Intellia Therapeutics Inc (NTLA) 2025 Q3 法說會逐字稿

Hello, and welcome to Intellia Therapeutics third-quarter 2025 financial results conference call. My name is Rocco, and I will be your conference operator today. Please be advised that today's conference is being recorded.

大家好，歡迎參加 Intellia Therapeutics 2025 年第三季財務業績電話會議。我叫羅科，今天我將擔任你們的會議接線生。請注意，今天的會議正在錄影。

I will now turn the conference over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed, sir.

現在我將把會議交給 Intellia 的投資人關係和企業傳播副總裁 Jason Fredette。請繼續，先生。

Thank you, Rocco, and hello, everyone. Earlier this afternoon, we issued a press release and filed our 10-Q outlining our recent business updates and our third quarter financial results. These documents can be found on the Investors and Media section of Intellia's website at intelliatx.com.

謝謝你，羅科，大家好。今天下午早些時候，我們發布了一份新聞稿，並提交了 10-Q 表格，概述了我們最近的業務進展和第三季財務表現。這些文件可以在 Intellia 網站 intelliatx.com 的「投資者和媒體」部分找到。

At this time, I would like to take a moment to remind listeners that during this call, Intellia management may make certain forward-looking statements. We ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.

在此，我想提醒各位聽眾，在本次電話會議中，Intellia 管理階層可能會發表一些前瞻性聲明。請您參閱我們在 sec.gov 網站上提交給美國證券交易委員會的文件，以了解潛在的風險和不確定性。本次電話會議中提供的所有資訊均為截至今日的最新信息，除非法律要求，否則 Intellia 不承擔更新此資訊的義務。

Joining me on the call are John Leonard, our Chief Executive Officer; and Ed Dulac, our Chief Financial Officer.

與我一同參加電話會議的有我們的執行長約翰·倫納德和我們的財務長艾德·杜拉克。

With that, I'll turn the call over to John.

接下來，我會把電話交給約翰。

Thanks, Jason, and thanks to all of you who have tuned in for today's call. In terms of the agenda for today, we'll begin with the status of our nex-z program in ATTR amyloidosis since that is obviously top of mind for all of you. We then will provide an update on the significant progress we have made with lonvo-z, which is being developed as a potential onetime treatment for patients with hereditary angioedema or HAE, and we will close with Ed's financial review.

謝謝傑森，也謝謝今天所有收聽電話會議的朋友們。就今天的議程而言，我們將首先介紹我們在 ATTR 澱粉樣變性方面的 nex-z 項目的進展情況，因為這顯然是大家最關心的問題。接下來，我們將介紹我們在 lonvo-z 方面取得的重大進展，lonvo-z 正在被開發為一種潛在的一次性治療遺傳性血管性水腫 (HAE) 患者的方法，最後我們將進行 Ed 的財務回顧。

First, for nex-z. Since the start of 2024, we've been enrolling patients in MAGNITUDE, our Phase III clinical trial for ATTR amyloidosis with cardiomyopathy. And we've been enrolling MAGNITUDE-2 for patients with hereditary ATTR amyloidosis with polyneuropathy since the start of 2025. Both trials have advanced rapidly, which we believe demonstrates patients' interest in a potential onetime treatment option.

首先，對於 nex-z。自 2024 年初以來，我們一直在招募患者參與 MAGNITUDE，這是我們針對伴隨心肌病變的 ATTR 澱粉樣變性的 III 期臨床試驗。自 2025 年初以來，我們一直在招募患有遺傳性 ATTR 澱粉樣變性伴隨多發性神經病變的患​​者參與 MAGNITUDE-2 研究。這兩項試驗都進展迅速，我們認為這表明患者對一次性治療方案很感興趣。

On October 24, a patient was admitted to the hospital after reporting abdominal pain to his principal investigator. This is a patient with ATTR cardiomyopathy in his early '80s who enrolled in MAGNITUDE and received a dose of nex-z on September 30. The patient's labs showed that his AST and ALT levels exceeded 3x the upper limit of normal and that his bilirubin exceeded 2x the upper limit of normal. These levels triggered a protocol-specified pause on patient dosing and screening for MAGNITUDE in the interest of patient safety. We decided to also pause patient dosing and screening in MAGNITUDE-2 as a precaution.

10月24日，一名患者向其主要研究者報告腹痛後入院治療。這是一位 80 歲出頭的 ATTR 心肌病變患者，他參加了 MAGNITUDE 研究，並於 9 月 30 日接受了 nex-z 的治療。患者的實驗室檢查結果顯示，他的 AST 和 ALT 水平超過正常上限的 3 倍，膽紅素超過正常上限的 2 倍。這些水準觸發了依照協議規定的暫停病患給藥和 MAGNITUDE 篩檢的措施，以保障病患安全。出於謹慎考慮，我們也決定暫停 MAGNITUDE-2 中的患者給藥和篩選。

On October 29, the FDA notified us verbally that it had placed a clinical hold on MAGNITUDE and MAGNITUDE-2. We are now awaiting the FDA's formal clinical hold letter. We were very saddened to learn that the patient passed away last night. We have been advised by the treating physician that this is a case with complicating comorbidities, and the case is being further evaluated.

10 月 29 日，FDA 口頭通知我們，已暫停 MAGNITUDE 和 MAGNITUDE-2 的臨床試驗。我們現在正在等待FDA的正式臨床試驗暫停函。得知患者昨晚過世，我們感到非常悲痛。主治醫師告知我們，這是一個伴隨多種併發症的病例，目前正在對該病例進行進一步評估。

Since learning of this case, we've taken a number of actions in the interest of patient safety. For instance, we've mandated that clinical sites collect additional labs from patients in the initial weeks following dosing to detect potential liver elevation sooner. An internal team has been closely reviewing the blinded safety data, baseline characteristics, among other factors, to identify potential contributors to the liver-related events seen in MAGNITUDE.

自從得知此案以來，我們已採取多項措施保障病人安全。例如，我們已強制要求臨床中心在給藥後的最初幾週內收集患者的額外實驗室檢查結果，以便儘早發現潛在的肝功能異常。內部團隊一直在密切審查盲法安全性資料、基線特徵以及其他因素，以確定 MAGNITUDE 研究中觀察到的肝臟相關事件的潛在影響因素。

We've been working with the trial's independent data safety monitoring committees as we consider other potential monitoring and risk mitigation strategies. And of course, we are engaging with global regulatory authorities and other stakeholders to understand their perspectives, concerns and requirements so we can develop a plan that would allow us to resume enrollment as soon as appropriate. Not surprisingly, given the clinical hold, we are unable to maintain our milestone guidance for nex-z, and we expect to provide an update once we finalize the plan with regulators.

我們正在與試驗的獨立資料安全監測委員會合作，考慮其他潛在的監測和風險緩解策略。當然，我們也在與全球監管機構和其他利害關係人進行溝通，了解他們的觀點、擔憂和要求，以便我們能夠制定一個計劃，讓我們能夠在適當的時候盡快恢復招生。不出所料，鑑於臨床試驗暫停，我們無法維持對 nex-z 的里程碑指導，我們預計在與監管機構最終確定計劃後會提供最新消息。

Simply put, a lot has transpired over the past couple of weeks and in recent hours, and there is still much work ahead. There's a lot of focus on the safety profile of nex-z at this stage as there should be. That said, we continue to believe in this product candidate's potential to address important unmet needs for patients with ATTR amyloidosis. This is based on a few key factors.

簡而言之，過去幾週和最近幾個小時發生了很多事情，但前方還有很多工作要做。現階段，人們非常關注 nex-z 的安全性能，這是理所當然的。儘管如此，我們仍然相信該候選產品有潛力滿足 ATTR 澱粉樣變性患者的重要未滿足需求。這是基於幾個關鍵因素得出的結論。

First, ATTR amyloidosis is a disease with high mortality. While undeniable progress has been made in this treatment, current therapies only slow its advance and most patients continue to face progressive morbidity and mortality. Second, we've enrolled more than 650 patients in MAGNITUDE and 47 patients in MAGNITUDE-2. To date, Grade 4 liver transaminase elevations have been reported in less than 1% of all patients enrolled in MAGNITUDE. Each of these cases has been observed approximately 3 to 5 weeks following randomization and dosing.

首先，ATTR澱粉樣變性是一種死亡率很高的疾病。雖然這種治療方法已經取得了不可否認的進展，但目前的療法只能減緩其發展速度，大多數患者仍面臨病情加重和死亡的風險。其次，我們在 MAGNITUDE 研究中招募了 650 多名患者，在 MAGNITUDE-2 研究中招募了 47 名患者。迄今為止，MAGNITUDE 研究中的所有患者中，報告出現 4 級肝轉氨酶升高的比例不到 1%。這些病例均在隨機分組和給藥後約 3 至 5 週內觀察到。

There have been no Grade 4 liver transaminase elevations in MAGNITUDE-2. And third, we are highly encouraged by the data from our ongoing Phase I clinical trial of nex-z. On Monday, in a late-breaker oral session at the 2025 AHA Scientific Sessions in New Orleans, we will have the opportunity to share longer-term data for nex-z that we believe demonstrates its potential to improve various disease measures and mortality.

MAGNITUDE-2 中未出現 4 級肝轉氨酶升高。第三，我們正在進行的 nex-z I 期臨床試驗的數據令我們倍受鼓舞。週一，在 2025 年新奧爾良舉行的 AHA 科學會議的最新進展口頭報告環節中，我們將有機會分享 nex-z 的長期數據，我們相信這些數據證明了它在改善各種疾病指標和死亡率方面的潛力。

Let's move on to lonvo-z, which is being investigated in our ongoing HAELO Phase III clinical trial for HAE. Over the course of 2025, we've made considerable progress in this trial. Enrollment was completed in September, less than 9 months after we dosed our first patient. This puts us on track to share top line data by mid-2026, submit a BLA to the FDA in the second half of 2026, and prepare for an anticipated commercial launch in the U.S. in the first half of 2027.

接下來我們來看看lonvo-z，我們正在進行HAELO III期臨床試驗，研究其對HAE的療效。在 2025 年期間，我們在這項試驗中取得了相當大的進展。9 月完成了病患招募，距離我們給第一位病患用藥不到 9 個月。這將使我們預計在 2026 年年中分享主要數據，在 2026 年下半年向 FDA 提交生物製品許可申請 (BLA)，並為預計在 2027 年上半年在美國的商業上市做好準備。

We believe lonvo-z could completely redefine the HAE treatment landscape. We aim to reset expectations and the standard of care for patients living with this debilitating disease by completely eliminating attacks and the need for other HAE medications for a majority of patients, all with one dose.

我們相信lonvo-z能夠徹底改變HAE的治療格局。我們的目標是透過一次給藥，徹底消除大多數患者的病情發作，並消除他們對其他 HAE 藥物的需求，從而重新定義患有這種衰弱性疾病的患者的期望和護理標準。

This Saturday, at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting in Orlando, we will be presenting longer-term safety and efficacy data from all of the patients who received a 50-milligram dose of lonvo-z in our Phase I/II clinical trial.

本週六，在奧蘭多舉行的美國過敏、氣喘和免疫學會年度科學會議上，我們將公佈在我們的 I/II 期臨床試驗中接受 50 毫克 lonvo-z 劑量的所有患者的長期安全性和有效性數據。

I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results for the third quarter 2025.

現在我將把電話交給我們的財務長艾德，他將介紹我們 2025 年第三季的財務表現。

Thank you, John, and good evening, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our clinical pipeline and build important capabilities required for future success. Our cash, cash equivalents and marketable securities were $669.9 million as of September 30, 2025, compared to $861.7 million as of December 31, 2024. During the third quarter, we raised approximately $115 million from our ATM facility. When combined with the benefits of the restructuring initiatives we implemented in early 2025, this enables us to extend our cash runway into mid-2027 and through lonvo-z's anticipated commercial launch in the U.S. for HAE.

謝謝你，約翰，大家晚上好。Intellia 持續保持穩健的資產負債表，使我們能夠推進臨床研發項目，並建立未來成功所需的關鍵能力。截至 2025 年 9 月 30 日，我們的現金、現金等價物及有價證券為 6.699 億美元，截至 2024 年 12 月 31 日為 8.617 億美元。第三季度，我們透過ATM機籌集了約1.15億美元。結合我們在 2025 年初實施的重組計劃帶來的好處，這將使我們能夠將現金儲備延長至 2027 年中期，並持續到 lonvo-z 在美國為 HAE 進行預期的商業化推出。

Collaboration revenue was $13.8 million during the third quarter of 2025 compared to $9.1 million during the prior year quarter. The $4.7 million increase was mainly driven by cost reimbursements related to our collaboration with Regeneron Pharmaceuticals. R&D expenses were $94.7 million during the third quarter of 2025 compared to $123.4 million during the prior year quarter. The $28.7 million decrease was primarily driven by employee-related expenses, stock-based compensation, research materials and contracted services, offset by an increase in the advancement of our lead programs.

2025 年第三季合作收入為 1,380 萬美元，而去年同期為 910 萬美元。470萬美元的成長主要是由於與我們和Regeneron Pharmaceuticals合作相關的成本補償。2025 年第三季研發費用為 9,470 萬美元，而去年同期為 1.234 億美元。2870萬美元的減少主要是由於員工相關支出、股票選擇權補償、研究材料和合約服務，但被我們領先專案推進方面的成長所抵消。

Stock-based compensation expense included within R&D was $12.2 million for the third quarter of 2025. G&A expenses were $30.5 million during the third quarter of 2025 compared to $30.5 million during the prior year quarter. Stock-based compensation expense included within G&A was $7.4 million for the third quarter of 2025. Finally, net loss for the third quarter of 2025 was $101.3 million, down from $135.7 million for the prior year quarter. We continue to expect a year-over-year decline in GAAP operating expenses of at least 10%. And as stated before, our cash runway is expected to fund operations into the middle of 2027.

2025 年第三季研發費用中包含的股票選擇權補償支出為 1,220 萬美元。2025 年第三季一般及行政費用為 3,050 萬美元，與去年同期相同。2025 年第三季計入 G&A 的股權激勵費用為 740 萬美元。最後，2025 年第三季淨虧損為 1.013 億美元，低於去年同期的 1.357 億美元。我們繼續預期 GAAP 營運費用將年減至少 10%。如同先前所述，我們的現金儲備預計可以維持營運到 2027 年年中。

With that, we are ready to begin our question-and-answer session. Before we do, we would like to let you know in advance that we will be unable to answer some of your questions given a variety of factors, including the fact that we are still awaiting the FDA's clinical hold letter and a more thorough evaluation of the patient's case. We appreciate your patience and understanding.

接下來，我們將開始問答環節。在此之前，我們想提前告知您，由於多種因素，包括我們仍在等待 FDA 的臨床暫停函以及對患者病例進行更徹底的評估，我們將無法回答您的一些問題。感謝您的耐心與體諒。

Operator, would you please open the line for questions?

接線員，請問可以接通提問線路嗎？

(Operator Instructions) Gena Wang, Barclays.

（操作說明）Gena Wang，巴克萊銀行。

I'm really sorry to hear the unfortunate event. I know you are still collecting tons of data, but just wondering if any initial hypothesis of the reason for liver enzyme elevation since this is a 1 month after dosing. Is that because of lipid nanoparticle Cas9 or age-related or disease? Any initial thoughts that would be fantastic. And the related question is, you shared the color on Grade 4, less than 1% in ATTR cardiomyopathy.

聽到這件不幸的事，我深感遺憾。我知道你們還在收集大量數據，但只是想知道，在給藥一個月後，對於肝酵素升高的原因是否有初步假設。這是由於脂質奈米顆粒Cas9引起的，還是與年齡或疾病有關？任何初步想法都非常感謝。相關的問題是，您分享了 4 級顏色，在 ATTR 心肌病變中不到 1%。

How is that rate for ATTR polyneuropathy and the HAE patient population?

ATTR 多發性神經病變和 HAE 患者族群的發生率如何？

So Gena, thank you for the question. At this point in time, we can only speculate, which we're not going to do in terms of what's the source of the liver function test abnormalities. As you pointed out in your question, we've seen across the entire study with over 650 patients enrolled, an incidence of less than 1%. This particular case is distinct from what we've seen. It was a very complicated clinical course with other comorbidities that may have had some influence in the outcome of the patient.

吉娜，謝謝你的提問。目前我們只能進行推測，但我們不會就肝功能檢查異常的原因進行推測。正如您在問題中指出的那樣，在整個研究中，超過 650 名患者參與，發病率低於 1%。這個案例與我們以往遇到的情況截然不同。這是一個非常複雜的臨床過程，伴隨其他合併症，這些合併症可能對患者的預後產生了一定影響。

Of the other cases that have occurred, all of those cases have either resolved or resolving and no one is in the hospital.

其他已發生的病例，全部都已解決或正在解決，目前無人住院。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特，傑富瑞。

Maybe one more on the patient. I know you can't say much, but you mentioned the other comorbidities. Can you say what those were and also potentially whether the patient was managed in the United States or ex U.S.? And then, yes, I guess, if you can't answer those, if you could talk about just potential risk mitigation strategies that you could implement going forward.

或許還要再加一張關於病人的照片。我知道你不能說太多，但你提到了其他合併症。能說說這些具體是什麼嗎？還有，患者是在美國境內還是境外接受治療的？那麼，是的，我想，如果您無法回答這些問題，能否談談您今後可以實施的潛在風險緩解策略？

Yes. At this point, Maury, we can't go into the comorbidities. I can only say that the patient had a very complicated medical course, and these other comorbidities may have influenced the ultimate outcome along with the hepatic abnormalities. We're not commenting on geography. I can only assure you that the patient received what we believe to be excellent medical care, and we have no reason to believe that there was any shortfall in taking care of the patient.

是的。莫里，目前我們還不能討論合併症的問題。我只能說，該患者的病情非常複雜，除了肝臟異常之外，其他合併症可能也影響了最終結果。我們不評論地理方面的問題。我只能向您保證，我們認為患者得到了非常好的醫療護理，我們沒有任何理由相信在照顧患者方面有任何不足。

With respect to risk mitigation strategies, that's ongoing work. As you might imagine, we're doing as comprehensive analysis as we're able to do, looking at all of the data we've collected, coming up with any potential hypothesis. The ultimate goal would be to find a way to exclude patients who may be at risk, should we identify it or impose interventions that could deal with the liver function test abnormalities if they do occur.

至於風險緩解策略，那是一項持續進行的工作。正如您所料，我們正在進行盡可能全面的分析，查看我們收集的所有數據，並提出任何可能的假設。最終目標是找到一種方法，排除可能有風險的患者（如果我們發現這種情況），或採取乾預措施來應對可能出現的肝功能檢查異常。

Alec Stranahan, Bank of America.

亞歷克·斯特拉納漢，美國銀行。

I guess, how many ATTR patients are currently within that 3- to 5-week post-dose window on the study right now?

我想問一下，目前有多少 ATTR 患者處於研究中給藥後 3 至 5 週的觀察期內？

I can't give you precise numbers, but it's -- the vast majority of patients have passed through it. And with each passing day, there's a smaller and smaller set of patients who have yet to go through it.

我無法提供確切的數字，但絕大多數患者都經歷過這個過程。隨著時間的推移，尚未經歷過這種痛苦的病人越來越少。

Mani Foroohar, Leerink Partners.

Mani Foroohar，Leerink Partners。

My condolences, a tough outcome for the patient for sure. So let me dive in a little bit on a hypothetical that I've received from a number of clients, which is if this hold were to remain for an extended period of time, what does that mean for the ongoing OpEx spend of the company? i.e., I know it extends the duration to whenever we get a potential pivotal outcome for the study. But does it change the total amount of spend over the course of the study? Is your spend at a normal level during this hold or at least some activities interrupted?

深表同情，對病人來說無疑是個艱難的結果。那麼，讓我稍微深入探討一下我從一些客戶那裡收到的一個假設性問題，那就是如果這種凍結狀態持續很長時間，這對公司持續的營運支出意味著什麼？也就是說，我知道它會將研究持續時間延長到我們獲得研究的潛在關鍵結果為止。但這是否會改變研究期間的總支出金額？在此期間，您的消費是否維持在正常水準？或至少某些活動是否受到影響？

How should we think from a financial modeling perspective, recognizing that, that, of course, is a secondary concern to the moral obligations for the patient?

從財務建模的角度來看，我們該如何思考？當然，我們必須認識到，財務建模是次要的，而病人的道德義務才是首要考慮因素。

Thanks for the question. It was a little garbled, Mani, but I think you were asking how does the hold play into the financial runway of the company and how do we manage through it. I think there's going to be a two-part answer. Ed can speak to the runway and how we currently view it.

謝謝你的提問。馬尼，你剛才說的有點含糊不清，但我想你是在問，這種凍結措施對公司的財務狀況有何影響，以及我們如何應對這種情況。我認為答案會包含兩個部分。艾德可以談談T台以及我們目前對它的看法。

As you can imagine, our priority is going through the data and coming up with the best possible path forward. And that is job one at this point, and it's something that we're working very, very hard to do. The goal is to be up and running as soon as appropriate so that we can regain what was a very substantial momentum as we said. We had enrolled over 650 patients, and that's I think just a really stellar record. But maybe, Ed, you can say a few words about the runway and how we're thinking about this may impact that.

正如您所想，我們的首要任務是分析數據，找出最佳的前進方向。這就是我們目前的首要任務，也是我們正在非常努力地完成的事情。我們的目標是盡快恢復運營，以便重新獲得我們之前所說的非常強勁的發展勢頭。我們已經招募了超過 650 名患者，我認為這是一個非常出色的記錄。不過，艾德，或許你可以談談跑道的情況，以及我們對此的看法可能會對它產生什麼影響。

Of course. Thanks, John. Yes, I would say we -- it's premature to be too precise with any guidance. But as we sit here today, based on the information we know, as we indicated, the time lines and the plans for lonvo-z are unabated. So we continue to operationalize that study as we have been.

當然。謝謝你，約翰。是的，我認為現在給出任何具體的指導意見都為時過早。但就我們目前掌握的資訊來看，正如我們之前所指出的，lonvo-z 的時間表和計劃並沒有改變。因此，我們將繼續以以往的方式進行這項研究。

While we are on clinical hold and therefore, unable to enroll new patients or screen for patients, as we reported, we do have now more than 650 patients in MAGNITUDE and we have 47 patients on MAGNITUDE-2 that still remain on study, are still being managed according to the protocol. So the appropriate follow-up. So that will continue as we work our way through our clinical hold.

雖然我們目前處於臨床暫停狀態，因此無法招募新患者或篩選患者，但正如我們之前報導的那樣，MAGNITUDE 目前有 650 多名患者，MAGNITUDE-2 中有 47 名患者仍在研究中，並仍在按照方案進行管理。因此，需要採取適當的後續行動。所以，在我們逐步完成臨床觀察期間，這種情況還會持續下去。

Maybe to your point, the only thing that changes is the incremental cost of dosing per patient. So in many ways, near term as we work our way through the clinical hold, you could argue we're going to spend a little bit less money. We'll still have program management fees related to CRO costs and our own internal work, but the incremental cost per patient will not occur during this time, and we will reassess what the time lines look like once we have a clearer path on getting off clinical hold.

或許如你所說，唯一改變的是每位病患的額外用藥成本。因此，從很多方面來看，在短期內，隨著我們逐步度過臨床停工期，可以說我們會花少一點錢。我們仍需支付與 CRO 成本和我們自身內部工作相關的專案管理費，但在此期間不會產生每位患者的額外成本，一旦我們明確了解除臨床暫停的途徑，我們將重新評估時間表。

And then we don't talk much about it, but we do have research priorities within the organization, and that continues. So again, sitting here today, we don't see a substantial shift in the operating needs or the cash needs for the company, and we'll look to reevaluate that in a collaborative effort, including with the regulatory authorities in the weeks and months to come.

然後我們很少談論它，但我們組織內部確實有研究重點，而且這種情況會持續下去。所以，就目前的情況來看，我們認為公司的營運需求或現金需求不會發生實質變化，我們將在未來幾週和幾個月內與監管機構等各方合作，重新評估這種情況。

Yanan Zhu, Wells Fargo Securities.

朱亞楠，富國證券。

Sorry to hear the update about the patient. I was wondering, when you talk about comorbidities, is there any liver-related comorbidities? And then additionally, when you talk about less than 1% of the enrolled patients have Grade 4 enzyme elevation, could you -- are you able to disclose how many cases of Grade 4 liver enzyme situation has happened and how many are still resolving?

聽到病人的最新情況，我感到很遺憾。我想問一下，當您談到合併症時，是否有與肝臟相關的合併症？此外，當您提到入組患者中只有不到 1% 的人出現 4 級酶升高時，您能否透露已經發生了多少例 4 級肝酶升高病例，以及有多少例仍在恢復中？

Thanks, Yanan. The 1% applies to the more than 650 patients. I remind you, this is an ongoing placebo-controlled double-blinded study. And what's attributed to what in precise numbers by case, et cetera, is not possible for us to get into. But you should think of this as less than 1% across that number.

謝謝亞楠。這 1% 指的是超過 650 名患者。我提醒各位，這是一項正在進行的安慰劑對照雙盲研究。至於具體病例的確切數字等因素，我們不可能深入探究。但你應該認為這只佔該數字的不到 1%。

With respect to the comorbidities, it's not something we can get into at this point. I can assure you that there's an ongoing evaluation where we'll get more information that I think will be very helpful to understand the clinical course that this patient experienced. And we'll present that information at the appropriate time once we have it. But until that information is in our hand, I think it's premature to discuss.

至於合併症，我們現在還無法深入探討。我可以向你保證，我們正在進行持續的評估，從中我們將獲得更多信息，我認為這將非常有助於了解這位患者所經歷的臨床過程。一旦我們掌握了相關信息，我們會在適當的時候公佈。但在掌握相關資訊之前，我認為現在討論還為時過早。

Troy Langford, TD Cowen.

特洛伊·蘭福德，TD Cowen。

My condolences on the unfortunate update today. I guess just to kind of follow on to some of the other -- some of the previous questions. Is there anything that you all can do preclinically to try and disprove any sort of causation between nex-z treatment and the safety event? And then I know you all can't say that much, but is there -- if you all can provide any sort of color on potential time lines or next steps with the FDA around reinitiation of the study, I think that would help a lot.

對於今天這個不幸的消息，我深表哀悼。我想就之前的一些問題做個補充說明。各位能否在臨床前階段做些什麼，以嘗試排除Nex-Z治療與安全事件之間存在任何因果關係？我知道你們不能透露太多，但是——如果你們能提供一些關於重啟這項研究的潛在時間表或與 FDA 的後續步驟的信息，我認為這將非常有幫助。

Yes. I can't speak for the FDA, and we're certainly waiting for the letter that we expect to receive from them, the hold -- clinical hold letter. And that will be obviously very influential in how we think about -- going about getting back the protocol up and running. With respect to preclinically evaluating, it's hard to know at this point. But as I said before, we're looking at every source of information that we have to see if there is some way that we can identify patients who may be at increased risk.

是的。我不能代表 FDA 發言，我們當然也在等待我們預期會收到的來自他們的信函，即暫停函——臨床試驗暫停函。這顯然會對我們如何思考——如何恢復協議的運作——產生非常大的影響。至於臨床前評估方面，目前還很難說。但正如我之前所說，我們正在研究我們掌握的每一個資訊來源，看看是否有辦法識別出可能面臨更高風險的患者。

And when we find that information, I'm sure we'll be talking about it in a way that will be meaningful, but only when we're convinced that we have that information well in hand.

當我們找到這些資訊時，我相信我們會以有意義的方式討論它，但前提是我們確信我們已經完全掌握了這些資訊。

Brian Cheng, JPMorgan.

Brian Cheng，摩根大通。

Ed, earlier this year in January, I remember that you said that the ATM would be used at an opportunistic time. And looking at your 10-Q, $128 million this quarter was executed through the ATM. What changed your mind here in executing the ATM? And is the ATM your path going forward in raising additional cash?

艾德，我記得今年一月的時候你說過，ATM機將會在某個適當的時機被使用。從你們的 10-Q 表格來看，本季有 1.28 億美元是透過 ATM 完成的。是什麼讓你改變了主意，決定執行ATM計畫？那麼，ATM機是你未來籌集額外資金的途徑嗎？

Brian, thanks for the question. And Ed, do you want to talk about how we think about the various tools for raising funds?

布萊恩，謝謝你的提問。艾德，你想談談我們如何看待各種募款工具嗎？

Yes. So we've often talked about ATM as not a primary strategy, but a tool within the toolkit to raise capital for the company. We're not going to comment on specifics going forward, but we do believe in having options. And so whether it's traditional equity that's often done in biotech, including the use of the ATM, you should expect us to continue to have that available to us and potentially circumstances dependent to utilize that strategy. But there are others for a company like ours that is approaching Phase III data and has a BLA filing.

是的。因此，我們經常談到 ATM 不是主要策略，而是公司籌集資金的工具之一。我們不會對未來的具體細節發表評論，但我們相信應該有多種選擇。因此，無論是生物技術領域常用的傳統股權融資方式（包括使用ATM），您都應該期望我們繼續擁有這種融資方式，並且可能會根據具體情況採用這種策略。但對於像我們這樣即將獲得 III 期臨床試驗數據並已提交 BLA 申請的公司來說，還有其他選擇。

And so whether it's collaborations that we could consider, debt structures or more creative financing opportunities, I do believe we have the balance sheet to get to those milestones and multiple options to consider to improve the balance sheet in the future.

因此，無論是我們可以考慮的合作、債務結構或更具創意的融資機會，我相信我們擁有實現這些里程碑的資產負債表，並且有多種選擇可以考慮在未來改善資產負債表。

Jay Olson, Oppenheimer.

傑伊·奧爾森，奧本海默。

We're sorry to hear this news. Since you mentioned there are no Grade 4 liver transaminase elevations in MAGNITUDE-2, can you just talk about any notable differences in the baseline characteristics for MAGNITUDE versus MAGNITUDE-2? And any particular changes you may be considering to the enrollment criteria?

聽到這個消息我們感到很遺憾。既然您提到 MAGNITUDE-2 中沒有 4 級肝轉氨酶升高，您能否談談 MAGNITUDE 與 MAGNITUDE-2 的基線特徵有哪些顯著差異？您是否正在考慮對招生標準進行任何具體更改？

The primary difference is the indication itself. Patients in MAGNITUDE-2, as I'm sure you know, have polyneuropathy, which is a manifestation of TTR amyloidosis. And in MAGNITUDE, it's cardiomyopathy as the primary manifestation. Other than that, the differences tend to be really minimal, and I would think of it as on a continuum with respect to the drug as a whole.

主要區別在於適應症本身。如您所知，MAGNITUDE-2 中的患者患有多發性神經病變，這是 TTR 澱粉樣變性的表現。而 MAGNITUDE 的主要表現是心肌病變。除此之外，兩者之間的差異往往非常小，我認為就藥物整體而言，它是一個連續體。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

I was just wondering if we step back, whether you could just help us understand the steps from here apart from the FDA letter.

我只是想問，如果我們退一步講，除了FDA的信函之外，您是否可以幫助我們理解接下來的步驟？

Well, central to the way forward is the FDA letter and coming to terms with what they'll require. But you can imagine that we're already working very hard with all of the information that we've accumulated. We're looking clinical information, preclinical information, manufacturing, et cetera. All of this is part of a very, very comprehensive analysis to see if there is any indication of a particular thing or a characteristic that puts patients at risk.

嗯，前進方向的關鍵在於FDA的信函以及接受他們提出的要求。但你可以想像，我們已經在利用累積的所有資訊進行非常努力的工作了。我們正在尋找臨床資訊、臨床前資訊、生產製造等資訊。所有這些都是為了進行非常非常全面的分析，以確定是否存在任何跡象表明某種特定因素或特徵會使患者面臨風險。

While we do that, we wait for the FDA and the information that it requests. And as that information -- as that letter becomes available to us, we'll think through what we need to do and we believe we'll have the tools to address what we imagine may be things that are of interest to them, and we will work very, very closely with them to come up with the best possible plan that we think is an appropriate way to mitigate risk.

同時，我們將等待美國食品藥物管理局（FDA）及其要求提供的資訊。一旦我們收到那封信，我們將仔細考慮我們需要做什麼，我們相信我們將擁有解決我們認為他們可能感興趣問題的工具，我們將與他們非常密切地合作，制定我們認為能夠適當降低風險的最佳方案。

Jack Allen, Baird.

傑克艾倫，貝爾德。

I also wanted to pass along my condolences, a tough update here. Stepping back, I was hoping you could help remind us of the differences in the construct as it relates to the ATTR candidate as compared to HAE. I believe they're using different LNPs, but could you help me understand that, and then also obviously targeting different genetic diseases as well?

我也想表達我的慰問，這真是個令人難過的消息。退一步講，我希望您能幫我們回憶一下，ATTR 候選人與 HAE 候選人在結構上的差異。我認為他們使用的是不同的LNP，您能幫我理解嗎？而且他們顯然也針對不同的遺傳疾病？

Yes. Thanks for the question. As we've shared elsewhere, the LNP is the same. That is the lipid constituents, the mRNA is the same. It's the guide RNA that differs between the two.

是的。謝謝你的提問。正如我們在其他地方提到的，自由黨/國家黨聯盟也是如此。那是脂質成分，mRNA 是一樣的。兩者之間的差異在於引導RNA。

but that leads to a totally different sort of outcome in patients. So ultimately, the patients themselves are different. The disease that they have is different and the gene that is targeted is different. So we view lonvo-z and nex-z as absolutely distinct from each other and the patient experience thus far aligns with that.

但這會導致患者出現完全不同的結果。所以歸根究底，患者本身是不同的。他們患的疾病不同，所針對的基因也不同。因此，我們認為 lonvo-z 和 nex-z 完全不同，到目前為止，患者的體驗也與此相符。

Silvan Tuerkcan, Citizens.

Silvan Tuerkcan，公民。

My condolences as well to the clinical team. My question is do you add any additional liver monitoring in the lonvo-z trial in HAE? And I'm asking because if the percentage is less than 1% on 650 patients, if you do the math, less than a patient in the HAE trial, right? So any chances you can pick up slight liver increases there before there's a potential launch?

我也向臨床團隊表達慰問。我的問題是，在HAE患者的lonvo-z試驗中，是否需要額外的肝臟監測？我這麼問是因為，如果 650 名患者中的比例小於 1%，那麼算下來，這甚至比 HAE 試驗中的一名患者還要少，對吧？那麼，在產品上市之前，有沒有可能會偵測到肝臟指標的輕微升高？

Well, first of all, the lonvo-z HAELO trial is completely enrolled. And as we said at a prior update, that patient population is fully enrolled, and they've all passed through this initial window for the patients randomized in the primary evaluation part of the study. The monitoring that we have is not as intense as what we have in the nex-z trial. But again, our experience to date has been quite distinct. And if there were an issue that we would expect to be able to see it with the monitoring that we do have.

首先，lonvo-z HAELO 試驗已全部招募完畢。正如我們在先前的更新中所說，患者群體已全部入組，並且所有參與研究主要評估部分隨機分組的患者都已通過了初始窗口期。我們目前的監測力道不如nex-z試驗中的監測力道大。但話說回來，我們迄今為止的經歷卻截然不同。如果存在問題，我們預計能夠透過我們現有的監控手段發現它。

I would say that an additional aspect to point out is that on Saturday, as we said in our comments, we'll be presenting at the AACI meeting, the combined pooled experience that we have of all patients who have received a 50-milligram dose for lonvo-z, and you'll be able to see the same not only clinical performance, but safety performance that we're seeing ourselves.

我想指出的另一點是，正如我們在評論中所說，我們將在周六的 AACI 會議上展示我們收集的所有接受 50 毫克 lonvo-z 治療的患者的綜合經驗，您將能夠看到與我們自己所看到的相同的臨床表現和安全性表現。

Jonathan Miller, Evercore ISI.

Jonathan Miller，Evercore ISI。

My condolences as well to the family of the patient and to you guys, tough update. I guess I would love to dig further into the comprehensive analysis that you said you were doing. Obviously, you're going back over the individual patient. But how deep are you going across both the nex-z and the lonvo-z patient populations thus far? And can you maybe put some guidelines around what sorts of cases you would consider to be possibly fitting the pattern versus the sorts of cases you would be excluding?

我也向患者家屬和你們表示慰問，這個消息令人難過。我很想深入了解您所說的正在進行的全面分析。顯然，你是在回顧個別患者的病情。但到目前為止，你們對 nex-z 和 lonvo-z 患者群體的調查深度有多深？您能否給予一些指導原則，說明哪些類型的案例可能符合這種模式，以及哪些類型的案例會被排除在外？

I'm thinking of patients who have subclinical liver enzyme elevations that might fit a timing pattern. How do you adjudicate whether you think those are part of this signal or not?

我想到的是一些肝酵素亞臨床升高的患者，他們的肝酵素升高可能符合某種時間模式。你如何判斷這些是否屬於該訊號的一部分？

The first point I would make is that the lonvo-z experience is distinct from what we see with nex-z. But with respect to nex-z, you're correct in that we'll have more information coming from this particular patient, which I think can be potentially very illuminating in terms of understanding the patient's clinical course. But other than that, when I say comprehensive analysis, I mean comprehensive. And we're looking broadly. We're looking deeply and the sorts of things that you're raising are all on the list of things for us to consider.

首先我要指出的是，lonvo-z 的體驗與我們在 nex-z 中看到的體驗截然不同。但就 nex-z 而言，您說得對，我們將從這位特定患者那裡獲得更多信息，我認為這對於了解患者的臨床病程可能非常有啟發意義。但除此之外，我所說的全面分析，指的是真正的全面分析。我們正在進行廣泛的考察。我們正在深入調查，您提出的這些問題都在我們考慮的範圍內。

Whitney Ijem, Canaccord.

Whitney Ijem，Canaccord。

This is Angela Qian on for Whitney. I also want to express our condolences. So we understand you'll be increasing the monitoring of lab values after dosing. But can you give us a little bit more color on how often the lab values are being monitored previously? In this one patient, the levels were discovered when he had abdominal pain.

這裡是Angela Qian，為您報道惠特尼。我也想表達我們的慰問。因此，我們了解到您將在給藥後加強對實驗室數值的監測。能否詳細介紹一下之前實驗室數值的監測頻率？這名患者出現腹痛症狀時，才發現他的血液酒精濃度異常。

But in the other patients who did have elevations, how was that discovered?

但是，對於其他出現升高症狀的患者，又是如何發現的呢？

We've always monitored in the window, and that's how we are aware of what we've seen thus far. We've not only picked this up as a result of more intense monitoring. But what we've done as more information has become available to us is move to at least weekly monitoring for the first few weeks after a patient has been exposed to the drug to see if we're able to actually characterize the full course of what happens when it happens. Again, it's occurring in less than 1% of all of the patients that have been enrolled in the trial. And the notion there is that if there's information that can be acted on that, that's in the hands of the physicians who are caring for these patients.

我們一直透過窗口進行觀察，所以才知道目前為止我們所看到的情況。我們並非僅僅透過加強監測才發現這一點。但隨著我們獲得更多信息，我們採取的措施是，在患者接觸藥物後的最初幾週內，至少每週進行一次監測，以觀察我們是否能夠真正描述藥物作用的完整過程。再次強調，這種情況在所有參與試驗的患者中發生率不到 1%。這裡的想法是，如果有可以利用的信息，那麼這些信息就掌握在照顧這些病人的醫生手中。

Luca Issi, RBC Capital Markets.

伊西 (Luca Issi)，加拿大皇家銀行資本市場部。

This is Shelby on for Luca. Maybe a quick one on HAE. We appreciate that you don't see a lot of read-through here, but do you think the patient death in TTR could hurt the potential commercial opportunity for this indication? Any color there, much appreciated.

這是謝爾比替盧卡發言。或許可以簡單談談HAE。我們知道您可能沒有看到很多通讀全文的內容，但您認為 TTR 中的患者死亡是否會損害該適應症的潛在商業機會？任何顏色都可以，非常感謝。

I can only speculate at this time, I think between where we are today and completing the readout of our Phase III trial for HAELO, there's a lot of time and information to be accumulated that will characterize the benefit risk profile for lonvo-z. Again, I would point you to a presentation that will be given on Saturday, just a couple of days from now, where the combined experience of all of the patients, 32 that have received 50 milligrams and the efficacy profile, along with the safety profile is there for everyone to see. And we think that, that is largely going to be representative of what we think we'll see in our Phase III or clinical use of the product more broadly. So until we get all of that information, I don't think we're going to be in a position to talk about the commercial opportunity. But thus far, we very much like what we see.

目前我只能進行推測，我認為從我們今天所處的位置到完成 HAELO III 期試驗的結果公佈之間，還有很多時間和資訊需要積累，才能確定 lonvo-z 的獲益風險概況。我再次提醒大家，我們將在幾天後的周六進行一次演講，屆時將匯總所有患者（32 名接受 50 毫克治療的患者）的經驗，並展示療效和安全性概況，供大家參考。我們認為，這在很大程度上將代表我們在產品 III 期或更廣泛的臨床應用中將會看到的情況。所以，在我們獲得所有這些資訊之前，我認為我們還無法討論商業機會。但就目前來看，我們非常滿意。

Myles Minter, William Blair.

邁爾斯·明特，威廉·布萊爾。

Sorry to hear about the update. It's a straightforward one. Do you have a cause of death? This is a cardiomyopathy trial. You will have deaths in the trial, unfortunately.

很遺憾聽到這個消息。這很簡單。你們知道死因嗎？這是一項心肌病變試驗。不幸的是，審判過程中會出現死亡事件。

Just wondering whether this was a CV-related event or as it seems maybe something beyond that?

我只是想知道這是否與簡歷有關，或者看起來像是另有隱情？

If I heard you right, I'm sorry, it was a little garbled. We'll give the information once we have all of the final material in hand. There are some things that are being done after the death to give us additional insights. And at the appropriate time, we'll share all of that.

如果我沒聽錯的話，抱歉，我剛才說得有點含糊不清。等我們拿到所有最終材料後，我們會提供相關資訊。有些事情是在人們去世後進行的，目的是為了給我們額外的見解。時機成熟時，我們會分享所有這些資訊。

Thank you. And that concludes our question-and-answer session. I'd like to turn the conference back over to CEO, John Leonard, for closing remarks.

謝謝。我們的問答環節到此結束。我謹將會議交還給執行長約翰·倫納德，請他作閉幕致詞。

So thank you all for joining us. We will look forward to speaking with you again when we have meaningful updates to share.

感謝各位的參與。我們將在有重要進展時再次與您聯繫。

Thank you. This concludes today's conference call. We thank you all for attending today's presentation. You may now disconnect your lines, and have a wonderful day.

謝謝。今天的電話會議到此結束。感謝各位蒞臨今天的報告會。現在您可以斷開線路了，祝您有美好的一天。