Uniqure NV (QURE) 2025 Q1 法說會逐字稿

Good day and thank you for standing by. Welcome to the uniQure first quarter, 2025 earnings conference call. (Operator Instructions) Please be advised that today's conference is being recorded. I would now like to turn the conference over to your speaker for today, Chiara Russo, Senior Director of Investor Relations. Please go ahead.

您好，感謝您的支持。歡迎參加 uniQure 2025 年第一季財報電話會議。（操作員指示）請注意，今天的會議正在錄音。現在，我想將會議交給今天的發言人、投資者關係高級總監 Chiara Russo。請繼續。

Thank you. Good morning and thank you for joining us for uniQure's inaugural quarterly earnings call. Earlier this morning, uniQure released its financial results for the first quarter of 2025. The press release is available on the Investors and Media section of our website at uniQure.com, and our 10-Q will be filed with the SEC later today.

謝謝。早安，感謝您參加 uniQure 的首次季度財報電話會議。今天早些時候，uniQure 發布了 2025 年第一季的財務業績。新聞稿可在我們網站 uniQure.com 的「投資者和媒體」部分查閱，我們的 10-Q 將於今天稍後提交給美國證券交易委員會 (SEC)。

Joining me on the call this morning are Matt Kapusta, Chief Executive Officer; Dr. Walid Abi-Saab, Chief Medical Officer; and Christian Klemt, our Chief Financial Officer. After our formal remarks, we'll open up the call for Q&A.

今天早上參加電話會議的還有執行長 Matt Kapusta、首席醫療官 Walid Abi-Saab 博士和財務長 Christian Klemt。正式發言後，我們將開始問答環節。

Please know that we'll be making forward-looking statements during this investor call. All statements, other than statements of historical fact, are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including without limitation, the factors described in uniQure's most recent SEC filings. Giving these risks, you should not put undue reliance on these forward-looking statements, and we assume no obligation to update these statements even if new information becomes available in the future.

請注意，我們將在本次投資者電話會議中做出前瞻性陳述。除歷史事實陳述外，所有陳述均為前瞻性陳述。它們是基於管理層的信念和假設以及截至本次電話會議之日管理層可獲得的資訊。由於多種原因，我們的實際結果可能與這些前瞻性聲明中預期的結果有重大差異，包括但不限於 uniQure 最新向美國證券交易委員會提交的文件中所述的因素。鑑於這些風險，您不應過度依賴這些前瞻性陳述，即使將來出現新資訊，我們也不承擔更新這些陳述的義務。

Now let me introduce Matt Kapusta, uniQure's CEO.

現在讓我介紹一下 uniQure 的執行長 Matt Kapusta。

Thanks, Chiara. And good morning, everyone. Thank you for joining our call today. I'm very pleased to share with you our first quarter of 2025 financial results and provide an update on the progress of our four clinical stage gene therapy programs. As we continue to advance our pipeline and drive AMT-130 closer to a planned BLA submission, we are commencing quarterly earnings calls to provide regular updates on our progress.

謝謝，Chiara。大家早安。感謝您今天參加我們的電話會議。我很高興與大家分享我們 2025 年第一季的財務業績，並介紹我們四個臨床階段基因治療計畫的進展。隨著我們繼續推進我們的產品線並推動 AMT-130 更接近計劃中的 BLA 提交，我們將開始召開季度收益電話會議，定期更新我們的進度。

I'm joined today by Dr. Walid Abi-Saab, our Chief Medical Officer; and Christian KleMt, our Chief Financial Officer, who'LL each provide updates on their respective areas.I'd like to begin by reflecting on what has been a truly remarkable last 12 months for uniQure and why we believe 2025 has the potential to be a transformational year for the company with multiple important value driving milestones ahead.

今天與我一起出席的還有我們的首席醫療官 Walid Abi-Saab 博士和我們的財務長 Christian KleMt，他們將分別提供各自領域的最新情況。我想先回顧過去 12 個月對 uniQure 來說真正非凡的一年，以及為什麼我們相信 2025 年有可能成為公司的轉型之年，未來將實現多個重要的價值驅動里程碑。

Last July, we presented compelling two-year data from our Huntington's program, demonstrating AMT-130's potential to meaningfully slow disease progression. Then in November, we announced alignment with the FDA on key elements of an accelerated approval pathway, which include the use of a natural history external control and cUHDRS as a registrational intermediate clinical endpoint.

去年 7 月，我們展示了亨廷頓舞蹈症計畫的兩年令人信服的數據，證明了 AMT-130 具有顯著減緩病情進展的潛力。隨後在 11 月，我們宣布與 FDA 就加速審批途徑的關鍵要素達成一致，其中包括使用自然史外部控制和 cUHDRS 作為註冊中間臨床終點。

In 2025, we continue to make strong progress with AMT-130. In April, the FDA granted breakthrough therapy designation, underscoring both the urgent need in Huntington's disease and the strength of our clinical data. In recent weeks, we've had multiple productive interactions with the FDA focused on preparing for a planned BLA submission, and we look forward to providing a detailed regulatory update later this quarter after we receive formal meeting minutes. We're also making good progress towards initiating CMC process validation, another important step in support of the planned BLA submission.

2025年，我們將繼續在AMT-130方面取得長足進步。今年 4 月，FDA 授予突破性療法認定，強調了亨廷頓舞蹈症的迫切需求和我們臨床數據的實力。最近幾週，我們與 FDA 進行了多次富有成效的互動，重點是準備提交計劃中的 BLA，我們期待在本季度晚些時候收到正式會議記錄後提供詳細的監管更新。我們在啟動 CMC 製程驗證方面也取得了良好進展，這是支援計劃中的 BLA 提交的另一個重要步驟。

In addition to the strong progress made with our Huntington's program, we've also expanded our clinical pipeline with the initiation of three additional clinical studies in refractory temporal lobe epilepsy or TLE, Fabry disease, and SOD1 ALS. In the quarter, we continue to advance enrollment in both our Fabry and SOD1 ALS studies. And we look forward to presenting initial Fabry data in the second half of 2025. We've completed the enrollment of the first two dose cohorts in our SOD1 ALS trial and currently have several patients screening for our TLE clinical study. We also expect to share preliminary results from the first patient dose in the TLE study at an upcoming scientific meeting later this month.

除了亨廷頓舞蹈症計畫的重大進展之外，我們還擴大了臨床研究管道，啟動了難治性顳葉癲癇或 TLE、法布瑞氏症和 SOD1 ALS 的另外三項臨床研究。本季度，我們繼續推進 Fabry 和 SOD1 ALS 研究的招募。我們期待在 2025 年下半年展示初步的法布瑞氏症數據。我們已經完成了 SOD1 ALS 試驗中前兩個劑量組的招募，目前有幾名患者正在接受 TLE 臨床研究的篩選。我們也預計將於本月稍後舉行的科學會議上分享 TLE 研究中第一位患者劑量的初步結果。

Lastly, uniQure continues to be in a strong financial position with more than $400 million of cash-on-hand as of March 31. Last year, we significantly reduced our cash burden with the divestiture of our GMP manufacturing facility and organizational restructuring. We further strengthened our balance sheet with the completion of a targeted $80 million follow-on offering earlier this year. Together these actions provide us the financial flexibility to advance our pipeline, including the planned BLA submission and launch of AMT-130 and support key data readouts from our other clinical programs.

最後，截至 3 月 31 日，uniQure 的財務狀況依然強勁，現金超過 4 億美元。去年，我們透過剝離 GMP 製造工廠和組織重組大大減輕了現金負擔。今年早些時候，我們完成了 8000 萬美元的目標後續發行，進一步增強了我們的資產負債表。這些舉措共同為我們提供了財務靈活性，以推進我們的產品線，包括計劃中的 BLA 提交和 AMT-130 的推出，並支持我們其他臨床項目的關鍵數據讀數。

Overall, I'm incredibly proud of the progress our team made in the first quarter. We delivered on our key objectives and remain on track to meet the strategic goals outlined for 2025. Our continued focus and disciplined execution position us well to what we expect will be a transformative year for uniQure.

總的來說，我為我們團隊在第一季的進步感到無比自豪。我們實現了關鍵目標，並將繼續朝著 2025 年戰略目標邁進。我們持續的專注和嚴謹的執行使我們有望迎來 uniQure 的變革之年。

I'll now turn the call over to Walid to provide a more detailed clinical update. Walid?

現在我將把電話轉給 Walid，讓他提供更詳細的臨床更新資訊。瓦利德？

Thank you, Matt. Good morning and good afternoon, everyone. During the first quarter of 2025, we made meaningful progress across our pipeline of clinical stage gene therapies.

謝謝你，馬特。大家早安，下午好。2025 年第一季度，我們在臨床階段基因療法研發方面取得了重大進展。

Let me start with AMT-130. AMT-130 for the treatment of Huntington's disease has made significant gains over the last 12 months, beginning in May of last year with the granting of the Regenerative Medicine Advanced Therapy or RMAT designation by the FDA, the first for Huntington's disease.

讓我從 AMT-130 開始。用於治療亨廷頓舞蹈症的 AMT-130 在過去 12 個月中取得了顯著進展，自去年 5 月 FDA 授予其再生醫學先進療法或 RMAT 稱號以來，這是針對亨廷頓舞蹈症的首個稱號。

In July, we announced positive long-term follow-up data on AMT-130, supporting dose-dependent slowing of Huntington's disease progression. In November, we successfully aligned with the FDA on key elements for an accelerated approval pathway, including the use of the Composite Unified Huntington's Disease Rating Scale or cUHDRS, a functional measure as an intermediate clinical endpoint. In February of this year, we completed enrollment of all 12 patients in the third cohort of the Phase 1/2 trial, and I'll be reviewing the short-term safety data with you in just a moment.

7 月，我們公佈了 AMT-130 的積極長期追蹤數據，支持劑量依賴性減緩亨廷頓舞蹈症的進展。11 月，我們成功地與 FDA 就加速審批途徑的關鍵要素達成一致，包括使用綜合統一亨廷頓氏病評分量表 (cUHDRS)，一種作為中期臨床終點的功能性測量。今年 2 月，我們完成了 1/2 期試驗第三組全部 12 名患者的入組，我稍後將與您一起回顧短期安全數據。

In April, AMT-130 was granted breakthrough therapy designation by the FDA, further underscoring the potential promise of this program and the urgent need for disease-modifying treatments for this devastating condition. Most importantly, we believe our interactions with the FDA in both the first and second quarters of this year have been productive. We expect to provide a more comprehensive regulatory update, including guidance on the planned BLA submission later this quarter and additional clinical data in the third quarter of this year.

今年 4 月，AMT-130 被 FDA 授予突破性療法認定，進一步凸顯了該計畫的潛在前景以及針對這種毀滅性疾病的疾病改良療法的迫切需求。最重要的是，我們相信今年第一季和第二季與 FDA 的互動都是富有成效的。我們預計將提供更全面的監管更新，包括本季稍後計劃提交的 BLA 指南以及今年第三季的更多臨床數據。

Now, I'd like to move on to Cohort 3. Based on our experiences from Cohort 1 and 2, which did not include prophylactic immunosuppression, we believe AMT-130 is generally safe and well-tolerated at both doses. Cohort 3, which completed enrollment in February, was designed to evaluate the impact of prophylactic immunosuppression regimen consisting of dexamethasone, sirolimus, and rituximab. This cohort includes 12 patients, blinded and randomized to receive either the high or low dose of AMT-130.

現在，我想談談第 3 組。根據我們從第 1 組和第 2 組中獲得的經驗（不包括預防性免疫抑制），我們認為 AMT-130 在兩種劑量下通常都是安全且耐受性良好的。第 3 組於 2 月完成招募，旨在評估由地塞米松、雷帕黴素和利妥昔單抗組成的預防性免疫抑制方案的影響。該隊列包括 12 名患者，他們被盲選並隨機分配接受高劑量或低劑量的 AMT-130。

Key observations from Cohort 3 are as follows: AMT-130 continues to be generally well-tolerated at both doses with no treatment-related serious adverse events reported. There were three serious adverse events related to immunosuppression, which were observed, mania, MRSA infection from an abrasion, and fever. All of which resolved fully with standard of care interventions. Peri-operative changes in CSF NfL were consistent with previously reported observations, reinforcing their association with the surgical procedure.

組 3 的主要觀察結果如下：AMT-130 在兩種劑量下仍普遍耐受性良好，未報告與治療相關的嚴重不良事件。觀察到三種與免疫抑制相關的嚴重不良事件，即躁症、擦傷引起的 MRSA 感染和發燒。所有這些問題都透過標準護理介入得到了徹底解決。腦脊髓液神經纖維層 (CSF NfL) 的圍手術期變化與先前報告的觀察結果一致，進一步證實了它們與手術過程之間的關聯。

Based on these results, we believe a short two-week course of steroids represents an appropriate and optimized immunosuppression strategy to accompany AMT-130. We view this as a favorable outcome and plan to review this data with external advisors in the near future. Importantly, we do not anticipate any impact on the potential timing of BLA submission.

根據這些結果，我們認為為期兩週的短期類固醇療程代表了與 AMT-130 配合使用的適當且優化的免疫抑制策略。我們認為這是一個有利的結果，並計劃在不久的將來與外部顧問一起審查這些數據。重要的是，我們預計這不會對 BLA 提交的潛在時間產生任何影響。

Moving on to mesial temporal lobe epilepsy, the team remains focused on driving patient enrollment in the Phase 1/2 trial of AMT-260. Following the implementation of FDA-cleared protocol amendments to broaden eligibility, the trial now has 12 active clinical sites with more expected to be activated throughout the year. We plan to present a case study for the first dose patients, including initial safety and exploratory efficacy data at the Epilepsy Therapies and Diagnostics Development Symposium on Thursday, May 29.

在研究內側顳葉癲癇時，團隊仍致力於推動患者參與 AMT-260 的 1/2 期試驗。在實施經 FDA 批准的擴大試驗資格的方案修正案後，該試驗目前擁有 12 個活躍的臨床地點，預計全年將有更多地點啟動。我們計劃在 5 月 29 日星期四的癲癇治療和診斷發展研討會上展示針對首劑患者的案例研究，包括初步安全性和探索性療效數據。

In Fabry disease, we announced a favorable safety review by the Independent Data Monitoring Committee and have now treated a total of four patients in the Phase 1/2 study. We expect to share initial patient data in the second half of this year.

在法布瑞氏症方面，我們宣布獨立數據監測委員會對這項療法進行了良好的安全性審查，目前已在 1/2 期研究中治療了總共 4 名患者。我們預計將在今年下半年分享初步病患數據。

Similarly, in the Phase 1/2 study of AMT-162 and SOD1 ALS, following the review of the initial safety data, the IDMC recommended proceeding with enrollment in the second cohort. The team has now completed enrollment in the second cohort and expects to initiate enrollment in the third cohort in the third quarter of this year.

同樣，在 AMT-162 和 SOD1 ALS 的 1/2 期研究中，在審查了初步安全數據後，IDMC 建議繼續進行第二組患者的招募。目前，該團隊已完成第二批學員的招生工作，預計今年第三季開始招募第三批學員。

Now, I will turn the call over to Christian for a financial update. Christian?

現在，我將把電話轉給克里斯蒂安，請他報告財務最新情況。基督教？

Thank you, Walid. I'll start off by sharing financial highlights for the first quarter of 2025. Please refer to the earnings press release issued this morning and our quarterly filing for additional details.

謝謝你，瓦利德。首先，我將分享 2025 年第一季的財務亮點。請參閱今天上午發布的收益新聞稿和我們的季度文件以了解更多詳細資訊。

Revenue for the first quarter was $1.6 million compared to $8.5 million in the same period to 2024. The decrease of $6.9 million in revenue was mainly from a decrease of $3.3 million of collaboration revenue and a decrease of $4 million in contract manufacturing revenue. Following the divestment of the Lexington facility in July 2024, revenue from contract manufacturing is recorded net of cost within our expenses.

第一季的營收為 160 萬美元，而 2024 年同期的營收為 850 萬美元。收入減少 690 萬美元，主要由於合作收入減少 330 萬美元，以及合約製造收入減少 400 萬美元。繼 2024 年 7 月剝離列剋星敦工廠後，合約製造收入扣除成本後計入我們的費用中。

Cost of contract manufacturing revenues were nil in the first quarter compared to $9.1 million for the same period in 2024. Again, following the divestment of the Lexington facility in July 2024, cost of contract manufacturing is recorded net of revenue within other expenses.

第一季合約製造收入成本為零，而 2024 年同期為 910 萬美元。同樣，在 2024 年 7 月剝離列剋星敦工廠後，合約製造成本被記錄在其他費用中的收入淨額中。

Research and development expenses were $36.1 million in the quarter, compared to $40.7 million during the same period in 2024. The majority of the cost reduction was related to a decrease in employee-related expenses and facility expenses. This was partially offset by a $5.8 million increase in external programs spend primarily related to the submission of BLA for the Huntington's program.

本季研發費用為 3,610 萬美元，而 2024 年同期為 4,070 萬美元。成本的減少主要與員工相關費用和設施費用的減少有關。這部分被外部項目支出增加 580 萬美元所抵消，主要與提交亨廷頓項目的 BLA 有關。

Selling, general, and administrative expenses were $10.9 million in the quarter, compared to $13.9 million during the same period in 2024. The decrease was again primarily due to a reduction of employee-related expenses.

本季銷售、一般及行政費用為 1,090 萬美元，而 2024 年同期為 1,390 萬美元。下降的主要原因還是員工相關費用的減少。

Cash, cash equivalents, and investment securities total $409 million as of March 31, 2025, compared to $367.5 million as of December 31, 2024. The increase is primarily related to the net proceeds of $80.5 million from a first quarter follow-on offering. This strong balance sheet provides uniQure with the resources, clinical and operational strategy, including the planned U.S. launch of AMT-130. We expect cash, cash equivalents, and investment securities will be sufficient to fund operations into the second half of 2027.

截至 2025 年 3 月 31 日，現金、現金等價物及投資證券總額為 4.09 億美元，而截至 2024 年 12 月 31 日為 3.675 億美元。這一增長主要與第一季後續發行的 8,050 萬美元淨收益有關。強勁的資產負債表為 uniQure 提供了資源、臨床和營運策略，包括計劃在美國推出的 AMT-130。我們預計現金、現金等價物和投資證券將足以支持 2027 年下半年的營運。

I'll now turn the call back over to Matt.

我現在將電話轉回給馬特。

Thanks for that update, Christian. As you've heard today, we believe 2025 will be a transformative year for uniQure. We continue to advance a robust pipeline of gene therapies and expect to present data from all of our clinical programs over the next 12 months.

謝謝你的更新，克里斯蒂安。正如您今天所聽到的，我們相信 2025 年將是 uniQure 的變革之年。我們將繼續推進強大的基因療法研發線，並預計在未來 12 個月內提供所有臨床項目的數據。

We look forward to continuing our productive engagement with the FDA on AMT-130 and expect to update you on our recent interactions, including the expected timing of a BLA submission later this quarter once we receive formal meeting minutes. In addition, we expect to share new data in the third quarter from our ongoing Phase 1/2 study to further support the planned BLA submission.

我們期待繼續與 FDA 就 AMT-130 進行富有成效的合作，並希望向您通報我們最近的互動情況，包括我們收到正式會議記錄後本季度晚些時候提交 BLA 的預計時間。此外，我們預計將在第三季分享我們正在進行的 1/2 期研究的新數據，以進一步支持計劃中的 BLA 提交。

We're extremely excited about the opportunities ahead of uniQure and remain focused on delivering innovative therapies that can improve the lives of the patients we serve. We look forward to keeping you updated on our continued progress.

我們對 uniQure 未來的機會感到非常興奮，並將繼續專注於提供能夠改善我們服務的患者生活的創新療法。我們期待向您通報我們持續取得的進展。

With that, we will open the call to take questions from our research analysts. Operator, please proceed.

接下來，我們將開始回答我們研究分析師的問題。接線員，請繼續。

(Operator Instructions)

（操作員指示）

Luca Issi, RBC.

盧卡·伊西（Luca Issi），RBC。

Thanks so much for taking my question and congrats on the progress. Maybe one for either Matt or Walid on the new CBER head, obviously, Ultragenyx is a company with a long history in rare disease, is on record saying that Dr. Prasad may not be the right guy for the job. I guess two questions. One, would you agree with Ultragenyx? And two, maybe bigger picture, how confident are you that all the productive conversations that you have had so far with CBER on Huntington will not be flipped upside down by the new leadership? Any comment there is much appreciated. Thank you.

非常感謝您回答我的問題，並祝賀您的進展。也許 Matt 或 Walid 可以出任新的 CBER 負責人，顯然，Ultragenyx 是一家在罕見疾病領域有著悠久歷史的公司，有記錄顯示，Prasad 博士可能不是該職位的合適人選。我想問兩個問題。首先，您同意 Ultragenyx 的看法嗎？第二，也許從更大的角度來看，您有多大信心，您迄今為止與 CBER 就亨廷頓進行的所有富有成效的對話不會被新領導層顛覆？任何評論都非常感謝。謝謝。

Thanks, Luca. First, let me just state that, honestly, I very much look forward to working with Dr. Prasad and really do appreciate his public service. The reality is that no matter who's the director of CBER, we believe strongly in our data and we believe in the end that this is going to carry the day.

謝謝，盧卡。首先，我只想坦白地說，我非常期待與普拉薩德博士合作，並且非常欣賞他的公共服務。事實是，無論誰擔任 CBER 主任，我們都堅信我們的數據，並且我們相信最終這將取得勝利。

I also want to point out something really important in terms of the reliance on surrogate biomarkers, which has been something that I think has come up over the last couple of days, you have to keep in mind that this is not our approach with AMT-130. We're going to be seeking accelerated approval based on three-plus years of clinical outcomes and utilizing a clinical measure as a primary endpoint. So honestly, I believe that this is a key differentiator for AMT-130 and I remain really encouraged about our path forward.

我還想指出關於依賴替代生物標記的一些非常重要的事情，我認為這是過去幾天出現的事情，你必須記住，這不是我們對 AMT-130 的方法。我們將根據三年以上的臨床結果尋求加速批准，並以臨床測量作為主要終點。所以說實話，我相信這是 AMT-130 的關鍵區別因素，我對我們的前進道路仍然充滿信心。

Got it. Thanks so much.

知道了。非常感謝。

Debjit Chattopadhyay, Guggenheim.

查托帕迪亞 (Debjit Chattopadhyay)，古根漢。

Good morning. Thanks for indulging me on two questions. Number one, how confident are you on the three-year follow-up data on the cUHDRS and what would you consider as a good outcome? And I have a follow-up.

早安.感謝您回答我兩個問題。第一，您對 cUHDRS 的三年追蹤資料有多大信心，您認為什麼樣的結果才算好？我還有一個後續問題。

Walid, do you want to answer that one?

瓦利德，你想回答這個問題嗎？

Sure. As you know, we've been monitoring these patients for a long time. We have not been doing any additional analysis on the data. But it's very clear, what we submitted to the FDA included data two years from these patients, but we also have some other patients on the low dose that have been treated even much longer than that. We have no indication at all that we lose any of the efficacy over time. As a result, we believe that the dose-dependent reduction in cUHDRS that we observed at the two-year data will be maintained when we evaluate the three-year data. So we feel very confident about our results going forward.

當然。如您所知，我們長期監測這些患者。我們沒有對數據進行任何額外的分析。但很明顯，我們提交給 FDA 的數據包括這些患者兩年的數據，但我們也有一些其他低劑量患者的治療時間甚至比這更長。我們根本沒有跡象表明我們會隨著時間的推移而失去任何功效。因此，我們相信，當我們評估三年數據時，我們在兩年數據中觀察到的 cUHDRS 劑量依賴性減少將會維持。因此，我們對未來的業績充滿信心。

Got it. I appreciate that. And the last question, will the third quarter update include the propensity match scoring based on the agreed-upon SAP or will that analysis be withheld for the BLA submission only? Thank you and congrats.

知道了。我很感激。最後一個問題，第三季更新是否會包括基於商定的 SAP 的傾向配對評分，還是僅為了 BLA 提交而保留該分析？謝謝，恭喜。

Thank you. So the plan is to essentially agree with the FDA and finalize the statistical analysis plan before we lock the database and analyze the data. And at that point, we will be sharing the topline results of this data. As we have to be careful the degree to which we share from the data because the data would have been not yet reviewed by the FDA. But it will be the analysis that we would have agreed to with the FDA.

謝謝。因此，該計劃基本上是與 FDA 達成協議並在我們鎖定資料庫和分析數據之前最終確定統計分析計劃。屆時，我們將分享這些數據的最終結果。因為我們必須謹慎對待資料共享的程度，因為這些資料尚未經過 FDA 的審查。但這將是我們與 FDA 達成一致的分析。

Paul Matteis, Stifel.

保羅·馬泰斯（Paul Matteis），Stifel。

Hey. Good morning. Thanks for taking my questions. I appreciate it. As it relates to the SAP and the different sort of permutations there, I was wondering if you can kind of walk through your approach to this recent meeting, what are the different things you suggested? That's one. Two, Matt and Walid, we talked at a conference earlier this year as it relates to the pros and cons of three-year versus two-year natural history comparisons with survivorship bias and things like that. So maybe you can just kind of give us an update on where your head is at.

嘿。早安.感謝您回答我的問題。我很感激。由於它與 SAP 及其不同類型的排列有關，我想知道您是否可以介紹一下您對最近這次會議的態度，您建議了哪些不同的事情？那是一個。第二，馬特和瓦利德，我們在今年早些時候的一次會議上討論了三年與兩年自然歷史比較的利弊以及倖存者偏差等問題。所以也許您可以向我們介紹一下您目前的想法。

And then, just in terms of waiting for the meeting minutes, I understand that that's the best practice, but are you waiting for the minutes to make sure you fully understand how the meeting went down and that you want to clarify things? Or is this more good housekeeping to not get in front of the FDA? Thanks so much.

然後，就等待會議記錄而言，我知道這是最佳做法，但您是否在等待會議記錄以確保您完全了解會議的進展並想要澄清一些事情？或者這是更好的管理方式，可以避免引起 FDA 的注意？非常感謝。

I'll just answer the last one and then in terms of the approach to the meeting or two versus three years, I'll give that to Walid. This is good housekeeping. This is just an appropriate thing to do. Best practice is to make sure you have the complete written responses. So it's really that simple. And then on the approach to the meeting and two versus three years, Walid, why don't you address those?

我只回答最後一個問題，然後關於會議方式或兩年或三年的問題，我會把這個問題交給瓦利德。這是很好的家事管理。這只是一件適當的事。最佳做法是確保您擁有完整的書面答案。所以其實就是這麼簡單。然後關於會議的方式以及兩年與三年的問題，瓦利德，你為什麼不談談這些問題呢？

I mean, look, this has been an ongoing study. We have people who have been also treated for up to four years. The overwhelming majority of patients would have three-year data and the assessment is to look at the totality of the data. So we must look at the most relevant data sets and that's the three-year because that's where the majority of patients are. Of course, we will be looking at the two years, we will be providing the four-year data, but the primary analysis will be based on the three-year data. And the reason for this is that you'd want to be able to continue to see the promising effects that we've seen at two years and are continuing to be manifested at three years and beyond. And so we cannot just look at the earlier part and ignore where the majority of the data are. That's really simply what this is about.

我的意思是，看，這是一項持續的研究。我們還有一些人接受了長達四年的治療。絕大多數患者都有三年的數據，評估就是查看全部數據。因此，我們必須查看最相關的資料集，那就是三年的資料集，因為大多數患者都處於三年的資料集中。當然，我們會關注兩年，也會提供四年的數據，但主要分析將基於三年的數據。這樣做的原因是，您希望能夠繼續看到我們在兩年內看到的良好效果，並在三年及以後繼續顯現。因此，我們不能只看前面的部分而忽略大部分資料在哪裡。這確實就是這件事的簡單內容。

Patrick Trucchio, H.C. Wainwright.

派崔克‧特魯基奧、H.C. 溫賴特。

Good morning. Just a clarification on now that you've held the Type B meetings on both CMC and the SAP for AMT-130, would you anticipate any additional regulatory interactions ahead of the BLA filing? And then separately, regarding the Cohort 3 update, I'm wondering if you can elaborate on the three immunosuppression-related SAEs reported in Cohort 3. And what changes, if any, were made to the protocols or perioperative management?

早安.現在您已經就 AMT-130 的 CMC 和 SAP 舉行了 B 類會議，請澄清一下，您是否預計在提交 BLA 申請之前還會有任何其他監管互動？然後，另外，關於第 3 組更新，我想知道您是否可以詳細說明第 3 組報告的三種與免疫抑制相關的 SAE。如果有的話，對方案或圍手術期管理做了哪些改變？

I'll address maybe the first question. We'll talk about the path forward when we provide a regulatory update. But I think as we stated in the prepared remarks, we've had very constructive interactions with the FDA. We've previously gotten very clear feedback. We obviously look forward to providing the regulatory update and we feel very encouraged about our path forward. Walid, do you want to address the Cohort 3?

我先回答第一個問題。當我們提供監管更新時，我們會討論未來的道路。但我認為，正如我們在準備好的發言中所述，我們與 FDA 進行了非常建設性的互動。我們之前已經得到了非常明確的回饋。我們顯然期待提供監管更新，並且我們對我們的前進道路感到非常鼓舞。瓦利德，你想向第 3 組發表演說嗎？

Yeah, sure. So maybe I can take a step back a little bit and kind of summarize why we did this. Starting with this, we believe that the AMT-130 is generally safe and well-tolerated based on our experience in Cohorts 1 and 2. In that context, there was no perioperative immunosuppression. And what we saw, there was some edema and CNS inflammation from the infusion, particularly at the high dose which manifested within several days of the procedure. But all of these serious adverse events resolved with either supportive therapy in two out of those four cases, and the other two resolved after a short course of steroid therapy.

是的，當然。所以也許我可以稍微退一步，總結一下我們為什麼要這樣做。從此開始，根據我們在第 1 組和第 2 組的經驗，我們相信 AMT-130 通常是安全且耐受性良好的。在這種情況下，沒有圍手術期免疫抑制。我們看到，輸液導致了一些水腫和中樞神經系統炎症，特別是在高劑量時，這在手術後的幾天內就顯現出來。但在這四例中，有兩例的嚴重不良事件透過支持療法得到解決，另外兩例在短期類固醇療法後得到解決。

Now in Cohort 3, we set out to evaluate the effects of a triple regimen, as I said, including steroids, rituximab and sirolimus. And we have not observed any drug-related adverse events attributable to AMT-130. We have observed three of those adverse events related to immunosuppression. Mania, which is a well-known adverse event of prolonged corticosteroid therapy; and infection and fever, which probably are related to the triple regimen of immunosuppression. And all of these events fully resolved with standard of care interventions.

現在在第 3 組中，我們開始評估三重療法的效果，正如我所說，包括類固醇、利妥昔單抗和雷帕黴素。我們還沒有觀察到任何與 AMT-130 有關的藥物不良事件。我們觀察到三起與免疫抑制有關的不良事件。躁症是長期皮質類固醇治療的眾所周知的不良事件；感染和發燒可能與三重免疫抑制方案有關。所有這些事件都透過標準護理幹預得到了完全解決。

So overall, we have, to some degree, answered our question. We believe we have a good outcome here. We think the optimal way going forward is most likely going to be a short two-week course of corticosteroids that would be given perioperatively with AMT-130. We will be double checking these and discussing with our external advisors. But if you ask me today my opinion, that would be my advice going forward.

總的來說，我們在某種程度上回答了我們的問題。我們相信我們會有一個好的結果。我們認為，最佳的治療方式很可能是在手術期間使用 AMT-130 進行為期兩週的短期皮質類固醇療程。我們將仔細檢查這些並與我們的外部顧問討論。但如果你今天問我的意見，那將是我今後的建議。

Terrific. Thanks so much.

了不起。非常感謝。

Joseph Schwartz, Leerink Partners.

Leerink Partners 的 Joseph Schwartz。

Hi. This is Jenny, on for Joe. Thank you for taking our questions. Just another one on Prasad. We've heard some strong and somewhat contradictory opinions about patient advocacy groups from him. We've heard him say that the patient voice is probably the most important one at the table. But then we've also heard him express concerns about these groups that take funding from pharmaceutical companies, especially if they've been vocal about lowering regulatory standards for approval.

你好。我是珍妮，代表喬發言。感謝您回答我們的問題。這只是關於普拉薩德的另一個。我們從他那裡聽到了一些關於病人權益團體的強烈且有些矛盾的觀點。我們聽他說過，病人的聲音可能是餐桌上最重要的聲音。但我們也聽到他對這些接受製藥公司資助的團體表示擔憂，特別是如果他們一直大聲疾呼降低審批監管標準。

In Huntington's, we're aware of the Huntington's Disease Society of America. What kind of relationship do you have with them? If they've interacted with the FDA. And also, would just love to hear your thoughts about the HD community in general since we know at least some of them were kind of hesitant about expediting development after (inaudible) plan. Thank you.

在亨廷頓舞蹈症方面，我們知道美國亨廷頓舞蹈症協會。你和他們是什麼樣的關係？如果他們與 FDA 有互動。此外，我們也想聽聽您對 HD 社群的整體看法，因為我們知道至少有些人對於在（聽不清楚）計畫之後加快發展有些猶豫。謝謝。

Walid, do you want to address that?

瓦利德，你想解決這個問題嗎？

Sure. Thanks, Matt. We've been having very long history working with CHDI and a number of other patient advocacy organization working in Huntington's disease. Honestly, we will not be here today, not other ones in the field, if there was no deep commitment from the patients, from the patient advocates, and also from all the experts to generate these very elaborate and very sophisticated natural history that really gave us the understanding of the course of the disease, regardless of the stage of Huntington's disease so that we can truly compare our trials to that. So without them, honestly, we will not be here today.

當然。謝謝，馬特。我們與 CHDI 以及其他一些致力於亨廷頓舞蹈症的患者權益組織有著長期的合作。說實話，如果沒有患者、患者權益倡導者以及所有專家的堅定承諾，我們今天就不會站在這裡，這個領域的其他人也不會站在這裡，沒有這些非常精細和復雜的自然史，真正讓我們了解疾病的進程，無論亨廷頓舞蹈症處於哪個階段，以便我們能夠真正地將我們的試驗與之進行比較。所以說實話，如果沒有他們，我們今天就不會在這裡。

These (inaudible) organization, I find them to be extremely balanced. They work with all organizations, they work with regulators, they work with various pharma and biotech company, and they make their data available to be used in a scientifically valid manner. I have never seen them favor one group versus the other. I think they're really well-respected. And actually last year, in the late October or early November time frame, there was a very important meeting that was held by the FDA that invited the patient organizations and heard from a number of them. I think that speaks to the respect that they have for them and the really equitable balance in the way they conduct themselves. So I really feel very fortunate that we have that relationship with them. I don't feel them to be biased at all. And honestly, without them, we would not be here today, not us and not other companies that you've seen recently who have used the natural history data.

我發現這些（聽不清楚）組織非常平衡。他們與所有組織合作，與監管機構合作，與各種製藥和生物技術公司合作，並以科學有效的方式提供數據以供使用。我從未見過他們偏袒某一群體而反對另一群體。我認為他們確實很受尊重。實際上，去年 10 月底或 11 月初，FDA 召開了一次非常重要的會議，邀請了患者組織並聽取了其中一些組織的意見。我認為這體現了人們對他們的尊重以及他們行為方式的真正公平平衡。所以我真的感到非常幸運我們能與他們建立這樣的關係。我根本不覺得他們有偏見。老實說，沒有他們，我們今天就不會在這裡，我們不會，您最近看到的其他使用自然歷史數據的公司也不會在這裡。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Hi. This is Lydia, on for Salveen. And thanks so much for taking our questions and congrats on all the progress. Maybe just on the third cohort of AMT-130, do you plan to include these data in the potential BLA filing, even though I think you've noted you don't believe they'll be necessary for the filing? Thanks so much.

你好。我是 Lydia，代表 Salveen。非常感謝您回答我們的問題，並祝賀我們取得的所有進展。也許只是在 AMT-130 的第三批中，您是否計劃將這些資料納入潛在的 BLA 文件中，即使我認為您已經指出您認為它們對於文件來說不是必需的？非常感謝。

Thank you. Matt, I assume I'm responding to this, so I'm going to go. Thank you for this question. Yes, of course, at the time we're submitting to BLA all data from all the patients that we have for as long as we have them as of the cutoff will be included in the data. So as such, the 12 patients, of course, will be part of the totality of the data for the FDA to review.

謝謝。馬特，我想我正在回應這個問題，所以我要走了。感謝您的提問。是的，當然，當我們向 BLA 提交資料時，我們擁有的所有患者的所有資料（只要我們在截止日期之前擁有這些資料）都將包含在資料中。因此，這 12 名患者當然將成為 FDA 審查的全部數據的一部分。

Thanks so much.

非常感謝。

Joseph Thome, TD Cowen.

約瑟夫·托米（Joseph Thome），考恩（Cowen）TD。

Good morning. Thank you for taking my question and congrats on the progress. Just to clarify, what's the latest data set that the FDA has seen in terms of a data cut versus what's been publicly released? And have they seen any of that Cohort 3 data with the updated immunosuppression regimen? And maybe just to be clear, the two-week immunosuppression with steroid that you're suggesting, is this identical to what the initial patients received in the study?

早安.感謝您回答我的問題，並祝賀您的進展。只是為了澄清一下，就資料剪輯而言，FDA 看到的最新資料集與公開發布的資料集相比是什麼？他們是否看到了更新的免疫抑制方案的第 3 組數據？也許只是為了澄清一下，您建議的兩週類固醇免疫抑制治療是否與研究中最初的患者接受的治療相同？

I'll take those two as well. So the data set that we shared with you back in July of 2024 last year included 21 patients who had crossed the two-year time point that was based on a data cut of March of 2024. When we met the with the FDA in November, that is the most recent data that we shared with them, which was based on the June of last year cut, which included three more patients at the high dose. So in total, they saw data from 24 patients at two years, 12 at the high dose, and 12 at the low dose. There has been no additional data shared with them since then, since our meetings with them, regarding SAP and the Natural History Protocol and CMC were about those specific topics without any review of data. So they did not see any additional data. They did not see any data from Cohort 3.

我也會選擇那兩個。因此，我們去年 2024 年 7 月與您分享的資料集包括 21 名已跨越兩年時間點的患者，該時間點基於 2024 年 3 月的數據截止。當我們在 11 月與 FDA 會面時，這是我們與他們分享的最新數據，該數據基於去年 6 月的削減，其中包括另外三名高劑量患者。因此，總的來說，他們觀察了 24 名患者兩年內的數據，其中 12 名患者接受高劑量治療，12 名患者接受低劑量治療。從那時起就沒有與他們分享過任何額外的數據，因為我們與他們就 SAP 和自然歷史協議和 CMC 進行的會議都是關於這些特定主題的，而沒有審查任何數據。所以他們沒有看到任何額外的數據。他們沒有看到來自第 3 組的任何數據。

Regarding the two-week steroids, so for first Cohorts 1 and 2, there were no systematic perio-operative immunosuppression given, including steroids. So this will be the first time that we would be using this regimen. The reason why we're choosing it is because two weeks of steroids is very commonly used in neurosurgical procedures. Two weeks of steroid therapy is also the adverse event profile of that immunosuppression. It's well-understood and considered to be very low. So that's why we're choosing it going forward.

關於兩週的類固醇，因此對於第一批 1 和 2，沒有給予系統的圍手術期免疫抑制，包括類固醇。這是我們第一次使用這種療法。我們之所以選擇它，是因為兩週的類固醇在神經外科手術中非常常用。兩週的類固醇治療也是免疫抑制的不良事件特徵。它很容易理解，並且被認為非常低。這就是我們繼續選擇它的原因。

Great. Thank you.

偉大的。謝謝。

Eliana Merle, UBS.

瑞銀的 Eliana Merle。

Hey guys. Thanks for taking the question. I'm just curious if you can update us on the latest in terms of the CMC work and specifically, how long you think the CMC requirements will take in order to complete, in order to be ready for filing? Since I think in the past, you've said the timing of the filing would be more driven by when you'd be able to complete the CMC requirements. And then just a second question just in terms of the selection of the natural history comparator and the composition of that, I guess, after you met with the FDA and discussed the (inaudible) plan, how confident are you that the natural history will look similar to the natural history that you've used before and when you presented the data? So just in terms of the composition of that. Thanks.

嘿，大家好。感謝您回答這個問題。我只是好奇您是否可以向我們介紹 CMC 工作方面的最新情況，具體來說，您認為完成 CMC 要求並準備好提交文件需要多長時間？因為我認為在過去，您曾說過提交申請的時間更多地取決於您何時能夠完成 CMC 要求。然後第二個問題是關於自然歷史比較器的選擇及其組成，我想，在您與 FDA 會面並討論了（聽不清）計劃之後，您有多大信心自然歷史看起來與您之前使用過的自然歷史以及您呈現的數據相似？僅就其組成而言。謝謝。

I'm going to be answering both questions. This is Walid again. So on the CMC, there are a series of well- agreed and thought through plans for this. We will be sharing with you the overall timeline for BLA submission when we provide the regulatory update at the end of the year. All of this is not new to us. As we've said before, we're leveraging the significant experience we have with HEMGENIX. We're manufacturing AMT-130 in the same place by generally the same people. And a lot of this has been leveraged and in discussing with the FDA. So we'll provide more granular information on this when we provide the regulatory update by the end of this -- in the second quarter.

我將回答這兩個問題。我又是瓦利德。因此，中央軍委對此制定了一系列經過深思熟慮和商定的計劃。當我們在年底提供監管更新時，我們將與您分享 BLA 提交的整體時間表。這一切對我們來說都不是新鮮事。正如我們之前所說，我們正在利用與 HEMGENIX 合作所獲得的豐富經驗。我們基本上由同一批人在同一個地方生產 AMT-130。其中許多內容已經被利用並與 FDA 進行了討論。因此，當我們在第二季末提供監管更新時，我們將提供更詳細的資訊。

On the selection of natural history, I think, we've discussed that we're evaluating a number of natural histories. We've had that discussion with the FDA. We will be updating you again as part of that regulatory update as to where we landed on this. I do not anticipate for this to have any significant difference on what we have been reporting so far or at least last time we reported it to you back in July of last year. So I think we're still going in the same direction. I don't expect any difference in the outcome.

關於自然歷史的選擇，我想，我們已經討論過我們正在評估許多自然歷史。我們已經與 FDA 討論過這個問題。作為監管更新的一部分，我們將再次向您通報我們對此的進展。我預計這與我們迄今為止的報告或至少我們去年 7 月向您報告的內容不會有任何重大差異。所以我認為我們仍然朝著同一個方向前進。我並不期望結果會有什麼不同。

Thanks.

謝謝。

Uy Ear, Mizuho.

尤伊·厄爾，瑞穗。

Hi. A couple of questions from us. Between the CMC meeting and your recent meeting with the FDA, were there any changes in the key personnel? And secondly, given the new CBER director, I know it's early, are you thinking -- have your thoughts on developing your current pipeline changed in any way? And just wanted to make sure, so it's the three-year data that will be used for AMT-130 filing, is that right? Thanks.

你好。我們有幾個問題。在 CMC 會議和您最近與 FDA 的會議之間，關鍵人員有沒有什麼變化？其次，考慮到新的 CBER 主任，我知道現在還為時過早，您是否想過——您對開發當前管道的想法是否有所改變？只是想確認一下，所以這是 AMT-130 申報的三年數據，對嗎？謝謝。

Okay. Very good. Matt, are you back on?

好的。非常好。馬特，你回來了嗎？

I think we're back. I think you've asked a few questions here. The first one was around the CMC and the personnel that we've interacted with at the FDA. We've had no material impact on anybody that is part of the review team that we obviously can see. There's some public record of people that have resigned. There's been at least 30 people that have been involved in our various interactions and there's been no material changes that we're aware of.

我想我們回來了。我想您在這裡問了幾個問題。第一個是關於 CMC 以及我們在 FDA 接觸過的人員。我們顯然沒有對審查團隊的任何人產生實質影響。有一些關於辭職人員的公開記錄。至少有 30 人參與了我們的各種互動，但據我們所知，沒有任何重大變化。

Just in terms of your second question about the other pipeline programs, we continue to be very encouraged about the programs that we have. We're going to be generating data across those programs over the course of the next 6 to 12 months, and we're very excited to do that. And obviously, we're hoping that we're able to determine a path forward and to establish a clinical proof of concept.

就您關於其他管道項目的第二個問題而言，我們對現有的項目仍然感到非常鼓舞。我們將在未來 6 到 12 個月內透過這些程式產生數據，我們對此感到非常高興。顯然，我們希望能夠找到前進的道路並建立臨床概念驗證。

And then just in terms of the two- to three-year data, I think as Walid mentioned, we'll obviously provide a more detailed update when we provide our regulatory update. I think what Walid is pointing out is that in the third quarter, we're going to have 27 patients at two years and 24 patients at three years. So no matter what we look at, it's going to be very important that the totality of the data continue to reflect the trends that we continue to see both at two years and three years.

然後就兩到三年的數據而言，我認為正如 Walid 所提到的，我們在提供監管更新時顯然會提供更詳細的更新。我認為 Walid 指出的是，在第三季度，我們將有 27 名兩年期患者和 24 名三年患者。因此，無論我們看什麼，重要的是整體數據能夠繼續反映我們在兩年和三年內持續看到的趨勢。

Thank you.

謝謝。

Suzanne van Voorthuizen, VLK.

蘇珊娜·範·沃特胡森（Suzanne van Voorthuizen），VLK。

Hi team. This is Suzanne from Kempen. Thanks for taking my questions. I know the focus is very much on the data and the BLA, but can you elaborate a bit on your preliminary thinking on the commercial plans and the rollout, the focus on centers, what you consider key target groups, et cetera? And secondly, can you share your current thinking on a potential filing in Europe and/or thoughts on the partnership ex-U.S.? Thank you.

大家好。我是來自肯彭的蘇珊娜。感謝您回答我的問題。我知道重點是數據和 BLA，但您能否詳細說明您對商業計劃和推廣的初步想法、中心重點、您認為的關鍵目標群體等等？其次，您能否分享一下您目前對在歐洲提交申請的想法和/或對美國以外合作關係的想法？謝謝。

Okay. So we will talk in more detail going forward about the commercial strategy. What I can tell you is, we're very excited about the potential here in Huntington's. Obviously, there's no disease-modifying treatments that are available for these patients. And we believe that being able to demonstrate meaningful slowing of disease progression would be a transformational leap forward for this community.

好的。因此，我們將更詳細地討論商業策略。我可以告訴你的是，我們對亨廷頓的潛力感到非常興奮。顯然，目前還沒有針對這些患者的疾病改良治療方法。我們相信，能夠證明疾病進展已有效減緩將為這個社區帶來變革性的飛躍。

Just in terms of prevalence, it's probably one of the largest genetically-defined diseases. And we honestly believe that we have a very good shot at being not only first to market, but best-in-class, so we're really excited about that. We're right now focused on regulatory interactions with the United States. And now that we've established an accelerated path forward, we'll be engaging with regulators in Europe, and we'll talk more about that.

僅從盛行率來看，它可能是最大的基因疾病之一。我們真誠地相信，我們不僅有機會率先進入市場，而且有機會成為同類產品中最好的，所以我們對此感到非常興奮。我們現在專注於與美國的監管互動。現在我們已經確定了一條加速前進的道路，我們將與歐洲的監管機構合作，並就此進行更多討論。

We are preparing for commercialization. As I said, we're very excited about this opportunity. No doubt, strategics are excited about this opportunity as well. This is a needle-moving area for both large biotechs and large pharma companies. So there's certainly a lot of strategic interest in Huntington's. And in the end, we're always going to do what's in the best interest of our shareholders.

我們正在為商業化做準備。正如我所說，我們對這個機會感到非常興奮。毫無疑問，戰略家們也對這個機會感到興奮。對於大型生物技術公司和大型製藥公司來說，這是一個具有重大意義的領域。因此，亨廷頓肯定有很多戰略利益。最終，我們總是會做最符合股東利益的事。

Sami Corwin, William Blair.

薩米·科溫、威廉·布萊爾。

Hey there. Thanks for taking my questions and congrats on the progress. I guess as you kind of think about the longer term strategy for AMT-130, how are you thinking about potentially evaluating it in patients with earlier stage or later stage disease? And then I was also curious if you could give us, provide any color, I guess, on the number of physicians in the U.S. who would be capable of performing the administration necessary for AMT-130. Thank you.

嘿。感謝您回答我的問題，並祝賀您的進展。我想，當您考慮 AMT-130 的長期策略時，您會如何考慮對早期或晚期疾病患者進行潛在評估？然後我還想知道您是否可以告訴我們，美國有多少醫生能夠執行 AMT-130 所需的管理。謝謝。

Walid, do you want to answer that?

瓦利德，你想回答這個問題嗎？

So right now, as you know, in this first trial, we evaluated patients who are early manifest because we believe that this is the best chance to maximize the functions, to preserve as much functions as possible, but also at the same time, that we will need to have enough time to evaluate them to see whether there is an impact on the course of the disease. If you take people much earlier, pre-symptomatic stage, then it's going to take you much, much longer to be able to show evidence of stopping or slowing disease progression.

因此，如您所知，現在在第一次試驗中，我們對早期出現症狀的患者進行了評估，因為我們相信這是最大限度地發揮功能、盡可能保留功能的最佳機會，但同時，我們需要有足夠的時間來評估他們，看看是否會對疾病的進程產生影響。如果在症狀出現之前的早期階段就對患者進行治療，那麼需要更長的時間才能顯示出阻止或減緩病情進展的證據。

As we now move forward with this, of course, there will be great interest to try and figure out whether you can intervene earlier or later. And those are really early stages right now that we need to be discussing those with the regulators to see what would be the best path going forward. There's no good reason to believe that you should be excluding patients depending on the stage of the disease. At the same time, we need to be able to generate data to convince us that actually those people are set to benefit from it.

當然，隨著我們繼續推進這項工作，人們會非常感興趣地嘗試弄清楚是否可以提前或推遲進行幹預。目前這些還處於早期階段，我們需要與監管機構進行討論，以了解未來的最佳發展方向。沒有充分的理由相信你應該根據疾病的階段排除患者。同時，我們需要能夠產生數據來讓我們相信這些人確實會從中受益。

I know I'm not giving you a real answer, but this is really early days in our thinking about it, and we need to engage with the regulators to have a much better idea about how we would be approaching for both patients, those who are earlier and pre-symptomatic, and what would be the end point in that case and how long we should treat them, and those who are maybe further advanced. There, I would imagine, the limitation would be about being able to reach the deep structures of the brain where we need to inject our therapy in a safe manner. In other words, if there's not significant atrophy that happened such that it will be a bit unsafe to be able to get there. But that usually is a discussion that the neurosurgeon will be able to have. So I know it's not a very clean answer to your question, but this is our thinking as of today. Was there something else? I'm sorry, I might have missed another piece of your question.

我知道我沒有給你一個真正的答案，但我們對此的思考還處於早期階段，我們需要與監管機構合作，以便更好地了解我們將如何對待這兩種患者，即早期和症狀出現前的患者，以及這種情況下最終的治療結果是什麼，我們應該治療多長時間，以及那些可能病情更嚴重的患者。我想，限制在於能否以安全的方式到達我們需要注入治療的大腦深層結構。換句話說，如果沒有發生嚴重的萎縮，那麼到達那裡就會有點不安全。但這通常是神經外科醫師能夠進行的討論。所以我知道這不是對你的問題的一個非常明確的答案，但這是我們今天的想法。還有別的事嗎？抱歉，我可能忽略了您問題的另一部分。

Yes. How many physicians in the U.S. could be capable of performing the administration procedure?

是的。美國有多少醫生能夠執行該給藥程序？

Right. So when we looked at this, there are upward of 50 sites who can do this. And really, this is not a very complicated procedure. I mean, this is something that's been used right now for administering chemotherapy, using sort of essentially a guided administration intraparenchymally in the brain using a frame. This is used commonly by neurosurgeon. It's not very complicated. So essentially, in our case, we need to have centers that essentially can do that but also will have access to an MRI because, as you know, we do this to maximize the chances that we don't cut corners, this is one and done, so we need to make sure that whoever is getting that therapy is getting the most out of it. So we're not navigating blind. We'll do it under MRI guided. We look exactly where we're injecting. And the neurosurgeon can adjust the course and make sure that these structures are appropriately filled. So those are really the two conditions. But when we look, there's plenty of centers in the U.S. I said more than 50 that can do it. And yeah, I think that's my answer to your question.

正確的。因此，當我們查看這一點時，發現有超過 50 個網站可以做到這一點。事實上，這並不是一個非常複雜的過程。我的意思是，這是目前用於實施化療的方法，本質上是使用框架在腦實質內進行引導給藥。這是神經外科醫師常用的方法。這不是很複雜。因此，從本質上講，就我們的情況而言，我們需要有能夠做到這一點的中心，但同時也要有 MRI 的使用權，因為如你所知，我們這樣做是為了最大限度地不偷工減料，這是一次性的，所以我們需要確保接受這種治療的人都能從中獲得最大的益處。所以我們並不是盲目航行。我們將在 MRI 引導下進行。我們仔細觀察注射的位置。神經外科醫生可以調整過程並確保這些結構得到適當填充。所以這確實是兩個條件。但當我們觀察時，會發現美國有很多中心，我說超過 50 個可以做到這一點。是的，我想這就是我對你的問題的回答。

Sounds good. Thanks.

聽起來不錯。謝謝。

Yanan Zhu, Wells Fargo.

朱亞南，富國銀行。

Great. Thanks for taking our questions and for the very helpful call. So maybe a couple of follow-up questions on topics already discussed on the length of follow-up for the data in the following package and also the control arm. On the length of follow up, I think, based on what I heard, it's maybe a discussion between two- or three-year, that might be the range. I just wanted to ask -- could you confirm this is not going to be even longer follow-up than a three-year follow-up for the filing?

偉大的。感謝您回答我們的問題並打來非常有幫助的電話。因此，也許針對已經討論過的主題，還有關於後續包中資料的追蹤長度以及對照組的幾個後續問題。關於後續跟進的時間長度，我認為，根據我所聽到的，可能需要討論兩年或三年，這可能是一個範圍。我只是想問一下——您能否確認這不會是比三年的跟進時間更長的跟進時間？

And on the external control, sounds like there shouldn't be much surprise, compared with what you have been thinking or what you have reported. But just wanted to confirm that in terms of the natural history study that you are looking forward to using, it is the same track HD in that study and not a different study like enroll HD or perhaps it doesn't matter. Please help with those questions. Thanks.

至於外部控制，與您所想的或所報告的相比，聽起來應該不會有太多令人驚訝的事情。但只是想確認一下，就您期待使用的自然歷史研究而言，它是該研究中的相同軌道 HD，而不是像註冊 HD 這樣的不同研究，或者也許這並不重要。請幫忙解答這些問題。謝謝。

Sure. On the first question, we have already discussed this last November with the FDA and agreed that the data cutoff of end of June of this year, 2025, will be the data cutoff and that we will use the totality of the data to support a BLA submission. At that time, we will have, as Matt said, 27 patients with two years of follow-up, 24 patients with three-year follow-up, 8 patients with four years, and actually, 1 patient with five years. But the totality of the data will be received. The primary analysis will be done on the three-year data because that's where the majority of the patients that is going to generate meaningful understanding of the rate of progression of the disease.

當然。關於第一個問題，我們去年 11 月已經與 FDA 討論過這個問題，並同意將今年 6 月底（2025 年）的數據截止日期作為數據截止日期，我們將使用全部數據來支持 BLA 提交。屆時，正如馬特所說，我們將有 27 名患者進行兩年的隨訪，24 名患者進行三年的隨訪，8 名患者進行四年的隨訪，實際上還有 1 名患者進行五年的隨訪。但全部資料都會被接收。主要分析將針對三年的數據進行，因為這是大多數患者的數據，將對疾病進展速度產生有意義的了解。

Regarding external control. Also, we communicated that last time when we met with the FDA, we were asked to evaluate systematically all the available natural history protocols and Enroll HD is one of the largest ones. Track and Predict-HD, we've used previously because they control the steroidal volume. But now, we've gone through this and systematically evaluated this. We've had discussions with the FDA and agreed on the one that we will be using as a primary. This will be part of our feedback to you when we provide the regulatory feedback. Again, I think you also answered the question in the question itself, which says it doesn't matter. Honestly, I don't think it does matter that much between those, the results between Enroll, Track, and Predict in terms of the course of the disease provided that you do the appropriate matching to your patient population generates virtually the same rate of decline that you see.

關於外部控制。此外，我們上次與 FDA 會面時，被要求系統地評估所有可用的自然歷史協議，而 Enroll HD 是其中最大的協議之一。我們以前使用過 Track and Predict-HD，因為它們可以控制類固醇的體積。但現在，我們已經經歷了這一切，並對此進行了系統性的評估。我們已經與 FDA 進行了討論，並就我們將使用的主要藥物達成了一致。這將是我們在提供監管回饋時向您回饋的一部分。再說一次，我認為你也在問題本身中回答了這個問題，那就是這並不重要。老實說，我認為它們之間並沒有太大關係，只要您對患者群體進行適當的匹配，登記、追蹤和預測之間的結果在疾病進程方面就會產生幾乎相同的下降率。

Incidentally, if I may, you have seen probably recently data from PTC where they've used external control, compared it to a natural history. In that case, it was Enroll-HD. They looked at the rate of decline in cUHDRS after two years and it came out at 1.1. If you recall, that's very close to the data that we shared with you last year in July where we use Track and Predict and we came out to virtually the same number. So that should give you and us confidence that in general, if you do the appropriate matching of your patient population, you're going to end up in the same place after two years or in our case, three years.

順便說一句，如果可以的話，您可能最近看到了 PTC 的數據，他們使用了外部控制，並將其與自然歷史進行了比較。在這種情況下，它是 Enroll-HD。他們觀察了兩年後cUHDRS的下降率，結果顯示為1.1。如果你還記得的話，這與我們去年7月分享的數據非常接近，當時我們使用了追蹤和預測系統，得出的數字幾乎相同。因此，這應該會讓您和我們有信心，一般來說，如果您對患者群體進行適當匹配，那麼兩年後，或者在我們的情況下，三年後，您將回到同一個地方。

Yes, indeed, that is what we saw. So thank you for clarifying all of that. Maybe as a quick follow-up, would the team care to share your view on PTC's data and their drug as a potential competitive consideration? Thanks.

是的，確實如此，我們看到的就是這樣。感謝您澄清這一切。也許作為快速的後續行動，團隊是否願意分享您對 PTC 數據及其藥物的看法，作為潛在的競爭考慮？謝謝。

Well, perhaps Matt can speak about the competitive piece of it. From a scientific point of view, I do not think it's appropriate for us to comment on a competitor's data, especially when we don't see the full data set, it's not in a scientific presentation, or a peer-reviewed publication. It's very difficult to do that and I don't think it's appropriate for us to comment on that. Turn it over to you, Matt.

好吧，也許馬特可以談談其中的競爭部分。從科學的角度來看，我認為我們不適合評論競爭對手的數據，特別是當我們沒有看到完整的數據集，它不在科學報告中，也不是同行評審的出版物中。要做到這一點非常困難，我認為我們不宜對此發表評論。交給你吧，馬特。

I mean, I would just focus on our data. I think our data that we presented last year showed an approximately 80% slowing of disease progression based on the composite UHDRS. We're very comfortable with the bioavailability of our drug, because we can see real time the filling of the structures when it's administered. And we're also very comfortable with our our target, right, which not only suppresses the full length mutant huntingtin protein, but also the short highly toxic exon 1 fragment which certainly provides differentiation. So we're focused on our data. Really encouraged by it. And also believes that our administration and our target makes us potentially best-in-class.

我的意思是，我只會關注我們的數據。我認為我們去年提供的數據顯示，根據綜合 UHDRS，疾病進展減緩了約 80%。我們對我們的藥物的生物利用度非常滿意，因為我們可以即時看到藥物給藥時結構的填充情況。我們對我們的目標也很滿意，對吧，它不僅可以抑制全長突變亨廷頓蛋白，還可以抑制短的高毒性外顯子 1 片段，這無疑提供了分化。所以我們專注於我們的數據。確實受到了鼓舞。並且相信我們的管理和目標使我們有可能成為一流的。

Got it. Thanks. And congrats on the progress.

知道了。謝謝。並祝賀你的進展。

(Operator Instructions)

（操作員指示）

Debjit Chattopadhyay, Guggenheim.

查托帕迪亞 (Debjit Chattopadhyay)，古根漢。

Hey. Thanks for letting me back in again. Just another follow-up for me. Has there been a discussion on what a future confirmatory study could look like? Or would you not need one since cUHDRS is not a surrogate endpoint?

嘿。謝謝你再次讓我回來。對我來說這只是另一個後續行動。是否討論過未來的驗證性研究會是什麼樣子？還是你不需要它，因為 cUHDRS 不是替代終點？

We have discussed with the FDA back in November last year. And actually at the time, we had a proposal in place. The FDA said, we're not prepared to discuss what would the confirmatory study would look like until we have a chance to review the data that you submit to us as part of the BLA submission that we agreed to with them. So at this point, the agency is not ready to discuss this. Our interpretation is that it can be as optimistic as maybe more longer term data from this study, maybe looking at total functional capacity data from our study at a longer time point, maybe adding another core to our study or a completely new independent study, but it would not be placebo-controlled, in our opinion.

我們早在去年 11 月就與 FDA 進行討論。事實上，當時我們已經有一個提案了。FDA 表示，在我們有機會審查您作為我們與他們達成一致的 BLA 提交的一部分提交給我們的數據之前，我們還沒有準備好討論確認性研究會是什麼樣子。因此目前該機構還沒有準備好討論此事。我們的解釋是，它可以像這項研究一樣樂觀，也許可以從這項研究中獲得更多長期數據，也許可以從我們的研究中查看更長時間點的總體功能能力數據，也許在我們的研究中添加另一個核心或進行一項全新的獨立研究，但在我們看來，它不會受到安慰劑對照。

But again, to some degree, this is speculation on our part because the agency did not want to discuss that. What we know for sure is that this will not be -- or it's not expected based on what the agency has told us so far to have to be completed and done and about to start or halfway conducted before we can file for BLA for accelerated approval. So we don't think it's going to slow us down at all. And that was clear from our interaction with the FDA.

但從某種程度上來說，這只是我們的猜測，因為該機構不想討論這個問題。我們可以肯定的是，這不會發生——或者根據該機構迄今為止告訴我們的情況，預計不會發生這種情況，我們必須在即將開始或進行到一半時才能申請 BLA 加速批准。因此我們認為這根本不會減慢我們的速度。從我們與 FDA 的互動中可以清楚看出這一點。

Thank you.

謝謝。

At this time, I'm not showing any more questions in the queue. I'll turn the call back to Matt Kapusta for closing remarks. Please go ahead.

目前，隊列中不再顯示任何問題。我將把電話轉回給馬特·卡普斯塔 (Matt Kapusta) 來做結束語。請繼續。

Thank you very much, operator. Really appreciate everybody dialing in to the call. We look forward to providing additional updates very shortly. Thank you so much.

非常感謝，接線生。非常感謝各位撥通電話。我們期待很快提供更多更新。太感謝了。

This does conclude today's conference call. Thank you all for joining. You may now disconnect.

今天的電話會議到此結束。感謝大家的加入。您現在可以斷開連線。