Uniqure NV (QURE) 2025 Q2 法說會逐字稿

Good day and thank you for standing by. Welcome to the Uniqure second-quarter 2025 earnings conference call. (Operator Instructions) Please be advised that today's conference is being recorded.

您好，感謝您的支持。歡迎參加 Uniqure 2025 年第二季財報電話會議。（操作員指示）請注意，今天的會議正在錄音。

I would now like to hand the conference over to your speaker today, Chiara Russo, Senior Director of Investor Relations. Please go ahead.

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。

Good morning and thank you for joining us for Uniqure second quarter of 2025 earnings call. Earlier this morning, Uniqure released its financial results for the second quarter of 2025. And our press release is available on the investors and media section of our website at uniqure.com. Our 10-Q was also filed with the SEC earlier this morning.

早安，感謝您參加 Uniqure 2025 年第二季財報電話會議。今天早些時候，Uniqure 發布了 2025 年第二季的財務表現。我們的新聞稿可在我們網站uniqure.com的投資者和媒體版中查看。我們的10-Q報表也已於今天早上提交給美國證券交易委員會（SEC）。

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

今天與我一起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。正式發言結束後，我們將開始問答環節。

Before we begin, please know that we will 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 beliefs and assumptions and on information available to management only as of the date of this conference call.

在我們開始之前，請注意，我們將在本次投資者電話會議中做出前瞻性陳述。除歷史事實陳述之外的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。

The 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. Given these risks, you should not place 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.

由於多種原因，包括但不限於 Uniqure 最近向美國證券交易委員會提交的文件中所述的因素，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。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 today's second quarter conference call. The first half of 2025 has been tremendously productive for the company as we advance AMT-130 towards potentially becoming the first disease modifying therapy for Huntington's disease.

謝謝，Chiara，大家早安。感謝您參加今天的第二季電話會議。2025 年上半年對公司來說是碩果累累的一年，因為我們推動 AMT-130 的發展，有望成為首個治療亨廷頓舞蹈症的疾病改良療法。

Our momentum is strong across four key areas: clinical advancement, regulatory alignment, BLA readiness, and commercial launch preparation. We also made advancements across our broader clinical pipeline, including AMT-191 for Fabry disease, AMT-260 for mesial temporal lobe epilepsy, and AMT-162 for SOD1 ALS. With pivotal topline data from AMT-130 and initial clinical data from AMT-191 in Fabry, both expected in September, we believe the second half of 2025 is shaping up to be an eventful period for Uniqure.

我們在四個關鍵領域發展勢頭強勁：臨床進展、監管協調、 BLA 準備和商業發布準備。我們也在更廣泛的臨床管線中取得了進展，包括用於治療法布瑞氏症的 AMT-191、用於治療內側顳葉癲癇的 AMT-260 和用於治療 SOD1 ALS 的 AMT-162。AMT-130 的關鍵頂線數據和 AMT-191 在法布瑞氏症的初步臨床數據預計將於 9 月公佈，我們相信 2025 年下半年將成為 Uniqure 的多事之秋。

Turning to AMT-130. In Q2, we continued to have productive interactions with the FDA, including receipt of breakthrough therapy designation in April and further regulatory alignment. AMT-130 remains the only investigational therapy in Huntington's disease to have either breakthrough therapy designation or regenerative medicine advanced therapy, or RMAT, designation granted by the FDA.

轉向 AMT-130。在第二季度，我們繼續與 FDA 進行富有成效的互動，包括 4 月獲得突破性療法認定以及進一步的監管協調。AMT-130 仍然是唯一獲得 FDA 授予的突破性療法認定或再生醫學先進療法（RMAT）認定的亨廷頓氏症研究療法。

In June, we achieved alignment with the FDA on both our statistical analysis plan and CMC requirements for planned BLA submission in the first quarter of 2026. Our primary efficacy analysis will compare the three-year change in cUHDRS in high-dose patients to a propensity score matched external control arm, using data from the Enroll-HD natural history study.

6 月，我們在統計分析計劃和 CMC 要求方面與 FDA 達成一致，計劃於 2026 年第一季提交 BLA。我們的主要療效分析將使用 Enroll-HD 自然史研究的數據，比較高劑量患者 cUHDRS 的三年變化與傾向評分匹配的外部對照組。

In addition, the FDA agreed that we can leverage our experience from HEMGENIX in validating the AMT-130 manufacturing process and that our process performance qualification can be limited to one such batch, supplemented by additional commercial scale GMP batches. Following FDA guidance, we've made significant progress in preparing for the planned BLA submission.

此外，FDA 同意我們可以利用 HEMGENIX 的經驗來驗證 AMT-130 製造工藝，並且我們的工藝性能鑑定可以僅限於一個這樣的批次，並輔以額外的商業規模 GMP 批次。根據 FDA 的指導，我們在準備計劃的 BLA 提交方面取得了重大進展。

Manufacturing of two scale, pre-PPQ GMP batches is now complete. And we've initiated our formal PPQ campaign. We also recently submitted our final statistical analysis plan to the FDA, which Walid will discuss in more detail shortly.

兩個規模、PPQ 前 GMP 批次的生產現已完成。我們已經啟動了正式的 PPQ 活動。我們最近也向 FDA 提交了最終的統計分析計劃，Walid 將很快對此進行更詳細的討論。

On the commercial planning front, we continue to make disciplined investments in preparation for a potential 2026 launch. In June, we appointed an experienced leader, Kylie Okeefe, as Chief Customer and Strategy Officer. And our HR team is actively recruiting key roles across medical affairs, market access, commercial operations, and other critical areas. The team is making strong progress on an integrated launch strategy, and we look forward to sharing more details in the future.

在商業規劃方面，我們繼續進行嚴謹的投資，為 2026 年的潛在推出做準備。6 月，我們任命了經驗豐富的領導者 Kylie Okeefe 擔任首席客戶和策略長。我們的人力資源團隊正在積極招募醫療事務、市場准入、商業營運和其他關鍵領域的關鍵職位。該團隊在綜合發布策略方面正在取得重大進展，我們期待在未來分享更多細節。

Now turning to our broader pipeline. In May, we shared encouraging early data from the first patient treated with AMT-260 for mesial temporal lobe epilepsy. Over the first five months of follow-up, the patient experienced a 92% reduction in seizure frequency, with no significant adverse events.

現在轉向我們更廣泛的管道。五月，我們分享了第一位接受 AMT-260 治療內側顳葉癲癇的患者的令人鼓舞的早期數據。在前五個月的追蹤中，患者的癲癇發作頻率減少了 92%，並且沒有明顯的不良事件。

This early result has sparked strong interest among investigators and the epilepsy community. I'm pleased to say that we have 14 clinical sites in the US that continue to screen patients for this study.

這一早期結果引起了研究人員和癲癇界的強烈興趣。我很高興地說，我們在美國有 14 個臨床站點繼續為這項研究篩選患者。

During the second quarter, we also continued to advance our Fabry and SOD1 ALS studies and look forward to presenting initial Fabry data at the ICIEM conference in early September. Overall, I'm incredibly proud of the team's execution and dedication towards advancing these important therapies.

在第二季度，我們也繼續推動法布瑞氏症和 SOD1 ALS 研究，並期待在 9 月初的 ICIEM 會議上展示初步法布瑞氏症數據。總的來說，我為團隊在推廣這些重要療法方面的執行力和奉獻精神感到無比自豪。

In the first half of 2025, we delivered on several key goals and remain on track for what we believe could be a transformational second half marked by meaningful data updates, regulatory progress, and continued momentum towards the planned BLA submission of AMT-130.

2025 年上半年，我們實現了幾個關鍵目標，並將繼續朝著我們認為可能具有變革性的下半年邁進，這將以有意義的數據更新、監管進展以及繼續按計劃提交 AMT-130 BLA 為標誌。

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

現在我將把電話轉給瓦利德，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 second quarter of 2025, we continue to make meaningful advancement across our portfolio of clinical stage gene therapies.

謝謝你，馬特。大家早安，下午好。2025 年第二季度，我們將繼續在臨床階段基因療法組合中取得有意義的進展。

Let me start with AMT-130. In April, AMT-130 was granted breakthrough therapy designation by the FDA. This recognition, a first in Huntington's disease, was based on the Phase 1/2 data showing the potential to slow disease progression and underscored both the urgent need for effective treatments for Huntington's disease and the potential therapeutic benefits of AMT-130.

讓我從 AMT-130 開始。今年 4 月，AMT-130 被 FDA 授予突破性療法稱號。這項認可是亨廷頓舞蹈症領域的首次認可，基於 1/2 期數據顯示其具有減緩疾病進展的潛力，並強調了對亨廷頓舞蹈症有效治療的迫切需求和 AMT-130 的潛在治療益處。

As you know, our recent FDA interactions have been highly productive. Following two type B meetings in the first and second quarter, we announced in July alignment with the agency on the statistical analysis plan and CMC requirements for AMT-130. The FDA agreed that the three-year change in cUHDRS measured against a propensity score adjusted external control constructed using enrolled HD data set could serve as the registrational endpoint for an accelerated approval DLA.

如您所知，我們最近與 FDA 的互動非常有成效。在第一季和第二季舉行了兩次 B 類會議之後，我們在 7 月宣布與該機構就 AMT-130 的統計分析計劃和 CMC 要求達成一致。FDA 同意，使用註冊的 HD 資料集建立的傾向評分調整外部控制來衡量的 cUHDRS 三年變化可以作為加速批准 DLA 的註冊終點。

The agency also endorsed our CMC strategy, stating that it should be possible to validate the AMT-130 manufacturing process by leveraging prior knowledge and experience from HEMGENIX, Unicure's approval -- approved commercial gene therapy for hemophilia B.

該機構也認可了我們的 CMC 策略，指出應該可以利用 HEMGENIX（Unicure 批准的 B 型血友病商業基因療法）的先前知識和經驗來驗證 AMT-130 製造工藝。

This approach, supplemented with data from additional full-scale GMP batches and a single successful PPQ run, may be sufficient to support process validation for the BLA submission. As Matt just mentioned, we have completed those GMP batches, and the PPQ campaign is currently underway.

這種方法，加上額外全尺寸 GMP 批次和單次成功的 PPQ 運行的數據，可能足以支援 BLA 提交的製程驗證。正如馬特剛才提到的，我們已經完成了那些 GMP 批次，PPQ 活動目前正在進行中。

As stated in the press release this morning, we have submitted the final SAP using a propensity score matched external control derived from the enroll HD data set for the primary analysis. A number of additional analyses, including a propensity score weighted external control, will be submitted as sensitivity and supplemental analysis.

正如今天上午的新聞稿中所述，我們已經提交了最終的 SAP，使用從註冊 HD 資料集中得出的傾向分數匹配外部控制進行主要分析。一些額外的分析，包括傾向得分加權的外部控制，將作為敏感性和補充分析提交。

This update reflects an alignment with the FDA's stated preference and recommendation for propensity score-matched natural history controls. The FDA will receive both the propensity score-matched and propensity score-weighted analysis as disclosed previously.

此次更新反映了與 FDA 所聲明的傾向評分匹配自然歷史控制的偏好和建議的一致性。FDA 將收到先前披露的傾向得分配對分析和傾向得分加權分析。

Turning now to clinical progress, I'm incredibly pleased to report that the AMT-130 clinical team has successfully completed the June 30 cutoff date for the three-year data, keeping us on track for the expected September data update. I'm also pleased to announce a fourth cohort in the Phase 1/2 trial of AMT-130 expected to initiate in the third quarter.

現在談到臨床進展，我非常高興地報告，AMT-130 臨床團隊已成功完成 6 月 30 日的三年數據截止日期，使我們能夠按計劃進行預期的 9 月數據更新。我也很高興地宣布，AMT-130 第 1/2 期試驗的第四組患者預計將於第三季啟動。

This open label single-arm US study will evaluate safety of the high dose of AMT-130 in at least six patients with lower striatal volumes. Patients who would have previously been excluded based on the criteria of a minimal striatal volume can now be considered, potentially expanding access to treatment. We expect to have full enrollment by the fourth quarter of 2025.

這項開放標籤單臂美國研究將評估至少六名紋狀體體積較低的患者使用高劑量 AMT-130 的安全性。以前根據紋狀體體積最小的標準而被排除的患者現在可以被考慮，從而有可能擴大治療的機會。我們預計到 2025 年第四季將實現全部招生。

Finally, in September, we plan to present topline data of our Phase 1/2 of AMT-130. We currently plan to disclose safety and tolerability data through 36 months follow-up, as well as other topline data, including cUHDRS and TFC at both those levels compared to a propensity score-matched natural history control. We also plan on providing CSF NfL data at both doses compared to baseline at 36 months.

最後，我們計劃在 9 月公佈 AMT-130 第 1/2 階段的頂線數據。我們目前計劃透過 36 個月的追蹤來揭露安全性和耐受性數據，以及其他頂線數據，包括與傾向評分匹配的自然史對照相比，這兩個等級的 cUHDRS 和 TFC。我們還計劃提供兩種劑量的 CSF NfL 數據，並與 36 個月時的基線進行比較。

Moving on to AMT-260 for mesial temporal lobe epilepsy. In late May, we shared initial data from the first subject in the gentle Phase 1/2a study at the Epilepsy Therapies & Diagnostic Development Symposium. We observed a 92% reduction in seizure frequency over the first five months of follow-up with no serious adverse events.

繼續使用 AMT-260 治療內側顳葉癲癇。5 月下旬，我們在癲癇治療與診斷發展研討會上分享了溫和的 1/2a 期研究中第一位受試者的初步數據。我們觀察到，在追蹤的前五個月內，癲癇發作頻率減少了 92%，且沒有發生嚴重不良事件。

While additional follow-up on this first trial participant and enrollment of additional participants in this trial are needed, this case study provides an early signal that suggests our miRNA-based GRIK2 targeted gene therapy can potentially suppress seizure activity in this type of patients. This early data has generated enthusiasm among investigators and trial sites, as well as interest within the broader epilepsy community, which is eager for differentiated novel treatment options.

雖然需要對第一位試驗參與者進行進一步的追蹤並招募更多參與者參加此次試驗，但該案例研究提供了一個早期訊號，表明我們基於 miRNA 的 GRIK2 標靶基因療法可以潛在地抑制此類患者的癲癇發作活動。這些早期數據引起了研究人員和試驗點的熱情，也引起了更廣泛的癲癇社群的興趣，他們渴望找到差異化的新治療方案。

So trial recruitment remains challenging. I'm very proud to say that additional sites have been activated, and we expect to have additional patients enrolled before the end of the year.

因此試驗招募仍然具有挑戰性。我很自豪地說，更多的站點已經啟動，我們預計在今年年底之前將有更多的患者入組。

Moving to AMT-191 for Fabry disease. The Phase 1/2a clinical trial continues to enroll patients and we expect to present initial safety and exploratory efficacy data at the 2025 International Congress of Inborn Errors of Metabolism, or ICIEM, conference on September 1 in Kyoto, Japan.

轉向 AMT-191 治療法布瑞氏症。1/2a 期臨床試驗繼續招募患者，我們預計將於 9 月 1 日在日本京都舉行的 2025 年國際先天性代謝錯誤大會 (ICIEM) 上展示初步安全性和探索性療效數據。

Lastly, I'll touch on AMT-162 for SOD1 ALS. We continue to do patients in the Phase 1/2 episode 1 clinical trial. And we anticipate sharing the study's initial safety and biomarker data in the first half of 2026.

最後，我將談談用於 SOD1 ALS 的 AMT-162。我們繼續對處於第 1/2 期第 1 集臨床試驗的患者進行治療。我們預計將在 2026 年上半年分享該研究的初步安全性和生物標記數據。

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

現在，我將把電話轉給克里斯蒂安，告知財務最新情況。基督教？

Thank you, Walid. I'll start off by sharing the financial highlights of the second 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 年第二季的財務亮點。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情。

Revenue for the first quarter was $5.3 million compared to $11.1 million in the same period 2024. The decrease of $5.8 million in revenue resulted from a $3.4 million increase in licensed revenue, a decrease of $7.1 million in collaboration revenue, and a decrease of $2.1 million from contract manufacturing of HEMEGENIX for CSL Behring.

第一季營收為 530 萬美元，而 2024 年同期為 1,110 萬美元。收入減少 580 萬美元，原因是授權收入增加 340 萬美元，合作收入減少 710 萬美元，以及為 CSL Behring 承包生產 HEMEGENIX 的收入減少 210 萬美元。

As noted in the first quarter, following the divestment of the Lexington facility in July 2024, revenue from contract manufacturing is recorded net cost within other expenses. Cost of contract manufacturing revenues were nil for the three months ended June 30, 2025, compared to $7.2 million for the same period in 2024. Again, following the divestment of the Lexington facility in July of last year, cost of contract manufacturing is recorded net of revenue within other expenses.

正如第一季所指出的，在 2024 年 7 月剝離列剋星敦工廠後，合約製造收入被記錄為其他費用中的淨成本。截至 2025 年 6 月 30 日的三個月，合約製造收入成本為零，而 2024 年同期為 720 萬美元。同樣，繼去年 7 月剝離列剋星敦工廠之後，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 $35.4 million for the three-month ended June 30, 2025, compared to $33.7 million during the same period in 2024. The $1.7 million increase was related to an increase of $6.3 million in external program spent and the $4 million higher expenses related to an increase in fair value of contingent consideration.

截至 2025 年 6 月 30 日的三個月，研發費用為 3,540 萬美元，而 2024 年同期為 3,370 萬美元。170 萬美元的增幅與外部項目支出增加 630 萬美元以及或有對價公允價值增加相關的 400 萬美元費用增加有關。

This was offset by a decrease of $4.7 million in employee-related expenses, a decrease of $2.1 million in facility expenses, and a $1.8 million decrease in costs related to pre-clinical supplies. Selling general and administrative expenses were $13.5 million for the three months ended June 30, 2025, compared to $15.8 million during the same period in 2024.

但員工相關費用減少 470 萬美元、設施費用減少 210 萬美元以及臨床前用品相關成本減少 180 萬美元抵消了這一影響。截至 2025 年 6 月 30 日的三個月，銷售一般及行政費用為 1,350 萬美元，而 2024 年同期為 1,580 萬美元。

The $2.3 million decrease was primarily related to a $1.6 million decrease in employee-related expenses and the $0.6 million dollar decrease in professional fees compared to the prior year period. Cash, cash equivalents, and investment securities total of $377 million as of June 30, 2025, compared to $367.5 million as of December 31, 2024. The increase is primarily related to the net proceeds of $180.5 million from our first quarter full-on offering.

230 萬美元的減少主要與員工相關費用與去年同期相比減少 160 萬美元以及專業費用減少 60 萬美元有關。截至 2025 年 6 月 30 日，現金、現金等價物及投資證券總額為 3.77 億美元，而截至 2024 年 12 月 31 日為 3.675 億美元。這一增長主要與我們第一季全面發行所得的 1.805 億美元淨收益有關。

With this strong balance sheet, we believe Uniqure is well positioned to execute its clinical and operational priorities, including the planned commercialization of AMT-130 in the US in 2026. We expect cash, cash equivalents, and investment securities will be sufficient to fund operations into the second half of 2027.

憑藉強勁的資產負債表，我們相信 Uniqure 完全有能力執行其臨床和營運重點，包括計劃於 2026 年在美國實現 AMT-130 的商業化。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 now turn the call back over to Matt.

現在我把電話轉回給馬特。

Thanks for the update, Christian. As you've heard today, our strong execution during the first half of 2025 has positioned us for what we believe will be an exciting and pivotal second half of the year. We've achieved regulatory alignment on an accelerated approval pathway for AMT-130, submitted our final statistical analysis plan, initiated our PPQ campaign, and continued to advance key BLA preparation activities.

謝謝你的更新，克里斯蒂安。正如大家今天所聽到的，我們在 2025 年上半年的強勁執行力為我們奠定了基礎，我們相信這將是令人興奮且關鍵的下半年。我們已經在 AMT-130 的加速審批途徑上實現了監管協調，提交了最終統計分析計劃，啟動了 PPQ 活動，並繼續推進關鍵的 BLA 準備活動。

We very much look forward to presenting top-line pivotal data anticipated in September, which we expect will support a planned BLA submission in the first quarter of 2026, and if approved, commence a US commercial launch later that year. At the same time, we're progressing our broader pipeline with encouraging early data in mesial temporal lobe epilepsy and initial Fabry data on track for September.

我們非常期待在 9 月公佈最重要的關鍵數據，我們預計這些數據將支持在 2026 年第一季度提交計劃中的 BLA，並且如果獲得批准，將於當年晚些時候開始在美國進行商業發布。同時，我們正在推動更廣泛的研發管線，預計 9 月將公佈內側顳葉癲癇的早期數據和法布瑞氏症的初步數據。

Our mission remains clear, to deliver transformative therapies for patients with serious unmet needs. We are focused, well-resourced, and energized for the opportunities ahead. And we look forward to keeping you updated on our progress in the months to come.

我們的使命始終明確，為有嚴重未滿足需求的患者提供變革性療法。我們集中精力、資源充足、充滿活力地迎接未來的機會。我們期待在未來幾個月內向您通報我們的進展。

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

接下來，我們將開始回答研究分析師的提問。接線員，請繼續。

(Operator Instructions) Debjit Chattopadhyay, Guggenheim.

（操作員指示）Debjit Chattopadhyay，古根漢。

Hey, good morning, and thanks for taking my question. I have one on a follow up as well. So number one, does the FDA expect a minimum threshold for clinical benefit versus the Enroll-HD on cUHDRS?

嘿，早上好，感謝您回答我的問題。我還有一個後續行動。那麼第一點，FDA 是否期望與 cUHDRS 上的 Enroll-HD 相比，有一個臨床益處的最低閾值？

Walid, you want to answer that one?

瓦利德，你想回答這個問題嗎？

Sure. In discussions with the FDA, a minimum clinical effect has not been requested nor has it been included in the SAP plan. Having said that, we will be submitting the three-year data, which we expect that will show a substantial level of evidence that would support accelerated approval after the FDA review.

當然。在與 FDA 的討論中，並未要求最低臨床效果，也沒有將其納入 SAP 計劃。話雖如此，我們將提交三年的數據，我們預計這些數據將顯示大量證據，支持 FDA 審查後加速批准。

Appreciate that. And our understanding is that the company has written feedback. So how certain are you that the FDA senior leadership won't renege on what's already been communicated to the company?

非常感謝。據我們了解，該公司已收到書面回饋。那麼，您有多確定 FDA 高層領導不會違背已經傳達給公司的訊息？

Yeah, Debjit, obviously, we're watching what's going on in the space. We know what's publicly available in those situations. Each of these situations are very nuanced. All of our interactions with the FDA have been very encouraging and very supportive. And as we said in the past numerous times, we have very clear and unambiguous feedback with the FDA.

是的，Debjit，顯然我們正在關注太空中發生的事情。我們知道在這些情況下哪些資訊是可以公開的。每種情況都非常微妙。我們與 FDA 的所有互動都非常令人鼓舞且非常支持。正如我們過去多次說過的那樣，我們向 FDA 提供了非常明確和明確的回饋。

In terms of our situation, it is different meaningfully in so much that we're moving forward with clinical outcomes data and long-term clinical outcomes data as opposed to relying on a surrogate biomarker. So we believe this is a robust approach. We're focused on controlling and executing on what we can control. And we're feeling very optimistic about our path forward.

就我們的情況而言，它有很大不同，因為我們正在推進臨床結果數據和長期臨床結果數據，而不是依賴替代生物標記。因此我們相信這是一種強而有力的方法。我們專注於控制和執行我們能夠控制的事情。我們對未來的道路感到非常樂觀。

Joseph Schwartz, Leerink Partners.

Leerink Partners 的 Joseph Schwartz。

Hi, guys, this is Jenny on for Joe. Thank you for taking your question. Could you walk us through the AMT-130 procedure and what this would look like from a patient's perspective, including the time commitment? And how are you thinking about who would be appropriate for the surgery and how should we think about the commercial population? Do you think there's a particular subset of patients who are more likely to be early adopters? Thank you.

大家好，我是珍妮，為喬播報。感謝您回答問題。您能否向我們介紹一下 AMT-130 手術過程以及從患者的角度來看過程是怎樣的，包括需要投入的時間？您如何看待哪些人適合接受手術以及我們應該如何考慮商業人群？您是否認為有一部分患者更有可能成為早期採用者？謝謝。

Walid, you want to talk about the procedure?

瓦利德，你想談談這個過程嗎？

Sure. The procedure is really one that is not complicated technically. I mean, if you speak to neurosurgeons who've done any neurosurgical administration to treat tumors or any deep brain stimulation, this is really fairly low complexity procedure, at least that's how the neurosurgeons described it to us.

當然。從技術上來說，該過程實際上並不複雜。我的意思是，如果你與做過任何神經外科手術治療腫瘤或任何深部腦部刺激的神經外科醫生交談，這實際上是一種相當低複雜度的手術，至少神經外科醫生是這麼向我們描述的。

Patients usually get an MRI ahead of time so that we can plan the trajectory. The neurosurgeon will plan the trajectory based on the MRI because, of course, there's specific anatomical differences for each patient that the surgeon needs to take into consideration. And on the day of the surgery, the patients come into the hospital in the morning and then they get admitted to neurosurgery. And using MRI guided registration, essentially probes are inserted in the brain under direct visualization of the MRI.

患者通常會事先接受核磁共振檢查，以便我們可以規劃治療軌跡。神經外科醫生將根據 MRI 來規劃手術軌跡，因為每個患者都有特定的解剖差異，外科醫生需要考慮這些差異。手術當天，患者早上入院，然後進入神經外科。使用 MRI 引導配準，基本上可以在 MRI 直接可視化的情況下將探針插入大腦。

And the infusion, there will be drilling of a hole in the brain through which the catheter is infused, is introduced. And then through direct visualization, we observe the infusion of the product, which is mixed with the contrast material that is MRI compatible, gadolinium. And that way, the neurosurgeon can observe live as they administering the therapy that it's actually reaching its target. That's a very important aspect in what we do.

進行輸液時，需要在大腦上鑽一個孔，並透過該孔插入導管進行輸液。然後透過直接觀察，我們觀察到產品的輸注，該產品與 MRI 相容的造影劑钆混合。這樣，神經外科醫生在實施治療時就可以即時觀察治療是否真正達到了目標。這是我們工作中非常重要的一個面向。

Now, the infusion has to occur at a slow rate to make sure that the product diffuses appropriately to the right structure. And that actually is what consumes most of the time. So a lot of the time during the procedure, which has to be done 6 times because we administered 3 times on each side of the brain, is what it takes actually most of the time. And usually, that takes a number of hours at the end of which, essentially, the patient wakes up.

現在，輸液必須以緩慢的速度進行，以確保產品適當地擴散到正確的結構。而這其實就是大部分時間被消耗的事情。因此，在手術過程中，我們花了大量的時間，因為我們對大腦的每一側進行了 3 次手術，所以必須進行 6 次，這實際上是手術所需的大部分時間。通常，這需要幾個小時，之後病人就會醒來。

And usually, they stay like 24 hours, I believe. And then they will be discharged, and often they tend to recover very quickly because, again, it's a very minimal -- how should I say? Very minimally invasive from the perspective of the size of the probe that are introduced. And often patients within a few days, they get back to work. At least that's been our experience in our trial.

我相信，它們通常會停留 24 小時左右。然後他們就會出院，而且他們往往恢復得很快，因為，再說一次，這是一個非常小的——我該怎麼說呢？從引入的探針尺寸來看，這是非常微創的。通常患者幾天之內就能恢復工作。至少這是我們在試驗中的經驗。

And I'll go back to you, Matt, for details on the target patient population and the commercial question.

馬特，我會再向您詢問有關目標患者群體和商業問題的詳細資訊。

Yeah, I mean, I think, the reality is there's nothing for these patients. There's no disease modifying therapy. And so I believe that the overwhelming majority of patients that are eligible are going to become informed about it and I think seriously consider therapy.

是的，我的意思是，我認為，現實情況是這些病人甚麼都得不到。沒有任何可以改變病情的療法。因此我相信絕大多數符合條件的患者都會了解這一點，我認為他們會認真考慮接受治療。

In terms of our inclusion criteria, we're largely looking at Stage 2 and Stage 3 patients, which are typically patients that are considered early manifest. So they have developed some form of symptomology. And they've been tested and confirmed genetically that that they have Huntington's disease that will become 100% penetrant. So that's definitely going to be our focus. And I think it's going to be -- as I said, it's going to be something that now that there is at least a treatment option that it's hard to imagine that all or majority of all patients are going to seriously consider and become informed about our therapy.

就我們的納入標準而言，我們主要關注第 2 階段和第 3 階段患者，這些患者通常被認為是早期表現的患者。因此他們已經形成了某種形式的症狀學。他們已經透過基因檢測確認患有亨廷頓氏舞蹈症，並且這種疾病的滲透率將達到 100%。所以這肯定會成為我們的重點。我認為，正如我所說，現在至少有一種治療選擇，很難想像所有或大多數患者都會認真考慮並了解我們的治療方法。

Thank you. That's really helpful.

謝謝。這真的很有幫助。

Paul Matteis, Stifel.

保羅‧馬泰斯 (Paul Matteis)，Stifel。

Great. Good morning, guys. Thanks for taking my questions. We noticed this morning that you said you're going to be using propensity matched in this analysis, not propensity weighted. Can you just talk about where that comes from? Is that something that the FDA requested? And then specifically, how does that compare to the data that we saw in the last cut in 2024? If it's a different methodology than what we're going to see here, is this going to be apples and oranges, the 80% number for 130 still stand? And then if you don't mind, I just have one follow up. Thank you.

偉大的。大家早安。感謝您回答我的問題。我們今天早上註意到，您說您將在這次分析中使用傾向匹配，而不是傾向加權。你能說說這是從何而來的嗎？這是 FDA 要求的嗎？那麼具體來說，這與我們在 2024 年上次削減中看到的數據相比如何？如果它採用與我們在這裡看到的方法不同的方法，那麼這是否會是蘋果和橘子，130 的 80% 這個數字仍然成立嗎？如果您不介意的話，我只想跟進一件事。謝謝。

Walid, do you want to go and answer that?

瓦利德，你想去回答這個問題嗎？

Thanks. Yeah, thanks, Paul. Yeah, we've indicated previously when we reported back after meeting with the FDA that the FDA's stated preference was for propensity score matching. We've also consulted with our external statistical experts. And when we took all of these into consideration, we decided to submit the SAP that's aligned with the FDA preference using propensity score matching as the primary endpoint. Having said that, the agency will also continue to receive both the propensity score matching and the propensity score weighting analysis just as we stated before.

謝謝。是的，謝謝，保羅。是的，我們先前在與 FDA 會面後報告時就指出，FDA 表示傾向於傾向評分匹配。我們也諮詢了外部統計專家。當我們考慮到所有這些因素時，我們決定提交符合 FDA 偏好的 SAP，並使用傾向評分配對作為主要終點。話雖如此，正如我們之前所說，該機構也將繼續接受傾向分數配對和傾向分數加權分析。

Now, in constructing, the natural history database as we were evaluating -- excuse me, the most appropriate natural history database to use, we had to construct the annual decline over a period of three years of patients using a variety of methodologies, propensity score rating, matching, exact matching, number of these. And using the enrolled database, we found that the propensity score methodology in whichever form is quite robust, leading very similar estimate of decline after three years regardless of the methodologies.

現在，在建立我們正在評估的自然史資料庫時——對不起，這是最合適的自然史資料庫，我們必須使用各種方法、傾向評分、配對、精確配對等來建立三年內病患的年度下降。使用已登記的資料庫，我們發現無論哪種形式的傾向評分方法都非常穩健，無論採用何種方法，三年後的下降估計值都非常相似。

So to answer your question, I will not expect that the results will be materially different, if we use propensity score matching, propensity score reading. And considering the FDA's preference, we decided to go that route, be more aligned with them. But we will be submitting both anyway.

因此，回答你的問題，如果我們使用傾向分數配對、傾向分數讀數，我不會期望結果會有實質的差異。考慮到 FDA 的偏好，我們決定採取這種方式，與他們保持一致。但無論如何我們都會提交這兩項文件。

Okay, thank you. That's super helpful. And then look, I know this is extraordinarily subjective, and ultimately, in Huntington's, there's nothing, but how are you guys thinking about the bar on disease slowing in this three-year analysis. And look, again, understanding that Huntington's doesn't have any disease modifying treatments. I would think you'd want the data to hold up to some degree. Just first of all for the best of the drug and second of all to be confident in your regulatory alignment. So investors and analysts are trying to draw this line, how would you draw this line?

好的，謝謝。這非常有幫助。然後看看，我知道這是非常主觀的，最終，在亨廷頓舞蹈症中，沒有什麼，但是你們如何看待在這三年的分析中疾病減緩的標準。再看看，要知道亨丁頓舞蹈症並沒有任何可以改善病情的治療方法。我認為您希望數據能夠保持一定程度。首先，要確保藥物的最佳效果，其次，要對監管合規性充滿信心。因此投資者和分析師正在試圖劃出這條線，您將如何劃出這條線？

Yeah. Sorry, I assume I'm going to continue. I'm just going to give it to you. Apologies.

是的。抱歉，我想我會繼續。我只是要把它給你。抱歉。

No, go ahead, Walid.

不，繼續吧，瓦利德。

Yeah, I mean, I think we're asked that question a lot. It's an important question. Honestly, as you said, there's nothing for these patients, Matt mentioned that before. When we talk to a number of KOLs, what they tell us is like anything that is -- that would reduce the disease progression by 25% to 30% would be great.

是的，我的意思是，我想我們經常被問到這個問題。這是一個重要的問題。老實說，正如你所說，這些病人沒有什麼可做的，馬特之前提到過這一點。當我們與一些關鍵意見領袖交談時，他們告訴我們，任何能夠將病情進展減少 25% 至 30% 的方法都是很好的。

It would add potentially many years of quality of life to these patients who have nothing. But from our perspective, just like you said, we would like our data to continue to show any meaningful, slowing of disease progression that will be something that the agency will consider appropriate for approval but also the patients will find clinically meaningful. That is we believe in our mechanism of action. We saw the data at two years. We feel optimistic that the three-year data will continue to show a meaningful improvement that will both satisfy the patients but also the FDA.

這可能會為那些一無所有的患者增加很多年的生活品質。但從我們的角度來看，就像您所說的那樣，我們希望我們的數據能夠繼續顯示任何有意義的、減緩疾病進展的跡象，這將是該機構認為適合批准的，而且患者也會發現具有臨床意義的。也就是說，我們相信我們的行動機制。我們看到了兩年後的數據。我們樂觀地認為，三年的數據將繼續顯示出有意義的改善，這將使患者和 FDA 都滿意。

Joseph Thome, TD Cowen.

約瑟夫·托米（Joseph Thome），考恩（Cowen）TD。

Hi, there, good morning. Thank you for taking my questions. I have one question and one follow up if I can. I guess, just given the back and forth with Sarepta over the course of this week, has that changed at all your thinking on how you're approaching the launch in any way, whether you want to do a stage launch just target number of surgeons, be a little bit more cautious at the beginning? Or how you're thinking about that?

嗨，大家好，早安。感謝您回答我的問題。如果可以的話，我有一個問題和一個後續問題。我想，考慮到本週與 Sarepta 的反覆交涉，這是否改變了您對如何以任何方式進行發布的想法，您是否想進行分階段發布，只針對目標外科醫生數量，一開始要更加謹慎一些？或者您對此有何看法？

Obviously, so many differences between these dates and age and everything like that. But I guess, are there any learnings that you've taken from the past week? And then second, do you expect there to be a minimal striatal volume on the label? I only ask because I notice you're initiating a fourth cohort with a smaller striatal volume. So just thinking that that's going to be a formal label expansion, or if this would be more just a used guideline for clinicians in the field. Thank you.

顯然，這些日期、年齡等等之間存在很大差異。但我想，你從過去一周學到了什麼嗎？其次，您是否認為標籤上會有最小紋狀體體積？我之所以問這個問題，是因為我注意到您正在啟動第四個隊列，其紋狀體體積較小。因此，我只是認為這將是一個正式的標籤擴展，或者這是否只是該領域臨床醫生使用的指南。謝謝。

Yeah, Walid, maybe I'll take the first one, you take the second one. So yeah, I mean, honestly, we've always operated in a way where patient safety is our utmost priority. So it's not like anything going on in the sector is going to change that view.

是的，瓦利德，也許我會選第一個，你選第二個。是的，我的意思是，說實話，我們始終以病人安全為首要任務。因此，該行業發生的任何事情都不會改變這種觀點。

I think we've always thought that for AMT-130 that there are going to be, at the time of launch, centers of excellence that have experience with the surgical procedure that are conducting these procedures. And we're going to be -- it's something that we're going to be continually monitoring as we launch the product. But at the same time, we treated 45 patients. I think we really believe the AMT-130 is generally safe and well tolerated.

我認為我們一直認為，對於 AMT-130，在推出時將會有一個具有外科手術經驗的卓越中心來執行這些手術。我們將在推出產品時持續監控這一點。但同時，我們治療了45名患者。我認為我們確實相信 AMT-130 總體上是安全且耐受性良好的。

I'll also mention that our administration of AMT-130 is a local administration. So the systemic exposure that occurs when we administer AMT-130 is meaningfully less than a gene therapy that is systemically administered. And we have just simply not seen any liver toxicity associated with AMT-130. We're also utilizing an AAV5 vector that has been studied with systemic administration vis a vis HEMGENIX.

我還要提到，我們對 AMT-130 的管理是地方管理。因此，當我們使用 AMT-130 時發生的全身暴露明顯低於全身使用的基因療法。我們只是沒有看到任何與 AMT-130 相關的肝毒性。我們也利用了已透過 HEMGENIX 系統給藥研究過的 AAV5 載體。

And we've also not seen any significant adverse events associated with HEMGENIX or AAV5 in that context as well, even with systemic administration. So it's very important to understand these technical differences with the administration. But nothing's going to change our view, that patient safety is always going to be at the top of our priorities.

而且，即使是全身給藥，我們也沒有看到與 HEMGENIX 或 AAV5 相關的任何重大不良事件。因此，了解與管理層之間的這些技術差異非常重要。但沒有什麼能改變我們的觀點，那就是病人安全永遠是我們的首要任務。

Okay. So on the striatal volume, I'm just taking a step back. The way this came to be was as the study was initially designed some six years ago or so. Out of the abundance of caution, we want to make sure that we have a striatal volume that would be large enough so we can safely administer the product to these patients.

好的。因此，關於紋狀體體積，我只是退後一步。這項研究最初是在大約六年前設計的。出於謹慎考慮，我們希望確保紋狀體體積足夠大，以便我們可以安全地將產品給予這些患者。

But over the years, and as we've accumulated a lot of experience with more than 40 total of 45 reparent administrations to date, the experience that we accumulated with our neurosurgeons and in discussions with them, we are -- we've decided that we should be relaxing these criteria and now evaluating an approach where we will use the neurosurgeon's clinical judgment whether they can reach the targeted structure safely without fixing a specific minimum volume.

但多年來，我們迄今為止已經進行了 40 多次共計 45 次復位手術，積累了豐富的經驗，這些經驗是我們與神經外科醫生共同討論的結果，我們決定應該放寬這些標準，現在正在評估一種方法，我們將使用神經外科醫生的臨床判斷來確定他們是否可以在不固定特定最小體積的情況下安全地到達目標結構。

And in order for us to study that, we needed to include patients who have otherwise would have been excluded from our trial, those with lower striatal volume, to start generating safety data with this. Now, whether this will be in the label or not, those discussions have not taken place. With the FDA, that would be something that would have to occur later in the review process.

為了研究這一點，我們需要納入那些原本會被排除在試驗之外的患者，也就是那些紋狀體體積較低的患者，以開始產生安全數據。現在，無論這是否會出現在標籤中，這些討論都尚未進行。對 FDA 來說，這將是審查過程後期必須發生的事情。

Of course, generating these data and depending on the outcome of the safety profile of this, those will be included in the safety update. And we'll be part of our discussions with the agency, but it's premature right now to be able to speculate or give guidance as to what we think the label would look like.

當然，產生這些資料並根據其安全性概況的結果，這些資料將包含在安全性更新中。我們將與該機構進行討論，但現在就推測或指導我們認為的標籤是什麼樣子還為時過早。

Sushila Hernandez, Van Lanschot Kempen.

蘇西拉·埃爾南德斯，範·蘭肖特·肯彭。

Yes, thank you for taking my question. Also, just to follow up on the fourth cohort. So what do you hope to expect to see in this patient population? And then the second question, what are the next steps for AMT-260? Are you expecting to add more sites? Thank you.

是的，感謝您回答我的問題。另外，只是為了跟進第四批人員的狀況。那麼您希望在這個患者群體中看到什麼呢？那麼第二個問題，AMT-260 的下一步計畫是什麼？您是否希望新增更多網站？謝謝。

Matt, I suppose I'll take both, right? So with the fourth cohort, the expectations in the short term is to document the safety of the procedure that we can administer this safely that the neurosurgeons that we have and the system that we have in place to be able to evaluate whether we can safely administer AMT-130 for those who would have otherwise been excluded from our trial because they would have a lower striatal volume. The system is in place. It operates well, and we can administer it.

馬特，我想我會選擇兩者，對嗎？因此，對於第四批患者，短期內的期望是記錄該手術的安全性，以便我們能夠安全地實施該手術，我們現有的神經外科醫生和系統能夠評估我們是否可以安全地為那些原本會被排除在我們試驗之外的患者施用 AMT-130，因為他們的紋狀體體積較小。該系統已經到位。它運作良好，我們可以管理它。

And then, of course, we will be monitoring them for efficacy and so on and so forth. But I personally do not foresee where there would be any difference once we established that the AMT-130 is actually effective in slowing disease progression. There's no reason for this to be different based in arbitrary cut off for striatal volume.

然後，當然，我們會監測它們的功效等等。但我個人不認為一旦我們確定 AMT-130 確實能有效減緩病情進展，會有什麼不同。沒有理由因為紋狀體體積的任意截止而有所不同。

In terms of AMT-260, yes, indeed, as Matt said, we have increased the number of sites. We now have 14 active. There's a lot of activity since we've disclosed the data on that first patient with the very positive results. They've been received very positively. We've seen a very significant uptick in screening activities. And we really do feel quite confident that we will be getting a number of additional patients in the second half of the year.

就 AMT-260 而言，是的，確實，正如馬特所說，我們增加了站點數量。我們現在有 14 個活躍用戶。自從我們揭露了第一位取得非常正面結果的患者的數據以來，我們開展了許多活動。他們受到了非常積極的歡迎。我們看到篩檢活動顯著增加。我們確實非常有信心，今年下半年我們將會接收更多病患。

Patrick Trucchio, H.C. Wainright.

派崔克‧特魯基奧、H.C. 溫賴特。

Good morning, everyone, and congratulations on the project on the progress. This is Luis in for Patrick. First question, just thinking ahead of -- are there any differences? Do you expect any differences from regulatory path to approval in Europe versus the US on the 130? And on 160, how should we think about the planned Phase 2 portion look like in terms of patients? Will we plan to enroll the same disease, stage patients with or also include non-legal patients as well? Thank you so much.

大家早安，祝賀專案取得進展。這是路易斯代替派崔克。第一個問題，只是提前思考一下──有什麼不同嗎？您認為歐洲和美國在 130 藥物審批方面的監管路徑有何不同？關於 160，從患者角度來看，我們應該如何考慮計劃中的第 2 階段部分？我們是否計劃招募患有相同疾病、處於相同階段的患者，或也包括非法定患者？太感謝了。

Yeah, just I'll maybe take the first one while, Walid, you can address the second one. So we have not yet met with EMA to solicit scientific advice with respect to the registrational path forward. Our focus right now is on the US. And of course, we'll expect to have the three-year data presented, which we think could be also important information, to furnish EMA when we have those scientific advice discussions. So you we'll look to have them in the near term. And once we do, we'll make sure we provide an update to the market.

是的，我可能只會解決第一個問題，而 Walid，你可以解決第二個問題。因此，我們尚未與 EMA 會面，就註冊路徑的進展徵求科學建議。我們現在的焦點是美國。當然，我們希望獲得三年的數據，我們認為這也是重要的信息，以便在我們進行科學建議討論時為 EMA 提供信息。因此我們希望在短期內獲得它們。一旦我們這樣做了，我們一定會向市場提供最新資訊。

Regarding AMT-260, in terms of designs of the Phase 2 study, it's premature to discuss that. The reality is that we do Phase 1 to learn from it. So that will also dictate the design of the subsequent trial. But in terms of the patient population, we start with those with -- on the non-dominant because that way, you establish the risk-benefit profile and then you start branching out to those with dominant disease.

關於 AMT-260，就第二階段研究的設計而言，現在討論還為時過早。事實上，我們進行第一階段是為了從中學習。這也將決定後續試驗的設計。但就患者群體而言，我們從非顯性疾病患者開始，因為這樣，你就可以確定風險效益狀況，然後開始擴展到顯性疾病患者。

I think the next natural step will be also to look at bilateral. The reality is that it's those with dominant and bilateral is where the high unmet need is because those would be unlikely to benefit from invasive therapy like ablation, laser ablation, or resection surgery. But that's the thinking that we have around expansion as we advance in the program.

我認為下一步自然也是考慮雙邊關係。事實是，那些具有顯性或雙側性病變的患者存在著很大的未滿足需求，因為他們不太可能從消融、雷射消融或切除手術等侵入性治療中受益。但這就是我們在推進該計劃的過程中對擴張的想法。

Eliana Merle, UBS.

瑞銀的 Eliana Merle。

Hey, this is Jasmine on for Eli. Thank you for taking our question. So first, can you give any color on what you plan to talk about and learn from the previous BLA meeting with the FDA in 4Q and will we get an update after this meeting? And then secondly, on the Huntington's commercial opportunity, how many sites in the US are capable of doing the administration procedure? And based on the study enrollment criteria, can you give an estimate of the prevalence of patients that would be eligible in the US? Thank you.

嘿，這是為 Eli 表演的 Jasmine。感謝您回答我們的問題。那麼首先，您能否透露一下您計劃在第四季度與 FDA 舉行的 BLA 會議上討論和學習的內容，我們會在這次會議後得到最新消息嗎？其次，關於亨廷頓的商業機會，美國有多少個地點有能力進行管理程序？根據研究入選標準，您能否估計美國符合條件的患者的盛行率？謝謝。

Yeah, so I mean, I'll answer the last question first, Walid, and then you can answer the first question if that's okay. So yeah, I mean, in terms of the commercial potential, there's 35,000 patients that are currently diagnosed with Huntington's disease. And then there's probably 3 times as many people that have Huntington's disease but have not been genetically confirmed because there's obviously nothing for those patients.

是的，所以我的意思是，我先回答最後一個問題，瓦利德，然後你可以回答第一個問題，如果可以的話。是的，就商業潛力而言，目前有 35,000 名患者被診斷出患有亨廷頓舞蹈症。患有亨廷頓舞蹈症但尚未透過基因確診的人數可能是原來的三倍，因為顯然對這些患者沒有任何治療方法。

Our view is that there's going to be -- we'll provide obviously more detail on this. But the overwhelming majority of the patients that are diagnosed have Stage 2 and Stage 3. Because typically, the diagnosis of Huntington's disease happens once there's symptom onset. So there's going to be many thousands of patients that in our view are going to be eligible for the procedure.

我們的觀點是——我們顯然會提供更多關於此的細節。但絕大多數確診的患者都處於第 2 期和第 3 期。因為通常情況下，亨廷頓舞蹈症的診斷是在症狀出現後進行的。因此，我們認為將有數千名患者有資格接受該手術。

The last part of this was the number of sites that are capable of doing the procedure. Just to be very clear, this is not a novel procedure. This is a very standard procedure for a neurosurgeon. There's probably somewhere between 50 to 55 sites that have the neurosurgical expertise and the imaging equipment to be able to do this procedure.

最後一部分是能夠執行該程式的站點數量。需要明確的是，這並不是一個新穎的程序。對於神經外科醫生來說，這是一個非常標準的程序。大概有 50 到 55 個站點擁有神經外科專業知識和影像設備，可以進行此項手術。

We don't even think we need to be in every one of those centers to address the market. And certainly, at launch, there's going to be a center of excellence strategy. And then I'll hand it over to Walid to answer the first part of your question.

我們甚至認為我們不需要進入每一個中心來滿足市場需求。當然，在發佈時，將會有一個卓越中心策略。然後我將把時間交給瓦利德來回答你問題的第一部分。

Yeah, thank you. So for the PBLA meeting, we will be meeting with the FDA, of course, and sharing with them the top line results from our Phase 3 data and as also as well as any updates on CMC activities and discuss with them. There are some elements of the typical technical procedures and technical questions and logistics that way, whether the data that we have is acceptable to them and whether the totality of the data would support moving forward and submitting the BLA.

是的，謝謝。因此，對於 PBLA 會議，我們當然會與 FDA 會面，並與他們分享我們第 3 階段數據的頂線結果以及 CMC 活動的任何更新並與他們討論。有一些典型的技術程序、技術問題和物流要素，我們擁有的數據是否可以被他們接受，以及全部數據是否支持繼續推進和提交 BLA。

That's the plan. And as usual, after we have meetings with the regulators, once we receive feedback, we usually have always been communicating back to you guys the outcome of these meetings. So we will do that again.

這就是計劃。像往常一樣，在我們與監管機構舉行會議後，一旦我們收到回饋，我們通常都會向你們通報這些會議的結果。因此我們會再做一次。

Luca Issi, RBC.

盧卡·伊西，RBC。

Great, thanks so much for taking my question. Maybe circling back on regulatory, have you actually met or maybe had some informal conversations with [Renee Prasad]? I think many investors argued that the final decision to approve this drug will ultimately come down to the very senior leadership at [Ceber] similar to Sarepta with Peter Mark. So I was just curious if you already had interactions with him and if you have any insights that you can share there.

太好了，非常感謝您回答我的問題。回到監管問題，你是否真的見過或進行過一些非正式的談話？[蕾妮普拉薩德]？我認為許多投資者認為，批准這種藥物的最終決定權最終將落在 Ceber 的高層領導手中，就像 Sarepta 和 Peter Mark 一樣。所以我只是好奇您是否已經與他有過互動，以及您是否有任何見解可以分享。

And then maybe second, can you just maybe clarify what do you think that the ongoing data for Huntington can lead to full approval, given the chasing function? Or is it fair for us to assume that this is going to lead to accelerated approval that's still the base case scenario? And if so, if it is approval, can you maybe talk through how you're thinking about the timing of starting a confirmatory trial? Thanks so much.

然後也許第二點，您能否澄清一下，考慮到追逐功能，您認為亨廷頓的持續數據可以導致完全批准嗎？或者我們可以公平地假設這將導致加速批准，這仍然是基本情況？如果是的話，如果獲得批准，您能否談談您如何考慮開始確認性試驗的時機？非常感謝。

Yeah. So our last interaction with the FDA occurred in late April. Renee was appointed, he didn't attend our meeting, but he was in charge at that point in time. I have been -- I was fortunate enough to attend the CEO listening tour with Dr. Makary and Dr. Prasad in Boston. So I had a chance to meet with him and to understand his perspectives and approaches.

是的。我們與 FDA 的最後一次互動發生在四月下旬。雷內被任命了，他沒有參加我們的會議，但當時他是負責人。我非常榮幸能夠與 Makary 博士和 Prasad 博士一起參加在波士頓舉行的 CEO 聆聽之旅。因此我有機會與他會面並了解他的觀點和方法。

What he made very clear is that he is very interested and willing to evaluate additional data sets other than randomized controlled studies. Dr. Prasad is an epidemiologist by training. And he deeply understands the use of external controls and synthetic cohorts in order to evaluate therapeutic benefit. So I'm confident that given the statements that Dr. Prasad has made, that he's open and supportive of faster accelerated pathways for cell gene therapies that are addressing severe unmet needs, like Huntington's disease.

他明確表示，他非常感興趣並願意評估除隨機對照研究之外的其他數據集。Prasad 博士是一位受過專業訓練的流行病學家。他深刻地理解使用外部控制和合成隊列來評估治療效果。因此，我相信，鑑於普拉薩德博士所發表的聲明，他對加速細胞基因治療的進程持開放態度並支持這一進程，這些治療正在解決亨廷頓氏病等嚴重的未滿足需求。

Just in terms of the full approval, accelerate approval, our base case of course and what we're going to be seeking is accelerated approval. Having said that, the FDA did make it very clear to us that the Phase 1/2 study results can be used and leveraged to support full approval. So to the extent that additional evidence is going to be required for confirmation associated with full approval, and that data can be incremental to what we already have established and generated from the Phase 1/2 study thus far.

就全面批准、加速批准而言，當然這是我們的基本情況，而我們要尋求的是加速批准。話雖如此，FDA 確實向我們明確表示，第 1/2 階段研究結果可用於支持全面批准。因此，在需要額外證據來確認與完全批准相關的範圍內，這些數據可以增加到我們迄今為止從第 1/2 階段研究中已經建立和產生的數據。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Hi, good morning. This is Lydia on for Salveen. Thanks so much for taking our questions. Just another on AMT-130 ahead of the September update. Could you just speak to how consistent the 2.5-year data has been versus the 2-year data we saw last year? Thank you so much.

嗨，早安。我是 Salveen 的 Lydia。非常感謝您回答我們的問題。這只是 9 月更新之前關於 AMT-130 的另一則文章。能否說一下 2.5 年的數據與我們去年看到的 2 年數據有多一致？太感謝了。

Walid?

瓦利德？

Yeah, thanks, Lydiea. Well, we have not conducted any formal analysis on the data since one with the June 30 cutoff of 2024, which served the basis for the November 2024 meeting with the FDA. So we do not have the data that you are describing. The next analysis will be the one that June 30 cut off of this year, which we will be communicating to you guys in September, the 3-year data cut off.

是的，謝謝，莉迪婭。嗯，自從 2024 年 6 月 30 日截止的數據以來，我們還沒有對數據進行任何正式分析，該分析是 2024 年 11 月與 FDA 會面的基礎。所以我們沒有您所描述的數據。下次分析將是今年 6 月 30 日截止的數據，我們將在 9 月向大家通報 3 年數據截止。

(Operator Instructions) Yanan Zhu, Wells Fargo Securities.

（操作員指示） 朱亞南，富國證券。

Great. Thanks for taking our questions. On the topic of propensity matched versus propensity score weighted analysis methodologies, I was wondering in the data you have submitted to FDA for your SAP proposal, could you comment on whether those two methodologies are not --? The data look similar with each other. And I also wondering whether the approach of which one to use affects the sample size that you can use for the external control arm.

偉大的。感謝您回答我們的問題。關於傾向配對與傾向評分加權分析方法的話題，我想知道，在您提交給 FDA 的 SAP 提案資料中，您能否評論一下這兩種方法是否--？這些數據看起來彼此相似。我還想知道使用哪種方法是否會影響可用於外部控制臂的樣本大小。

Walid why don't you go ahead and answer those questions.

瓦利德，你為什麼不繼續回答這些問題？

Thanks, Matt. Yeah, very good question. So to be clear, what the SAP that we submitted to the agency does not include the results. It includes the methodologies. What I was trying to describe earlier is in our -- as we are evaluating the natural history protocol to evaluate which natural history database Enroll track, HD, predict HD would be most appropriate to be compared to.

謝謝，馬特。是的，非常好的問題。因此需要明確的是，我們向該機構提交的 SAP 並不包括結果。它包括方法論。我之前試圖描述的是——我們正在評估自然歷史協議，以評估哪個自然歷史資料庫註冊軌跡、HD、預測 HD 最適合進行比較。

We've employed various propensity score methodologies to essentially select the patients that meet the baseline criteria for our patient -- for our subjects in our trial and observe what is the decline after three years using these various methodologies. And what gives us a lot of confidence both in the methodology itself, the propensity score methodology, is the fact that whether we use propensity score waiting or matching.

我們採用了各種傾向評分方法來選擇符合我們患者基線標準的患者——作為我們試驗中的受試者，並觀察使用這些不同的方法三年後的下降情況。而讓我們對方法論本身，即傾向得分方法論充滿信心的事實是，無論我們使用傾向分數等待或配對。

And by the way, there are multiple ways to match. You can have optimal matching, you can have greedy matching, full matching. I can go on and on and we can go into a lot of details maybe offline if you want to. Those will generate various different levels of size of control. But at the end, the estimate around the score in cUHDRS or in TFC, the decline after three years tend to be generally very similar and not materially different.

順便說一下，匹配的方法有很多種。您可以進行最佳匹配，可以進行貪婪匹配，也可以進行完全匹配。我可以繼續說下去，如果你願意的話，我們可以討論很多細節，也許可以離線討論。這些將產生各種不同等級的控制規模。但最終，根據 cUHDRS 或 TFC 的分數估計，三年後的下降趨勢通常非常相似，並沒有實質差異。

And that's what gives us confidence that these methodologies will yield similar results once you compare our data and subtract the three-year change in our data from the change in the natural history control. But that analysis, comparing our three-year data to that data has not been done yet, so I need to be very clear on that.

這使我們相信，一旦比較我們的數據並從自然歷史控制的變化中減去我們數據的三年變化，這些方法將產生類似的結果。但是，將我們的三年數據與該數據進行比較的分析尚未完成，所以我需要非常清楚地說明這一點。

In terms of the size of the external control, yes, of course, the propensity score weighting is the one that utilizes essentially all of the controls that you have available that meet the criteria for your trial. In the case of cUHDRS, it's somewhere around 3,000. That's the propensity score weighting. And it uses a variety of methodology to be able to allow to include everybody, which contributes to a varying degree based on how closely they resemble your sample.

就外部控制的規模而言，是的，當然，傾向分數加權基本上利用了所有可用的、符合試驗標準的控制。就 cUHDRS 而言，這個數字大約是 3,000。這就是傾向分數加權。它使用多種方法來將每個人納入其中，根據他們與樣本的相似程度，其貢獻程度也有所不同。

Matching uses a proportion of those patients. And again, there are different types of matching. You can have a very simple matching 1 to 1. You have matching one of your patients to maybe 2030 of the control, depending on how large the control group is. And there are many ways that you can tailor this optimal matching or full matching and so on and so forth. And those could lead somewhere around maybe 200, 300 if you want to do 20 or 30 fold your patients in your trial, to 600 if you want to do full matching. And those are the types of different types of methodologies.

配對使用這些患者的一部分。再次強調，配對有多種類型。您可以進行非常簡單的 1 對 1 匹配。您需要將一名患者與大約 2030 名對照組進行匹配，具體取決於對照組的規模。您可以透過多種方式來定制這種最佳匹配或完全匹配等等。如果您希望在試驗中對 20 或 30 倍的患者進行匹配，那麼可能需要大約 200 或 300 個患者；如果您希望進行完全匹配，那麼可能需要 600 個患者。這些就是不同類型的方法論。

I apologize, I might have gone a bit too much in the details, but I like that topic so much that I can speak on it for a long time. But you should rest assured that the estimate of change after three years tend to be fairly similar regardless of the of the method you use. And that gives us very good confidence that the results will not be materially different when we compare them to the change in our patients.

抱歉，我可能講得有點太詳細了，但我非常喜歡這個話題，所以我可以就此談論很長時間。但您應該放心，無論您使用何種方法，三年後的變化估計值往往相當相似。這讓我們非常有信心，當我們將結果與患者的變化進行比較時，結果不會有實質的差異。

Sami Corwin, William Blair.

薩米·科溫、威廉·布萊爾。

Good morning. Congrats on the update. Thanks for taking my questions. I guess, I was curious if FDA provided any guidance as to what they're looking for with NfL for it to be used as a supportive biomarker. If they're looking to see if levels return to or below baseline and that'll be sufficient, or if there'll need to be some specific magnitude of reduction beyond baseline shown.

早安.恭喜更新。感謝您回答我的問題。我想，我很好奇 FDA 是否提供了任何指導，說明他們希望將 NfL 用作支持性生物標記。如果他們想看看水平是否恢復到基線或低於基線，那就足夠了，或者是否需要顯示超出基線的某個特定幅度的減少。

And then follow up, I was curious. We've seen with some other gene therapy trials, one of the key limiting factors for commercialization, seems to be the availability of beds as well as hospital staff. And if you think that may be a limiting factor for the launch of AMT-130 as well. Thank you.

然後繼續跟進，我很好奇。我們在其他一些基因治療試驗中看到，商業化的一個關鍵限制因素似乎是病床和醫院工作人員的可用性。如果您認為這也可能是 AMT-130 推出的限制因素。謝謝。

Walid, do you want to answer the first one?

瓦利德，你想回答第一個問題嗎？

Thanks, Matt. Yeah. So to be clear, the NfL topic has not been a topic of discussion with the agency. We were the one who brought it up back in November of last year when we asked the question actually, whether NFL data could be supported. And the FDA said yes that the NfL data could be supported. But there's been no discussion at all about whether there should be any correlation with the cUHDRS or what change should be from baseline or anything.

謝謝，馬特。是的。因此需要明確的是，NFL 主題尚未成為該機構討論的主題。去年 11 月，我們提出了這個問題，當時我們問的是 NFL 數據是否可以得到支持。FDA 也表示可以支持 NfL 數據。但是，根本沒有討論是否應該與 cUHDRS 有任何關聯，或者應該從基線發生什麼變化等等。

The difficulty with this is that -- and I think it's a relevant question as well, relevant to the update that we're going to have at three years that when we presented data to you last time, we use two-year data because there are data available from an external study looking at longitudinal two-year change from baseline and CSF, NfL levels. Unfortunately, we don't -- no such data exists for the three years' time point, which will limit interpretation of our upcoming data.

困難在於——我認為這也是一個相關的問題，與我們將在三年後進行的更新相關，上次我們向您展示數據時，我們使用兩年的數據，因為有外部研究的數據可以查看從基線和 CSF、NfL 水平縱向兩年的變化。不幸的是，我們沒有——三年時間點上沒有這樣的數據，這將限制我們對即將獲得的數據的解釋。

So it becomes a little bit difficult to figure out. Okay, so what does good look like? We know what that looks like in NfL when you have increases and so on and so forth. We know that patients usually go up by about 15% a year. And clearly, our data at two years show that we are both doses were below baseline.

所以這變得有點難以弄清楚。好的，那麼好看是什麼樣子的呢？我們知道，當 NFL 的比賽人數增加等等時，情況會是什麼樣子。我們知道，患者數量通常每年增加約15%。顯然，我們兩年的數據表明，兩種劑量都低於基線。

So we were looking forward to see what our three data would look like, but it would be a bit difficult because we don't have an external competitor. But going back to your original question, there's been no specific discussions with the FDA about what the NfL data should look like. But we were -- I guess, our expectations are -- and we're confident in our data that the NfL data will continue to support our primary clinical endpoint of cUHDRS.

因此，我們期待看到我們的三個數據會是什麼樣子，但這會有點困難，因為我們沒有外部競爭對手。但回到你最初的問題，我們還沒有與 FDA 進行過關於 NfL 數據應該是什麼樣子的具體討論。但我們——我想，我們的期望是——並且我們對我們的數據充滿信心，NfL 數據將繼續支持我們的主要臨床終點 cUHDRS。

Yeah, and maybe just the second question. We don't think capacity of bed is something that is going to be a significant factor in the launch of our product. I mean, remember this is not cell therapy where patients have to be preconditioned, immunabated, spend weeks in the hospital. I've often talked about the last patient we treated earlier this year was admitted to the hospital on a Tuesday morning, completed the procedure on Tuesday, and was discharged from the hospital Wednesday morning. So I don't think that's a factor that we think is going to be a material one for our launch.

是的，也許只是第二個問題。我們認為床位容量不會成為我們產品推出的重要因素。我的意思是，請記住這不是細胞療法，細胞療法不需要患者進行預處理、免疫，也不需要住院數週。我經常談到我們今年早些時候治療的最後一位患者，他於週二早上入院，週二完成手術，週三早上出院。因此，我認為這不會成為我們產品發布的重要因素。

Kristen Kluska, Cantor Fitzgerald.

克里斯汀·克魯斯卡，坎托·費茲傑拉。

Hi, this is Rick Miller on for Kristen. Thanks for taking our question. Just one from us. Can you walk us through the natural history comparators that could inform the external comparator that we could see in the September update? And how should -- and should we be expecting to see Enroll HD comparators at that time or any other analysis? Thank you.

大家好，我是瑞克米勒，為克莉絲汀播報。感謝您回答我們的問題。我們只有一個。您能否向我們介紹自然歷史比較器，以便我們在 9 月更新中看到外部比較器？那麼我們應該如何——以及我們應該期待看到當時的 Enroll HD 比較器或任何其他分析嗎？謝謝。

Walid?

瓦利德？

Thank you. Yes, so as part of our meeting with the FDA back in November, we were -- we discussed with the FDA how to proceed to evaluate the various natural history databases that we could use. And we asked whether we should include Enroll HD because it has a very large database. And the FDA encouraged us to do so, which we did.

謝謝。是的，作為我們 11 月與 FDA 會議的一部分，我們與 FDA 討論如何繼續評估我們可以使用的各種自然歷史資料庫。我們詢問是否應該包括 Enroll HD，因為它擁有非常大的資料庫。FDA 鼓勵我們這樣做，我們也這麼做了。

And the follow-up meeting that we had with them back in April, we walked them through all of our assessments, comparing the natural history for a variety of reasons which I could perhaps take offline and walk you through this. The Enroll HD was deemed the one that's the best fit for us to compare to. And we made that proposal, and the FDA agreed with us that Enroll HD will be the comparison.

在我們四月與他們舉行的後續會議上，我們向他們介紹了所有的評估，並比較了各種原因的自然歷史，我可能可以將其離線並向您介紹這一點。Enroll HD 被認為是最適合我們比較的產品。我們提出了這個建議，FDA 也同意我們以 Enroll HD 作為比較對象。

So the data that you will see in September will be a comparison of our data to the Enroll HD three-year data using propensity score matching as a primary endpoint. As again, as I said before, we will be including a number of other sensitivity analysis, including propensity score weighting as well and submit to the FDA.

因此，您將在 9 月看到的數據將是我們的數據與 Enroll HD 三年數據的比較，使用傾向評分配對作為主要終點。正如我之前所說，我們將包括許多其他敏感性分析，包括傾向評分加權，並提交給 FDA。

This includes the question-and-answer session in today's conference call. Thank you for participating. You may now disconnect.

這包括今天電話會議中的問答環節。感謝您的參與。您現在可以斷開連線。