Intellia Therapeutics Inc (NTLA) 2024 Q4 法說會逐字稿

Good morning and welcome to Intellia Therapeutics' fourth quarter and full year 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. This conference is being recorded at the company's request and will be available on the company's website following the end of the call.

早安，歡迎參加 Intellia Therapeutics 2024 年第四季和全年財務業績電話會議。我叫德魯，今天我將擔任您的會議主持人。正式發言之後，我們將開始問答環節。應本公司要求，本次會議正在進行錄音，會議結束後將在公司網站上發布。

(Operator Instructions)

（操作員指令）

I will now turn the conference over to Brittany Chaves, manager of investor relations at Intellia. Please proceed.

現在，我將會議交給 Intellia 投資者關係經理 Brittany Chaves。請繼續。

Thank you, operator, and good morning everyone. Welcome to Intellia Therapeutic's fourth quarter and full year 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 intellia.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 Therapeutic 2024 年第四季和全年財報電話會議。今天早些時候，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 intellia.com 的投資者和媒體部分找到。本次電話會議將進行現場直播，重播將存檔於公司網站。

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 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.

現在，我想花一點時間提醒聽眾，在本次電話會議中，Intellia 管理層可能會做出某些前瞻性陳述，並請您參考我們在 sec.gov 上提供的 SEC 文件，以討論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天的最新信息，除非法律要求，否則 Intellia 不承擔更新這些資訊的義務。

Joining me from Intellia are John Leonard, Chief Executive Officer; David Lebwohl, Chief Medical Officer; Ed Dulac, Chief Financial Officer; and Birgit Schultes, our Chief Scientific Officer, who will join for Q&A. John will begin with the recent business highlights. David will then provide updates on our clinical pipeline progress, and Ed will review our financials before we open the call for questions.

與我一起出席的還有 Intellia 的執行長 John Leonard； David Lebwohl，首席醫療官；財務長 Ed Dulac；以及我們的首席科學官 Birgit Schultes 將參與問答環節。約翰將從近期的業務亮點開始。然後，David 將提供我們臨床管道進展的最新信息，而 Ed 將在我們開始提問之前審查我們的財務狀況。

With that, I will now turn the call over to John, our Chief Executive Officer.

說完這些，我現在將電話轉給我們的執行長約翰。

Thank you, Brittany. Good morning, everyone, and thank you all for joining us today. We're off to a strong start in 2025 with renewed focus on our operational execution. With growing support and interest from investigators and patients, we're making remarkable headway with enrollment across our latest studies. We see significant promise with NLA 2002 for the treatment of hereditary angioedema, where we expect a complete enrollment in our Phase 3 study HAELO in the second half of 2025.

謝謝你，布列塔尼。大家早安，感謝大家今天的參加。2025 年我們將迎來良好的開端，並重新專注於我們的營運執行。隨著研究人員和患者的支持和興趣日益增加，我們在最新研究的招募方面取得了顯著進展。我們看到 NLA 2002 在治療遺傳性血管性水腫方面具有巨大的前景，我們預計 2025 年下半年我們的 3 期研究 HAELO 將會完成全部患者入組。

We are similarly encouraged by the pace of enrollment with our Phase 3 studies for transthyretin amyloidosis. And expect enrollment in MAGNITUDE, our cardiomyopathy study to exceed 550 total patients by year end. Both HAE and TTR represent substantial market opportunities, and we have doubled down on our efforts to ready the company for the rapidly approaching commercial phase.

我們同樣對甲狀腺素澱粉樣變性 III 期研究的招募速度感到鼓舞。預計到年底，參與我們的心肌病變研究 MAGNITUDE 的患者總數將超過 550 名。HAE 和 TTR 都代表著巨大的市場機會，我們已加倍努力幫助公司為快速臨近的商業階段做好準備。

In November, we presented positive extended follow-up data from patients in the ongoing Phase 1 trial of Nex-z, previously known as NTLA-2001, in patients with transthyretin or ATTR amyloidosis. The Phase 1 data offered compelling evidence that deep and persistently low levels of TTR reduction achieved with Nex-z may favorably impact disease progression for people living with ATTR amyloidosis. David will review these results in greater detail.

11 月，我們公佈了正在進行的 Nex-z（之前稱為 NTLA-2001）第 1 期試驗中來自轉甲狀腺素蛋白或 ATTR 澱粉樣變性患者的積極擴展隨訪數據。階段 1 數據提供了令人信服的證據，表明 Nex-z 實現的深度和持續低水平 TTR 降低可能對 ATTR 澱粉樣變性患者的病情進展產生有利影響。大衛將更詳細地回顧這些結果。

We are actively screening patients with ATTR amyloidosis with polyneuropathy in our Phase 3 MAGNITUDE-2 study and are on track to dose the first patient in the coming weeks. As you may recall, this pivotal trial is an efficient study with expected enrollment of 50 patients. We plan to measure mNIS + 7 at 18 months and serum TTR levels as key endpoints in the study. We expect enrollment to be completed in 2026, enabling their second BLA filing by 2028.

我們正在第 3 階段 MAGNITUDE-2 研究中積極篩選患有多發性神經病變的 ATTR 澱粉樣變性患者，並計劃在未來幾週內為第一位患者給藥。您可能還記得，這項關鍵試驗是一項高效研究，預計將招募 50 名患者。我們計劃測量 18 個月時的 mNIS + 7 和血清 TTR 水平作為研究的關鍵終點。我們預計招生工作將於 2026 年完成，並於 2028 年提交第二份 BLA 申請。

Last month, we announced the first patient had been dosed with NTLA-2002 in HAELO, our Phase 3 study in HAE. Enthusiasm for NTLA-2002 from patients and our investigators is high. And we believe this Phase 3 study will enroll rapidly, enabling us to submit a BLA filing in 2026.

上個月，我們宣布第一位患者已在 HAELO（HAELO 的第三階段研究）中接受 NTLA-2002 治療。患者和我們的研究人員對 NTLA-2002 的熱情很高。我們相信這項 3 期研究將會迅速招募患者，使我們能夠在 2026 年提交 BLA 文件。

At the beginning of this year, we conducted a pipeline prioritization to focus our resources and efforts on these late stage and high value programs NTLA-2002 and Nex-z. We discontinued our work on NTLA-3001 in favor of a second-generation approach, and we'll now look to see human proof of concept for our insertion technology by Regeneron in their hemophilia A program.

今年年初，我們進行了管道優先排序，將我們的資源和精力集中在這些後期和高價值項目 NTLA-2002 和 Nex-z 上。我們停止了 NTLA-3001 的研究，轉而採用第二代方法，現在我們將期待 Regeneron 在他們的血友病 A 項目中對我們的插入技術進行人體概念驗證。

As we look ahead to the rest of the year, we are well positioned for near-term value creation. We have three Phase 3 programs actively recruiting and one singular focus, getting the work done to enable three launches between 2027 and 2030. We're excited by our progress and by our prospects, so we look forward to sharing data from both of our programs later this year.

展望今年剩餘時間，我們已為近期價值創造做好了充分準備。我們有三個第三階段的專案正在積極招募，只有一個重點，那就是完成工作以便在 2027 年至 2030 年之間進行三次發射。我們對我們的進展和前景感到非常興奮，因此我們期待在今年稍後分享我們兩個項目的數據。

Lastly, I would like to take this time to welcome Birgit Schultes, our newly appointed Chief Scientific Officer. She's an outstanding scientist with over 20 years of experience in drug development and biotechnology, including the clinical development of cell therapies and complex biologic products. She has experienced with our entire suite of gene editing technologies and is leading our more concentrated in vivo and ex vivo research efforts.

最後，我想藉此機會歡迎我們新任命的首席科學官 Birgit Schultes。她是一位傑出的科學家，在藥物開發和生物技術方面擁有 20 多年的經驗，包括細胞療法和複雜生物產品的臨床開發。她熟悉我們的全套基因編輯技術，並領導我們更集中的體內和體外研究工作。

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

現在我將電話轉交給我們的首席醫療官 David Lebwohl，他將提供有關我們的臨床計劃的最新進展。大衛。

Thanks, John. I'll begin with 2002 in development for HAE. As John noted, we dosed the first patient with 2002 in our HAELO Phase 3 study last month. As a reminder, the HAELO study is a 60-patient global randomized double-blind placebo controlled study. This is an exciting milestone for Intellia and the HAE community. We see high interest for 2002, which we believe will drive rapid enrollment of our Phase 3 study and commercial uptake once approved.

謝謝，約翰。我將從 2002 年 HAE 的開發開始。正如約翰所說，上個月我們在 HAELO 第三階段研究中為第一位患者註射了 2002。提醒一下，HAELO 研究是一項針對 60 名患者的全球隨機雙盲安慰劑對照研究。對於 Intellia 和 HAE 社群來說，這是一個令人興奮的里程碑。我們對 2002 年表現出了很高的興趣，我們相信這將推動我們第三階段研究的快速招募和一旦獲得批准後的商業化應用。

Based on the promising data we've presented thus far, we believe patients could achieve a functional cure. In other words, freedom from HAE attacks and independence from chronically administered prophylactic medications that are commonly used to treat this disease.

根據我們迄今為止提供的有希望的數據，我們相信患者可以實現功能性治癒。換句話說，就是不再遭受 HAE 的攻擊，也不用再長期服用通常用於治療疾病的預防性藥物。

We plan to prevent longer term data from the Phase 1/2 study later this year, including patients in the Phase 2 portion who initially received a 25 mg dose or placebo and were subsequently given the 50 mg dose of 2002 selected for the Phase 3 study. With HAELO well underway, we believe 2002 is well positioned to be the first ever one-time treatment for people living with HAE.

我們計劃在今年稍後獲取第 1/2 階段研究的長期數據，包括第 2 階段患者，他們最初接受 25 毫克劑量或安慰劑，隨後接受第 3 階段研究中選定的 50 毫克劑量。隨著 HAELO 的順利開展，我們相信 2002 年將有望成為 HAE 患者的首個一次性治療方案。

The therapy is administered with a simple infusion and no need for extended steroids or other preparative drugs. This transformative therapy would also be the first approved using in vivo CRISPR gene editing.

此療法透過簡單的輸液進行，無需延長類固醇或其他準備藥物。這種變革性療法也是首個獲準使用體內 CRISPR 基因編輯的療法。

Let's move on to the Nex-z in development for the treatment of ATTR amyloidosis. Starting with ATTR amyloidosis with cardiomyopathy, enrollment in the pivotal phase through MAGNITUDE study is progressing ahead of our target enrollment projections, and we expect cumulative enrollment to exceed 550 total patients by year end.

讓我們繼續討論正在開髮用於治療 ATTR 澱粉樣變性的 Nex-z。從 ATTR 澱粉樣變性心肌病變開始，透過 MAGNITUDE 研究進入關鍵階段的招募工作正在超越我們的目標招募預測，我們預計到年底累計招募人數將超過 550 名患者。

In November, we presented data from the Phase 1 study at the 2024 American Heart Association Scientific Sessions and published the findings in the New England Journal of Medicine. Across all 36 patients, a single dose of Nex-z led to rapid, deep, and sustained serum TTR reduction, regardless of baseline levels through the latest follow-up.

11 月，我們在 2024 年美國心臟協會科學會議上展示了第 1 階段研究的數據，並在《新英格蘭醫學雜誌》上發表了研究結果。在所有 36 名患者中，單劑量 Nex-z 均可導致血清 TTR 快速、深度和持續降低，無論最新隨訪的基線水平如何。

At month 12, the mean serum TTR reduction was 90% from baseline, and the mean absolute residual serum TTR concentration was 17 mcg per ML. All patients achieve deep and durable TTR reduction after a one-time infusion. Notably, the TPR reduction occurred rapidly with the [nadir] reached at 28 days. When every day matters, achieving PTR reduction as quickly as possible is crucial in this life-threatening illness.

在第 12 個月時，平均血清 TTR 較基線減少 90%，平均絕對殘留血清 TTR 濃度為每毫升 17 微克。所有患者在一次性輸注後均達到深度和持久的 TTR 減少。值得注意的是，TPR 下降迅速，在第 28 天達到最低點。當每一天都至關重要時，盡快減少 PTR 對於這種危及生命的疾病至關重要。

With TPR silencers, the reported mean reduction was approximately 80%, which is not reached until six months after starting chronic treatment. Now we have observed that the very low levels of circulating TTR seen with Nex are associated with disease stabilization or improvement across several markers of cardiac progression at month 12 compared to baseline.

使用 TPR 消音器後，報告的平均減少量約為 80%，這一數字在開始慢性治療六個月後才達到。現在我們觀察到，與基線相比，Nex 中觀察到的非常低的循環 TTR 水平與第 12 個月的疾病穩定或心臟進展的幾個標誌物的改善有關。

These favorable results were observed even though half of the patients met criteria for Class 3 heart failure, and about 30% had a mutated TTR gene. Both characteristics of patients with more rapidly worsening disease. This is a significant insight because when patients are untreated, disease progression as measured by these markers is typically evident within 12 months.

儘管一半的患者符合 3 級心臟衰竭的標準，且約 30% 的患者患有 TTR 基因突變，但仍觀察到了這些有利的結果。這兩種特徵都顯示患者的病情會迅速惡化。這是一個重要的見解，因為當患者未經治療時，透過這些標記測量的病情進展通常在 12 個月內顯現出來。

In addition to the favorable results across markers of cardiac disease progression, we have also observed a low rate of cardiac hospitalizations in our Phase 1 study despite the advanced patient population treated with Nex-z. This event rate, if reproduced in our pivotal trial, will be associated with a compelling clinical benefit for patients suffering from ATTR cardiomyopathy.

除了心臟病進展標記方面取得的良好結果外，我們還在第 1 階段研究中觀察到，儘管使用 Nex-z 治療的晚期患者群體中，心臟病住院率仍然很低。如果在我們的關鍵試驗中重現該事件發生率，將為患有 ATTR 心肌病變的患者帶來令人信服的臨床益處。

Now on to ATTR amyloidosis with polyneuropathy. Patients are actively screening in the Phase 3 magnitude tube study, and we're on track to dose the first patient in the coming weeks. At last November's investor event, we presented data from the Phase 1 study. Across all 33 patients who received the dose of 0.3 mg per kilogram or higher, the mean serum TTR reduction was 91%. And the mean absolute residual serum TTR concentration was 20 micrograms per ML at month 12.

現在討論伴隨多發性神經病變的 ATTR 澱粉樣變性。患者正在第三階段量級管研究中積極篩檢，我們計劃在未來幾週內為第一位患者給藥。在去年 11 月的投資人活動中，我們展示了第一階段研究的數據。在所有 33 名接受 0.3 毫克/公斤或更高劑量的患者中，平均血清 TTR 降低率為 91%。第 12 個月時平均絕對殘留血清 TTR 濃度為每毫升 20 微克。

Consistent with the observations of ATTR CM, the rapid, deep, and durable reduction in serum TTR observed in all patients was accompanied by evidence of disease stabilization or improvement across multiple clinical measures of neuropathy. Across [nis] mNIS + 7, and MDMI, there were favorable trends of clinical benefit at month 12 compared to baseline levels with further improvements noted in nis and MDMI in the part 1 patients for whom 24 months of follow up was available.

與 ATTR CM 的觀察結果一致，所有患者血清 TTR 均迅速、大幅、持久地降低，並伴隨神經病變多項臨床指標穩定或改善的證據。在 [nis] mNIS + 7 和 MDMI 中，與基線水平相比，第 12 個月的臨床益處呈現有利趨勢，並且第 1 部分患者的 nis 和 MDMI 進一步改善，可對其進行 24 個月的隨訪。

Nex-z has continued to demonstrate a favorable safety and tolerability profile. In recognition of the potential clinical importance of Nex-z for the treatment of ATTR VPN, the FDA granted Nex-z regenerative medicine advanced therapy designation or RMAT. This will enable closer collaboration with the FDA as we approach a BLA filing in 2028.

Nex-z 繼續表現出良好的安全性和耐受性。鑑於 Nex-z 對 ATTR VPN 治療的潛在臨床重要性，FDA 授予 Nex-z 再生醫學先進治療頭銜或 RMAT。當我們在 2028 年提交 BLA 申請時，這將使我們與 FDA 能夠進行更密切的合作。

We look forward to presenting longer term data from both ATTR CM and ATTR VPN patients in the Phase 1 study later this year. The data will include updated measures of clinical efficacy and safety. Regarding our research platform, we're dedicated to using our toolbox to bring forward breakthrough products both in vivo and ex-vivo. You'll hear more about that in the time to come.

我們期待在今年稍後的第 1 階段研究中展示來自 ATTR CM 和 ATTR VPN 患者的長期數據。數據將包括臨床療效和安全性的最新指標。關於我們的研究平台，我們致力於利用我們的工具箱來推出體內和體外的突破性產品。您稍後會聽到更多有關此內容的消息。

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

現在，我將電話轉交給我們的財務長 Ed，他將提供有關截至 2024 年第四季的財務業績的最新資訊。

Thank you, David. Good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform. Our cash equivalents, and marketable securities were approximately $861.7 million as of December 31, 2024, compared to $1 billion as of December 31, 2023. Our collaboration revenue was $12.9 million during the fourth quarter of 2024 compared to negative $1.9 million during the fourth quarter of 2023. The $14.8 million increase was mainly driven by the Regeneron license and collaboration agreement.

謝謝你，大衛。大家早安。Intellia 繼續保持穩健的資產負債表，這使我們能夠執行我們的管道和平台。截至 2024 年 12 月 31 日，我們的現金等價物和有價證券約為 8.617 億美元，而截至 2023 年 12 月 31 日為 10 億美元。2024 年第四季度，我們的合作收入為 1,290 萬美元，而 2023 年第四季為負 190 萬美元。1,480 萬美元的成長主要得益於 Regeneron 的授權和合作協議。

R&D expenses were $116.9 million during the fourth quarter of 2024 compared to $109 million during the fourth quarter of 2023. The $7.9 million increase was primarily driven by the advancement of our lead programs.

2024 年第四季的研發費用為 1.169 億美元，而 2023 年第四季的研發費用為 1.09 億美元。790 萬美元的成長主要得益於我們主導專案的進展。

Stock-based compensation included in R&D expense was $24.4 million for the fourth quarter of 2024. G&A expenses were $32.4 million during the fourth quarter of 2024 compared to $29 million during the prior year quarter. The $3.4 million dollar increase was primarily related to stock-based compensation. Stock-based compensation included in G&A expenses was $15.2 million for the fourth quarter.

2024 年第四季，研發費用中包含的股票薪酬為 2,440 萬美元。2024 年第四季的 G&A 費用為 3,240 萬美元，而去年同期為 2,900 萬美元。340萬美元的增幅主要與股票薪酬有關。第四季一般及行政開支中包含的股票薪酬為 1,520 萬美元。

As we turn our focus to the future, I want to share a few thoughts regarding the restructuring we announced on January 9 and how this changes the complexion of our GAAP operating expenses. In the first quarter of 2025, we expect to incur wind down costs associated with certain programs like NTLA-3001 that have been discontinued or deprioritized. We expect the difficult decisions made to reduce our workforce and focus our pipeline will result in year over year declines in GAAP operating expenses of approximately 5% to 10%.

當我們將目光轉向未來時，我想分享一些關於我們在 1 月 9 日宣布的重組的想法，以及這將如何改變我們的 GAAP 營運費用的面貌。在 2025 年第一季度，我們預計將產生與某些已停止或降低優先順序的項目（如 NTLA-3001）相關的逐步淘汰成本。我們預計，減少員工人數並集中精力於產品線的艱難決定將導致 GAAP 營業費用年減約 5% 至 10%。

The operating leverage and savings created in 2025 are expected to benefit the company over the next couple of years and allow us to make important investments in commercial infrastructure and capabilities while keeping total company expenses below the level of reported results in 2024.

預計 2025 年創造的營運槓桿和節約將在未來幾年使公司受益，並使我們能夠對商業基礎設施和能力進行重要投資，同時將公司總支出保持在 2024 年報告業績水平以下。

While we anticipate greater sales and marketing investments in 2027 to support a successful commercial launch of NTLA-2002 and HAE, the company's capital needs to support multiple Phase 3 studies will begin to diminish during that year as some of these programs complete enrollment and supporting costs naturally wind down. We expect to occur approximately $8 million in severance and other employee termination related costs. Finally, we expect our cash balance to fund our operating plans into the first half of 2027.

雖然我們預計 2027 年將增加銷售和行銷投資以支持 NTLA-2002 和 HAE 的成功商業發布，但隨著其中一些專案完成招募和支援成本自然減少，該公司支援多個 3 期研究的資金需求將在當年開始減少。我們預計將發生約 800 萬美元的遣散費和其他員工解僱相關費用。最後，我們預計我們的現金餘額將為我們的 2027 年上半年的營運計畫提供資金。

Thanks, Ed. In conclusion, Intellia continues to deliver on the promise of gene editing, and we look forward to sharing more clinical progress with you mid-year.

謝謝，埃德。總而言之，Intellia 繼續履行基因編輯的承諾，我們期待在年中與您分享更多的臨床進展。

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.

現在，我們將開始回答大家的提問。為了盡力解答盡可能多的問題，我們只能回答每個來電者的一個問題。接線生，您現在可以開始問答環節了。

(Operator Instructions)

（操作員指令）

Mani Foroohar, SVB Securities.

SVB 證券的 Mani Foroohar。

Thanks for taking the call, guys. . Can we have -- can you help to give us a little bit of an update on the tempo of OpEx decline over the course of this year? And as you execute on the restructuring and looking out over the course of the next several years, there's been a lot of concern around from investors around OpEx ramps as you have large pivotal studies growing. Can you clarify that a little bit to the extent to which that OpEx ramp is going to happen or the extent to which we should think more in terms of stabilization from clinical trial costs around the pivotal stage?

謝謝你們接聽電話。。您能否幫我們稍微介紹一下今年營運支出下降的速度？隨著您執行重組並展望未來幾年，您會發現，隨著大型關鍵研究的開展，投資者對營運支出 (OpEx) 的成長非常擔憂。您能否稍微澄清一下，營運成本將在多大程度上增加，或者我們應該在多大程度上考慮關鍵階段臨床試驗成本的穩定性更多？

I know this is a little bit of a compound question, but broadly if you could help people help us, I suppose, trace out. Trajectory of that OpEx over the course of those pivotal trials, that was really helpful.

我知道這是一個有點複雜的問題，但從廣義上講，如果你能幫助人們幫助我們，我想，你可以找出答案。在這些關鍵試驗過程中的 OpEx 軌跡確實很有幫助。

So Mani from Leerink, thank you for the question. Obviously, Ed made some comments about the rate of spend and how the restructuring addresses that, but maybe Ed, you can give some additional details what you think the trajectory of spend is going to be over the coming years here.

所以，感謝 Leerink 的 Mani 提出這個問題。顯然，艾德對支出率以及重組如何解決這個問題發表了一些評論，但也許艾德，你可以提供一些額外的細節，說明你認為未來幾年的支出走勢。

Yeah, so I'll say a few things. Thanks for the question, Mani. As we reported operating results this morning, operating expenses on a GAAP basis were up, I think, 7% year over year. That's pretty consistent with how the company has had momentum in terms of supporting this evolution from a research-based company into a clinical stage organization. That evolution as is expected to continue. So we are committed to fully investing in the clinical programs that we have. That's reflected in the financial guidance that we have provided for 2025, and we are very committed to building the US infrastructure, at least initially, to support the launch of NTLA-2002 in the US.

是的，那我就說幾句。謝謝你的提問，Mani。正如我們今天早上報告的經營業績一樣，我認為，根據 GAAP 計算的經營費用同比增長了 7%。這與公司從研究型公司轉變為臨床階段公司的勢頭十分一致。預計這種演變還將繼續。因此，我們致力於全力投資我們現有的臨床項目。這反映在我們為 2025 年提供的財務指導中，並且我們非常致力於建立美國基礎設施，至少在最初階段，以支援在美國發射 NTLA-2002。

In my prepared remarks, I gave commentary to help with 2025 guidance. If I could put a little bit more color on this year in particular, the first quarter will be a little bit noisy. Having announced this in January 9, we have some wind down costs associated with some of the programs. But you'll begin to see the effect already in the first quarter, and that benefit will continue to accrue throughout the course of 2025.

在我準備好的發言中，我給了有助於 2025 年指導的評論。如果我可以特別對今年的情況進行更詳細的描述的話，第一季將會有些喧鬧。自 1 月 9 日宣布這項消息以來，我們已經產生了一些與部分項目相關的清算成本。但您將在第一季開始看到其效果，而這種好處將在整個 2025 年持續累積。

What makes this dynamic and complicated to be overly prescriptive at this point is the reality of what you described as the three Phase 3 studies that we have ongoing. So those costs are well underway for magnitude and cardiomyopathy. There are costs now associated with the HAELO study for which we dose the first patient, and we still expect to dose the first patient in our third Phase 3 study MAGNITUDE-2. So you'll see some increase in costs that are offsetting the benefits that will come with the restructuring. So too will offset the cost of the restructuring will be the investment that we make in the US for the commercial infrastructure that's required.

目前，讓這種動態和複雜情況變得過於規範的原因是，您所描述的我們正在進行的三個第三階段研究的現實情況。因此，對於心肌病變而言，這些成本已經在進行中了。目前，我們為第一位患者提供藥物的 HAELO 研究存在相關費用，我們仍預計在第三階段 3 期研究 MAGNITUDE-2 中為第一位患者提供藥物。因此，你會看到成本的增加會抵銷重組帶來的好處。我們在美國所需的商業基礎設施的投資也將抵消重組成本。

As you get beyond 2025 though, we kind of hit steady state. We're fully enrolled in HAELO at that point by 2026. We'll be well on our way within the MAGNITUDE-2 study and we'll be substantially on our way with MAGNITUDE. So we kind of hit steady state in 2026. And for which we'll get into 2027, costs will begin to naturally sunset and wind down for the HAELO program, then MAGNITUDE-2, and then ultimately, MAGNITUDE.

然而，到了 2025 年以後，我們就會達到穩定狀態。到 2026 年，我們將全面加入 HAELO。我們將在 MAGNITUDE-2 研究中順利前行，並且我們將在 MAGNITUDE 研究中取得實質進展。因此我們在 2026 年將達到穩定狀態。到 2027 年，HAELO 計劃的成本將開始自然下降並逐漸減少，然後是 MAGNITUDE-2，最終是 MAGNITUDE。

So I think it's important just to take a step back. We have made significant restructuring efforts that allows us to make the investments we need in the new priorities for the company, particularly clinically and commercially oriented. And it's hard for me to see a scenario in 2025-2026 or at least through the first part of 2027, where our OpeEx is at the level of what we've seen this past year in 2024. So I do think peak operating expenses are behind us. The only thing we'll have to assess closer to the launch will be what incremental investments we need to support NTA 2002 and HAE.

因此我認為退一步考慮是很重要的。我們進行了重大的重組努力，這使我們能夠對公司的新重點（特別是臨床和商業導向）進行必要的投資。而且我很難想像在 2025 年至 2026 年，或至少在 2027 年上半年，我們的 OpeEx 會達到 2024 年去年的水準。因此我確實認為營運費用高峰已經過去了。在發射前我們唯一需要評估的是需要多少增量投資來支援 NTA 2002 和 HAE。

That's very helpful. I take the question. I know you guys have a lot of other people online as well.

這非常有幫助。我回答這個問題。我知道你們網路上還有很多其他人。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特（Maury Raycroft），傑富瑞（Jefferies）。

Hi, good morning. Thanks for taking my question. For for Nex-z or 2001, what's the latest regarding your assumptions on Phase 3 events or rate based on longer-term data that you have? And are you saying more on what would enable the interim analysis for the MAGNITUDE-3 study at this point?

嗨，早安。感謝您回答我的問題。對於 Nex-z 或 2001，根據您掌握的長期數據，您對第 3 階段事件或速率的最新假設是什麼？您能否進一步說明此時如何進行 MAGNITUDE-3 研究中期分析？

Maybe David, you can address how we're thinking about the event rates for the magnitude study and lay out some of our initial thinking for the interim analysis.

也許戴維，您可以談談我們如何考慮量級研究的事件發生率，並闡述我們對中期分析的一些初步想法。

Yeah. So this study is enrolling at a very good rate. We're ahead of what our projections were. And the evolution of events, we expect to be similar to the other recent studies [Acarainus and lutricerin] So now there is a lot of data available on events rates in this disease. The management of disease has not changed significantly from the time of that trial -- of those trials. So that's what we're expecting. We haven't said exactly what that is publicly, but you could see it from the historical data.

是的。因此這項研究的參與率非常高。我們的業績超出了預期。我們預計事件的演變將與其他近期研究 [Acarainus 和 lutricerin] 類似，因此現在有許多關於該疾病事件發生率的數據。自那次試驗以來，疾病的治療方式並沒有重大變化。這正是我們所期待的。我們沒有公開說明具體情況，但你可以從歷史數據中看到。

In terms of the interim analysis, what we have said is what we've seen in our trial is that from the Phase 1 are results that look quite favorable. They look very good. There is a low event rate in this population, suggesting that the patients are benefiting from therapy both in terms of stabilization and even improvement. And this does look different from all the other treatments for TPR that are out there in which the patients as a population continue to get worse.

就中期分析而言，我們說過，我們在試驗中看到的是，從第一階段來看，結果看起來相當有利。它們看起來非常好。此族群的事件發生率較低，顯示患者在穩定甚至改善病情方面均受益於治療。這看起來確實與現有的其他 TPR 治療方法不同，這些治療方法會導致患者整體的病情持續惡化。

So based on that, we are obviously going to follow up this data carefully this year. We'll be seeing the evolution of the events in our in our magnitude trial. But based on that, we will be able to in the future give more better estimates about the interim. But there is, based on what we're seeing, a good possibility that we could see favorable findings at the interim analysis that would allow us to stop the program earlier. So we will, but there'll be more details about this from us as as time goes on.

因此基於此，我們今年顯然會密切關注這些數據。我們將在我們的量級審判中見證事件的演變。但基於此，我們將來就能對中期數據做出更精確的估計。但根據我們所看到的情況，我們很有可能在中期分析中看到有利的結果，這將使我們能夠提前停止該計劃。我們會的，但隨著時間的推移，我們會公佈更多有關此問題的細節。

Got it. That's helpful. Thanks for taking my question.

知道了。這很有幫助。感謝您回答我的問題。

Luca Issi, RBC.

盧卡·伊西（Luca Issi），RBC。

Oh great, thanks so much for taking our question. This is Lisa on for Luca. We saw earlier this week that an [Nilon] is moving forward with the next generation TTR silencer, and they're proceeding with a pivotal trial design which is about 2 times the size of their [Helios B trial]. So, we're just curious if this larger trial sizes made you reflect on the MAGNITUDE study. And if you are considering making any trial changes such as increasing your patient population size, any color here would be helpful. Thanks.

哦，太好了，非常感謝您回答我們的問題。這是 Lisa 為 Luca 表演的。本週早些時候，我們看到 [Nilon] 正在推進下一代 TTR 消音器的研究，他們正在進行一項關鍵的試驗設計，其尺寸大約是其現有消音器的 2 倍[Helios B 試驗]。所以，我們只是好奇，這次更大規模的試驗是否讓您對 MAGNITUDE 研究進行了反思。如果您正在考慮進行任何試驗變更（例如增加患者數量），此處的任何顏色都會有所幫助。謝謝。

Thanks, Lisa. Maybe I can make a couple of comments and David, if you see fit to add, be my guest.

謝謝，麗莎。也許我可以提出幾點評論，大衛，如果你認為有必要補充的話，請隨意。

We always look at data and we always look at what the competition is doing and think about that very carefully in terms of what it means for the program that we're carrying out. Any information that we can gather that helps us think more clearly and accurately about where we're going is always helpful.

我們總是關注數據，關注競爭對手在做什麼，並仔細思考這對我們正在實施的專案意味著什麼。我們收集的任何信息，只要能幫助我們更清楚、更準確地思考我們要去哪裡，總是有幫助的。

We do see important differences, however, and David has touched on, how we're using some of the clinical data that we've accumulated already in observations that come from patients who've been treated with our own drug. I think for details in terms of how Eylum is approaching their work, I would encourage you to ask them.

然而，我們確實看到了重要的差異，大衛也提到了我們如何利用我們已經在接受我們自己的藥物治療的患者的觀察中累積的一些臨床數據。我想，關於 Eylum 如何處理他們的工作細節，我鼓勵你去詢問他們。

However, I imagine that one of the considerations will be they're looking to achieve an effect on top of [TAFF], which was not seen, in the earlier study, and I'm sure they're doubling down to try to capture that. We think we'll be in a really strong position with respect to that category of patients. And also, my guess would be that the proportion of patients who are taking [tefamitus] will only increase over time and so there'll be a far greater proportion of patients taking that drug in their study as that plays out. Those are some top line comments.

然而，我想其中一個考慮因素是他們希望在早期的研究中未見到的 [TAFF] 之上取得效果，而且我相信他們正在加倍努力嘗試實現這一點。我們認為，對於該類患者，我們將處於非常有利的地位。此外，我猜測服用 [tefamitus] 的患者比例只會隨著時間的推移而增加，因此隨著研究的進行，服用該藥物的患者比例將會大大增加。以上是一些最重要的評論。

I'm sure they have their reasons for some additional details. But with respect to our own work, we're quite pleased with the design we have. And as David said, As we continue to look at event rates as they occur in our own Phase 1 patient population, that influences how we think about adjusting, if at all, the trial that we're doing.

我確信他們需要更多細節是有理由的。但就我們自己的工作而言，我們對我們的設計非常滿意。正如戴維所說，當我們繼續關注我們自己的第 1 階段患者群體中發生的事件發生率時，這會影響我們如何考慮調整我們正在進行的試驗（如果有的話）。

You just mention one observation about the I announcement is that you see that they are talking more and more about how important it is to get to lower levels of TPR. And that was actually used slides very close to our slides showing that as an AL amyloidosis, you see that patients who get very low levels have a better result, as well as in polyneuropathy, the greater the TTR reduction the better result. So this is good to see in the sense that they are now agreeing with the hypothesis that we have about lowering of TTR.

您剛才提到了關於 I 公告的一個觀察，那就是您發現他們越來越多地談論達到較低 TPR 水平的重要性。實際上，所使用的幻燈片與我們的幻燈片非常接近，表明對於 AL 澱粉樣變性，您會看到水平非常低的患者的結果更好，對於多發性神經病，TTR 減少越多，結果越好。因此，很高興看到他們現在同意我們關於降低 TTR 的假設。

Kostas Biliouris, BMO Capital Markets.

Kostas Biliouris，BMO 資本市場。

Hi, this is Yuri on Kostas. Congrats on the progress and thanks for taking a question. So we have another question on [Eresteron]. Can you provide your thoughts on the potential competition from Eresteron and ATTR CM that has (inaudible) dosing saying strong TPR knockdown and can launch around the same time as Nex-z? Thank you.

你好，我是科斯塔斯的尤里。恭喜您的進展，並感謝您提出問題。我們還有另一個問題[Eresteron]。您能否談談對 Eresteron 和 ATTR CM 的潛在競爭的看法？謝謝。

(multiple speakers) I'm sorry, it was a little unclear. Well, I don't know if it'll launch around the same time. We'll see how that all plays out. Clearly, people are trying to move very quickly, to get improved therapies to the market. Our basic perspective, I think, was captured by David, which is this is all about reading TTR levels from the body to the greatest extent possible. And what we've seen thus far, certainly in the patient population is that we've gotten to extremely low levels.

（多位發言者）抱歉，我說得有點不清楚。嗯，我不知道它是否會在同一時間推出。我們將拭目以待這一切將如何發展。顯然，人們正在努力迅速採取行動，將改良的治療方法推向市場。我認為，我們的基本觀點已經被 David 抓住了，那就是這一切都是為了盡可能地從身體中讀取 TTR 水平。到目前為止，我們已經看到，在患者群體中，感染率已經降至極低的水平。

We've presented not just percentage reduction, but the absolute levels of TTR, which I think is the more meaningful measure, just with respect to [Bambootra], which is what we expect to be in the market sooner. We're talking about levels that are about a third with Nex-z that compared to what's been reported for drug. So we'll see how it plays out with the compound for (inaudible)

我們展示的不僅僅是百分比的減少，還有 TTR 的絕對水平，我認為這是更有意義的衡量標準，僅就 [Bambootra] 而言，我們預計它將更快上市。我們正在討論 Nex-z 的含量，與已報告的藥物相比，其含量約為三分之一。因此，我們將看看它如何與化合物一起發揮作用（聽不清楚）

But we think that certainly a one and done therapy that allows physicians and patients being treated by them to have access to the drug that will have benefits essentially that are in place we suspect for the rest of their lives will be critically important. And I would point out that when it comes to pricing of these drugs, access to insurance, the authorization procedures that are necessary to have year-on-year dosing, we think we'll be in an advantage position. So we like where we are. And as you heard from David, the study is progressing well. We expect that, we will meet our objectives and look forward to bringing the product to the market.

但我們認為，一次性治療可以讓醫生和接受他們治療的患者獲得這種藥物，我們懷疑這種藥物將對他們的餘生產生益處，這一點至關重要。我想指出的是，在這些藥品的定價、保險管道以及逐年用藥所需的授權程序方面，我們認為我們將處於優勢地位。所以我們喜歡我們現在的處境。正如您從戴維那裡聽到的，這項研究進展順利。我們期望，我們將實現我們的目標，並期待將產品推向市場。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you. What makes you feel confident to pick 550 patient numbers by year end for the enrollment regarding the ATTR (inaudible) trial? Does that mean you will complete your trial enrollment in first half '26 for the total 765 patients?

謝謝。是什麼讓您有信心在年底前挑選出 550 名患者參加 ATTR（聽不清楚）試驗？這是否意味著您將在 26 年上半年完成總共 765 名患者的試驗招募？

Gena, thanks for the question. You know us well, we underpromise and overdeliver. And that's been the guidelines for how we've run the company and how we talk about who we are, where we're going, and how we do our work. When I say 550 patients by the end of the year, you can count on that being a very highly likely outcome.

吉娜，謝謝你的提問。您很了解我們，我們承諾的少，兌現的多。這就是我們經營公司、談論我們是誰、我們要去哪裡、以及我們如何進行工作的指導方針。當我說到年底將有 550 名患者時，你可以相信這是一個非常可能的結果。

Yes, we've said that we expect enrollment of the study to be done by 2027 in almost any scenario that we can imagine, even if we were to adjust the trial once we see the (inaudible) data or as we get additional exposure to our own event rates, we are confident that we will fall within that time frame. But meanwhile, you can count on those 550 patients being enrolled because I see the enrollment rates and we're not going to give patient by patient updates, but it's rolling robustly and doing very well.

是的，我們已經說過，在我們可以想像的幾乎任何情況下，我們都預計到 2027 年研究的招募工作將完成，即使我們在看到（聽不清楚）數據或當我們進一步了解我們自己的事件發生率時調整試驗，我們有信心我們將在那個時間範圍內完成。但同時，您可以指望這 550 名患者能夠入組，因為我看到了入組率，我們不會逐個患者地提供最新情況，但進展順利，效果非常好。

Joseph Thome, TD Cowan.

約瑟夫·托米（Joseph Thome），考恩（Cowan）TD。

Hi, there. Good morning and thank you for taking my question. Maybe just one sort of a commercial approach here. We've seen some gene therapies enter the market for chronic conditions where there's an established standard of care, and some of them had some issues with reimbursement and leading the company to even discontinue it. Pfizer did with [13AB gene] therapy last week, I guess.

你好呀。早上好，感謝您回答我的問題。這也許只是一種商業方法。我們已經看到一些基因療法進入慢性病治療市場，這些治療市場已經有既定的治療標準，但有些療法有報銷問題，甚至導致公司停止治療。我想，輝瑞上週就推出了 [13AB 基因] 療法。

What can you do now to kind of make sure that the reimbursement environment is favorable and you can drum up patient interest, so that specifically in HAE where there is that established standard of care, you'll be commercially viable? Thank you.

現在您可以做些什麼來確保報銷環境有利，並能激起患者的興趣，以便特別是在 HAE 領域，有了既定的護理標準，您就能具有商業可行性？謝謝。

Well, it's an important question, and when we think about -- I would start by pointing out that we don't think gene therapy, certainly the application of AAV to supply missing genetic function is the relevant comparator. Gene editing, which is a really readily straightforward application procedure, is something quite different from the compounds that you mentioned.

嗯，這是一個重要的問題，當我們思考時——我首先要指出的是，我們不認為基因療法，當然應用 AAV 來提供缺失的基因功能是相關的比較器。基因編輯是一種非常直接的應用程序，與您提到的化合物完全不同。

I just remind you and the other listeners that when we think about dosing patients with their drug, there is a very straightforward treatment regimen that consists of a single dose of dexamethasone the day before therapy. And then on an outpatient basis and I repeat, outpatient basis, patients come in, get another dose of dexamethasone, some antihistamines, a two to four-hour infusion, and go home. That is the regimen.

我只是提醒您和其他聽眾，當我們考慮給患者服用藥物時，有一個非常簡單的治療方案，即在治療前一天服用一劑地塞米松。然後在門診，我再說一遍，門診，病人進來，再服用一劑地塞米松，一些抗組織胺藥，進行兩到四小時的輸液，然後回家。這就是養生之道。

Extended steroids, biological product handling, etc, just doesn't apply in this case. So with respect to, as you said, drumming up interest, it starts with the performance of the drug. And in the case of HAE, remember what we've presented thus far, an entirely new category of response for these patients. We're talking about following a single application, patients having, what we have been calling, a functional cure, which is the absence of attacks and the absence of the need to take any ongoing therapy.

在這種情況下，延長類固醇、生物​​處理等並不適用。因此，正如您所說，激發興趣首先要從藥物的性能開始。就 HAE 而言，請記住我們迄今為止所介紹的，針對這些患者的一種全新反應類別。我們談論的是，患者透過一次應用就能獲得我們所說的功能性治愈，即不再發作，也不需要進行任何持續治療。

If you ask patients what they want, that is exactly what they're looking for. So I think a good proxy for how the drug will be received in the marketplace will be the enrollment of the study. And I can report at this time that, well, we've certainly talked about dosing our first patient, we have patients waiting at multiple clinical trial sites, so we expect this to go very well. And I think that's an indication of patient response.

如果你問病人想要什麼，那正是他們所尋找的。因此，我認為，衡量該藥物在市場上的接受程度的一個好指標是研究的參與程度。我現在可以報告，我們已經討論過為我們的第一位患者給藥，我們有患者在多個臨床試驗地點等待，所以我們預計一切會非常順利。我認為這是患者反應的表現。

With respect to payers, that work is already underway. And we think we will have a very favorable profile that we'll be able to present to the not just the patients themselves but to the physicians and the payers. And so we look forward to talking more about that as the year goes on.

對於付款人而言，這項工作已經在進行中。我們認為，我們將擁有一個非常有利的形象，不僅能夠呈現給患者，還能呈現給醫生和付款人。因此，我們期待在未來的幾年中對此進行更多討論。

Great. Thank you very much.

偉大的。非常感謝。

Alec Stranahan, Bank of America.

美國銀行的亞歷克‧斯特拉納漢 (Alec Stranahan)。

Hey guys, this is Matthew on for Alec. Thanks for taking our question. Maybe a quick one from us on the HAE phase 12 follow-ups. Looking at sort of the incomplete responders, any color on how these patients are doing currently with a longer follow up period and what you're expecting or hoping to see in the next update in 2025?

嘿夥計們，我是馬修，代替亞歷克。感謝您回答我們的問題。也許我們可以快速介紹一下 HAE 第 12 期的後續情況。看看那些不完全回應的患者，您能透露一下這些患者在較長的追蹤期內目前的情況嗎？

Thanks for the question. I'll start with a topic sentence or two and then David can fill in some of the details, but I would just point out that the nomenclature used is probably inappropriate. Every single patient has responded and every single patient is better off than the patient was before they came into the trial. Most of the patients that we reported in that short 16-week observation period for Phase 2 had a response that we've have been terming a functional cure, that is, they've been able to abandon their therapy and they have no ongoing attacks.

謝謝你的提問。我會以一兩句主題句開始，然後大衛可以填寫一些細節，但我只想指出，所使用的術語可能不合適。每位患者都對試驗產生了反應，並且每位患者的情況都比參加試驗之前有所好轉。我們報告稱，在第 2 階段短短 16 週的觀察期內，大多數患者都出現了我們稱之為功能性治癒的反應，也就是說，他們能夠放棄治療並且不再出現持續發作。

We've treated patients or offered to patients who are in the placebo arm in the Phase 2 study or in the 25 mg dose, the opportunity to be redosed at the Phase 3 dose of 50 mg. And we'll be in a position to report on those patients and the extended follow up of the other patients from both for the duration of those patients who have already achieved a functional cure and those patients who had not yet achieved that during the 16 week observation period. I would point out in our phase one work we've seen that patients mature in terms of the response over time. And we expect that to be occurring as well for patients in the Phase 2 stage.

我們已經對處於第 2 階段研究的安慰劑組或 25 毫克劑量的患者進行了治療，或為他們提供了以第 3 階段 50 毫克劑量重新服藥的機會。我們將報告這些患者的情況以及其他患者的長期追蹤情況，包括 16 週觀察期內已經達到功能性治癒的患者和尚未達到功能性治癒的患者。我想指出的是，在我們第一階段的工作中，我們已經看到患者的反應隨著時間的推移而逐漸成熟。我們預計這也會發生在第二階段的患者身上。

David, if you want to provide any other color?

大衛，你想提供其他顏色嗎？

Yeah, that's the most important thing, obviously we're going to wait until we give our report about how those patients are doing. But to just reiterate what John has mentioned, what we've seen over time is that patients improve. It may be related to the fact that they now know they're on the drug. But it certainly is what we've been seeing, and we will talk to you more about that and these patients from the Phase 2 later this year.

是的，這是最重要的事情，顯然我們要等到我們提交關於這些病人狀況的報告後才能決定。但只是重申約翰提到的，隨著時間的推移，我們看到患者的情況有所改善。這可能與他們現在知道自己在服用該藥物有關。但這確實是我們所看到的，我們將在今年稍後與您更多地討論這一點以及第二階段的患者情況。

Thanks.

謝謝。

Brian Cheng, JPMorgan.

摩根大通的 Brian Cheng。

Thanks for taking our questions, good morning. Maybe going back to HAE, how should we think through the gating factor as you get ready for the BLA filing? Outside of the clinical package that we're waiting for from HAELO, What are some of the other important items that you need to align between now and then? Thank you.

感謝您回答我們的提問，早安。也許回到 HAE，在您準備 BLA 申請時，我們應該如何考慮限制因素？除了我們正在等待 HAELO 提供的臨床方案之外，從現在到那時，您還需要協調哪些其他重要事項？謝謝。

Maybe I'll say a few words and then David you could add just in terms of being in a position to file the BLAs. I mean, we've said that our objective is to file a BLA in 2026. I can say next year now, it's becoming quite close. And obviously, based on some of the earlier questions, we're thinking about the market and being prepared for that. But in terms of the product itself and the filing that we're putting in place, obviously that will consist of the pre-clinical package which is done.

也許我會說幾句話，然後 David 您可以補充提交 BLA 的事宜。我的意思是，我們已經說過我們的目標是在 2026 年提交 BLA。我現在就可以說明年就已經非常接近了。顯然，基於先前的一些問題，我們正在考慮市場並為此做好準備。但就產品本身和我們正在進行的備案而言，顯然這將包括已完成的臨床前包裝。

It has the continued observation of our Phase 1 and Phase 2 patient population and then the Phase 3 data that will come from the phase -- from the HAELO study, which we'll be reporting out in the first part of next year, as that study completes.

我們將繼續觀察第 1 階段和第 2 階段的患者族群，然後觀察來自 HAELO 研究的第 3 階段數據，我們將在明年上半年研究完成時報告相關結果。

It's important to note that the product itself is in really good shape. We're using the commercial form of the product in our Phase 3 trial. So some of those things that can take place where some companies try to bridge the commercial product, that work is done. And we think we're going to be in a really good position to move very quickly. I would add that we have RMAT designation for the product and that already puts us in a strong position to deal in an accelerated fashion with the FDA. We've been using that designation to our advantage, and we expect that that will be very meaningful as the review ensues.

值得注意的是，產品本身的狀況確實良好。我們在第 3 階段試驗中使用該產品的商業形式。因此，一些公司嘗試將商業產品結合起來，這項工作已經完成。我們認為我們將處於非常有利的位置，可以快速採取行動。我想補充一點，我們的產品已獲得 RMAT 認證，這已經使我們有能力以加速的方式與 FDA 打交道。我們一直在利用這個頭銜來發揮我們的優勢，我們期望，隨著審查的進行，這將變得非常有意義。

Just to add that we've had multiple interactions with the FDA, very favorable interactions, and all the things that John is saying we think we will be ready for the BLA.

補充一點，我們已經與 FDA 進行了多次互動，互動非常有利，而且正如約翰所說的，我們認為我們已經為 BLA 做好準備。

Rick Bienkowski, Cantor Fitzgerald.

比恩科夫斯基 (Rick Bienkowski)、康托‧費茲傑拉 (Cantor Fitzgerald)。

Hey, good morning and thanks for taking the question. I wanted to follow up on Ed's comments around the marketing build out for 2002 and the associated cost. Could you comment on how big of a sales force you anticipate needing to launch 2002 and what other preparations need to be built out prior to a commercial launch?

嘿，早上好，感謝您回答這個問題。我想跟進 Ed 對 2002 年行銷建設及其相關成本的評論。您能否透露一下預計需要多大規模的銷售隊伍來推出 2002 以及在商業發布之前還需要做哪些其他準備？

And if I heard correctly, it sounded like most of the spend would take place in 2027. So I just wanted to confirm you don't anticipate significant spend here in 2026.

如果我沒聽錯的話，聽起來大部分支出將發生在 2027 年。所以我只是想確認您預計 2026 年這裡不會有大量支出。

Yeah, thanks, Rick. So we're not going to describe the size of the sales force. I think we look at the opportunity as a well defined market, patients know each other. There's good patient advocacy groups. It's a well established market opportunity. We think the footprint to operationalize that is relatively tidy and neat for a company our size, and so we're very confident in our ability to create that infrastructure and have a very successful launch.

是的，謝謝，里克。所以我們不會描述銷售隊伍的規模。我認為我們將這個機會視為一個明確界定的市場，患者彼此了解。有很好的患者權益團體。這是一個完善的市場機會。我們認為，對於我們這樣規模的公司來說，實現這一目標的足跡相對清晰明了，因此我們對創建該基礎設施並成功發布的能力非常有信心。

The investment in this broader commercial consideration started already in 2024. We've brought in senior leadership that has very relevant experience, particularly in HAE, and we have very clear plans in 2025 and 2026 to further extend that leadership team. We've had a number of questions today already on market access and pricing considerations. We've made that important higher. So we have more senior leadership coming on board in 2025.

對這項更廣泛的商業考慮的投資早在 2024 年就已開始。我們引進了具有豐富相關經驗的高階領導層，尤其是在 HAE 方面，並且我們制定了非常明確的計劃，以在 2025 年和 2026 年進一步擴大領導團隊。今天我們已經收到了許多關於市場准入和定價考慮的問題。我們已經讓這項重要性更加凸顯。因此，我們將在 2025 年迎來更多高階領導。

As we get into 2026, with the BLA filing, we're sort of at T-minus 24 or 12 months and in, and so we'll think about hiring additional marketing and salesforce at that time. So we don't think it's a significant investment relative to the other aspects of our business, particularly the clinical expenses, but we've got a very clear two year plan on the expertise we need hiring plan to achieve that such that we're ready for launch in 2027.

隨著我們進入 2026 年並提交 BLA 申請，我們大約處於 T 減 24 或 12 個月的時間，因此我們會考慮在那時僱用額外的營銷和銷售人員。因此，我們認為相對於我們業務的其他方面，特別是臨床費用，這並不是一項重大投資，但我們對實現這一目標所需的專業知識和招聘計劃有一個非常明確的兩年計劃，以便我們準備好在 2027 年推出。

William Pickering, Bernstein.

威廉‧皮克林，伯恩斯坦。

Hi, thank you for taking the question also on HAE, you talked about how some patients may be experiencing pseudo attacks that will potentially go away with the longer follow up, especially if they know they have been treated. So it sounds like the data you collect in the long term observation portion of Phase 3 could be pretty important to demonstrating functional cure, and I think that will be collected after you submit the original BLA.

你好，謝謝您回答關於 HAE 的問題，您談到一些患者可能會經歷假性發作，這些發作可能會隨著長期隨訪而消失，特別是如果他們知道自己已經接受治療的話。因此聽起來您在第 3 階段的長期觀察部分收集的數據對於證明功能性治癒可能非常重要，我認為這些數據將在您提交原始 BLA 後收集。

So I was wondering if you thought about how long you'd want to follow those patients, in the long-term observation before submitting a supplemental filing, would it need to be the full 104 weeks, or could you do it sooner if it's clearly apparent that all the attacks have stopped? Thank you.

所以我想知道，在提交補充文件之前的長期觀察中，您是否考慮過要追蹤這些患者多長時間，是否需要整整 104 週，或者如果很明顯所有發作都已停止，您是否可以更快地完成？謝謝。

David, can you outline how we think of long term follow up and what's shared with the FDA and when?

大衛，您能概述一下我們如何考慮長期跟進以及何時與 FDA 分享哪些資訊嗎？

Yeah, so, it is true we won't have 104 weeks at the time of the initial filing. However, by the time we do have the approval, we will be close to having all that data on the patients, including recall many patients crossing over in the Phase 1 and 2 experience or receiving the drug in Phase 1 and 2. So we would think about a supplemental BLA fairly soon after the initial approval as we think about it right now.

是的，所以，在首次提交申請時我們確實不會有 104 週。然而，當我們獲得批准時，我們將接近獲得有關患者的所有數據，包括回憶起許多在第 1 階段和第 2 階段經歷交叉或在第 1 階段和第 2 階段接受藥物治療的患者。因此，我們會在初步批准後不久考慮補充 BLA，就像我們現在考慮的那樣。

And of course we'll be following those patients for 15 years. Lots of data to come over there.

當然，我們會跟蹤這些病人15年。那裡有大量的數據。

Beyond the 104, yeah, but we'll have the 15 year follow up.

是的，超過 104，但我們將進行 15 年的追蹤。

Jay Olsson, Oppenheimer.

傑伊‧奧爾森 (Jay Olsson)、奧本海默。

Oh hey, thanks for providing this update. I wanted to follow up on the commercialization of 2002. It sounds like you're planning on building out a commercial infrastructure in the US. I was wondering what your thoughts are for commercializing 2002 outside the US and whether or not that might be a partnership opportunity? Thank you.

哦，嘿，感謝您提供此更新。我想跟進 2002 年的商業化。聽起來你正計劃在美國建造商業基礎設施。我想知道您對在美國以外地區商業化 2002 有何看法，以及這是否可能是合作機會？謝謝。

Thanks for the question. We are focusing primarily on the US, and we want to make sure that that is well conceived and well carried out. We are thinking through our options for how we would extend outside the United States, and there's a variety of different approaches that we might pursue and a partnership option is one of those possibilities. But we haven't decided exactly how we're going to pursue that just yet.

謝謝你的提問。我們主要關注美國，我們希望確保這項計劃得到良好的構思和實施。我們正在考慮如何拓展美國以外的業務，我們可能會採取多種不同的方式，合作就是其中一種可能性。但我們尚未決定具體如何實現這一目標。

Great, thanks for taking the question.

太好了，謝謝您回答這個問題。

Silvan Tuerkcan, Citizens JMP.

Silvan Tuerkcan，公民 JMP。

Thanks for taking my question. Just a quick question about, I guess, the upcoming quad AI presentation where you plan to show additional quality of life data in HAE. Can you just characterize a little bit like what we may see there and how that could help us understand your opportunity in HAE? Thank you.

感謝您回答我的問題。我想這只是一個簡單的問題，關於即將舉行的四重 AI 演示，您計劃在其中展示 HAE 中的其他生活品質數據。您能否稍微描述一下我們在那裡可能看到的情況，以及這如何幫助我們了解您在 HAE 中的機會？謝謝。

David, do you want to speak (multiple speakers)

大衛，你想說話嗎（多位發言者）

-- your details of the results yet. Please stand by and watch that presentation. As you can imagine, a therapy that is very easy to take from the beginning and then patients having no events after that, think about you being a patient is very favorable. So look forward to seeing those results.

—— 您尚未知道結果的詳細資訊。請稍候並觀看該演示。你可以想像，這種療法從一開始就非常容易進行，之後患者沒有任何事件發生，想想你作為一個患者是非常有利的。所以期待看到這些結果。

Thank you.

謝謝。

Yanan Zhu, Wells Fargo Securities.

朱亞南，富國證券。

Great. Thanks for taking our questions. Just wondering for the long-term ATTR data readout this year, what might be the incremental learnings to inform -- further inform product profile? Thank you.

偉大的。感謝您回答我們的問題。只是想知道今年的長期 ATTR 數據讀數，可能有哪些增量學習可以告知——進一步告知產品概況？謝謝。

Maybe I can address that. We would present essentially the results the categories of assays, etc. That you've already seen extended over on the order of a year or so. What does that mean? As David referenced in earlier comments, we're looking for a continued low rate of progression of the disease. I think it would be very interesting to see if any additional patients have approved, improved relative to where they were at baseline. I certainly wouldn't rule that out.

也許我可以解決這個問題。我們將主要展示分析類別等的結果。這些結果已經延續了大約一年左右的時間。這意味著什麼？正如大衛在先前的評論中提到的，我們預計疾病的進展速度將持續處於較低水平。我認為觀察是否有其他患者獲得批准，或相對於基線情況有所改善，將會非常有趣。我當然不會排除這種可能性。

And we'll look for continued confirmation of what we think is a very low event rate and think through how that relates to our own Phase 3 trial. But bottom line, what we're seeing is the first clinical manifestations of what we think is a very low TTR level. And what that means for these patients. And thus far with the results that were published in the New England Journal and presented at AHA in November, those results are very exciting, and we think very important for these patients with severe cardiomyopathy.

我們將繼續確認我們認為的非常低的事件發生率，並思考這與我們自己的第三階段試驗的關係。但最重要的是，我們看到的是我們認為非常低的 TTR 水平的首批臨床表現。這對這些病人意味著什麼。到目前為止，研究結果已經發表在《新英格蘭醫學雜誌》上並於 11 月在 AHA 上展示，這些結果非常令人興奮，我們認為這對於患有嚴重心肌病變的患者非常重要。

Great, thanks for the color.

太棒了，謝謝你的顏色。

Liisa Bayko, Evercore ISI.

Liisa Bayko，Evercore ISI。

Hi, there. Thanks for taking the question. I'd love to just get a little bit more color on how you're thinking about the attack free rate in the context of your reduction in cal crime and how you -- how you're thinking about potentially trying to of all this number so it can be a little bit even greater number of patients who are attack free and Phase 3? Any color additional work you've done there and what's been the preliminary feedback I guess on the data as well at this point from the community physicians, etc? Thanks.

你好呀。感謝您回答這個問題。我很想更詳細地了解一下，您在降低加州犯罪率的背景下是如何考慮無發作率的，以及您如何考慮嘗試降低所有這些數字，以便使無發作率和第三階段的患者數量稍微多一些？您在那裡做了什麼額外的工作？我猜目前社區醫師對這些數據的初步回饋是什麼？謝謝。

Maybe a general comment on [Calacrine] and its relationship to attacks. It's not strictly linear. There may be some patients that for just variability in the patient population reasons react a little bit differently. But what we do know is that as you go below 60% reduction, attack rates start to fall precipitously. And as you get to the very low levels that we've achieved, it's even beyond that.

也許是對 [Calacrine] 及其與攻擊的關係的一般性評論。它並不是嚴格線性的。可能有些患者由於患者群體的差異性原因，反應略有不同。但我們確實知道，當減少量低於 60% 時，發生率就會開始急劇下降。而當你達到我們已經達到的非常低的水平時，它甚至超越了那個水平。

Part of the challenge for observing these attacks are the consequences of a double blind study and medical treatment for patients who don't know if they receive drugs or not, act on any, let's say, twitch or early indication that they may or may not be having an attack, which is what the medical guide is for them to behave. So Smaller, shorter-term studies can be influenced by bad behavior, which again is appropriate medical therapy. We think that with extended observation, that will likely lessen.

觀察這些發作的部分挑戰在於雙盲研究和醫療的後果，因為患者不知道他們是否接受藥物治療，不知道他們是否會根據任何跡象（例如抽搐或早期跡象）採取行動，而這些跡象表明他們可能會或可能不會發作，而這正是醫療指南為他們提供的行為指導。因此，規模較小、期限較短的研究可能會受到不良行為的影響，而這又是適當的醫學療法。我們認為，隨著觀察的深入，這種情況可能會減輕。

I think that an important aspect from what we've seen in work already presented, particularly when we look at the Phase 1 results and add that to the phase 2 results, is the longer patients go, the more confident they are, and we see attack rates falling to very low levels. And I think there'll be an opportunity later this year to see how that plays out with the additional patients and the additional follow up that we've accumulated.

我認為，從我們已經呈現的研究結果來看，一個重要的方面是，特別是當我們查看第 1 階段的結果並將其添加到第 2 階段的結果時，患者治療的時間越長，他們就越有信心，並且我們看到發病率下降到非常低的水平。我認為今年稍後我們將有機會觀察這項措施對於我們累積的更多患者和更多後續行動將如何發揮作用。

Just mentioning the Phase 3, difference in the Phase 3 is we do follow the patients for a longer period of time. Instead of the 16-week follow-up, the follow-up is between weeks 5 and 28. We also think we'll support, seeing a better result there.

剛才提到第 3 階段，第 3 階段的不同之處在於我們確實會更長時間地追蹤患者。追蹤期不是 16 週，而是在第 5 週至第 28 週之間。我們也認為我們會提供支持，並在那裡看到更好的結果。

Thank you.

謝謝。

Myles Minter, William Blair.

邁爾斯·明特、威廉·布萊爾。

Hey team, this is John on for Miles. Thanks so much for taking our question. I was just wondering if you could give us any updates on how stabilizer usage in the MAGNITUDE study is tracking compared to your original projections, which I believe were for around 50% usage in the study? Thanks.

嘿，各位，我是代替邁爾斯的約翰。非常感謝您回答我們的問題。我只是想知道您是否可以向我們提供有關 MAGNITUDE 研究中穩定劑使用情況的最新情況，與您最初的預測相比如何，我認為研究中的穩定劑使用率約為 50%？謝謝。

Yeah, I think we had said it would be at least 50%, but David, you want to give some insight here.

是的，我認為我們說過至少會是 50%，但 David，你想在這裡提供一些見解。

What we are seeing is greater usage of families around the world, in particular, the UK has now supplied that to the patients there. We actually think this is actually going in a good direction in terms of our ultimate results, because what we think is important to show is that we can have a significant benefit over to formatuve, that hasn't been shown yet for any other agent. And that finding we think will be part of superior efficacy that we might see that would drive the usage of our drugs.

我們看到世界各地家庭的使用率越來越高，特別是英國現在已經向那裡的患者提供了這種藥物。我們實際上認為，就我們的最終結果而言，這實際上是朝著好的方向發展的，因為我們認為重要的是要表明，我們比 formatuve 具有顯著的優勢，而這一點尚未在任何其他藥物上得到證實。我們認為，這項發現將成為推動我們藥物使用卓越療效的一部分。

Helpful, thank you.

很有幫助，謝謝。

David Lebowitz, Citi.

花旗銀行的 David Lebowitz。

Thank you very much for taking my question. This is a follow up from my earlier question. On HAE, there's a lot of talk about the possibility of a functional cure. I would imagine that that's not the bar ultimately that you see for success. What do you see as the bar for success?

非常感謝您回答我的問題。這是我之前的問題的後續。關於 HAE，人們有很多關於功能性治癒可能性的討論。我可以想像這並不是你最終所看到的成功的標準。您認為成功的標準是什麼？

Well, we think the functional cure aspect is the key driver for how patients are going to want to use this drug. But what we see in our market research, whether it's patients or physicians, is that patients are not looking for marginal improvements in the interval between using prophylaxis or on demeaning therapy that takes effect faster than existing therapy. That's -- that market is largely satisfied as what we can tell.

嗯，我們認為功能性治癒是患者如何使用這種藥物的關鍵驅動因素。但我們在市場調查中發現，無論是患者還是醫生，患者並不期望在使用預防措施或比現有療法見效更快的降級療法之間獲得微小的改善。據我們所知，市場基本上已經感到滿意。

What patients are looking for is a completely new category of response, and that is, in fact, a functional cure basis. We think we will have many patients who are achieving functional care. In fact, what we've seen thus far is the a large majority of patients already have achieved that in early observation. So that I think will be a very important driver.

患者所尋求的是一種全新的反應類別，事實上，這是一種功能性治癒的基礎。我們認為將會有許多患者獲得功能性護理。事實上，到目前為止我們看到的是，絕大多數患者在早期觀察中已經實現了這個目標。所以我認為這將是一個非常重要的驅動力。

I would add that on the more routine measurements of attack rate reductions, we have data that is competitive with any other agent that's been presented. And as observation periods are extended, what we see is that attack rates for any of those patients thus far who have continued to have attacks, the attack rate is very low. So we think on any category of potential competition, we're in a really strong position.

我想補充一點，在更常規的發病率降低測量中，我們擁有與任何其他已提出的藥物具有競爭力的數據。隨著觀察期的延長，我們發現，迄今為止，任何持續發作的患者的發生率都非常低。因此我們認為，在任何潛在競爭類別中，我們都處於非常有利的地位。

Thank you so much for the answer.

非常感謝您的回答。

Andy Chen, Wolf Research.

安迪陳 (Andy Chen)，沃爾夫研究公司。

Hey, Brandon on for Andy. Another question from us on competition and rolling. So by our calculation, Helios be enrolled about 380 patients per year. You're planning to do 375 here as a follow-up therapy, which appears to be quite fast. It's -- is it reasonable to use the ratio between that 380 and 275 to determine doctor enthusiasm and patient enthusiasm for your TTR gene therapy? And Do you have any other hard quantitative metrics to show the magnitude of patient enthusiasm for your product compared to competition? Thank you.

嘿，布蘭登代替安迪上場。我們還有一個關於比賽和滾動的問題。所以根據我們的計算，Helios 每年會招募約 380 名患者。您計劃在這裡進行 375 作為後續治療，看起來相當快。使用 380 和 275 之間的比率來確定醫生和患者對 TTR 基因療法的熱情是否合理？並且，您是否還有其他硬性量化指標來顯示與競爭對手相比患者對您的產品的熱情程度？謝謝。

Not unreasonable to use ratios like that, but at best that is a very blunt instrument in terms of determining how enrollment's going. I would start by just using the numbers we've provided. As I said earlier in the call, there's a very high likelihood that we will have in excess of those 550 patients. And we expect to be in a position where the study finishes well within the guidance that we've already given. So if there's reason to give additional updates as time goes on, we'll consider that. But I would not look for routine updates in terms of the numbers of patients that are coming into the study.

使用這樣的比率並非不合理，但在確定入學情況方面，這充其量是一種非常遲鈍的工具。我將首先使用我們提供的數字。正如我早些時候在電話中所說的那樣，我們很有可能接收超過 550 名患者。我們期望這項研究能夠在我們已經給予的指導範圍內順利完成。因此，如果隨著時間的推移有理由提供更多更新，我們會考慮。但我不會尋求參與研究的患者數量的定期更新。

And just to mention what we're saying, there is a very high level of enthusiasm from the physicians, and we're hearing it coming through as well from their patients joining the trial. So we're excited about what we're seeing in the field.

正如我們所說，醫生們的熱情非常高，而且我們從參加試驗的患者那裡也聽到了同樣的熱情。因此，我們對現場看到的一切感到非常興奮。

Thank you.

謝謝。

Terence Flynn, Morgan Stanley.

摩根士丹利的特倫斯弗林 (Terence Flynn)。

Hi, thanks for taking the questions. I was just wondering on the [Regeneron] collaboration, just wondering if you can walk us through kind of the next milestones that we should anticipate here or when we could learn more about the profile. Thank you.

嗨，感謝您回答這些問題。我只是對 [Regeneron] 的合作感到好奇，只是想知道您是否可以向我們介紹一下我們應該期待的下一個里程碑，或者我們何時可以了解更多有關概況的信息。謝謝。

Just a couple of high-level comments. The regenerating collaboration with Nex-z is a 25% interest on their part and 75% interest on ours. That's been in place for some time now. There is a point where they'll need to make a determination whether or not they're going to opt in for a coke commercialization partnership and we look forward to seeing that decision and planning around that so. I don't know, Ed, if you think there's any other milestones that are important to mention at this point.

這只是幾條高層的評論。與 Nex-z 的再生合作，他們擁有 25% 的權益，我們擁有 75% 的權益。這一情況已經存在有一段時間了。他們需要確定是否要加入可口可樂商業化合作夥伴關係，我們期待看到這一決定並圍繞這一決定進行規劃。艾德，我不知道您是否認為此時還有其他重要的里程碑值得一提。

I think that's it. And just to double down on John's point, it's a co-promotion in the US that they have the right. The economics don't change. And so what's going to drive that is sort of the timeline to commercialization as we think about PN indication in particular. I think we've been very prudent in sort of providing guidance on timelines for that. But if you think about alternatives in terms of interim analysis or accelerated approval processes, that timeline could come in. So we're not necessarily terribly far away from that, but that next milestone for them to opt into a US code promote is an important one and that's on the horizon.

我認為就是這樣。為了強調約翰的觀點，這是在美國進行的共同宣傳，以證明他們擁有這項權利。經濟狀況不會改變。因此，當我們特別考慮 PN 指徵時，推動這一點的將是商業化的時間表。我認為我們在提供時間表指導方面非常謹慎。但如果你從中期分析或加速審批流程的角度考慮替代方案，那麼這個時間表就可能出現。因此，我們距離這個目標並不遙遠，但對他們來說，選擇加入美國代碼推廣的下一個里程碑是重要的，而且即將實現。

Salveen Richter, Goldman Sachs.

高盛的薩爾文·里希特（Salveen Richter）。

Hey, this is Mark on Salveen and thanks so much for taking our question. You guys briefly mentioned earlier that you, discontinued until like 3001 for a second-generation approach. I was wondering if you could talk more about that. Were there any signals you were seeing with the original 2001 that were unfavorable and any commentary on the second generation approach?

嘿，我是 Salveen 的馬克，非常感謝您回答我們的問題。你們之前簡單提到過，直到 3001 年才停止使用第二代方法。我想知道您是否可以進一步談論這個問題。您是否發現 2001 年原版中存在任何不利的訊號？對第二代方法有何評論？

There was nothing on 3001 from a clinical point of view. We stopped just short of dosing a patient. The pre-clinical studies we've talked about in the past. We -- as we look at that area, we made a decision on how to pursue 3001 in the context of the prioritization and restructuring that we announced in January. And we think that the gene writer approach that we've described elsewhere has significant utility in the disease and at an appropriate time, we'll be in a position to talk about that.

從臨床角度來看，3001 沒有任何問題。我們差點就給病人用藥了。我們過去討論過的臨床前研究。當我們審視這一領域時，我們根據一月份宣布的優先順序和重組，決定瞭如何推進 3001 計畫。我們認為，我們在其他地方描述的基因編寫方法對這種疾病有重要用途，在適當的時候，我們會討論這個問題。

This concludes the question-and-answer session and Intellia Therapeutics' fourth quarter and full year 2024 financial results conference call. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect your line.

問答環節和 Intellia Therapeutics 2024 年第四季和全年財務業績電話會議到此結束。會議現已結束。感謝您參加今天的演講。現在您可以斷開線路了。