Intellia Therapeutics Inc (NTLA) 2024 Q3 法說會逐字稿

Good morning and welcome to Intellia Therapeutics third quarter, 2024 financial results conference call. My name is Drew and I will be your conference operator today following formal remarks, we will open the call up for a question and answer session.

早安，歡迎參加 Intellia Therapeutics 2024 年第三季財務業績電話會議。我叫德魯，今天我將擔任你們的會議主持人，在正式發言後，我們將開始問答環節。

(Operator Instructions)

（操作員說明）

I will now turn the conference over to Lina Li, Senior Director of Investor Relations and Corporate Communications at Intellia. Please proceed.

我現在將會議交給 Intellia 投資者關係和企業傳播高級總監 Lina Li。請繼續。

Thank you operator and good morning, everyone. Welcome to Intellia Therapeutics third quarter, 2024 earnings call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the investors and media section of Intellia's website, at www.intelliatx.com. This call is being broadcast live and a replay will be archived on the company's website.

謝謝接線員，大家早安。歡迎參加 Intellia Therapeutics 2024 年第三季財報電話會議。今天早上早些時候，Intellia 發布了一份新聞稿，概述了該公司本季的進展以及今天電話會議討論的主題。此新聞稿可在 Intellia 網站 www.intelliatx.com 的投資者和媒體部分找到。這次電話會議正在現場直播，重播將在公司網站上存檔。

At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our sec filings available at sec.gov for a discussion of potential risks and uncertainty.

此時，我想花一點時間提醒聽眾，在這次電話會議中，Intellia 管理層可能會做出某些前瞻性聲明，並要求您參考sec.gov 上提供的我們的SEC 文件，以討論潛在風險和不確定性。

All information presented on this call is current as of today and Intellia undertakes no duty to update this information unless required by law.

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 from Intellia, you are JOHN LEONARD, Chief Executive Officer, DAVID LEBWOHL, Chief Medical Officer, LAURA SEPP-LORENZINO, Chief Scientific Officer, and EDWARD DULAC, Chief Financial Officer. John will begin with recent business highlights, David will provide updates on our clinical pipeline progress, Laura will then provide R&D updates and Edward will review our financials before we open the call for questions. With that, I will now turn the call over to John, our Chief Executive Officer.

來自 Intellia 的各位是執行長 JOHN LEONARD、首席醫療官 DAVID LEBWOHL、首席科學官 LAURA SEPP-LORENZINO 和首席財務官 EDWARD DULAC。約翰將從最近的業務亮點開始，大衛將提供我們臨床管道進展的最新信息，勞拉將提供研發更新，愛德華將在我們開始提問之前審查我們的財務狀況。現在，我將把電話轉給我們的執行長約翰。

Thank you Lina. Good morning everyone and thank you all for joining us today. At Intellia, we are ushering in a new era of medicine in the third quarter and more recent period, we've made substantial progress in our efforts to bring promising highly differentiated and potentially curative CRISPR based gene editing treatments to patients. In October at the American College of Allergy Asthma and Immunology Annual Scientific Meeting, we presented unprecedented positive results from our phase two study of NTLA-2002 for the treatment of hereditary angioedema. These results showed that a simple one time infusion of NTLA-2002 offers patients the potential for a functional cure. For people living with HAE current treatment options are limited to chronically administered prophylactic therapies to prevent or manage attacks and the use of on demand therapy to control breakthrough attacks, because of this available therapies place emphasis on attack rate reductions for their lifelong treatments. However, our market research is clear, patients want to lead a normal life, when that is free of attacks, free of chronic treatment and free of mental burden around potential triggers and the loss of access to their therapies.

謝謝你莉娜。大家早安，感謝大家今天加入我們。在 Intellia，我們在第三季和最近一段時間迎來了醫學的新時代，我們在為患者帶來有前途的高度差異化和潛在治癒性 CRISPR 基因編輯治療方面取得了實質進展。10 月，在美國過敏氣喘和免疫學學會年度科學會議上，我們展示了 NTLA-2002 用於治療遺傳性血管性水腫的二期研究的前所未有的積極結果。這些結果表明，簡單的一次性輸注 NTLA-2002 為患者提供了功能性治癒的可能性。對於 HAE 患者，目前的治療選擇僅限於長期預防性治療以預防或控制發作，以及使用按需治療來控制突破性發作，因為這種可用的療法強調終身治療的發作率降低。然而，我們的市場研究很明確，患者希望過正常的生活，不受攻擊、不受長期治療、不受潛在觸發因素​​造成的精神負擔以及無法獲得治療的影響。

The emerging profile for NTLA-2002 provides hope that a single intervention may lead to the complete elimination of angioedema attacks and remove the need for subsequent prophylaxis therapy for most patients. The opportunity to deliver such a profile will create significant value for patients and the health care system as a whole. We're extremely encouraged by our phase two results and we're actively screening patients in the phase three HAELO study. The strong enthusiasm for a NTLA-2002 from patients and our investigators strengthens our conviction that the phase three will enroll rapidly, enabling us to submit a plan BLA in 2026.

NTLA-2002 的新進展為人們帶來了希望，即單次幹預可能會導致完全消除血管性水腫發作，並消除大多數患者隨後進行預防性治療的需要。提供此類資料的機會將為患者和整個醫療保健系統創造巨大的價值。我們對第二階段的結果感到非常鼓舞，我們正在積極篩選第三階段 HAELO 研究中的患者。患者和我們的研究人員對 NTLA-2002 的強烈熱情增強了我們的信念，即第三階段將迅速入組，使我們能夠在 2026 年提交 BLA 計劃。

In addition, we're making excellent progress across our other late stage trials. As announced this morning, the FDA cleared our IND application for MAGNITUDE-2, our phase three trial of Nex-z for patients with hereditary ATTR amyloidosis with polyneuropathy. We expect to initiate the study in the coming days. Since dosing our first cardiomyopathy patient in March, we continue to see strong momentum in our phase three MAGNITUDE-2 study, and enrollment is tracking ahead of our internal projections. With three active phase three studies expected by year end, we are leading the field of in vivo CRISPR-based medicines. Intellia is ushering in a new era of medicine with the prospect of a functional cure for patients suffering from HAE and a treatment that may change the course of the disease for people with ATTR amyloidosis.

此外，我們在其他後期試驗中也取得了巨大進展。正如今天早上宣布的那樣，FDA 批准了我們的 MAGNITUDE-2 IND 申請，這是我們針對遺傳性 ATTR 澱粉樣變性伴多發性神經病患者進行 Nex-z 的三期試驗。我們預計在未來幾天內啟動這項研究。自從 3 月對第一位心肌病變患者進行給藥以來，我們繼續看到第三階段 MAGNITUDE-2 研究的強勁勢頭，並且入組進度領先於我們的內部預測。預計到年底將進行三項活躍的三期研究，我們在基於 CRISPR 的體內藥物領域處於領先地位。Intellia 正在開創醫學的新時代，有望為 HAE 患者提供功能性治愈，並為 ATTR 澱粉樣變性患者提供可能改變病程的治療方法。

I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs. David.

我現在將把電話轉交給我們的首席醫療官 David Lebwohl，他將提供我們臨床計畫的最新資訊。大衛.

Thanks John.

謝謝約翰。

I'll begin with NTLA-2002 in development for hereditary angioedema or HAE.

我將從開發用於遺傳性血管性水腫或 HAE 的 NTLA-2002 開始。

As John noted, we presented phase I data which demonstrated that a single dose of NTLA-2002 could both eliminate attacks and eliminate the need for further treatment.

正如 John 指出的，我們提供的 I 期數據表明，單劑 NTLA-2002 既可以消除發作，又無需進一步治療。

In the 50 mg arm, 8 of 11 patients had no attacks during the 16 week primary observation period after a single dose of NTLA-2002.

在 50 mg 組中，11 名患者中有 8 名在單劑量 NTLA-2002 後 16 週的主要觀察期內未出現發作。

These groundbreaking results highlight how NTLA-2002 has the potential to reset the standard of care for HAE.

這些突破性的結果凸顯了 NTLA-2002 如何有可能重新設定 HAE 的照護標準。

We are encouraged by the findings thus far from the post primary observation period in the phase two as well.

到目前為止，第二階段初步觀察期後的發現也令我們感到鼓舞。

The eight patients who are attack free in the 50 mg cohort, remain attack free with no HAE directed therapy for a median of eight months, so far. Moreover, the three patients who are not yet attack free, achieved clinically meaningful attack rate reductions.

到目前為止，50 mg 組中 8 名未發作的患者在未接受 HAE 指導治療的情況下，中位數時間為 8 個月。此外，三名尚未消除發作的患者實現了具有臨床意義的發作率降低。

Based on our phase one observations, we expect these patients to show continued improvement or become attack free as they have more time to adjust to the new normal.

根據我們第一階段的觀察，我們預期這些患者會表現出持續的改善或不再發作，因為他們有更多的時間來適應新的常態。

We are continuing to follow all patients and look forward to presenting longer follow up data, next year.

我們將繼續追蹤所有患者，並期待明年提供更長的追蹤數據。

With NTLA-2002, we believe we are creating a new standard for patient outcomes in HAE, where 12 out of 15 patients or 80% of patients who receive the 50 mg dose in the phase 1/2 study appear functionally cured of their disease. That is patients were attack free without the need for further treatment.

透過 NTLA-2002，我們相信我們正在為 HAE 患者的結果制定一個新標準，在 1/2 期研究中接受 50 mg 劑量的 15 名患者中有 12 名或 80% 的患者的疾病出現功能性治癒。也就是說，患者沒有發作，無需進一步治療。

This is unprecedented and suggests an emerging product profile that is unmatched by other HAE therapies, either currently approved or in development.

這是史無前例的，顯示了一種新興的產品特徵，是目前已批准或正在開發的其​​他 HAE 療法無法比擬的。

Importantly, our market research indicates that NTLA-2002's emerging product profile aligns directly with the needs and priorities of patients and physicians.

重要的是，我們的市場研究表明 NTLA-2002 的新興產品概況直接符合患者和醫生的需求和優先事項。

As such, we expect broad interest and demand for NTLA-2002, that will drive rapid enrollment of our phase three study and commercial uptake, once approved. We are now actively screening patients in the Haelo phase three study, a global randomized double blind placebo controlled study.

因此，我們預計 NTLA-2002 會產生廣泛的興趣和需求，一旦獲得批准，這將推動我們第三階段研究的快速註冊和商業應用。我們現在正在積極篩檢 Haelo 第三期研究的患者，這是一項全球隨機雙盲安慰劑對照研究。

Importantly, our phase three study will extend the primary observation period and look at the number of HAE attacks from weeks 5 to 28 as its primary endpoint. This is designed to provide a cleaner read into the drug's effects once CACR reduction has reached its steady state about a month after therapy.

重要的是，我們的第三階段研究將延長主要觀察期，並將第 5 週至第 28 週的 HAE 發作次數作為主要終點。這樣做的目的是為了在治療後大約一個月 CACR 降低達到穩定狀態後，更清楚地了解藥物的效果。

As previously guided, we expect to submit a DLA filing in 2026 from the 60 patient study.

按照先前的指導，我們預計將在 2026 年提交 60 名患者研究的 DLA 備案。

In summary, we believe NTLA-2002 is well positioned to be the first approved in vivo CRISPR gene editing treatment, and a truly transformative one time treatment for people living with HAE.

總之，我們相信 NTLA-2002 完全有能力成為第一個獲得批准的體內 CRISPR 基因編輯治療方法，並且是針對 HAE 患者的真正變革性的一次性治療方法。

Switching to Nex-z, also known as NTLA-200, in development for the treatment of ATTR amyloidosis. This multisystem disease primarily manifests as either cardiomyopathy due to amyloid deposits in the heart or polyneuropathy through the progressive accumulation of protein deposits in the nervous system.

改用 Nex-z（也稱為 NTLA-200），正在開發用於治療 ATTR 澱粉樣變性。這種多系統疾病主要表現為心臟中澱粉樣蛋白沉積引起的心肌病變或因神經系統中蛋白質沉積逐漸累積而引起的多發性神經病變。

We announced today that the US FDA cleared our IND application to initiate a phase three trial in patients with hereditary ATTR amyloidosis with polyneuropathy.

我們今天宣布，美國 FDA 批准了我們的 IND 申請，啟動針對遺傳性 ATTR 澱粉樣變性伴隨多發性神經病變患者的第三期試驗。

This marks our fourth consecutive IND clearance within 30 days of submission for in vivo therapies we have developed. An unparalleled regulatory track record in the field of gene editing and testament to our high standard for drug development.

這標誌著我們在提交我們開發的體內療法後的 30 天內連續第四次獲得 IND 批准。在基因編輯領域無與倫比的監管記錄證明了我們藥物開發的高標準。

Our MAGNITUDE-2 phase three trial is an international randomized double blind placebo controlled study.

我們的 MAGNITUDE-2 三期試驗是一項國際隨機雙盲安慰劑對照研究。

50 patients will be enrolled and randomized 1 to 1 to receive a single 55 mg infusion of Nex-z or placebo. Patients randomized to the placebo arm will be eligible for optional crossover to receive Nex-z. The primary end points are the change from baseline in mNIS+7 at month 18 and serum TTR at day 29.

將招募 50 名患者，並以 1 比 1 的比例隨機接受單次 55 毫克 Nex-z 或安慰劑輸注。隨機分配至安慰劑組的患者將有資格選擇交叉接受 Nex-z 治療。主要終點是第 18 個月的 mNIS+7 和第 29 天的血清 TTR 相對於基線的變化。

In polyneuropathy, there is a positive correlation between greater TTR protein reduction and improved clinical benefit. To date, no other agent approved or in clinical development has demonstrated consistent, deep, and durable TTR reduction like Nex-z, which gives us tremendous confidence in our ability to positively impact patient outcomes in the MAGNITUDE-2 study. We expect to initiate the study at ex US sites in the coming days. Simultaneously, the rapid enrollment of the MAGNITUDE-2 trial in patients with cardiomyopathy continues to track ahead of our internal projections based on strong patient and physician interest. In total, we are actively enrolling patients at over 60 sites and have received regulatory clearance in more than 20 countries for the phase three study.

在多發性神經病變中，TTR 蛋白減少量增加與臨床效益改善之間有正相關。到目前為止，還沒有其他已批准或處於臨床開發階段的藥物能夠像 Nex-z 那樣表現出一致、深度和持久的 TTR 降低，這讓我們對 MAGNITUDE-2 研究中積極影響患者結果的能力充滿信心。我們預計未來幾天將在美國以外的地點啟動這項研究。同時，基於患者和醫生的強烈興趣，心肌病變患者的 MAGNITUDE-2 試驗的快速入組繼續領先於我們的內部預測。總的來說，我們正在 60 多個地點積極招募患者，並已獲得 20 多個國家的監管機構批准進行第三階段研究。

Findings in a recent publication of a competitor's clinical data in ATTR-CM indicate that there is a major opportunity to improve patients' clinical outcomes beyond what current therapies provide. In our ongoing phase one study, we demonstrated that all patients with cardiomyopathy achieved rapid deep and durable TTR reduction with Nex-z, more consistent and greater mean reductions than that reported with TTR silencers.

最近在 ATTR-CM 上發表的競爭對手臨床數據的研究結果表明，有一個重大機會可以改善患者的臨床結果，超越目前的治療方法。在我們正在進行的第一階段研究中，我們證明所有心肌病變患者都透過 Nex-z 實現了快速深度和持久的 TTR 降低，比使用 TTR 消音器報告的結果更一致和更大的平均降低。

As such, our early clinical data suggest Nex-z could significantly reduce total TTR exposures which in turn might provide greater clinical benefit for patients.

因此，我們的早期臨床數據表明 Nex-z 可以顯著減少總 TTR 暴露，這反過來可能為患者提供更大的臨床益處。

Next Saturday, November 16th, we will be presenting new findings from the ongoing phase one study as a late breaking oral presentation at the American Heart Association Scientific Sessions.

下週六，即 11 月 16 日，我們將在美國心臟協會科學會議上以最新的口頭報告形式介紹正在進行的第一階段研究的新發現。

On the occasion of AHA's 100th anniversary, we will be presenting data at the opening session titled celebrating a century of cardiovascular science, from prevention to treatment to cure.

在 AHA 成立 100 週年之際，我們將在題為慶祝心血管科學百年：從預防到治療再到治癒的開幕會議上展示數據。

These data will provide insights into the emerging clinical profile of Nex-z and the hypothesis that greater TTR reduction leads to better clinical outcomes.

這些數據將為 Nex-z 的新興臨床概況提供深入見解，並提供 TTR 降低幅度更大可帶來更好臨床結果的假設。

The update will include data from all 36 patients within the cardiomyopathy arm including important measures of clinical and functional benefit.

此次更新將包括心肌病變組所有 36 名患者的數據，包括臨床和功能益處的重要指標。

This includes safety, reduction of TTR, and disease progression markers such as NT pro-BNP, troponin, Fixit watt test at month 12 compared to baseline.

這包括安全性、TTR 的減少以及疾病進展標記物，例如與基線相比的第 12 個月的 NT pro-BNP、肌鈣蛋白、Fixit watt 測試。

We look forward to reviewing these data on an investor webcast taking place that same day, where we will also provide an update on the polyneuropathy arm.

我們期待在同一天舉行的投資者網路廣播中審查這些數據，我們還將提供有關多發性神經病部門的最新資訊。

I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the NTLA-3001 program and our R&D efforts.

現在我將把電話轉給我們的首席科學官 Laura，她將提供有關 NTLA-3001 計劃和我們研發工作的最新資訊。

Thank you, David. Good morning, everyone.

謝謝你，大衛。大家早安。

We're advancing our science beyond in vivo therapies and into our first in vivo gene insertion programs in the clinic. NTLA-3001 is our first wholly owned, in vivo gene insertion program for alpha-1 antitrypsin deficiency associated lung disease. It is designed to precisely insert the wild type SERPINA1 gene which encodes the alpha-1 antitrypsin protein.

我們正在將我們的科學推進到超越體內療法並進入臨床的第一個體內基因插入計畫。NTLA-3001 是我們第一個全資擁有的針對 α-1 抗胰蛋白酶缺乏相關肺部疾病的體內基因插入計畫。它旨在精確插入編碼 alpha-1 抗胰蛋白酶蛋白的野生型 SERPINA1 基因。

In previous, we presented non-human primate data. We've demonstrated the ability to produce fully functional alpha-1 protein at normal levels after a single dose. Notably, these normal levels of alpha-1 protein were durable through two years of follow up in the completed study. We're on track to those of first patient in the phase 1/2 study of NTLA-3001 by year end.

之前，我們提供了非人類靈長類動物數據。我們已經證明，單次劑量後能夠以正常水平產生功能齊全的 α-1 蛋白。值得注意的是，這些正常的 α-1 蛋白質水平在已完成的研究的兩年追蹤中持續存在。我們預計在年底前迎來 NTLA-3001 1/2 期研究中的首例患者。

If we're able to translate what we have seen in non-human primates to humans, we believe this will be a major step forward for alpha-1 patients and the field of gene editing. As human success, it would unlock a whole new category of diseases, which require a gain of function that we could pursue with our modular insertion platform.

如果我們能夠將在非人類靈長類動物中看到的現象轉化為人類，我們相信這將是 alpha-1 患者和基因編輯領域向前邁出的重要一步。隨著人類的成功，它將解鎖一類全新的疾病，這需要我們透過模組化插入平台來獲得功能。

In parallel, we're continuing to advance our toolbox of novel gene editing and delivery technologies to extend the reach of CRISPR based gene editing for in vivo and ex vivo therapeutic applications. This includes advancing gene editing programs in five different tissues outside the level, either independently or in collaboration with partners.

同時，我們正在繼續改進我們的新型基因編輯和傳遞技術工具箱，以擴大基於 CRISPR 的基因編輯在體內和離體治療應用的範圍。這包括獨立或與合作夥伴合作在五個不同組織中推進基因編輯計劃。

We're proud of all the recent process and look forward to providing more updates as we advance our platform and pipeline.

我們對最近的所有流程感到自豪，並期待在我們推進我們的平台和管道時提供更多更新。

I now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of third quarter, 2024.

我現在將電話轉交給我們的財務長 Ed，他將提供截至 2024 年第三季我們財務業績的最新資訊。

Thank you, Laura and good morning everyone.

謝謝勞拉，大家早安。

Intellia continues to maintain a solid balance sheet, that allows us to execute on our pipeline and platform.

Intellia 繼續保持穩健的資產負債表，使我們能夠在我們的管道和平台上執行。

Our cash, cash equivalent and marketable securities were approximately $944.7 million as of September 30th 2024, compared to $1 billion as of December 31st 2023. The decrease was driven by cash used to fund operations of approximately $335 million.

截至 2024 年 9 月 30 日，我們的現金、現金等價物及有價證券約為 9.447 億美元，截至 2023 年 12 月 31 日為 10 億美元。減少的原因是用於營運的現金約為 3.35 億美元。

The decrease was offset in part by $176.9 million of net equity proceeds from the company's at-the-market program. $47 million of collaborator reimbursements including a one time $30 million payment received in April, related to the company's technology collaboration with Regeneron, $37.2 million of interest income and $6.5 million in proceeds from employee based stock plans.

該減少額被公司市場計劃的 1.769 億美元淨股本收益部分抵銷。 4700 萬美元的合作者報銷，包括 4 月收到的與該公司與 Regeneron 的技術合作有關的一次性付款 3000 萬美元、3720 萬美元的利息收入以及來自員工股票計劃的 650 萬美元收益。

Our collaboration revenue was $9.1 million during the third quarter of 2024, compared to $12 million during the third quarter of 2023. The $2.9 million decrease was mainly driven by a reduction in revenue related to the Advents License and Collaboration Agreement. R&D expenses were $123.4 million during the third quarter of 2024, compared to $113.7 million, during the third quarter of 2023. The $9.7 million increase was primarily driven by the advancement of our lead programs.

2024 年第三季我們的協作收入為 910 萬美元，而 2023 年第三季為 1,200 萬美元。減少 290 萬美元主要是由於與 Advents 許可和合作協議相關的收入減少。2024 年第三季的研發費用為 1.234 億美元，而 2023 年第三季的研發費用為 1.137 億美元。970 萬美元的成長主要是由我們主導專案的進展所推動的。

Stock based compensation included in R&D expense was $24.2 million for the third quarter.

第三季研發費用中包含的股票薪酬為 2,420 萬美元。

G&A expenses were $30.5 million during the third quarter of 2024, compared to $29.4 million during the third quarter of 2023. The $1.1 million increase was primarily related to stock based compensation.

2024 年第三季的一般管理費用為 3,050 萬美元，而 2023 年第三季為 2,940 萬美元。110 萬美元的成長主要與股票薪酬相關。

Stock based compensation included within G&A expense was $15.4 million for the third quarter of 2024.

2024 年第三季一般管理費用中包含的股票薪酬為 1,540 萬美元。

Finally, we expect our cash balance to fund our operating plans until late 2026.

最後，我們預計我們的現金餘額可以為我們的營運計劃提供資金，直到 2026 年底。

Thanks Ed.

謝謝埃德。

In conclusion, Intellia continues to deliver on the promise of gene editing and we look forward to presenting the Nex-z phase one update next week at AHA with that, we will now open the call for your questions to do our best to address as many questions as possible. We will only be able to take one question per caller operator. You may now open the call for Q&A.

總而言之，Intellia 繼續兌現基因編輯的承諾，我們期待下週在 AHA 上展示 Nex-z 第一階段更新，我們現在將開始徵集您的問題，以盡最大努力解決盡可能多的問題盡可能提出問題。我們只能回答每個呼叫接線員一個問題。您現在可以發起問答電話。

We will now begin the question and answer session to ask a question.

我們現在開始問答環節來提問。

(Operator Instructions)

（操作員說明）

Rick Bienkowski with Cantor Fitzgerald.

里克·賓科斯基和康托·菲茨傑拉德。

Hey, good morning and thank you for taking the question. I was just hoping to get more color on the pace of enrollment in the one.

嘿，早上好，謝謝你提出問題。我只是希望能夠對這項計畫的招生速度有更多的了解。

Just looking at the clinical trial record on clinicaltrials.gov. The estimated primary completion is listed at December 2027. So, could you just walk me through the assumptions there for the pace of enrollment? Given that the primary endpoint is event driven?

只需查看 ClinicalTrials.gov 上的臨床試驗記錄即可。預計主要竣工時間為 2027 年 12 月。那麼，您能否向我介紹一下招生速度的假設呢？鑑於主要終點是事件驅動的？

Thanks for the question, Rick, as we've said, you can use the Haelo study as a good proxy with similar assumptions. You know, that the study has 765 patients. We have global sites activated and the final sites are being activated as we speak here. So as we said in our comments here, we're enrolling ahead of our projections, and as we get further insight, there may be an opportunity to update that down the road. But in the meanwhile, things are progressing very, very well.

感謝您提出問題，Rick，正如我們所說，您可以使用 Haelo 研究作為具有類似假設的良好代理。你知道，這項研究有 765 名患者。我們已經啟動了全球站點，正如我們在這裡所說的那樣，最終站點也正在啟動。因此，正如我們在此處的評論中所說，我們將在預測之前進行註冊，隨著我們獲得進一步的了解，未來可能有機會進行更新。但同時，事情進展得非常非常順利。

Alec Strahan with Bank of America.

美國銀行的亞歷克‧斯特拉恩 (Alec Strahan)。

Hey guys, this is Matthew on for Alec. Thanks for taking our question. Just one quick one for us. You know, as you think about extending into later stage clinical trials, just thinking about your capital allocation priorities, given you have a lot going on in the pipeline and sort of how you're thinking about in vivo versus ex vivo going forward.

大家好，我是亞歷克的馬修。感謝您提出我們的問題。對我們來說只是一個快速的。你知道，當你考慮擴展到後期臨床試驗時，只需考慮你的資本分配優先事項，因為你有很多事情正在進行中，以及你如何考慮體內與離體的未來。

So maybe Ed can address that and we'll follow up as necessary.

也許艾德可以解決這個問題，我們會根據需要採取後續行動。

Yeah, thanks for the question. I mean, we exited, the third quarter, about $945 million in cash, and as we look at our two or three year plan. I think we've laid out at JP Morgan earlier this year, three year priorities, strategic priorities through 2026, and so as I look at the company today, we clearly have a focus on the three phase three studies, which will be up and running before the end of the year, and that's clearly a focus. We do have some exciting programs related to NTLA-3001 our first gene insertion program, which is an important proof of concept for us as well as sort of burgeoning opportunities as well, and then we've been very prominent in just investing across the platform. So I look at our existing cash burn at roughly $100 million over the last couple of quarters as a reasonable estimate that should go up. But I feel like we have a very conservative plan in place. One that takes our existing cash balance and gets us well into the fourth quarter of 2026.

是的，謝謝你的提問。我的意思是，我們在第三季退出了約 9.45 億美元的現金，並考慮到了我們的兩三年計畫。我認為我們今年早些時候已經在摩根大通制定了三年優先事項、到2026 年的戰略優先事項，因此，當我今天審視該公司時，我們顯然將重點放在三階段的研究上，這些研究將在年底前運行，這顯然是一個焦點。我們確實有一些與NTLA-3001 相關的令人興奮的項目，我們的第一個基因插入項目，這對我們來說是一個重要的概念證明，也是一種新興的機會，然後我們在跨平台投資方面非常突出。因此，我認為過去幾季我們現有的現金消耗約為 1 億美元，這是一個合理的估計，應該會上升。但我覺得我們制定了一個非常保守的計畫。它利用我們現有的現金餘額，讓我們順利進入 2026 年第四季。

Yanan Zhu with Wells Fargo Securities.

富國銀行證券的朱亞楠。

Great. Thanks for taking our questions. Wondering first, congrats on the clearance from FDA to conduct the phase three study in ATTR polyneuropathy. I was just struck by two things from the trial design. One is that it is a placebo controlled study and not for example, active arm control study, and the other is that the patient, the study size is very small, 50 patients. That's not even half of the size of the silencer studies. So, could you comment on this, you know, the the ability to obtain such a study design? And what does it mean? And also will patients on the on either arm allowed to receive silencer or other active treatment during the study? Thank you.

偉大的。感謝您回答我們的問題。首先，恭喜 FDA 批准進行 ATTR 多發性神經病變的第三期研究。我對試驗設計中的兩件事感到震驚。一是這是安慰劑對照研究，而不是主動臂對照研究，二是針對患者，研究規模非常小，只有 50 名患者。這還不到消音器研究規模的一半。那麼，您能否評論一下獲得這樣的研究設計的能力？這意味著什麼？在研究期間，任一手臂的患者是否都可以接受消音器或其他積極治療？謝謝。

So, thanks for the question.

所以，謝謝你的提問。

First of all, it's important to note that the effect size of TTR reduction is very, very large in patients with polyneuropathy that's been established. We have pretty good insight as to the effects as a function of PTR reduction and as we've shared elsewhere, our TTR reduction is profound and we expect that to continue into this patient population in phase three. A placebo controlled trial is possible based on our agreement with the FDA and other regulatory agents. It will give us a very solid readout on the performance and safety of the drug and by carrying it out outside the United States where many of these other therapies are not currently available. It allows the study to be enrolled promptly and we'll be in a position to share the data when we have it.

首先，需要注意的是，對於已確診的多發性神經病變患者來說，TTR 降低的效果非常非常大。我們對 PTR 減少所帶來的影響有很好的了解，正如我們在其他地方分享的那樣，我們的 TTR 減少是深遠的，我們預計這種情況將在第三階段的患者群體中持續下去。根據我們與 FDA 和其他監管機構的協議，可以進行安慰劑對照試驗。它將為我們提供有關該藥物的性能和安全性的非常可靠的信息，並通過在美國以外的地方進行該藥物的實施，而目前許多其他療法尚不可用。它使研究能夠迅速註冊，並且我們在獲得數據後就能夠共享數據。

And David, you can speak to any other details that you think are pertinent to that study or silence.

大衛，你可以談論你認為與該研究或沉默相關的任何其他細節。

Thank you, John. You know, I think what you're seeing in this small study is a great collaboration with the FDA as we talk to them about the best way to go forward all the other drugs have been approved, the placebo controlled study study. So that, that makes a lot of sense as well for, for our drug.

謝謝你，約翰。你知道，我認為你在這項小型研究中看到的是與 FDA 的良好合作，因為我們與他們討論了推進所有其他藥物已獲批准的最佳方式，即安慰劑對照研究。因此，這對我們的藥物來說也很有意義。

And again, silencers are not available in the country where the studies are being conducted. So patients will not be receiving silences.

再說一遍，進行研究的國家沒有消音器。因此患者不會受到沉默。

Got it. Thank you.

知道了。謝謝。

Mani Foroohar with Leerink Partners.

Mani Foroohar 與 Leerink Partners。

Hi, good morning. This is CJ on Mani. My question regarding the phase three Haelo study, I just noticed that patients are randomized 2 to 1 there versus 1 to 1 in MAGNITUDE-2. So I was just wondering if you thought this 2 to 1 enrollment was thought to accelerate patient enrollment in the study. Thank You.

嗨，早安。這是 CJ 在 Mani 上的報道。我關於第三階段 Haelo 研究的問題，我剛剛注意到患者被隨機分為 2 比 1，而 MAGNITUDE-2 中的患者是 1 比 1。所以我只是想知道您是否認為這種 2 比 1 的入組會加速研究中的患者入組。謝謝。

David, do you want to speak to the randomization scheme?

大衛，你想談談隨機方案嗎？

The benefit of a 2 to 1 randomization is, is for the patients themselves. It's attractive to them that they'll have two thirds chance to start on the active drug right away. They also all these patients will be able to cross over if they wish as well at the end of the primary observation period. So it's also attractive to patients for that reason, with all that in place, we do anticipate very rapid enrollment as we saw in the phase two as well.

2 比 1 隨機化的好處是對病人本身。對他們來說很有吸引力的是，他們將有三分之二的機會立即開始服用活性藥物。如果他們願意，所有這些患者也可以在主要觀察期結束時進行交叉。因此，由於這個原因，它對患者也很有吸引力，在所有這些都到位的情況下，我們確實預計入組速度會非常快，就像我們在第二階段看到的那樣。

The number of patients you know, by having 2 to 1. Also, you have more information on the active arm as part of the at the FDA BLA submission that will be coming up in 2026.

您認識的患者數為 2 比 1。此外，作為將於 2026 年提交的 FDA BLA 提交文件的一部分，您還可以獲得更多有關主動臂的資訊。

Kostas Biliouris with BMO Capital Markets.

BMO 資本市場的 Kostas Biliouris。

Good morning, everyone. Thanks for taking our questions and congrats on the progress. One question from us on the AATB program, given that the gene that you inserted isn't under the control of the natural promoter and under infection patients need about 2 times to 3 times more AAT protein. Can you remind us, how do you ensure that this additional AAT protein is there during infections? Thank you.

大家早安。感謝您提出我們的問題並祝賀我們的進展。我們就 AATB 計劃提出一個問題，考慮到您插入的基因不受天然啟動子的控制，並且感染患者需要大約 2 到 3 倍的 AAT 蛋白。您能否提醒我們，如何確保感染期間有這種額外的 AAT 蛋白？謝謝。

Thanks for the question, Kostas. We base our excitement over the alpha-1 program on the preclinical where as you point out the natural trans gene is driven by the albumin promoter, and with that in nonhuman primates, we've achieved normal levels of the protein. I would not expect that to be module the typical response to infection because it will be driven by the album promoter.

謝謝你的提問，科斯塔斯。我們對 alpha-1 計劃的興奮是基於臨床前，正如您指出的，天然轉基因是由白蛋白啟動子驅動的，並且在非人靈長類動物中，我們已經達到了正常的蛋白質水平。我不希望這成為對感染的典型反應，因為它將由專輯發起人驅動。

But what we prioritize is normalizing the protein because it's primary, it's the primary defect in patients with the disease, and we think that that's going to be the primary determinant of the success of the product.

但我們優先考慮的是使蛋白質正常化，因為它是主要的，是疾病患者的主要缺陷，我們認為這將是產品成功的主要決定因素。

Joseph Thome with TD Cowen.

約瑟夫·托姆和 TD Cowen。

Hi there. Good morning. Congrats on the progress and thank you for taking my question. Maybe just on the MAGNITUDE-2 study as the TTR serum reduction is going to be a day 29 read and the MS is 18 months. Are you able to take a look at serum TTR ahead of that 18 month time point while maintaining some sort of blind? Or should we anticipate both of those readouts coming at once? And then secondly, on a submission for PN, how much does the submission NPN depend on also success in MAGNITUDE-1 for CM or are these completely uncoupled? Thank you.

你好呀。早安.恭喜您的進展，並感謝您提出我的問題。也許只是在 MAGNITUDE-2 研究中，因為 TTR 血清減少將在第 29 天讀取，MS 為 18 個月。您是否能夠在 18 個月的時間點之前查看血清 TTR，同時保持某種盲法？或者我們應該預期這兩個讀數會同時出現？其次，在提交 PN 時，提交 NPN 在多大程度上取決於 CM 的 MAGNITUDE-1 的成功，還是這些完全無關？謝謝。

Maybe I can address that and David can fill in blanks. The two programs to neuropathy and cardiomyopathy are independent of each other and are determined by the study designs in each of those particular indications. We talked earlier on the call here about the Cardiomyopathy program and how to think about that polyneuropathy program as was pointed out, we'll have an 18 month observation period that's set in time, sort of a landmark design. But the two are independent of each other. We would expect that safety will be supplementary from each of the programs as data accumulates. But in terms of the efficacy read, they're entirely independent. The study is blinded and we will not be in a position where we will be sharing data prematurely before the complete data readout. So don't look for TTR and then the ultimate clinical outcomes, it will be the full set of data as it becomes available. David, if you have anything to add to that be my guest.

也許我可以解決這個問題，大衛可以填補空白。針對神經病變和心肌病變的兩個計劃是相互獨立的，並且由每個特定適應症的研究設計決定。我們早些時候在電話會議上討論了心肌病變計劃以及如何考慮多發性神經病變計劃，正如所指出的，我們將及時設定 18 個月的觀察期，這是一個里程碑式的設計。但兩者是互相獨立的。我們預計，隨著數據的積累，每個程序都會補充安全性。但就功效而言，它們是完全獨立的。這項研究是盲目的，我們不會在完整的數據讀出之前過早地共享數據。因此，不要先尋找 TTR，然後再尋找最終的臨床結果，它將是可用的全套數據。大衛，如果你有什麼要補充的，請來吧。

But just to add to the observation that you've seen in our data that all patients have a major reduction in TTR. So we won't be looking at that data. What we know from our experience is that all patients will be able to achieve a rapid and deep reduction in TTR and that that is maintained in probably permanently as far as we know, but certainly over two years at this point. So we will see that at the time of unblinding as John says, and we pretty much know what to expect in that data.

但只是補充一下您在我們的數據中看到的觀察結果：所有患者的 TTR 均顯著降低。所以我們不會查看這些數據。我們從經驗中得知，所有患者都能夠實現 TTR 的快速和深度降低，據我們所知，這種情況可能會永久保持，但目前肯定會超過兩年。因此，正如約翰所說，我們將在揭盲時看到這一點，我們幾乎知道在這些數據中會發生什麼。

Thank you.

謝謝。

Gena Wang with Barclays.

王吉娜與巴克萊銀行。

Hi, it's Tony on for Gina. So on, ATTR can you remind us of your assumptions for silence or drop in rate and any strategies to address this if it ends up being higher than expected?

大家好，我是托尼為吉娜代言。那麼，ATTR 您能否提醒我們您對利率沉默或下降的假設，以及如果最終利率高於預期，有什麼解決此問題的策略？

David, do you want to speak to the silence dropping? Right.

大衛，你想談談沉默嗎？正確的。

Yeah, we we have figured that into a trial, we haven't given the exact way that will happen. We should mention we think it's less likely now that we've seen the Haelo's data that there will be much drop in. What we've seen is that there is some addition to TTR to the (inaudible) in that trial, but probably not enough to justify payers to pay for both drugs together. So what we expect to see is that patients will continue on their TEFA in our study they possibly may switch to nutrien if payers allow that. But even that switch, we don't think will have any effect on our primary endpoint.

是的，我們已經在試驗中考慮到了這一點，但我們還沒有給出具體的方式。我們應該要提到的是，我們認為現在我們已經看到 Haelo 的數據，大幅下降的可能性較小。我們看到的是，該試驗中 TTR 有所增加（聽不清楚），但可能不足以證明付款人有理由同時支付兩種藥物的費用。因此，我們期望看到的是，在我們的研究中，患者將繼續使用 TEFA，如果付款人允許，他們可能會轉向營養品。但即使是這種轉變，我們也不認為會對我們的主要終點產生任何影響。

Got it. Thank you.

知道了。謝謝。

Maury Raycroft with Jefferies.

莫里·雷克羅夫特和傑弗里斯。

Hi, good morning. Congrats on the projects and thanks for taking my question. I was wondering if you could just talk more about how you're setting expectations for the AHA update for biomarkers and the relationship or correlation to functional capacity. I'm wondering if you'll show individual patient data and potentially cardiac remodeling or imaging data as well.

嗨，早安。恭喜這些項目，並感謝您提出我的問題。我想知道您是否可以更多地談談您如何為生物標誌物的 AHA 更新設定期望以及與功能能力的關係或相關性。我想知道您是否會顯示個別患者數據以及潛在的心臟重塑或影像數據。

I think I can start with that question and David can fill in some additional information.

我想我可以從這個問題開始，大衛可以填寫一些額外的資訊。

As we said in our comments, we're very enthusiastic about sharing the data at the upcoming AHA meeting, and we're honored to be featured in the opening session of the meeting, which is something that you know is, is addressing the next century of cardio cardiac therapies'. Very excited to be a part of that.

正如我們在評論中所說，我們非常熱衷於在即將舉行的 AHA 會議上分享數據，我們很榮幸能夠參加會議的開幕會議，正如您所知，我們正在討論下一個會議心臟治療的世紀」。很高興能成為其中的一部分。

As we've long said, we'll share biomarker data, functional data and clinical information on these patients, and in terms of how we think about that meaning of that information. First, we're excited about what we see because it relates for the first time, the extent of the TTR reduction that we're achieving with those particular readouts, and we think it will yield a real insight into how we think about the MAGNITUDE-2 study and how we expect that the drug to perform in that particular study, David, if you want to share any other comments.

正如我們長期以來所說，我們將分享這些患者的生物標記數據、功能數據和臨床訊息，以及我們如何看待這些資訊的含義。首先，我們對所看到的感到興奮，因為它第一次與我們透過這些特定讀數實現的 TTR 降低程度相關，我們認為它將讓我們真正了解我們如何看待幅度-2 研究以及我們期望該藥物在該特定研究中的表現，大衛，如果您想分享任何其他評論。

Just as you see the date on November 16th recall that in the recent phase three, the active arms continue to show worsening in terms of these biomarkers for B&P continues to rise, six minute walk continues to go down, even though they're better than placebo, they are still worsening in the population as a whole. So it's important to observe. As you see our data, our data is also a very robust test of this, of the ability of deep TTR reductions to make a big clinical difference, and that's because 50% of our patients are class three instead of the 10% or so you see in the other studies, in a full 31% of the patients have variant disease, which is really the very aggressive disease in this, in ATTR-CM and that those patients as well in the, in the other studies in around 10% to 12%.

正如您看到 11 月 16 日的日期，回想一下，在最近的第三階段，活躍手臂的這些生物標誌物繼續惡化，B&P 繼續上升，六分鐘步行繼續下降，儘管它們比安慰劑，整體人群的情況仍在惡化。所以觀察很重要。正如您所看到的我們的數據，我們的數據也是對此的非常有力的測試，深度TTR 降低是否能夠產生巨大的臨床差異，這是因為我們50% 的患者屬於三級，而不是您的10 % 左右。變異性疾病。

So you will be seeing all 36 patients in the study because they've reached all reached one year and you will see the data for these patients comparing baseline to one year.

因此，您將看到研究中的所有 36 名患者，因為他們都已達到一年，您將看到這些患者的基線與一年的數據進行比較。

Got it. Thanks for taking my question.

知道了。感謝您提出我的問題。

Ryan Forcep with Guggenheim.

瑞安·福普與古根漢。

Hi, this is Ryan from Debjit's team. What factors do you think are the major contributors to enrollment being ahead of schedule in the MAGNITUDE-2 ATTR-CM study, and do you think these factors apply to MAGNITUDE-2.

大家好，我是 Debjit 團隊的 Ryan。您認為哪些因素是 MAGNITUDE-2 ATTR-CM 研究提前入組的主要因素，您認為這些因素是否適用於 MAGNITUDE-2。

What investigators tell us is they've been extremely excited with the extent of the TTR reduction and the safety profile that they've seen with the drug to the state. We've seen a confirmation with competitor programs that lowering TTR is meaningful for patients and the deep, consistent and enduring reductions that we've achieved with the drug. Thus far, I think is really excited treating physicians around the world. We would anticipate that this will apply also to the MAGNITUDE-2 study and recall that in many of these countries, this kind of therapy is not available for patients, generally speaking, and we know that there's great enthusiasm with all the sites that we've spoken to.

調查人員告訴我們，他們對 TTR 降低的程度以及該藥物在該州看到的安全狀況感到非常興奮。我們已經看到競爭對手的項目證實降低 TTR 對患者有意義，我們使用該藥物實現了深度、一致和持久的降低。到目前為止，我認為世界各地的治療醫生都非常興奮。我們預計這也適用於 MAGNITUDE-2 研究，並記得在許多國家，一般來說，患者無法獲得這種治療，我們知道我們的所有網站都充滿熱情。

Dae Gon Ha with Stifel.

Dae Gon Ha 與 Stifel。

Hey Greg, good morning. Thanks for taking our questions and congrats on the progress question on AATD, just thinking about the phase one that's going to embark by the end of the year. If you can comment on any flexibility in that trial protocol to include any liver disease patients, I know that was supposed to be more of a 2003 purview. But given the biology and the potential say facilitation of polymer excretion from the cells once you have more M protein, just wondering if you can add in a little bit of that sentinel cohort, if you will just to see the benefit there. Thanks so much.

嘿格雷格，早安。感謝您提出我們的問題，並對 AATD 的進展問題表示祝賀，我們只想到今年年底將開始的第一階段。如果您可以對該試驗方案中納入任何肝病患者的靈活性發表評論，我知道這應該更多地屬於 2003 年的範圍。但考慮到生物學和潛在的說法，一旦你有更多的 M 蛋白，就會促進細胞中的聚合物排泄，只是想知道你是否可以添加一點點哨兵隊列，如果你願意看到那裡的好處。非常感謝。

David any pros including liver disease in the NTLA-3001 a trial?

David 在 NTLA-3001 試驗中是否有包括肝病在內的任何優點？

These patients will not be having a major, any kind of major liver disease. Those patients with liver disease really are best addressed by reducing the mutant protein as well as of course, giving the increased alpha-1 antitrypsin would be valuable to them as well. But without our ability to reduce the protein, we don't think we're doing them full justice.

這些患者不會患有任何類型的重大肝臟疾病。那些患有肝病的患者確實最好透過減少突變蛋白來治療，當然，增加 α-1 抗胰蛋白酶對他們也很有價值。但如果沒有我們減少蛋白質的能力，我們認為我們並沒有完全公正地對待它們。

The next question.

下一個問題。

Well, just to add that we're taking a extended approach to going after alpha-1, and in addition to NTLA-3001, which we think will teach us a lot about the insertion approach for alpha-1 disease and leads to a multiplicity of other diseases for which insertion may be the path forward. We're also bringing forward a gene writing program that would address not only the lung but also the liver.

好吧，補充一下，除了 NTLA-3001 之外，我們正在採取一種擴展的方法來追蹤 alpha-1，我們認為這將教會我們很多關於 alpha-1 疾病的插入方法，並導致多重性其他疾病的插入可能是前進的道路。我們也提出了基因寫入程序，不僅可以處理肺部，還可以處理肝臟。

Luca Issi with RBC.

加拿大皇家銀行 (RBC) 的 Luca Issi。

Oh, great. Thanks so much for taking our question. This is Lisa on, for Luca. Congrats on all the progress here team and, and getting the IND cleared for TTR polyneuropathy. Just one question on the on the study, I know the primary endpoint is mNIS+7 at 18 months.

哦，太好了。非常感謝您提出我們的問題。這是麗莎，為盧卡。恭喜團隊取得的所有進展，並獲得 TTR 多發性神經病變 IND 批准。只是關於這項研究的一個問題，我知道主要終點是 18 個月時的 mNIS+7。

However, I believe an ilum was able to file on just nine months of follow up. So I'm just curious if the 18 month endpoint was mostly needed to satisfy European regulators or did the FDA also request the longer follow up? Any color here would be helpful. Thanks so much.

然而，我相信一位 ilum 能夠在短短九個月的後續行動中提出申請。所以我只是好奇 18 個月的終點主要是為了滿足歐洲監管機構的需要，還是 FDA 也要求更長的追蹤時間？這裡任何顏色都會有幫助。非常感謝。

David, any comments to share on 18 months versus a different follow up time?

David，對於 18 個月與不同的追蹤時間有什麼意見可以分享嗎？

Yeah, we felt 18 months was, looking at the trials, we felt 18 months was the optimal time to really see the full benefit of the drug. It was not required by regulators, but it was really our own decision to do that.

是的，我們認為 18 個月是，從試驗來看，我們認為 18 個月是真正看到該藥物全部益處的最佳時間。監管機構並沒有要求這樣做，但這確實是我們自己的決定。

Salveen Richter with Goldman Sachs.

Salveen Richter 與高盛。

Hi, this is Mark on for Salveen. First congrats on the quarter and thank you for taking our questions. The recently presented phase two data from NTLA-2002 in HAE. Can you discuss the data in the context of read through to the recently initiated phase three Haelo study and any takeaways that you're applying to Haelo?

大家好，我是薩爾文的馬克。首先恭喜本季度，並感謝您回答我們的問題。最近在 HAE 中提供了 NTLA-2002 的第二階段資料。您能否在通讀最近啟動的第三階段 Haelo 研究以及您應用於 Haelo 的任何要點的背景下討論這些數據？

Well, thanks for the question and I I think it's really important to step back and consider what we've actually presented for NTLA-2002 thus far, if you take the 50 mg doses from both phase one and phase two studies, we now have, we've reported on 12 of 15 patients who have achieved what we're considering a functional cure. That means patients following a single dose and no other therapy thereafter, have no attacks, that is unique in space it's a new category of response. It is achieved in to our knowledge only with NTLA-2002 in this class of drug, we expect that similar outstanding results will come from our phase three trial. The study design is similar with the exception that we have an even longer follow up period to see further insights into how patients would respond with even a longer observation period. What we've seen in our phase one study is that while many patients get to a functional cure, fairly quickly, there are some patients that reach that only with some additional time. So we expect that we'll have very favorable results in our phase three program and look forward to sharing that as we go forward.

嗯，謝謝你的問題，我認為退後一步考慮一下我們迄今為止為 NTLA-2002 實際提出的內容非常重要，如果您從第一階段和第二階段研究中服用 50 毫克劑量，我們現在有，我們報告了15 名患者中的12 名已經實現了我們所認為的功能性治癒。這意味著接受單次劑量且此後不再接受其他治療的患者不會出現發作，這在太空中是獨一無二的，這是一種新的反應類別。據我們所知，此類藥物中只有 NTLA-2002 才能實現這一目標，我們預計我們的三期試驗也將獲得類似的出色結果。研究設計相似，但我們有更長的追蹤期，以進一步了解患者在更長的觀察期內將如何反應。我們在第一階段研究中看到，雖然許多患者相當快速地獲得功能性治愈，但也有一些患者需要一些額外的時間才能達到功能性治癒。因此，我們預計我們的第三階段計劃將取得非常有利的結果，並期待在我們前進的過程中分享這項成果。

Myles Minter with William Blair.

邁爾斯·明特和威廉·布萊爾。

Hi, Steve. This is John on for Miles. Thanks so much for taking our question. So for NTLA-3001 I was just wondering if you could give us any idea of how many patients you are looking to dose before reporting initial data, and what kind of target are you looking for for serum AAT levels in those lower dose cohorts?

嗨，史蒂夫。這是邁爾斯的約翰。非常感謝您提出我們的問題。因此，對於 NTLA-3001，我只是想知道在報告初始數據之前，您是否可以告訴我們您希望對多少患者進行給藥，以及您在那些較低劑量組中尋找什麼樣的血清 AAT 水平目標？

Thanks.

謝謝。

Thanks for the question. We've had a principle that we've applied since the outset with all of the clinical work that we've done here, which is that we report data when it's meaningful, consistent and interpretable and we'll apply that same standard here. Obviously, we're looking for a biomarker here, which is readily measured and that's the production of the native protein of wild type.

謝謝你的提問。我們從一開始就在我們在這裡所做的所有臨床工作中應用了一個原則，那就是我們在數據有意義、一致和可解釋時報告數據，並且我們將在這裡應用相同的標準。顯然，我們在這裡尋找一種易於測量的生物標記，即野生型天然蛋白質的產生。

And we said from the outset that our objective here is to normalize the levels of that protein, and that will be the basis for determining the success of the project.

我們從一開始就說過，我們的目標是使該蛋白質的水平正常化，這將是決定該計畫成功的基礎。

Joon Lee with Truist Securities.

Joon Lee，Truist 證券公司。

Hi, good morning. This is Median on for June and thanks for taking your question. Given your great progress for in vivo programs that you have any color on your future plans for using gene writing technology is really appreciated. For example, do you plan to use it for in vivo or this is more for your ex vivo program?

嗨，早安。這是六月的中位數，感謝您提出問題。鑑於您在體內程序方面取得的巨大進展，我們非常感謝您對未來使用基因寫入技術的計劃有任何意見。例如，您打算將其用於體內還是更多地用於您的體外程序？

Thanks for the question. It really goes to the heart of the strategy of the company where it's a three pronged approach. We start with a platform that has a complete set of tools not only on the editing side but also on the delivery side. So that as we look at any particular editing problem or in a position to choose what we think will be the best tool for the particular problem, and we apply those tools in both the in vivo and the ex vivo setting.

謝謝你的提問。這確實涉及公司策略的核心，即三管齊下的方法。我們從一個平台開始，該平台不僅在編輯方面而且在交付方面都擁有一套完整的工具。因此，當我們研究任何特定的編輯問題或能夠選擇我們認為針對特定問題的最佳工具時，我們會在體內和離體環境中應用這些工具。

We think that there are conditions for which gene writing is well suited. I don't think that's universally true. We think that there are certain instances especially in the ex vivo setting where base editing is useful where one is going to multiplex, and then of course, as we've shown with our ongoing phase three programs, archetypal CRISPR as exemplified by NTLA-2001 and NTLA-2002 as a profoundly successful results in terms of achieving the editing objectives that we're going after. So, you know, in, in short, we'll look at the, the particular programs and the editing that they need and, and apply the gene writing to that. One of the places where we think it's well suited is and as an adjunct to our alpha-1 program and that would be the first place where I would expect to see it.

我們認為基因寫入在某些條件下是非常適合的。我不認為這普遍正確。我們認為，在某些情況下，尤其是在離體環境中，鹼基編輯在進行多重分析時非常有用，當然，正如我們正在進行的第三階段專案所展示的，以NTLA-2001 為例的原型CRISPR NTLA-2002 在實現我們追求的編輯目標方面取得了巨大成功。所以，你知道，簡而言之，我們將研究他們​​需要的特定程式和編輯，並將基因寫入應用到其中。我們認為它非常適合的地方之一是作為我們 alpha-1 計劃的附屬品，這將是我期望看到它的第一個地方。

Jay Olson with Oppenheimer.

傑·奧爾森和奧本海默。

Oh, hey, congrats on all the progress, and thank you for taking the question. How are you thinking about the ex-US opportunity and strategy for NTLA-2002? Are you interested in partnering the program ex-US? Thank you.

哦，嘿，祝賀所有的進展，並感謝您提出問題。您如何看待 NTLA-2002 在美國以外的機會和策略？您有興趣在美國以外的地區合作該計劃嗎？謝謝。

Thanks for the question. Behind that is the assumption that there is a substantial commercial opportunity around the world, certainly in the developed markets, and we see that starting in the US and going beyond the US into Europe, and perhaps beyond that, our current plans are to be in a position to launch the drug ourselves. As we evaluate partnerships, we consider what they can bring to the table to extend our own reach and as appropriate as we learn more about that. We would share that strategy as we go forward.

謝謝你的提問。背後的假設是，世界各地，尤其是已開發市場，都存在大量商業機會，我們看到，從美國開始，超越美國進入歐洲，或許除此之外，我們目前的計劃是自己推出該藥物的地位。當我們評估合作關係時，我們會考慮他們可以為擴大我們的影響力帶來什麼，並在我們了解更多資訊後酌情考慮。我們將在前進過程中分享這項策略。

Great. Thank you so much.

偉大的。太感謝了。

Brian Cheng with JPMorgan.

摩根大通的布萊恩鄭 (Brian Cheng)。

Hi, good morning. Thanks for taking a question this morning. This is Shaun on for Brian, just speaking on the AATD program. Just curious about your thoughts on the back of some of the RNE data from your peers. How do you view NTLA-3001's differentiation versus theirs?

嗨，早安。感謝您今天早上提出問題。我是肖恩 (Shaun) 替布萊恩 (Brian) 發言，他剛剛就 AATD 計劃發表講話。只是想知道您對同行提供的一些 RNE 數據有何看法。您如何看待 NTLA-3001 與他們的差異化？

Thanks for the question.

謝謝你的提問。

As we've said elsewhere, we think the key determinant of success for the pulmonary pathology of the disease will be achieving high, essentially normal levels of wild type protein. Thus far, we are the only company that we're aware of that's presented that in the setting of the nonhuman primate, that is what we're looking for in our phase one study to determine whether or not we achieve those same similar proteins in humans. Obviously, we'll watch the space. There are competitive programs playing out, but it's very early. We'll see how successful people are even delivering their technologies and the performance of production of the normal protein over time.

正如我們在其他地方所說，我們認為疾病的肺部病理學成功的關鍵決定因素將是實現高水平、基本上正常的野生型蛋白質水平。到目前為止，我們是唯一一家據我們所知在非人靈長類動物的環境中提出的公司，這就是我們在第一階段研究中尋找的東西，以確定我們是否在非人類靈長類動物中獲得了那些相同的相似蛋白質。顯然，我們會觀察這個空間。有競賽節目正在上演，但現在還很早。隨著時間的推移，我們將看到成功的人們如何提供他們的技術和正常蛋白質的生產性能。

Silvan Tuerkcan with JMP Securities.

JMP 證券的 Silvan Tuerkcan。

Hey, good morning and congrats on the progress and thanks for taking my question. Just a quick one and I may have missed this, but for MAGNITUDE-2, congrats on the IND. But what when do we plan initiation in the US here for this trial, and what is the eventual split of patients involved in this trial in considering us versus ex-US? Thank you so much.

嘿，早上好，祝賀您取得的進展，感謝您提出我的問題。快速介紹一下，我可能錯過了這一點，但對於 MAGNITUDE-2，恭喜 IND。但是，我們計劃何時在美國啟動這項試驗，以及參與這項試驗的患者在考慮我們與美國以外的患者方面的最終比例如何？太感謝了。

Thanks for the question. We've tried to make it clear elsewhere that the study will be done outside the United States.

謝謝你的提問。我們試圖在其他地方明確表示這項研究將在美國境外進行。

It's there where one can readily conduct a placebo controlled trial, standards of care otherwise for these patients are similar around the world, We've worked on developing this protocol with the Food and Drug Administration in the United States and they will accept the program coming from patients that are studied outside the United States.

在那裡，人們可以輕鬆地進行安慰劑對照試驗，這些患者的護理標準在世界各地都是相似的，我們已經與美國食品和藥物管理局一起制定了這一方案，他們將接受即將推出的方案來自在美國境外研究的患者。

Great.

偉大的。

Thank you.

謝謝。

William Pickering with Bernstein.

威廉·皮克林和伯恩斯坦。

Hi, good morning. Thank you for taking my question. For the AATD program, do you have any plans to expand this study beyond the New Zealand site? And is it a reasonable base case that we would see data in 2025? Thank you.

嗨，早安。感謝您回答我的問題。對於 AATD 計劃，您是否有計劃將這項研究擴展到紐西蘭以外的地區？我們在 2025 年看到的數據是否合理？謝謝。

David, do you want to speak to any other sites besides New Zealand?

大衛，除了紐西蘭之外，您還想與其他網站交談嗎？

Yeah, we, we will be having other sites and we'll put them on gov.com as they come up. I should say it is possible that we'll have data, reasonable to think we have data in 2025.

是的，我們，我們將會有其他網站，當它們出現時我們會將它們放在 gov.com 上。我應該說我們有可能會獲得數據，有理由認為我們在 2025 年就會獲得數據。

Andy Chen with Wolfe Research.

沃爾夫研究中心的安迪陳。

Hi, Brendon on for Andy. So we know docs are excited about your ATTR therapy, but can you please compare the excitement relative to their excitement for stabilizers and silencers. So let's say you achieve similar efficacy on endpoints based on feedback. Now are docs much more likely to use gene editing compared to a silencer. For example, any, any safety concerns about using gene editing in a very old population? Thank you.

嗨，布倫登替補安迪。所以我們知道醫生對您的 ATTR 療法感到興奮，但是您能否將這種興奮與他們對穩定劑和消音劑的興奮進行比較。假設您根據回饋在端點上實現了類似的功效。與消音器相比，現在醫生更有可能使用基因編輯。例如，在高齡者中使用基因編輯有任何安全問題嗎？謝謝。

David's on the front line, talking to investigators. Can you speak to the enthusiasm for the investigators that we work with? Who by the way, many of them have worked with the silencers already. So they are in a position to be thinking about both those compounds.

大衛在前線與調查人員交談。您能談談對與我們合作的調查人員的熱情嗎？順便說一句，他們中的許多人已經使用過消音器。因此，他們可以考慮這兩種化合物。

Yeah, thanks John. I think you've heard our hypothesis for a number of years that deeper reductions in TTR will lead to better results.

是的，謝謝約翰。我想您已經聽過我們的假設很多年了，即進一步降低 TTR 將帶來更好的結果。

Our drug is also more rapid in getting down to low levels than silences as well as getting to those deeper levels and it is continuous. So the levels are staying continuously low instead of what might happen if you give infusions of drugs periodically.

我們的藥物也比沉默更快地下降到較低水平以及達到更深的水平，並且它是連續的。因此，這些水平持續保持在較低水平，而不是定期輸注藥物可能會發生的情況。

So based on that, that excitement about the low levels we're achieving, we have heard a lot of excitement from physicians thinking this could be better than silencers. That is something we want to prove in phase three. But that is, that's what we hear from investigators and that's why we think it's enrolling quite, quite briskly. There hasn't been any safety concerns raised in an elderly population. We've seen it well tolerated in all the patients including class three patients and some very sick patients, and all the patients were able to receive a full dose of the drug as part of their therapy in the trial.

基於此，我們對所達到的低水平感到興奮，我們聽到了很多醫生的興奮，他們認為這可能比消音器更好。這是我們想在第三階段證明的事情。但這就是我們從調查人員那裡聽到的，這就是為什麼我們認為它的招募速度非常非常快。老年人口中沒有出現任何安全問題。我們發現所有患者（包括三級患者和一些病情嚴重的患者）對它的耐受性良好，並且所有患者都能夠接受全劑量的藥物作為試驗中治療的一部分。

Maybe something to add is that we now have over three years of follow up in our earlier earliest dose patients, and the excellent safety profile that we reported in the early days has continued. We think many of the questions that surrounded gene editing are being addressed as as these programs. Enroll, I think another thing to keep in mind with respect to patients who are older, which typifies the wild type patient population. These patients live for a long time and you can look at the recently reported results and see that there's high levels of survival years after the patients have been dosed, and I think that speaks importantly to the role of these agents and what they can do for these patients, the evolving care of them, and ultimately, a pharmacoeconomic argument for treating patients like this who should derive the full benefit of the therapy. You know, one other thing with respect to older patients, it's I'm going to think of TTR cardiomyopathy as a heritable disease. In fact, in most cases, it's a disease of aging. 90% of the patients who suffer from the disease have wild type protein, and you can see that in the phase three trials have been reported. So, unfortunately, we're making many more of these patients annually as, as the population ages, and so it's not correct to think about it as a typical sort of genetic disease.

也許需要補充的是，我們現在對早期最早劑量的患者進行了三年多的隨訪，並且我們早期報告的出色安全性仍在繼續。我們認為圍繞基因編輯的許多問題正在像這些程式一樣解決。註冊，我認為對於年齡較大的患者，我認為另一件事要記住，這代表了野生型患者群體。這些患者的壽命很長，您可以查看最近報告的結果，發現患者在服藥數年後仍具有很高的生存率，我認為這很重要地說明了這些藥物的作用以及它們的作用這些患者，對他們不斷發展的護理，以及最終治療此類患者的藥物經濟學論證，這些患者應該從治療中獲得全部益處。您知道，關於老年患者的另一件事是，我將 TTR 心肌病變視為一種遺傳性疾病。事實上，在大多數情況下，這是一種老化疾病。 90%的患有這種疾病的患者都有野生型蛋白，你可以看到在三期試驗中已經報導了這一點。因此，不幸的是，隨著人口老化，我們每年都會產生更多的此類患者，因此將其視為典型的遺傳疾病是不正確的。

Whitney Ijem with Canaccord Genuity.

艾傑姆 (Whitney Ijem) 與 Canaccord Genuity。

Hi, good morning and thanks for taking our question. This is Juan on for Whitney. Just trying to understand the rationale for the NTLA-2001 point neuropathy IND given that the phase three will be run ex-US any color you can provide on that. Just want to make sure we're not missing any nuance here. Thank you.

你好，早安，感謝您提出我們的問題。這是惠特尼的胡安。只是想了解 NTLA-2001 點神經病 IND 的基本原理，因為第三階段將在美國境外進行，您可以提供任何顏色。只是想確保我們不會錯過任何細微差別。謝謝。

Why do we have an IND, do the study outside the United States?

為什麼我們有 IND，在美國境外進行研究？

Yeah. The reason is that when you plan a BLA in the United States, it's a good idea to get agreement with the FDA on the design of that study, and, and that's what we've obtained with this IND. They, they agreed to the study you're seeing presented today and this will go forward to a BLA in the US as well as around the world.

是的。原因是，當您在美國計劃 BLA 時，最好與 FDA 就該研究的設計達成一致，這就是我們透過該 IND 獲得的結果。他們同意你們今天看到的這項研究，這項研究將在美國以及世界各地提交 BLA。

This concludes our question and answer session. I would like to turn the conference back over to Lina Li for any closing remarks.

我們的問答環節到此結束。我想將會議轉回給李娜（Lina Li）做閉幕致詞。

Thanks Drew and thanks everyone for your questions today. We appreciate all of your continued support and look forward to connecting with everyone again after the AHA presentation on Saturday, November 16th. Have a great day.

謝謝德魯，也謝謝大家今天提出的問題。我們感謝您一直以來的支持，並期待在 11 月 16 日星期六的 AHA 演講之後再次與大家聯繫。祝你有美好的一天。

The conference has concluded. Thank you for attending. You may now disconnect your line.

會議結束了。感謝您的出席。現在您可以斷開線路。