. This maintenance approach would avoid the weight gain that is common when discontinuing GLP one and the associated metabolic risk avoid cycling.

我們也對 WVE-007 作為 GLP 出口的潛力感到興奮，只需每年服用一次或兩次即可實現長期健康體重維持。這種維持方法可以避免停止 GLP 時常見的體重增加以及相關的代謝風險避免循環。

Dosing is ongoing in our in light clinical trial of WV-007, for adults living with obesity and overweight, and I'm pleased to say that we have already completed enrollment in the first cohort.

我們正在對患有肥胖症和超重的成年人進行 WV-007 的輕度臨床試驗，我很高興地說，我們已經完成了第一批患者的招募。

We expect to deliver initial data from the trial in the second half of this year, which will include safety, tolerability and biomarkers reflective of healthy weight loss, turning to alpha one, antitrypsin deficiency and WVE-006 our GalNAc RNA editing oligonucleotide or Amer WVE-006 has the potential to be the first treatment for AETP that addresses the root cause of the disease with a convenient subcutaneously dose therapeutic we do not require IV administered LMPs or complex delivery vehicles like other treatments and developments and our approach vastly.

我們預計將在今年下半年提供試驗的初步數據，其中將包括安全性、耐受性和反映健康減肥、轉向 alpha one、抗胰蛋白酶缺乏症和 WVE-006 的生物標誌物，我們的 GalNAc RNA 編輯寡核苷酸或 Amer WVE-006 有可能成為第一個治療 AETP 的藥物，它通過方便的皮下治療它或複雜的輸送載體，我們的方法也大有不同。

Divers from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels.

DNA 編輯技術的多樣性依賴於高度活躍的、外源遞送的人工酶，這些酶可導致不可逆的旁觀者編輯和插入/缺失。

Our restoration clinical program started with healthy volunteers, and we have now completed all planned cohorts of both single and multi-dosing at dose levels higher than those planned for any cohort in the patient study.

我們的復健臨床計劃從健康志願者開始，現在我們已經完成了所有計劃的單劑量和多劑量給藥組，劑量水平高於患者研究中任何組的計劃劑量。

In our ATD patient study called restoration two, last year, we delivered a breakthrough in RNA medicines with the first ever clinical demonstration of RNA editing in humans with WVE-006 in our 200-milligram cohort, we observed mean 6.9 micromolar circulating Chem AAT and 10.8 micromolar of total AAT two weeks post single dose in the first two patient study, and observed increases in AAT from baseline as early as day three and as late as day 57 an impressive durability of effect 06 was well tolerated, with a favorable safety profile, including the completed restoration one clinical trial of healthy volunteers.

在去年名為「恢復二號」的 ATD 患者研究中，我們在 RNA 藥物方面取得了突破，在 200 毫克隊列中使用 WVE-006 首次在人體中進行了 RNA 編輯的臨床演示，在前兩名患者研究中，我們觀察到單劑量給藥兩週後平均循環 Chem AAT 為 6.9 微摩爾，總 AAT 為第三天 10.天就從基線增加，令人印象深刻的效果持久性 06 具有良好的耐受性，具有良好的安全性，包括已完成的健康志願者恢復一號臨床試驗。

Since this announcement, we have seen a surge in enrollment and demand among clinicians and patients to participate in the study. Multi dosing is underway in the 200-milligram cohort, where patients are receiving WVE-006 every other week, and our pre-clinical and clinical data support potential for extended dosing intervals and subsequent cohorts.

自從這次消息公佈以來，我們看到參與研究的臨床醫生和患者的人數和需求激增。200 毫克組正在進行多次給藥，患者每隔一周接受一次 WVE-006 治療，我們的臨床前和臨床數據支持延長給藥間隔和後續組的潛力。

We have also initiated the second single dose cohort at 400-milligrams, and we believe this higher single dose cohort, coupled with the multi dose 200-milligram cohort, will give us meaningful insights into extending the dosing interval. Looking ahead, we will have data from the full first cohort in 2025 including the complete single dose and multi dose portions.

我們也啟動了第二個 400 毫克單劑量組，我們相信這個更高的單劑量組加上 200 毫克多劑量組將為我們提供延長給藥間隔的有意義的見解。展望未來，我們將在 2025 年獲得第一批完整數據，包括完整的單劑量和多劑量部分。

We also plan to share data from the 400-milligram single dose cohort this year. These data will further inform the therapeutic potential of WVE-006 and our pipeline of RNA editing programs behind 006 we're advancing a wholly owned discovery pipeline addressing both hepatic and extra hepatic targets.

我們也計劃今年分享 400 毫克單劑量隊列的數據。這些數據將進一步說明 WVE-006 的治療潛力以及我們在 006 背後的 RNA 編輯程序管道，我們正在推進一條全資擁有的發現管道，以解決肝臟和肝外目標。

We unveiled three of these programs in our research day last year, which collectively provide the potential to address upwards of 10 million patients. As the year progresses, we plan on sharing new preclinical data from our hepatic and extra hepatic RNA editing programs with the goal of initiating clinical development of additional programs in 2026 in Duchenne, muscular dystrophy, all muscle biopsies have been collected, and we are on track to deliver 48-week data from our forward 53 clinical trial by the end of This month.

我們在去年的研究日上公佈了其中三個項目，它們總共有可能為超過 1000 萬名患者提供治療。隨著時間的推移，我們計劃分享來自肝臟和肝外 RNA 編輯計畫的新臨床前數據，目標是在 2026 年啟動針對杜氏肌肉營養不良症和肌肉營養不良症的更多計畫的臨床開發，所有肌肉活檢都已收集，我們預計在本月底之前提供來自前期 53 項臨床試驗的 48 週數據。

In the interim readout, last year, we demonstrated WVE and 531 potential to be a best in class therapeutic for up to 10% of the boys living with DMD amenable to exon 53 skipping, we observed highly consistent mean muscle content adjusted dystrophin of 9% evidence of improved muscle health, muscle concentrations that support monthly dosing intervals and distribution to myogenic stem cells, the progenitor cells for new myoblasts that give rise to new myocytes and ultimately aid in skeletal muscle regeneration.

在去年的中期報告中，我們證明了 WVE 和 531 有潛力成為多達 10% 的 DMD 男孩的最佳治療方法，這些男孩可以透過外顯子 53 跳躍獲得治療，我們觀察到高度一致的平均肌肉含量調整後的肌肉營養不良蛋白為9%，這表明肌肉健康狀況有所改善，肌肉濃度支持每月給藥間隔並分佈到成肌幹細胞，成肌幹細胞是新成肌細胞的祖細胞，可產生新的肌肉細胞並最終有助於骨骼肌再生。

Importantly, we also observed a safe and well tolerated profile. DMD is a devastating disease, and there is an urgent need for more effective and safe therapeutic options for patients, we frequently hear from caregivers about the burden of weekly IV dosing and the need for therapies that can distribute to the heart and diaphragm and reach stem cells, which would enhance functional benefit, improve quality of life and ultimately extend survival.

重要的是，我們還觀察到了安全性和耐受性良好的特性。DMD 是一種毀滅性疾病，迫切需要為患者提供更有效、更安全的治療選擇，我們經常聽到護理人員談到每週靜脈注射給藥的負擔，以及需要能夠分佈到心臟和橫膈膜並到達幹細胞的治療方法，這將增強功能益處，改善生活品質並最終延長生存期。

The upcoming 48-week data will include dystrophin from muscle biopsies, functional measures as well as safety and tolerability. We are also on track to deliver feedback from regulators by the end of the month.

即將公佈的 48 週數據將包括肌肉活檢中的肌肉營養不良蛋白、功能測量以及安全性和耐受性。我們也計劃在本月底前向監管機構提交回饋意見。

As a reminder, we have previously shared data from our portfolio of additional exons and pending positive updates on n5 31 we plan to advance a pipeline of oligonucleotides that addresses up to 40% of boys living with DMD, supported by our best in class muscle delivery, finally turning to WVE-003, our first in class allele selective oligonucleotide for the treatment of Huntington's disease.

提醒一下，我們之前已經分享了來自我們額外外顯子組合的數據，並且在 n5 31 獲得積極更新後，我們計劃推進一系列寡核苷酸，以解決多達 40% 的 DMD 男孩問題，並通過我們一流的肌肉輸送提供支持，最終轉向 WVE-003，這是我們用於治療亨廷頓氏病的首個等位基因。

HD impacts more than 200,000 people in the US and Europe alone, and there are no disease modifying therapies available. The disease is devastating, sometimes compared to having Alzheimer's, Parkinson's and ALS all at once, and is an autosomal dominant genetic disease that impacts multiple generations of family members.

光是在美國和歐洲就有超過 20 萬人患有亨丁頓舞蹈症，目前還沒有可以治癒該疾病的療法。這種疾病具有毀滅性，有時可堪比同時患上阿茲海默症、帕金森氏症和肌萎縮側索硬化症，是一種影響多代家庭成員的體染色體顯性遺傳疾病。

For more than 10 years, we have been committed to the HD community and to using our platform's exquisite specificity and unique chemistry to pioneer allele selective therapeutics by reducing mutant huntingtin at the mRNA and protein level WVE-003, addresses the underlying drivers of neurodegeneration in a. Patients by sparing wild type Huntington protein, which is critical to the health of the central nervous system.

十多年來，我們一直致力於亨廷頓氏舞蹈症 (HD) 社區服務，並利用我們平台的精湛特異性和獨特化學技術，透過在 mRNA 和蛋白質水平上減少突變亨廷頓蛋白來開創等位基因選擇性療法 WVE-003，解決神經退化性疾病的潛在驅動因素。透過保留對中樞神經系統健康至關重要的野生型亨廷頓蛋白來保護患者。

WVE-003 is uniquely positioned to address the full spectrum of HD from the early asymptomatic stage through the onset of symptoms and beyond. It is only through our platform's specificity of stereochemical control to best in class chemistry that allele selective silencing became possible to patients.

WVE-003 具有獨特的優勢，可解決亨丁頓舞蹈症的各個階段，從早期無症狀階段到症狀出現及之後。只有透過我們平台對最佳化學立體化學控制的特異性，才有可能對患者進行等位基因選擇性沉默。

Just last week, I attended the Annual CHDI Conference where our team had the opportunity to share our select HD clinical results and our plan to accelerate development of WVE-003 by using caudate atrophy as a primary endpoint, a known imaging marker that is potentially predictive of clinical outcomes.

就在上週，我參加了 CHDI 年度會議，在會上我們的團隊有機會分享我們精選的 HD 臨床結果以及我們以尾狀萎縮為主要終點（一種已知的可以預測臨床結果的成像標記）來加速 WVE-003 開發的計劃。

In addition to our podium and poster presentations, we had dozens of great conversations with HD researchers and advocates, and heard enormous enthusiasm for WVE-003 and our leadership in allele selective silencing as a reminder.

除了我們的講台和海報展示之外，我們還與亨廷頓氏病研究人員和倡導者進行了數十次精彩的對話，並聽到了人們對 WVE-003 和我們在等位基因選擇性沉默方面的領導地位的巨大熱情。

Data from our select HD trial showed potent and durable mutant huntingtin reductions of up to 46% and preservation of the wild type Huntington with just three doses of WVE-003.

我們選擇的亨廷頓舞蹈症 (HD) 試驗數據顯示，僅需三劑 WVE-003 即可有效且持久地減少高達 46% 的突變型亨廷頓舞蹈症，並保留野生型亨廷頓舞蹈症。

Importantly, there was a statistically significant correlation between allele selective mutant huntingtin reductions and slowing of caudate atrophy, marking the first time such a correlation has been observed in Huntington's disease.

重要的是，等位基因選擇性突變亨廷頓蛋白的減少和尾狀核萎縮的減緩之間存在統計學上的顯著相關性，這是在亨廷頓氏症中首次觀察到這種相關性。

Caudate is part of the striatum and one of the primary areas where HD manifests in the brain with atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about two to 4% per year.

尾狀核是紋狀體的一部分，也是亨廷頓氏舞蹈症在大腦中表現的主要區域之一，其萎縮在症狀出現前很多年就開始了，並以每年約 2% 至 4% 的速度持續穩定下降。

Correlations have been shown between caudate loss and clinical outcomes, and at the start of the year, we shared some of our own internal analyzes supporting such a correlation.

已經證明尾狀核丟失和臨床結果之間存在相關性，並且在今年年初，我們分享了一些支持這種相關性的內部分析。

Specifically, we looked at natural history data sets, including track and predict HD, which showed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset and disability by more than seven and a half years.

具體來說，我們研究了自然史資料集，包括追蹤和預測亨廷頓氏病，結果表明，尾狀核萎縮發生率絕對降低僅 1%，就會導致發病和殘疾延遲七年半以上。

This is a staggering number with meaningful implications for health and economic outcomes, and provides further evidence supporting rate of caudate atrophy as a primary endpoint for an efficient clinical trial.

這是一個驚人的數字，對健康和經濟結果具有重要意義，並提供了進一步的證據支持尾狀萎縮率作為有效臨床試驗的主要終點。

These data, along with the full clinical results from Select HD were both part of our engagement with FCA last year that led to supportive initial feedback. Preparation is ongoing for a global, potentially registrational phase two, three study of WVE-003 in adults with snip three and HD using caudate as a primary endpoint, and we remain on track to submit clinical trial applications, including an IND application for this phase two, three study in the second half of this year.

這些數據以及 Select HD 的完整臨床結果都是我們去年與 FCA 合作的一部分，並獲得了支持性的初步回饋。目前，我們正在為 WVE-003 進行一項全球性的、可能註冊的二期、三期研究做準備，該研究針對患有 snip three 和 HD 的成年人，以尾狀核為主要終點，我們仍在按計劃提交臨床試驗申請，包括在今年下半年提交這項二期、三期研究的 IND 申請。

In the interim, we've continued to receive substantial engagement in HD, including from potential strategic partners, and look forward to sharing more details on trial design and our path forward as the year progresses.

在此期間，我們繼續收到大量有關 HD 的參與，包括來自潛在策略合作夥伴的參與，並期待在未來分享更多有關試驗設計和未來發展方向的細節。

With that, I'll now turn the call over to Eric to share more detail on activity and provide an update on our emerging pipeline.

有了這些，我現在將電話轉給 Eric，讓他分享更多活動細節，並提供有關我們新興管道的最新資訊。

Thank you, Paul, and thank you to everyone joining us on the call today. As some of you may know, I spent the first part of my career as a physician scientist focusing on obesity and autocratic metabolic diseases.

謝謝你，保羅，也感謝今天參加我們電話會議的所有人。你們中的一些人可能知道，我職業生涯的初期是一名醫師科學家，專注於肥胖症和自主代謝疾病。

Last as a Professor of Medicine at Stanford, then five years at GSK as head of Human Genetics, genomic science and later target discovery across all therapeutic areas, before joining Wave last spring.

最後，他擔任史丹佛大學的醫學教授，然後在葛蘭素史克公司擔任了五年的人類遺傳學、基因組科學主管，後來瞄準了所有治療領域的發現，最後在去年春天加入 Wave。

For all of these reasons, I'm incredibly excited to talk about our (inaudible) program, our obesity program with strong support from human genetics. The benefits of such reports should not be underestimated as therapeutic targets supported by human addicts are, on average, associated with a two to four times higher probability of success in drug development when compared to targets without any genetic evidence.

基於所有這些原因，我非常高興談論我們的（聽不清楚）計劃，即得到人類遺傳學大力支持的肥胖計劃。此類報告的好處不容小覷，因為與沒有任何遺傳證據的目標相比，人類成癮者支持的治療目標平均與藥物開發成功率高出兩到四倍。

INHBE is a gene predominantly expressed in liver that produced a (inaudible) , which is created from liver and binds CIS receptor app seven in adipose tissue, in light of omnipresence of energy dense food liver in the Bini mRNA is upregulated, resulting in higher circulating active in E levels due to maladaptive response, and this promotes fast storage and an increase of abdominal BC, we chose to target the ligand in the bin E for several reasons.

INHBE 是一種主要在肝臟中表達的基因，它產生一種（聽不清），它由肝臟產生並與脂肪組織中的 CIS 受體 app 7 結合，鑑於肝臟中能量密集型食物的普遍存在，Bini mRNA 上調，導致由於適應不良反應導致循環活性 E 水平升高，這促進了快速儲存和腹部 BC 的增加，我們選擇針對 bin E 中選擇的配體有幾個原因。

First, using our best in class oligonucleotide chemistry to turn off protein production directly at the upstream source is the most efficient way to down regulate activity of this ligand receptor pair. And second, GalNAc-conjugates allow for a highly specific and efficient targeting deliver cells in a binary silencing leads to lower active and E levels, resulting in higher adipose like policies thereby decreased abdominal obesity, ultimately leading to healthy weight loss and an improved cardiometabolic profile.

首先，使用我們一流的寡核苷酸化學技術直接從上游源關閉蛋白質生產是下調此配體受體對活性最有效的方法。其次，GalNAc 結合物可以高度特異性和高效地靶向遞送細胞，二元沉默可降低活性和 E 水平，從而產生更高的脂肪樣政策，從而減少腹部肥胖，最終導致健康減肥和改善心臟代謝狀況。

Several large humanitarian studies have found that carries of heterozygous loss of function variants in the inhibitory gene have favorable metabolic profiles. Including reduced abdominal obesity and visceral fat, serum triglycerides, apo, B, fast and glucose. Hba1c, and decreases in several measures of liver disease, specifically alt, Corona, T1 an MRI, measure of liver inflammation and fibrosis and lower non-alcoholic fatty liver disease activity score.

幾項大型人道主義研究發現，抑制基因雜合功能喪失變異的帶因者俱有良好的代謝特徵。包括減少腹部肥胖和內臟脂肪、血清三酸甘油酯、載脂蛋白、B、空腹和葡萄糖。Hba1c，以及肝病的幾項指標下降，特別是 alt、Corona、T1 和 MRI、肝臟發炎和纖維化的指標以及非酒精性脂肪肝疾病活動評分降低。

Importantly, these carriers also have reduced risk of type two diabetes and coronary heart disease. So essentially, the outcome study has already been done using nature's experiment, which also supports the therapeutic threshold of 50% silencing of inability mRNA.

重要的是，這些帶因者罹患第二型糖尿病和冠狀動脈心臟病的風險也降低了。因此從本質上講，已經利用自然實驗完成了結果研究，該研究也支持沉默 50% 無效 mRNA 的治療閾值。

In addition to genetic studies and our convincing preclinical data, recent internal work has demonstrated a strong correlation of circulating active in E levels with BMI and blood samples from healthy individuals, providing an additional confirmation of the importance of this mechanism in driving obesity in humans.

除了基因研究和令人信服的臨床前數據外，最近的內部研究還證明了循環中活性 E 水平與健康個體的 BMI 和血液樣本之間存在很強的相關性，這進一步證實了這種機制在驅動人類肥胖方面的重要性。

As we've seen over the past several years, there have been incredible efforts to develop new therapies in the obesity space which treats the underlying causes of disease and subsequently drive meaningful outcomes for people living with obesity.

正如我們在過去幾年中所看到的，人們在肥胖領域做出了令人難以置信的努力來開發新的療法，以治療疾病的根本原因，並隨後為肥胖患者帶來有意義的結果。

It's important to step back and examine the approach for ARIN and beneath Gallic S RNA, within the broader context of current treatments such as GLP one, agonist and other therapies and development, although transformation for obesity medicine, GLP one drugs are associated with many disadvantages, as already mentioned by Paul several of these concerns have been highlighted recently, including in draft guidance from FDA earlier this year on developing therapies for weight reduction, which emphasized the agency's focus on establishing study standards that focus on sustained path loss, as opposed to pound by pound weight loss, which also involves drinking muscle mass.

重要的是回顧並研究 ARIN 和 Gallic S RNA 的方法，在當前治療（如 GLP 1、激動劑和其他療法和開發）的更廣泛背景下，儘管對於肥胖醫學來說，GLP 1 藥物存在許多缺點，正如 Paul 已經提到的那樣，其中一些問題最近已經得到強調，包括 FDA重點研究申請減肥療法的指導草案，該運動草案也強調

WVE-007, leverages an orthogonal approach from GLP one, focusing on peripheral action directly on fast tissue, rather than a centrally acting appetite regulation. Not only does this mean that we sidestep disadvantages of GLP ones, but it also opens up opportunities to position our therapy in relation to centrally acting drugs as an alternative addition or as an off ramp.

WVE-007 利用 GLP 的正交方法，專注於直接作用於快速組織的周邊作用，而不是中樞作用的食慾調節。這不僅意味著我們可以避開 GLP 療法的缺點，而且還為我們提供了機會，讓我們的療法可以作為中樞作用藥物的替代補充或出口。

Three use cases supported by preclinical data that we presented at our research day last fall, our first in human study of WV 007 is called in light the studies designed to set safety, tolerability, pharmacokinetics, biomarkers for target engagement, body weight and composition and other measures of metabolic health.

我們在去年秋天的研究日上展示了三個由臨床前數據支持的用例，我們對 WV 007 進行的首次人體研究是根據旨在設定安全性、耐受性、藥物動力學、目標參與的生物標誌物、體重和體質以及其他代謝健康指標的研究而命名的。

The single dose portion of the trial in adults living with overweight or obesity is underway, and as Paul shared earlier, the first cohort is already fully enrolled. We're very excited about the progress we've made bringing this unique and transformative approach into the clinic, and look forward to sharing data from the trial in the second half of this year.

針對超重或肥胖成年人的單劑量試驗部分正在進行中，正如保羅之前分享的那樣，第一批患者已經全部入組。我們對將這種獨特而變革性的方法引入臨床所取得的進展感到非常興奮，並期待在今年下半年分享試驗數據。

Now turning to our emerging pipeline of RNA editing programs, we're continuing to advance WVE-006, in the phase one, b2, a restoration two study in patients with a ATD who have the homozygous bi CZ mutation.

現在轉向我們新興的 RNA 編輯程序管道，我們正在繼續推進 WVE-006，該研究處於第一階段 b2，是對患有純合雙 CZ 突變的 ATD 患者進行的恢復性二期研究。

Our initial proof of mechanism data demonstrated impressive potency, durability of effect with WVE-006 our expected data later this year will assess the ability of 006 to restore healthy mat protein levels with multiple doses as well as at higher dose level.

我們初步的機制數據證明表明，WVE-006 具有令人印象深刻的效力和持久的效果，我們預計今年稍後的數據將評估 006 通過多次劑量以及更高劑量水平恢復健康墊蛋白水平的能力。

These data will also provide valuable learning to our broader RNA editing pipeline, which we continue to advance towards the clinic. Last year, we shared pre-clinical data on three of our programs leveraging RNA editing, which are wholly owned and build on our learnings from WVE-006 all three programs are strongly supported by human genetics and offer novel ways to treat diseases in areas of high unmet needs.

這些數據也將為我們更廣泛的 RNA 編輯流程提供寶貴的經驗教訓，我們將繼續推動此流程向臨床應用的進展。去年，我們分享了三個利用 RNA 編輯的計畫的臨床前數據，這些計畫均為我們全資擁有，並以我們從 WVE-006 中獲得的經驗為基礎，所有三個計畫都得到了人類遺傳學的大力支持，並為治療高度未滿足需求領域的疾病提供了新方法。

These programs also feature readily accessible biomarkers and approaches to assess pharmacodynamics, along with established regulatory paths, as with WVE-006, they leverage galvanic conjugation for efficient delivery to liver.

這些項目還具有易於獲取的生物標記和評估藥效學的方法，以及既定的監管路徑，就像 WVE-006 一樣，它們利用電流結合有效地輸送到肝臟。

Our PLM three, three program aims to correct appeal a (technical difficulty) variant to revert homozygous carriers to live with liver disease to the heterozygous state, which we expect will dramatically decrease ketosis and fibrosis in I 140 8m driven liver disease.

我們的 PLM 三、三計劃旨在糾正上訴（技術難題）變異，將患有肝病的純合攜帶者恢復為雜合狀態，我們預計這將顯著降低 I 140 8m 驅動的肝病中的酮症和纖維化。

This program includes a large genetically defined population of 9 million people in the US and Europe that are not served by (inaudible) silencing or by other therapies and development together, our LDLR and APO B programs comprise a comprehensive package designed to substantially lower LDL cholesterol among people with familial hypercholesterolemia or SH both programs apply RNA editing technology aiming to upregulate LLR and to correct the dominant apobec mutation.

該計劃包括美國和歐洲 900 萬個基因定義的龐大群體，他們無法透過（聽不清楚）沉默或其他療法和開發共同獲得服務，我們的 LDLR 和 APO B 計劃包括一個綜合方案，旨在大幅降低家族性高膽固醇血症或 SH 患者的 LDL 膽固醇，這兩個計劃都應用 RNA 編輯技術，旨在上調 LLR 並糾正顯性的 apobec 突變性。

Respectively, fewer than 50% of people living with heterozygous FH reach their treatment goals with current options including spasms and PCS canine inhibitors, and our early data indicates that LDLR regulation and APB correction could result in over 90% of these individuals reaching their treatment goal. This initial disease indication of FH includes 1 million people in the.

分別而言，不到 50% 的雜合子 FH 患者透過目前的治療選擇（包括痙攣和 PCS 犬抑制劑）達到治療目標，而我們的早期數據表明，LDLR 調節和 APB 校正可使超過 90% 的此類患者達到治療目標。FH 的初始疾病指徵包括了 100 萬人。

US and Europe. Additionally, our LDL RF regulation approach has massive upside expansion opportunities to people with statin intolerance or prior cardiovascular disease with poorly controlled LDL cholesterol, two groups that comprise over 30 million people in the US and Europe combined, we anticipate sharing new preclinical data from hepatic as well as hepatic programs this year, and we expect to initiate clinical development on multiple RNA editing programs in 2026 with that, I'd like to turn the call over to Kyle to provide an update on our financials.

美國和歐洲。此外，我們的 LDL RF 調節方法對於對他汀類藥物不耐受或先前患有心血管疾病且 LDL 膽固醇控制不佳的人群具有巨大的上行擴展機會，這兩類人群在美國和歐洲合計超過 3000 萬人，我們預計今年將分享來自肝臟和肝臟項目的新臨床前數據，我們預計將在 2026 年啟動 2026 年的新臨床前數據。

Thanks, Eric. Our revenue for fourth quarter in full year 2024 was $83.7 million and $108.3 million respectively, compared to $29.1 million and $113.3 million in the prior year, quarter and year the quarter over quarter increase was proven primarily by the recognition of the remainder of the deferred revenue under our Takeda collaboration.

謝謝，埃里克。我們 2024 年全年第四季的營收分別為 8,370 萬美元和 1.083 億美元，而去年、本季和去年的營收分別為 2,910 萬美元和 1.133 億美元，季增成長主要得益於我們與武田合作下剩餘遞延營收的確認。

Research and Development expenses were $44.6 million in the fourth quarter of 2024 as compared to $34.1 million in the same period in 2023 research and development expenses for the full year were $159.7 million in 2024 as compared to $130.0 million in 2023 this increase was primarily driven by spending for our new humanity program, along with our AA TV and DMV programs, our GNA expenses were $16.1 million for the fourth quarter of 2024.

2024 年第四季的研發費用為 4,460 萬美元，而 2023 年同期為 3,410 萬美元，2024 年全年研發費用為 1.597 億美元，而 2023 年為 1.3 億美元，這一增長主要得益於我們新人道主義計劃的支出以及我們的 AA 200 萬美元和 DMV TV 10 萬美元。

As compared to $13.7 million in the prior year quarter, and $59 million for the full year of 2024 as compared to $51.3 million in 2023 our net income was $29 million for the fourth quarter of 2024 as compared to a net loss of $16.3 million in the prior year. Quarter.

與去年同期的 1,370 萬美元、2024 年全年的 5,900 萬美元（2023 年為 5,130 萬美元）相比，2024 年第四季我們的淨收入為 2,900 萬美元，而去年的淨虧損為 1,630 萬美元。四分之一.

Net loss of the full year is $96.7 million for 2024 as compared to $57.5 million in 2023 we ended the year with $302.1 million in cash and cash equivalents, compared to $200.4 million as of December 31 2023 the increase in cash year over year is primarily due to our financing proceeds and the receipt of milestone payments and research funding from GSK.

2024 年全年淨虧損為 9,670 萬美元，而 2023 年為 5,750 萬美元。截至 2023 年 12 月 31 日，我們的現金及現金等價物為 3.021 億美元，而 2023 年 12 月 31 日為 2.004 億美元。現金年增率主要歸因於我們的融資收益以及收到葛蘭素史克的里程碑付款和研究資金。

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

我們預計，我們目前的現金和現金等價物將足以支持到 2027 年的運營，值得注意的是，我們與 GSK 合作下免除的潛在未來里程碑和其他付款不包括在我們的現金流中。

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

現在我將電話轉回給保羅，請他作最後發言。

Thank you, Kyle. We are off to an incredible start in 2025 and are looking forward to multiple value accretive inflection points ahead, with expected milestones across all four of our clinical programs and data from our growing RNA editing pipeline.

謝謝你，凱爾。我們在 2025 年迎來了一個令人難以置信的開端，並期待未來出現多個價值增值的拐點，我們的所有四個臨床項目和不斷增長的 RNA 編輯管道的數據都有望取得里程碑式的進展。

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

說完這些，我將把問題交給操作員進行問答。操作員？

(Operator Instructions) Ron Feiner with JPMorgan.

（操作員指示）摩根大通的 Ron Feiner。

This is Ron on for Eric. We were hoping to ask about WVE-006, if you can give us a little bit more information on the level of protein we should expect at baseline. At the readout, I know that at the top line the news that you put out earlier, the baseline was zero.

這是羅恩 (Ron) 代替埃里克 (Eric) 上場。我們希望詢問有關 WVE-006 的問題，您是否可以提供一些有關我們預期基線蛋白質水平的更多資訊。在讀數時，我知道您之前發布的新聞的第一行，基線是零。

But kind of looking at other clinical trials, such as augmentation therapy, the baseline is flow is three to six for the total and about half that for the functional so just kind of trying to get level set on that. Thanks.

但看看其他臨床試驗，例如增強療法，基線流量是總流量的三到六，功能流量的大約一半，所以只是試圖在此基礎上設定水平。謝謝。

Yeah, thank you. I mean, if you remember, the baseline was below the lower limit of detection on the assay. But I think stepping back, as we look forward, we're highly encouraged that at the starting point of a single dose, the lowest single dose is 200 we saw what would be therapeutically relevant levels of not just total ad.

是的，謝謝。我的意思是，如果您還記得的話，基線低於檢測的下限。但我認為，退一步來看，當我們展望未來時，我們非常鼓舞，在單劑量的起點，最低單劑量是 200，我們看到了治療相關的水平，而不僅僅是總劑量。

So that was the 10.8 of the 11 micromolar. But I think the most important thing for people to follow as we continue to generate our data, as others generate data, is to really be tracking the M-protein levels across studies. T

這就是 11 微摩爾中的 10.8 微摩爾。但我認為，隨著我們和其他人繼續產生數據，人們需要關注的最重要的事情是真正追蹤研究中的 M 蛋白質水平。T

hat M-protein level is important because that is definitively zero. So ZV patients who are entering these studies don't make any M-AAT protein and so if we continue to track M-AAT protein levels and safe to imagine that over. 60% of the protein we saw at the M-level was, sorry, the total level was M-protein.

M 蛋白質水平很重要，因為它肯定為零。因此，參與這些研究的 ZV 患者不會產生任何 M-AAT 蛋白，因此如果我們繼續追蹤 M-AAT 蛋白質水平，就可以安全地想像這一點。我們在 M 水平上看到的蛋白質有 60% 是，抱歉，總水平是 M 蛋白。

That's highly indicative of the mechanism of action of editing, so it's the best way to benchmark across programs in terms of the impact of the therapeutics having on editing efficiencies and protein generation. And what should we follow to be consistent?

這高度表明了編輯的作用機制，因此它是在治療對編輯效率和蛋白質生成的影響方面對各個程序進行基準測試的最佳方法。我們應該遵循什麼來保持一致？

I say that because, well, historically, we've tracked as an industry, total at levels in the field of IV protein replacement, in editing and correction. One of the things that we saw pre clinically was that with time, you see a reduction of aggregates.

我之所以這麼說，是因為從歷史上看，我們作為一個行業，一直在追蹤 IV 蛋白替代、編輯和校正領域的總體水平。我們在臨床前觀察到的情況之一是，隨著時間的推移，你會看到聚集物的減少。

So if you have alpha one antitrypsin, these protein aggregates breaking up, they also go into serum, and so you can have changes in levels of serum total protein over time that's coming from a variety of sources, those that are directly related to the editing and those related to C protein coming out through the aggregate. So the most consistent way to follow editing efficiency is m protein, because it's zero in the ZV patients.

因此，如果您有 α 一抗胰蛋白酶，這些蛋白質聚集體就會分解，它們也會進入血清，因此，隨著時間的推移，您可能會發現血清總蛋白質水平發生變化，這些變化來自各種來源，有些與編輯直接相關，有些與通過聚集體出來的 C 蛋白有關。因此，追蹤編輯效率最一致的方法是 m 蛋白，因為在 ZV 患者中它為零。

Great. Thanks. And, maybe just one more on 007 when we're doing DEXA scanning, do we expect the pattern of lean muscle mass change, proportional or absolute treating to mirror that of the weight loss. And you know, how often are you going to do DEXA scanning compared to weight measurements?

偉大的。謝謝。而且，也許在 007 上再多問一個問題，當我們進行 DEXA 掃描時，我們是否期望瘦肌肉質量變化的模式、比例或絕對治療能夠反映體重減輕的情況。您知道嗎，與體重測量相比，您多久進行一次 DEXA 掃描？

Yeah, so we haven't broken up yet when the DEXA scans are coming in those intervals. But I think to your point, the importance of adding DEXA scan is to really replicate we saw in pre-clinical models, which is that weight loss that we saw definitive weight loss was coming off of fat.

是的，所以當 DEXA 掃描在這些間隔內進行時我們還沒有分手。但我認為，正如您所說，添加 DEXA 掃描的重要性在於真正複製我們在臨床前模型中看到的結果，即我們看到的明確的減肥效果來自脂肪。

So with all fat loss, with no change in muscle mass in the preclinical experiments across multiple systems where we run that single dose combination and on the withdraw study, so we have multiple examples of preserving muscle, sparing with fat, lowering and to your point, using DEXA scanning as part of that study will enable us to use that as one of the biomarkers that we can evaluate in healthy, sustainable weight loss in the clinic in this study.

因此，在我們運行單劑量組合的多個系統的臨床前實驗和停藥研究中，隨著脂肪的減少，肌肉質量沒有變化，因此我們有多個保留肌肉、節省脂肪、降低體重的例子，正如您所說，使用 DEXA 掃描作為該研究的一部分，使我們能夠將其用作生物標誌物之一，我們可以在本研究中在臨床上評估健康、可持續的減肥效果。

And then maybe one short one, what signal from the DEXA scanning would be indicative of a healthier weight loss versus a pattern with GLP ones. Okay,

然後也許有一個簡短的問題，與 GLP 模式相比，DEXA 掃描發出的什麼訊號可以顯示更健康的減肥效果。好的，

Yeah, we have not shared that. What we can share is we'll have multiple opportunities to index that DEXA scans across the study to give a dynamic range with which we can show that.

是的，我們還沒有分享過。我們可以分享的是，我們將有多個機會在整個研究中對 DEXA 掃描進行索引，以提供我們可以顯示的動態範圍。

Salim Syed with Mizuho Group.

瑞穗集團的 Salim Syed。

Great. Good morning, guys. Thanks for the questions, Paul, maybe just a few from us on DMD, since we're getting that read up pretty soon. Here the case confirmed for us. Are the discussions being had with the 48 week data, the discussions with regulators being had with the 48 week data?

偉大的。大家早安。謝謝你的提問，保羅，也許我們只是問了一些關於 DMD 的問題，因為我們很快就會讀到這些內容。此處我們證實了這一情況。是否正在進行有關 48 週數據的討論，是否正在與監管機構進行有關 48 週數據的討論？

Or is it just the 24 week and Could you perhaps, just as we get closer here, bookend the scenarios that we should be considering coming out on this readout. And then just two quick clarifications here, just remind us where, how much PMO switchers, if that's even a consideration in this current data set.

或者只是 24 週，也許，就在我們越來越接近這裡的時候，你能為我們在這份讀物上應該考慮的場景定下基調嗎？這裡只需簡單澄清兩點，提醒我們 PMO 切換器在哪裡、有多少，如果這在當前資料集中是一個考慮因素的話。

And then also, just as you're kind of considering, you know, with the current data that you have in hand just your pharmacoeconomic work, how you're preliminary thinking about pricing here. Thank you.

然後，正如您所考慮的，根據您手頭上現有的藥物經濟學數據，您是如何初步考慮定價的。謝謝。

Yeah, no. Thank you for the questions. And as you pointed out, this is around the process of this data. So one what's been consistent was that the agency is being engaged around our 24 week data, the data we had shared previously.

是的，不。謝謝您的提問。正如您所指出的，這是圍繞這些數據的處理。因此，始終一致的是，該機構正在關注我們的 24 週數據，即我們先前共享的數據。

Obviously, we'll continue to have these data as we move forward, but the data was from the existing data sets that we have, and as I mentioned, we anticipate having that feedback in line with the data from the 48 week study.

顯然，隨著我們不斷前進，我們將繼續擁有這些數據，但這些數據來自我們現有的數據集，正如我所提到的，我們預計該回饋將與 48 週研究的數據一致。

So that'll we'll be able to give an update both on the regulatory interactions as well as the data from the study as it relates to and sorry, Celine, there were a couple there, so I want to make sure we hit each one of those as we think about the variety of scenarios coming out of this.

這樣，我們將能夠提供有關監管互動以及與之相關的研究數據的最新信息，抱歉，席琳，那裡有幾個，所以我想確保我們在考慮由此產生的各種情景時能夠滿足其中的每一個。

I mean, I think one of the things that we've seen is the most consistent, highest level of dystrophin that's been seen before the 9% and so if we think about that consistency and that magnitude, I think we're going to learn a lot about what a subsequent six months staying on the same dosing regimen is going to do to dystrophin kinetics.

我的意思是，我認為我們所看到的情況之一是在 9% 之前看到的最一致、最高水平的肌營養不良蛋白，所以如果我們考慮這種一致性和這種程度，我認為我們將學到很多關於接下來六個月保持相同的給藥方案將對肌營養不良蛋白動力學產生什麼影響的知識。

So I think there's the opportunity to understand what happens with stabilization and plateauing of dystrophin, or frankly, increasing in dystrophin. So we're going to be able to. Assess that over the additional six months of dosing. I think the other thing that's going to be important with further dosing is we already saw, the initial study was improvement in muscle repair, right?

因此，我認為有機會了解肌肉營養不良蛋白的穩定性和平台期發生的情況，或者坦白說，肌肉營養不良蛋白的增加情況。所以我們將能夠做到。在額外六個月的服藥期間進行評估。我認為進一步給藥的另一個重要方面是我們已經看到，初步研究表明肌肉修復有所改善，對嗎？

We saw reductions in CKS. We saw muscle improve, health improvement getting to those regenerative stem cells. So a whole variety of features of improvement in muscle health. And what's going to be important to us as well is we will also be assessing that muscle architecture over the subsequent six months.

我們看到 CKS 減少了。我們看到肌肉得到改善，健康狀況因這些再生幹細胞而得到改善。因此，肌肉健康有多種改善特徵。對我們來說同樣重要的是，我們還將在接下來的六個月內評估肌肉結構。

So again, more opportunities to look at the impact of improvement in muscle health, muscle repair, and then lastly, and importantly, being able to assess clinical measurements. So while not powered for statistically significant clinical outcome measurements, it's still a relatively small study.

因此，再次強調，我們有更多的機會觀察肌肉健康改善、肌肉修復的影響，最後，也是最重要的，能夠評估臨床測量結果。因此，雖然它無法提供具有統計意義的臨床結果測量數據，但它仍然是一項規模相對較小的研究。

I think we do expect to observe trends, and so being able to look at 95% stride velocity, being able to look at time to ride and other sensitive markers will give us that opportunity to assess the translation of that improvement in dystrophin to muscle health and muscle integrity, ultimately to the impact on clinical measurements, we have done a number of early discussions, and do see a substantial opportunity in PMO switchers, both in our engagement with clinicians and patients.

我認為我們確實希望觀察趨勢，因此能夠觀察 95% 的步幅速度、能夠觀察騎行時間和其他敏感標記將使我們有機會評估肌營養不良蛋白的改善對肌肉健康和肌肉完整性的影響，最終對臨床測量產生影響，我們已經進行了一些早期討論，並且確實在 PMO 轉換器中看到了巨大的機會，無論是在我們與臨床醫生還是患者的互動中。

We also know that a substantial portion of the exon 53 patients are not on therapy, so there's an opportunity not just to switch those who are currently on therapies to a less frequent regimen with potential higher dystrophin and opportunities there without a change in safety, risk benefit profile.

我們也知道，外顯子 53 患者中有相當一部分沒有接受治療，因此我們不僅有機會將目前正在接受治療的患者轉換為頻率較低、可能產生更高肌肉營養不良蛋白的治療方案，而且還有機會在不改變安全性和風險收益狀況的情況下進行治療。

So we see that as a very important opportunity on switching but we do know that there's a large opportunity on patients who are not on existing therapies, and at this stage, we haven't yet to comment on our pharmacoeconomic analysis and pricing funds.

因此，我們認為這是一個非常重要的轉換機會，但我們確實知道，對於未使用現有療法的患者來說，這是一個很大的機會，目前，我們尚未對我們的藥物經濟分析和定價資金發表評論。

Joon Lee with Truist Securities.

Truist Securities 的 Joon Lee。

Congrats on the progress, and thanks for taking our questions. Correct me if I'm wrong, but our understanding is that pending outcome of the meeting PTC is having with the FDA in second quarter, there is a chance that Huntington lowering may be deemed an adequate surrogate endpoint reasonably likely to predict clinical outcome. If that is the case, would you still proceed with the MRI as a primary endpoint? And I have a quick follow up?

恭喜您的進展，並感謝您回答我們的問題。如果我錯了，請糾正我，但我們的理解是，等待 PTC 與 FDA 在第二季度舉行會議的結果，亨廷頓降低有可能被視為合理預測臨床結果的適當替代終點。如果是這樣，您還會繼續以 MRI 作為主要終點嗎？我還有後續事宜嗎？

Yes, and I think it's an important if, but yes, I think if they were to demonstrate data along clinical measurements correlating with mutant huntingtin, and the FDA were willing to accept that data as a clinical surrogate biomarker for Huntington's disease, meaning that mutant huntingtin lowering could be associated as a reasonably likely to predict clinical benefit, and the FDA were to make that an end point, then we're in a position to file up of our earlier data.

是的，我認為這是一個重要的“如果”，但是是的，我認為如果他們能夠展示與突變亨廷頓蛋白相關的臨床測量數據，並且 FDA 願意接受該數據作為亨廷頓病的臨床替代生物標誌物，這意味著突變亨廷頓蛋白的降低可以合理地預測臨床益處，並且 FDA 將其作為終點，那麼我們就可以提交我們早期的數據。

We have a placebo controlled data with the highest, I say, the most substantial lowering of mutant huntingtin that's been seen to date, at 46% lowering. And on top of mutant huntingtin lowering spares wild type, which we know is an important indicator to clinicians patients, but also to the agency itself.

我們有一個安慰劑對照數據，其中顯示了迄今為止觀察到的突變亨廷頓蛋白的最大降低，降低了 46%。除了降低突變型亨廷頓蛋白水平之外，我們還知道，這對臨床醫生、患者以及機構本身來說都是一個重要指標。

So we would deem that existing data set substantial to file and view the subsequent studies we run as confirmatory and make those changes. So if that changes as a regulatory endpoint. It's beneficial for the field and for us in particular,

因此，我們認為現有資料集值得歸檔，並將我們進行的後續研究視為確認，並做出這些變更。因此，如果監管終點發生變化。這對這個領域，尤其是對我們，都是有益的。

Great and then you mentioned Huntington, prevalence of more than 200,000 in the US and Europe alone, which is higher than the 50 to 60,000 historically cited by other companies. What changed? And you know, what kind of data are you looking at that tells you that the opportunity here might be much bigger than previously thought.

太好了，然後您提到了亨廷頓舞蹈症，僅在美國和歐洲就有超過 200,000 人患病，高於其他公司歷史上引用的 50 到 60,000 人。什麼改變了？你知道，你正在查看什麼樣的數據來告訴你這裡的機會可能比以前想像的要大得多。

I think historically, as numbers get cited in early data sets, they tend to oftentimes reflect the symptomatic HD, so patients who move to the diagnosis clinically on HD. And I think again, one of the main advantages of why we see allele specific silencing is so critical in the disease treatment paradigm for Huntington's disease, is that ability to move into that early setting.

我認為從歷史上看，隨著早期數據集中引用數字，它們往往反映出症狀性亨廷頓氏病，因此患者會在臨床上確診亨廷頓氏病。我再次認為，等位基因特異性沉默在亨廷頓舞蹈症的疾病治療模式中如此重要，其主要優勢之一是能夠進入早期階段。

And if we think about the work that was done over the last year by the Huntington's research community in restaging Huntington's disease, we used to have a designation between pre manifest and manifest as kind of a bifurcation.

如果我們思考一下亨廷頓舞蹈症研究界去年在重新分期亨廷頓舞蹈症方面所做的工作，我們過去常常將顯性前期和顯性期稱為一種分叉。

What's really been done in that restaging is realizing that Huntington's disease, disease starts well before the onset of symptoms, and that you can have substantial changes in caudate, on measurement, on MRI, before the onset of symptoms occurred where a patient would have historically been diagnosed with Huntington's disease.

重新分期的真正目的是認識到亨廷頓舞蹈症早在症狀出現之前就已經存在，並且在出現症狀之前，通過測量和 MRI 檢查，可以發現尾狀核發生了顯著變化，而患者此前可能被診斷患有亨廷頓舞蹈症。

So as we take that opportunity to say, if you have an allele specific therapy, meaning you can treat earlier in the disease setting, knock out the bad protein well before you get neurodegeneration, and preserve wild type protein so you don't exacerbate the onset of disease.

因此，我們藉此機會說，如果您有一種等位基因特異性療法，這意味著您可以在疾病早期進行治療，在出現神經退化性病變之前就消除壞蛋白質，並保留野生型蛋白質，這樣就不會加劇疾病的發生。

The real opportunity Huntington is to move early, early in the disease setting, to genetic diagnosis. And I think one of the things we'll all learn on. Um in the HD community is as more therapies continue to come forward and genetic testing continues to increase, the propensity and incidence of Huntington's may be well under predicted based on the current diagnostic criteria.

亨廷頓舞蹈症的真正機會在於及早、在疾病早期進行基因診斷。我認為這是我們所有人都會學到的一件事。在亨廷頓舞蹈症 (HD) 社區中，隨著越來越多的治療方法的出現和基因檢測的不斷增加，根據目前的診斷標準，亨廷頓舞蹈症的傾向和發病率可能被低估。

Joe Schwartz with Leerink Partners.

Leerink Partners 的 Joe Schwartz。

Great. Thanks very much. I was wondering, how should we think about how the effect of WBE 06 could look after multiple doses of 200-milligrams? Can you share any general insights that you have from your pre-clinical, healthy volunteer or modeling work so that we can appreciate how the kinetics might evolve from the strong single dose data you reported last year.

偉大的。非常感謝。我想知道，我們應該如何看待 WBE 06 在多次服用 200 毫克後的效果？您能否分享您從臨床前、健康志願者或建模工作中獲得的任何一般見解，以便我們能夠根據您去年報告的強有力的單劑量數據了解動力學如何演變。

Yeah. I mean, it's data not only that we have from 06 but with PN chemistry across multiple formats, what we've seen is every time we've gone from single doses to multi doses, we've seen higher intercellular retention of drug, translating to improvements in efficiency.

是的。我的意思是，我們不僅有 06 年的數據，而且還擁有跨多種格式的 PN 化學數據，我們看到的是，每次我們從單劑量到多劑量，我們都看到藥物的細胞間保留率更高，從而轉化為效率的提高。

So, as we said, and thank you for acknowledging with the early data from the single dose, we see already a substantial uptick in protein production, and we expect with multiple doses for that not just to be sustained, but actually to be increased.

因此，正如我們所說的，感謝您對單劑量早期數據的認可，我們已經看到蛋白質產量大幅上升，並且我們預計，通過多劑量接種，這種產量不僅可以維持，而且實際上還會增加。

And so the opportunity also exists, and this is important as we think about the future dosing regimens for the study is that we've seen consistently with multi dosing, also extension and durability, meaning drug stays in.

因此機會也存在，這一點很重要，因為我們考慮未來研究的給藥方案，我們已經看到多次給藥具有持續性、延長性和持久性，這意味著藥物可以留在體內。

So it's not just drug into the cell, it's retention, meaning decreasing drug out and therefore improving that potency and durability quotient. So we're going to learn two things from the 200-milligram moldy doses.

因此，這不僅僅是藥物進入細胞，而是保留，這意味著減少藥物流出，從而提高效力和耐久性商數。因此，我們將從 200 毫克發霉的劑量中了解到兩件事。

One is what continues to happen on the protein dynamics, but importantly, we're also going to see what happens with that durability. It's why this 400-next milligram cohort is important, because imagine we already saw the 200-milligram cohort, which is therapeutically relevant, levels of M-AAT protein.

一是蛋白質動力學將繼續發生什麼，但重要的是，我們還將觀察這種耐久性會發生什麼。這就是為什麼這個 400 毫克的群體很重要，因為想像我們已經看到了與治療相關的 200 毫克隊列的 M-AAT 蛋白水平。

That next window that we'll get on the dose response between two to four will be really important. And that data so that amplitude data, we've said this before, the amplitude data between single doses and what happens with the multi dose will continue to refine our modeling as we think about the prediction of the multi dose frequency in Cohort Two, and then ultimately, what the design of cohort three is that would lead to a potentially registration study.

我們將在下一個窗口期間獲得 2 到 4 個劑量反應，這將非常重要。我們之前說過，這些數據即幅度數據，單劑量之間的幅度數據以及多劑量發生的情況將繼續完善我們的模型，因為我們會考慮預測第二組中的多劑量頻率，最終，第三組中的設計將導致潛在的註冊研究。

Okay, thanks. And then for WVE-007, how long will patients be treated? By the time you share data this year? Do you hope to match the total weight loss effect of GLP one therapy at a similar time point, recognizing that these would be cross trial comparisons, of course, or should we focus on the amount of non-lean body mass changes, given this is a different mechanism,

好的，謝謝。那麼對於WVE-007，患者需要接受多久的治療呢？今年到時候分享數據嗎？您是否希望在相似的時間點達到與 GLP 單一療法相同的整體減重效果（當然，這些是交叉試驗比較），或者我們應該關注非瘦體重的變化量，因為這是一種不同的機制，

Absolutely. So we haven't provided the cutoff point yet. We'll continue to run the study, and we'll provide data from the study. But it's fair to say, as you think about the data from the single dose and thinking about the impressive durability of the opportunity of six month to 12-month durability, that the single dose data is really reflective of what you'd expect to see with long term treatment. Pre clinically, we saw weight loss similar to the GLP ones and semaglutides.

絕對地。所以我們還沒有提供截止點。我們將繼續進行這項研究，並提供研究數據。但公平地說，當您考慮單劑量數據並考慮六個月到十二個月的持久性機會的令人印象深刻的持久性時，單劑量數據確實反映了您期望透過長期治療看到的結果。在臨床前，我們看到了與 GLP 和司美格魯肽相似的體重減輕效果。

So I think the opportunity exists to follow weight I think what's going to be really important, as you brought up, is really to delineate this concept of weight loss in a very broad stroke category of muscle and fat, to really be able to break that down into fat loss.

因此，我認為存在追蹤體重的機會，我認為真正重要的是，正如您所說，在肌肉和脂肪的非常廣泛的類別中描述減肥的概念，以便真正能夠將其分解為脂肪減少。

And I think that's what we want to see in the upcoming study, is those changes in body composition, in addition to biomarker data. So I think the totality of that data to distinguish it from GLP one. So not just I think where we are currently is Every medicine is put up against the same because it's very much similar classes.

我認為，除了生物標記數據之外，我們還希望在即將進行的研究中看到身體組成的變化。所以我認為這些數據的總體可以將其與 GLP 區分開來。因此，我認為我們目前的情況不僅僅是每種藥物都面臨相同的問題，因為它們的類別非常相似。

And what's that impact to overarching weight loss at the expense of muscle with the properties that are very similar. I think the full opportunity in this initial data set is really distinguish this unique category of medicines from that GLP, one, where we're not doing essentially chemical starvation, we're driving a metabolic shift in phenotype. And so we believe that these data will be supportive in addressing that thesis and being able to demonstrate the difference of inhibiting as an independent mechanism for healthy, sustainable weight loss.

那麼，以非常相似的肌肉為代價來達到整體減肥效果會有什麼影響呢？我認為這個初始數據集的全部機會是真正將這一獨特的藥物類別與 GLP 區分開來，首先，我們不是在進行本質上的化學飢餓，而是在推動表型的代謝轉變。因此，我們相信這些數據將有助於解決該論點，並能夠證明抑製作為健康、可持續減肥的獨立機制的差異。

Roger Song - Jefferies.

羅傑宋 - 傑富瑞。

Great. Thanks for the question. So a couple questions on us. So the first one is for the ATD. I think Paul, you mentioned you. Are you expecting the. Higher dose on the multi dose and higher dose may be able to increase the M-protein production, correction and then total protein production.

偉大的。謝謝你的提問。所以我們有幾個問題。第一個是針對 ATD 的。我想保羅，你提到了你。您是否期待？多劑量中的較高劑量和較高劑量可能能夠增加 M 蛋白的產生、校正，然後增加總蛋白質的產生。

So my question is, do we know the coloration between the M-protein level and the total protein level versus the liver and the lung function given so far. We only have the replacement therapy, but we have some other genetic medicine try to increase the level a little bit higher than what you have seen being the set 200 meter web dose. Thank you.

所以我的問題是，我們是否知道迄今為止給出的肝臟和肺功能中 M 蛋白水平和總蛋白水平之間的差異。我們只有替代療法，但我們也有一些其他基因藥物，試圖將水平提高到比你所看到的設定的 200 米網劑量略高一點。謝謝。

Yeah. I mean, it's a wonderful question, going back to just the basis for RNA editing. And if we think about the basis that drove how 11 micromolar, which we all kind of cite, and you know, has been subsequently, there's been discussions around with IV protein replacement, where that level is setting, we have to kind of remember how we got to that level, to your question about what's required for lung and liver protection. And so if we do think about the heterozygous phenotype that 50% level of correction.

是的。我的意思是，這是一個非常好的問題，讓我們回到 RNA 編輯的基礎。如果我們思考一下驅動 11 微摩爾的基礎，我們都提到了這一點，你知道，隨後，圍繞靜脈蛋白質替代進行了討論，該水平的設定，我們必須記住我們是如何達到這個水平的，關於你的問題，即肺和肝臟保護需要什麼。因此，如果我們確實考慮雜合表型，那麼校正水準為 50%。

So the nature of that was about 11 micromolar, if you look at the kind of lower limits of that heterozygous population, that's that was the benchmark for setting that level of total protein, and it was really set off a dynamic range of essentially people who are walking around with one copy of a healthy Alpha One antitrypsin protein in the other within this folded copy, which isn't necessarily an apples to apples, when you imagine, when you're adding on protein on top of that, to set a level with replacement, those patients still have a reserve of me being able to make 50% M-protein in production.

因此，其性質約為 11 微摩爾，如果您查看雜合群體的下限，那就是設定總蛋白質水平的基準，並且它實際上設定了一個動態範圍，基本上是那些攜帶一個健康 Alpha One 抗胰蛋白酶蛋白副本的人，另一個副本位於這個折疊副本中，這並不一定是蘋果對蘋果，您可以想像，當您在此基礎上添加蛋白質以設置替代蛋白質 50% 時，這些

But we take this back to what we're doing in the field of editing. The thesis was, really, could we restore that heterozygous population back where we know that by doing that, that we could actually have them rely on the human clinical data that shows that those heterozygous patients have protection of lung function and liver function.

但我們把這回過頭來談談我們在編輯領域所做的事情。我們的論點是，我們能否將雜合子群體恢復到我們所知的水平，透過這樣做，我們實際上可以讓他們依賴人類臨床數據，這些數據表明這些雜合子患者的肺功能和肝功能受到保護。

What was encouraging, too, when we think about the benefit of RNA editing it by editing in the promoter region, we're really restoring that functional activity back to these patients. So we do need to think about RNA editing as a different category than how we think about protein replacement, because we're really restoring that function back to these patients.

同樣令人鼓舞的是，當我們考慮到透過編輯啟動子區域來編輯 RNA 的好處時，我們確實恢復了這些患者的功能活動。因此，我們確實需要將 RNA 編輯視為與蛋白質替代不同的類別，因為我們實際上正在為這些患者恢復該功能。

So we went back to our clinical data, and if you think about what we've already seen at 11 micromolar of total protein, and over 60% of that being M-protein, we've essentially recapitulated what you'd expect to see in that heterozygous patient. We're encouraged to see what happens over time with repeat dosing, and where the levels of protein can go, also M-protein, but also looking at the durability.

因此，我們回顧了我們的臨床數據，如果您想想我們已經看到的總蛋白質含量為 11 微摩爾，並且其中 60% 以上是 M 蛋白，那麼我們基本上重現了您期望在該雜合子患者身上看到的情況。我們很高興看到重複給藥後會發生什麼情況，以及蛋白質水平以及 M 蛋白的變化，同時也觀察其持久性。

But again, it's going to be great to see what happens as we increase that total level of protein, and what that level of correction can continue to be. So I think the key for us still remains that if you follow the translation of turning ZV patients again who have no baseline level of M-protein, and be able to correct them back to a heterozygous phenotype, looking at M-protein will enable us to be able to understand how well we can correct that there's a field in humans, and we're highly encouraged by our initial clinical data.

但是，當我們增加蛋白質的總水平時，看看會發生什麼，以及這種校正水平可以持續到什麼程度，這將是一件很棒的事情。因此，我認為對我們來說關鍵仍然在於，如果您再次遵循轉化 ZV 患者的翻譯，這些患者沒有基線 M 蛋白水平，並且能夠將其糾正回雜合表型，那麼觀察 M 蛋白將使我們能夠了解我們可以多好地糾正人類中存在的一個領域，我們對最初的臨床數據感到非常鼓舞。

Thank you. Maybe just a quick one for DMD, understanding you're talking with the FDA, and then for the potential regulatory path. So understanding you try also maybe be able to do some umbrella kind of a registrational trial. Would that be the topic we will get the update quarter, or there will be a coming a bit later? Thank you.

謝謝。也許只是對 DMD 的一個快速了解，了解您正在與 FDA 交談，然後了解潛在的監管途徑。因此，您或許可以嘗試進行某種綜合性的註冊試驗。這是我們在本季更新時會討論的主題嗎，還是稍後會討論？謝謝。

No thank you. I mean, as we said, the discussion encompass the data from the or initial interim data from the 24 weeks. But importantly, as we also said, it's about what's next for the program in terms of accelerated registration and confirmatory study design. So we'll be able to provide in totality and update as part of these data sets on next steps for the program.

不用了，謝謝。我的意思是，正如我們所說，討論涵蓋了 24 週的數據或初始中期數據。但重要的是，正如我們所說的，這關係到該計劃在加速註冊和確認性研究設計方面的下一步。因此，我們將能夠全面提供這些資料集，並作為該計劃後續步驟的一部分進行更新。

Luca Issi with RBC Capital Markets.

加拿大皇家銀行資本市場的 Luca Issi。

This is Lisa for Luca. Just wondering, how should we think about dosing for RNA editing versus DNA editing versus (inaudible)? So it looks like your second dose for a 180 is already at 400-milligrams versus we know (inaudible) is using an eight times lower dose in their pivotal study with Hae at about 50-milligrams, and Nylon is approved for TTR at a dose 16 times lower, at 25-milligrams.

這是 Luca 的 Lisa。我只是想知道，我們應該如何考慮 RNA 編輯、DNA 編輯和（聽不清楚）？因此看起來，180 的第二劑劑量已經是 400 毫克，而我們知道（聽不清楚）在他們的關鍵研究中使用的劑量要低 8 倍，Hae 的劑量約為 50 毫克，而 Nylon 獲準用於 TTR 的劑量要低 16 倍，為 25 毫克。

Appreciate that these are totally different mechanisms of action, but how should we think about total drug exposure here for ADAR, is there any. On the safety side with going to such high doses. Thanks so much.

要認清這些是完全不同的作用機制，但是我們該如何看待 ADAR 的總藥物暴露量呢？從安全角度考慮，服用如此高劑量。非常感謝。

Yeah. I mean, I think one of the things you have to look at is the 200-milligram is lower than in cholesterol. So I think sometimes you have to think about the calculations of doses of MiGs per gig, and what that is total drug delivered versus the absolute doses we're giving.

是的。我的意思是，我認為你必須考慮的事情之一是 200 毫克低於膽固醇。因此我認為有時你必須考慮每千兆位元組的米格劑量的計算，以及輸送的總藥物劑量與我們給予的絕對劑量。

These as absolute doses, not doses per kilogram for patients. Importantly, we this is the first time anybody has been exploring Adar editing to understand the kinetics of the enzyme. So what we do realize is the opportunity you have when you bring a whole new mechanism and modality forward and are frankly leading that for the field, is a real opportunity to be able to explore the ranges of what's possible.

這些是絕對劑量，而不是患者每公斤的劑量。重要的是，這是我們第一次探索 Adar 編輯來了解酶的動力學。因此，我們確實意識到，當你提出一種全新的機制和模式，並坦率地引領該領域時，你就擁有了一個真正的機會，可以探索各種可能性的範圍。

And so ultimately, what's important is dose, but dose to establish an efficacy threshold, but also a durability threshold. I mean, if we could be dosing this monthly, quarterly, less frequently, we're going to understand that. So there are nuances always across different enzymatic systems we understand and as a field.

因此，最終，重要的是劑量，但劑量不僅要建立功效閾值，還要建立耐久性閾值。我的意思是，如果我們可以每月、每季或以更低的頻率進行劑量控制，我們就能理解這一點。因此，我們所理解的不同酵素系統以及不同領域之間總是存在著細微差別。

What happens with siRNAs? Although it's important to note, in siRNAs, we're seeing things that are incredibly different than what's been seen with Alnylam before. I mean, we showed a 30 fold improvement in 802 loading Alnylam, which isn't just translating to better potency, it's translating to radically different durability the prospects for highly infrequent dosing, and so that's important to be able to think about the nuances of how this chemistry adds, and not just a potency quotient, but a durability quotient.

siRNA 會發生什麼情況？但值得注意的是，在 siRNA 中，我們看到的東西與之前在 Alnylam 中看到的東西截然不同。我的意思是，我們發現 802 負載 Alnylam 的改善幅度達到了 30 倍，這不僅意味著更好的效力，還意味著極低劑量給藥的前景具有根本不同的耐久性，因此重要的是能夠思考這種化學反應如何增加的細微差別，不僅僅是效力商，還有耐久性商。

I think the opportunity we also have for AATD specifically is to really understand the upper bound, I mean, our initial dose let us get to therapeutic levels within a heterozygous patient population, we're going to understand where one could go even beyond that.

我認為我們對 AATD 的具體機會是真正了解上限，我的意思是，我們的初始劑量讓我們在雜合子患者群體中達到治療水平，我們將了解甚至可以超越這個水平。

And so I think that opportunity of really being able to explore dose is important. Think the other thing to note is we've gone higher than all anticipated doses, even above the third cohort in the healthy volunteer study. So from a safety perspective, not just pre-clinical safety, but human clinical safety.

因此我認為真正探索劑量的機會很重要。另一件需要注意的事情是，我們的劑量已經高於所有預期劑量，甚至高於健康志願者研究中的第三組。因此，從安全角度來看，不僅是臨床前安全，還有人類臨床安全。

We have substantial single and multi-dose human safety data that does let us continue to explore the upper bounds of editing. And I think that's going to be important as we set the paradigm for, you know, what's going to what is good editing going to look like. And so I think ultimately dose is less important in the absence of what it's doing.

我們擁有大量單劑量和多劑量人體安全數據，這確實讓我們能夠繼續探索編輯的上限。我認為這很重要，因為我們要為好的編輯樹立典範。因此我認為，如果沒有實際作用，劑量最終就不那麼重要了。

And I think, you know, we're going to understand a lot between the two and four but also, importantly, what the repeat dosing at 200 does. So I think it's going to be exciting time for the field as we look across modalities and mechanisms and what levels of RNA protein editing and correction are going to be possible.

而且我認為，你知道，我們會了解很多關於 2 和 4 之間的事情，但同樣重要的是，我們會了解 200 次重複給藥會產生什麼效果。因此，我認為，當我們研究模式和機制以及 RNA 蛋白質編輯和校正的可能水平時，這將是該領域令人興奮的時刻。

Catherine Novack with Jones Trading.

瓊斯貿易公司的凱瑟琳‧諾瓦克 (Catherine Novack)。

I just wonder, you know, if you can give any more details about the multiple dose cohorts in ATD, you know, how many patients are you anticipating? Granularity as to when, in 2025, we should expect this. And then, you know, in conjunction with that, thoughts on the Maat threshold, you know, understanding that Z-protein is not functional, so we're not really looking at total AAT, do you think you know, consider the 20 micromolar M-AAT to be the threshold for success. Thanks.

我只是想知道，您是否可以提供有關 ATD 中多劑量組的更多詳細信息，您預計有多少患者？我們應該在 2025 年等到什麼時候才能實現這一目標。然後，您知道，與此同時，考慮 Maat 閾值，您知道，了解 Z 蛋白不起作用，所以我們實際上並不是在看總 AAT，您認為將 20 微摩爾 M-AAT 視為成功的閾值嗎？謝謝。

Yeah. So I think stepping back to each cohort, as we said, is eight patients with repeat dosing. So we've been very clear with what the number of patients are going to be, so that'll be the totality of that data set, and they'll have seven doses.

是的。因此，我認為，正如我們所說，每個組別都有八名患者重複服藥。因此，我們非常清楚患者的數量，這就是整個數據集的總和，他們將接種七劑疫苗。

So these patients are going to get a substantial amount of medicine repeated, which is going to let us, in a really nice way, look at that translation from single to multi dose, and we'll have that total data set from the single and the multi with which we can look at the dynamic effects of protein production.

因此，這些患者將會重複服用大量藥物，這將使我們能夠以一種非常好的方式觀察從單劑量到多劑量的轉化，並且我們將獲得單劑量和多劑量的總數據集，透過這些數據集我們可以觀察蛋白質生成的動態效應。

To your point, which is interesting is if we remember back to what the established threshold is for the therapeutic activity of a heterozygous patient. So assume 11 micromolar innator, 50% of that is m, and the other part is Z. We're already at 60% edited M-protein looking at that total.

對於你的觀點，有趣的是，如果我們回想一下雜合子患者治療活動的既定閾值是多少。因此假設有 11 微摩爾的內醯胺酶，其中 50% 是 m，另一部分是 Z。從總數來看，我們已經有 60% 的編輯 M 蛋白。

So to your point, we're still a measure. So I don't want anybody, wasn't sure or subject to interpretation, we're still going to show total protein as we do the study, so we'll be able to look at that relative ratio between total protein and then, specifically M-protein.

所以就你的觀點而言，我們仍然是一種衡量標準。因此，我不希望任何人不確定或需要解釋，我們仍然會在研究過程中展示總蛋白質，這樣我們就能查看總蛋白質和 M 蛋白之間的相對比率。

The reason we highlight protein is it is critical, because the M-protein is only, again, produced based on the medicine's ability to edit the transcript, and so it gives the most insight into editing efficiency, protein production.

我們強調蛋白質的原因是它至關重要，因為 M 蛋白只是基於藥物編輯轉錄本的能力而產生的，因此它能最深入地了解編輯效率和蛋白質的產生。

And so therefore we know that the MZ phenotype is a stable, safe phenotype, and so therefore what we want to do is continue to push those patients towards higher levels of m. Protein. So we have substantial activity at the 200-milligram. We're going to see what that does in repeat dosing.

因此我們知道 MZ 表型是一種穩定、安全的表型，因此我們想要做的就是繼續推動這些患者達到更高的 m 水平。蛋白質。因此我們在 200 毫克方面有大量活動。我們將觀察重複給藥會產生什麼效果。

And you know, it we could reasonably expect to see not just that a higher level of that M-protein, but really looking at how durable and sustainable that is as we think about dosing measurements.

你知道，我們可以合理地預期不僅會看到更高水平的 M 蛋白，而且在考慮劑量測量時，還能真正看到它的持久性和可持續性。

Got it. Thanks. And then I had just one more on your thoughts on siRNA obesity targets outside of inhibitory such as GPR75 for example. Is this something you could explore in conjunction with the inhibitory program? Thanks.

知道了。謝謝。然後我再問一下您對抑制以外的 siRNA 肥胖標靶（例如 GPR75）的看法。您可以結合抑製程序來探索這一點嗎？謝謝。

Yeah. We think about a whole range of potential ways of using both siRNA as well as editing that could target the field of metabolic disease, GPR75 is orthogonal. So you know, as we've mentioned, we do look at orthogonal approaches to treating obesity.

是的。我們考慮了一系列使用 siRNA 和編輯的潛在方法來針對代謝疾病領域，GPR75 是正交的。正如我們所提到的，我們確實在研究治療肥胖症的正交方法。

And with our siRNA technology, not talking about GPR75 at the moment, but we've shown substantial, durable, potent silencing in the CNS with potential for once a year, even potentially less frequently with administration.

利用我們的 siRNA 技術，雖然現在不討論 GPR75，但我們已經證明，它可以在中樞神經系統 (CNS) 中實現顯著、持久、有效的沉默，並且可能每年發生一次，甚至可能以更低的頻率給藥。

So we shared that data as part of the data, demonstrating and distinguishing differentiation between the state of the art chemistries that are for siRNA, and showing again how that's different and how we see better potency and durability with RNA chemistry, not just with gallon neck in the liver, but also in CNS. So we are evaluating a number of targets within the metabolic

因此，我們將該數據作為數據的一部分進行共享，展示和區分 siRNA 的最先進的化學方法之間的差異，並再次展示它們有何不同，以及我們如何看到 RNA 化學具有更好的效力和持久性，不僅在肝臟的加侖頸中，而且在中樞神經系統（CNS）中也是如此。因此，我們正在評估代謝中的一些目標

Ryan Deschner with Raymond James.

Ryan Deschner 與 Raymond James。

For the 007 program what a late stage clinical study assessing the therapeutic as more of a maintenance therapy actually look like? And what would you anticipate an initial label to look like for this program, regarding positioning as a mono add on, or maintenance therapy, if successful.

對於 007 計劃，將治療評估為維持治療的後期臨床研究實際上是什麼樣的？如果成功的話，您預計該計劃的初始​​標籤會是什麼樣子，將其定位為單一附加療法或維持療法。

Thank you. Yeah. So, I mean, we do think a lot about the opportunities, and I say more about the single dose and then the maintenance. So we're going to be generating that data as part of these data sets.

謝謝。是的。所以，我的意思是，我們確實考慮了很多機會，我更多地談論的是單劑量和維持。因此我們將把該資料作為這些資料集的一部分來產生。

So we're going to have a very good sense of behavior of inhibiting as a single agent therapy, and what level of healthy sustainable must see, and being able to drive that forward into a potentially registrational study, I think, the other study that you know we are excited to engage in, which is, as you alluded to, is that off ramp, and so being able to replicate that study that we have run, it is very feasible to look at GL patients on GLP ones that are stable on a GLP one, and then to be able to dose them with Trump.

因此，我們將對單一藥物療法的抑制行為有很好的認識，並且必須看到健康可持續的水平，並且能夠將其推動到一項潛在的註冊研究中，我認為，另一項研究，你知道我們很高興參與其中，正如你所提到的，這是出口坡道，因此能夠複製我們已經進行的研究，觀察 GLP 藥物中穩定的 GL 患者，然後能夠用川普給他們的他們。

And so the designing of those next studies are being planned. We are thinking about how to conduct those so that they could serve two purposes. Obviously, one, generate really important, meaningful data of how we help products potentially be used in clinic.

因此，下一步研究的設計正在計劃中。我們正在思考如何進行這些活動，以便它們可以達到雙重目的。顯然，首先，產生關於我們如何幫助產品在臨床上得到應用的真正重要、有意義的數據。

But two, to also support a label for registration, for reimbursement. So as we think about the total opportunity as both a mono therapy, but very, very important on this off ramp, I think that's going to be a really interesting study to be running real time, where patients who are going to be currently on those therapies now can be withdrawn so and studied in that context in a really substantial way. So we have those plans underway.

但其二，也支援註冊標籤，用於報銷。因此，當我們將整個機會視為單一療法，但在這個出口處卻非常非常重要時，我認為這將是一項非常有趣的實時研究，其中目前正在接受這些療法的患者可以退出，並在這種背景下進行非常實質性的研究。所以我們正在進行這些計劃。

Madison El-Saadi with B. Riley.

麥迪遜·埃爾薩迪 (Madison El-Saadi) 和 B. Riley。

Hi. Thanks for taking our question what are your plans for the MBA conference? Will you host an event around the conference to provide that regulatory update, and then second on 003 I know you had an updated analysis of CHDI, as you mentioned in your prepared remarks, just wondering if you could kind of remind us or characterize.

你好。感謝您回答我們的問題，您對 MBA 會議有什麼計劃？您是否會在會議期間舉辦一場活動來提供監管更新，然後關於 003，我知道您對 CHDI 進行了更新的分析，正如您在準備好的發言中提到的那樣，只是想知道您是否可以提醒我們或描述一下。

The previously reported NFL data in terms of change from baseline. And then secondly, how do you see 003, profile relative to the exile, one targeted candidates. Thanks.

先前報告的 NFL 數據相對於基線的變化。其次，您如何看待 003 相對於流亡者的形象，一個目標候選人。謝謝。

Yeah, wonderful. I'll take the MDA question first. So while our team has a presentation that was already scheduled to be prepared. The data will be coming, will not be presented at MTA coming up, I think timing wise, so I think there won't be a separate event around that.

是的，太棒了。我先回答 MDA 問題。因此，我們的團隊已經安排好了準備好的簡報。數據即將公佈，但不會在即將到來的 MTA 上展示，我認為時間上是明智的，所以我認為不會有單獨的活動。

So we do expect to have the full data as well as our regulatory update by the end of the month. We don't time, as we historically have always said, we don't. Of time our data releases around conferences, but rather when the data is ready for presentation. As it relates to the oh three, and I think this was a great conversation at CHDI.

因此，我們確實希望在月底之前獲得完整的數據以及監管更新。我們沒有時間，正如我們在歷史上一直說的那樣，我們沒有時間。我們的資料發佈時間不是在會議期間，而是在資料準備好展示時。因為它與三有關，我認為這是 CHDI 的一次很棒的對話。

We'll take the (inaudible) one off the table first, because I think there was a lot of discussion. We talked to translational medicine experts about a lot of concerns about the exon one hypothesis.

我們首先將（聽不清楚）這個問題排除在外，因為我認為我們已經進行了很多討論。我們與轉化醫學專家討論了許多有關外顯子一假說的擔憂。

And I think a lot of those concerns stem from the fact that when people went back and did the analysis of healthy brains on MRI, so patients who had autopsy but did not have HD, and those who did both steps to patients have exon one. So it was not specific for Huntington's disease.

我認為，許多擔憂源於這樣一個事實：當人們回去用 MRI 分析健康大腦時，那些進行屍檢但沒有患亨廷頓氏病的患者，以及對患者進行兩個步驟分析的患者都有外顯子一。所以它對亨廷頓舞蹈症沒有特異性。

And in fact, a lot of the model systems. And I think it's always important. And PhD is not unique in this. When you look at translational models to predict activity and what to expect in the clinic, it's always important to do more characterization on the animal mouse models.

事實上，有很多模型系統。我認為這始終很重要。而 PhD 在這方面並不是獨一無二的。當您查看轉化模型來預測活動以及臨床預期結果時，對動物小鼠模型進行更多表徵始終很重要。

And so today, there's been a lot of changes that happen in mice models that don't happen in humans. I should also add that a lot of the data that's being presented around exon one, and there was a presentation, I believe, at the Alnylam R&D Day actually use Wave allele specific oligonucleotides that were presented previously.

因此，今天，在小鼠模型中發生了許多在人類身上不會發生的變化。我還應該補充一點，圍繞外顯子一呈現的大量數據，以及我相信在 Alnylam 研發日上的演示，實際上使用了先前呈現的 Wave 等位基因特異性寡核苷酸。

And we had shared data that said that our allele specific oligonucleotides, and this was shared in the CHDI presentation, actually demonstrated a benefit, and that that target happened to also coincide with exon one, was picked up.

我們共享的數據表明，我們的等位基因特異性寡核苷酸（這在 CHDI 演示中進行了分享）實際上顯示出了益處，並且該目標恰好也與外顯子一相吻合，因此被選中。

And I think what ended up becoming is that that became an exon one study, but it was actually, very importantly, an allele specific oligonucleotide study that we had engaged with and work with some of the KOLs in the space we weren't referenced in the presentation, but it is important that a lot of the emerging, supported data on exon one are actually being generated with Wave Life specific oligonucleotides, which, as we would expect, if you reduce butane Huntington protein and preserve wild type, as we've shown, not just in preclinical studies, but ultimately in the clinic, You do see changes in potential benefits.

我認為最終的結果是一項外顯子一研究，但實際上，非常重要的是，這是一項等位基因特異性寡核苷酸研究，我們曾與該領域的一些 KOL 合作，但在演講中我們並沒有提到他們，重要的是，許多關於外顯子一的新興支持數據實際上是透過 Wave Life特異性寡核苷酸生成的，正如我們所期望的，如果減少丁烷亨廷頓蛋白並保留野生型，正如我們所展示的，不僅在臨床前研究中，而且最終在臨床中，您確實會看到潛在益處的變化。

So I highlight that around the Exxon one discussions to date, as it relates to the NFL studies, I think a couple important things you know.

因此，我想強調的是，圍繞埃克森美孚迄今為止的討論，由於它與 NFL 研究有關，我認為有幾件重要的事情你知道。

One again, in the full retrospective New England Journal analysis of the Tominersen and Generation HD, one study, there was no correlation between NFL and clinical outcomes.

再次，在《新英格蘭雜誌》對托米納森和 HD 世代的全面回顧性分析中，一項研究發現 NFL 和臨床結果之間沒有相關性。

So it's just an important reminder we were we did share the follow up from our FDA feedback last year, which we reiterated again that NFL was not the subject of that discussion, so we do follow it. It's important that I think everyone in the field is going to measure it and continue to look for those applications, but again, NFL hasn't correlated with outcome measurements.

因此，這只是一個重要的提醒，我們確實分享了去年 FDA 反饋的後續情況，我們再次重申 NFL 不是該討論的主題，因此我們確實會關注它。重要的是，我認為該領域的每個人都會對其進行測量並繼續尋找這些應用，但同樣，NFL 與結果測量沒有關聯。

Thank you. I'm showing no further questions. I will now turn the call back over to Dr. Paul Bolno for final remarks.

謝謝。我沒有其他問題。現在我將把電話轉回給保羅·博爾諾博士，請他做最後的演講。

Yeah. Thank you for joining our call this morning, we look forward to connecting with many of you this month, when we expect to share data from 453. Have a great day.

是的。感謝您今天早上參加我們的電話會議，我們期待本月與你們中的許多人進行聯繫，屆時我們預計將分享來自 453 的數據。祝你有美好的一天。

Let's conclude today's conference call. Thank you all for your participation, and you may now disconnect.

讓我們結束今天的電話會議。感謝大家的參與，現在您可以斷開連線了。