Uniqure NV (QURE) 2022 Q2 法說會逐字稿

Good day, and thank you for standing by. Welcome to the AMT-130 Huntington's Disease Program Update.

您好，感謝您的支持。歡迎來到 AMT-130 亨廷頓舞蹈症計畫更新。

(Operator Instructions)

（操作員指令）

Please be advised that today's conference is being recorded. And I would now like to hand the conference over to Ms. Maria Cantor, Chief Corporate Affairs Officer. Ms. Cantor, please go ahead.

請注意，今天的會議正在錄音。現在，我想將會議移交給首席公司事務官瑪麗亞·坎托女士。坎托女士，請繼續。

Good morning, and thank you for joining us. This morning, uniQure announced that it has postponed patient enrollment in the higher-dose cohort of the Phase I/II clinical trial of AMT-130 in Huntington's disease based on reported SUSAR events at this dose. We will discuss these events and provide an update on the program during this call. Joining me for the investor event and webcast are Matt Kapusta, our Chief Executive Officer; and Dr. Ricardo Dolmetsch, our President of Research and Development.

早安，感謝您加入我們。今天上午，uniQure 宣布，根據已報告的該劑量下的 SUSAR 事件，它已推遲了 AMT-130 治療亨廷頓舞蹈症的 I/II 期臨床試驗高劑量組的患者招募。我們將在本次電話會議中討論這些活動並提供有關該計劃的最新進展。與我一起參加投資者活動和網路直播的還有我們的執行長 Matt Kapusta；以及我們的研發總裁 Ricardo Dolmetsch 博士。

We'll be making forward-looking statements during this investor call. All statements, other than those 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 the factors described under the heading Risk Factors in uniQure's quarterly report on Form 10-Q filed today, August 8, 2022, and other securities filings. Given these risks and uncertainties, investors 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. Now let me introduce Matt Kapusta, uniQure's CEO.

我們將在本次投資者電話會議中發表前瞻性陳述。除歷史事實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。由於多種原因，我們的實際結果可能與這些前瞻性陳述中預期的結果有重大差異，包括 uniQure 於 2022 年 8 月 8 日今天提交的 10-Q 表季度報告和其他證券文件中「風險因素」標題下所述的因素。鑑於這些風險和不確定性，投資者不應過度依賴這些前瞻性陳述，即使將來出現新的信息，我們也不承擔更新這些陳述的義務。現在讓我介紹 uniQure 的執行長 Matt Kapusta。

Thank you, Maria, and good morning, everyone.

謝謝你，瑪麗亞，大家早安。

On June 23, we announced encouraging 12-month follow-up data from the low-dose cohort of our U.S. Phase I/II study that showed AMT-130 was generally well tolerated with neurofilament light levels near baseline in treated patients and meaningful lowering of mutant Huntington protein supportive of target engagement. As announced in our press release this morning, in July, we were informed of 2 suspected unexpected serious adverse reactions or SUSARs in the higher-dose cohort of our open-label Phase Ib/II clinical trial of AMT-130 in Europe. Both of these patients, which were the first 2 patients dosed at a single clinical study presented with globalized inflammatory responses and other related symptoms within 1 to 2 weeks after their procedures.

6 月 23 日，我們公佈了美國 I/II 期研究低劑量組令人鼓舞的 12 個月隨訪數據，該數據顯示 AMT-130 總體耐受性良好，接受治療的患者的神經絲輕鏈水平接近基線，突變型亨廷頓蛋白顯著降低，支持靶標參與。正如我們今天早上在新聞稿中宣布的那樣，7 月份，我們獲悉在歐洲進行的 AMT-130 開放標籤 Ib/II 期臨床試驗的高劑量組出現了 2 起疑似意外嚴重不良反應或 SUSAR。這兩名患者是單一臨床研究中接受治療的前兩名患者，他們在手術後 1 至 2 週內出現了全球發炎反應和其他相關症狀。

A third patient who had previously been treated with a higher dose of AMT-130 in the U.S. in March of this year experienced severe headache and other related symptoms also shortly after their procedure. That event was initially deemed by the investigator as not related to AMT-130, but related to the procedure. Upon further review and discussion with the clinical trial independent Data Safety Monitoring Board, or DSMB, we have reclassified and reported that patient's reaction as SUSAR. Importantly, these 3 patients are no longer hospitalized and have since fully or substantially recovered.

第三位患者今年 3 月在美國接受了更高劑量的 AMT-130 治療，但在治療後不久也出現了嚴重頭痛和其他相關症狀。研究人員最初認為該事件與 AMT-130 無關，但與手術有關。經過進一步審查並與臨床試驗獨立資料安全監測委員會（DSMB）討論，我們將該患者的反應重新歸類並報告為 SUSAR。重要的是，這 3 名患者已不再住院並且已完全或基本康復。

The DSMB does not view these events as a dose-limiting toxicity. And thus far in our investigation, we have not yet identified the root cause of these events. Nevertheless, we have the DSMB believe it is prudent to voluntarily and temporarily delay the enrollment in dosing of additional patients with a higher dose until we complete a comprehensive safety review in conjunction with our DSMB.

DSMB 不認為這些事件是劑量限制性毒性。到目前為止，我們的調查還沒有確定這些事件的根本原因。儘管如此，我們讓 DSMB 相信，明智的做法是自願並暫時推遲招募更多使用更高劑量的患者，直到我們與 DSMB 一起完成全面的安全審查。

During that time, we will continue our investigation to consider potential risk mitigation plans. We expect to do this over the next 60 to 90 days. This delay does not apply to any future procedures at the low dose where no significant adverse events related to AMT-130 have been reported. Thus far, a total of 36 patients have been enrolled across our U.S. and European clinical trials, including 26 patients treated with AMT-130 and 10 control patients. Of those treated, 14 patients have received a higher dose with some having -- now we followed for up to 1 year.

在此期間，我們將繼續調查，以考慮潛在的風險緩解計劃。我們預計在未來 60 到 90 天內完成此事。此延遲不適用於任何未來的低劑量程序，因為尚未報告與 AMT-130 相關的重大不良事件。到目前為止，我們在美國和歐洲的臨床試驗中共招募了 36 名患者，其中包括 26 名接受 AMT-130 治療的患者和 10 名對照組患者。在接受治療的患者中，有 14 名接受了更高劑量，其中一些患者——現在我們的追蹤時間長達 1 年。

An additional 12 patients have received a lower dose with some having now been followed for up to 2 years. Over the course of our studies, the independent DSMB has conducted 6 separate safety reviews. And aside from these 3 events, no other SUSARs have been reported. We do not expect this delay will have any impact on the data readouts in 2023. In the U.S. Phase I/II study, all 26 patients in the first 2 dose cohorts have been enrolled. And the company continues to expect to present 1- to 2-year follow-up data in the second quarter of 2023.

另外 12 名患者接受了較低劑量的治療，其中一些患者目前已接受長達 2 年的追蹤。在我們的研究過程中，獨立的 DSMB 進行了 6 次獨立的安全審查。除這 3 起事件外，尚未報告其他 SUSAR。我們預計這次延遲不會對 2023 年的數據讀數產生任何影響。而該公司仍預計將在 2023 年第二季公佈 1 至 2 年的追蹤數據。

And the European Phase Ib study -- Phase Ib/II study, the 6-patient lower-dose cohort is fully enrolled, and the company continues to expect to present 1-year follow-up data in 2023. 4 of 9 patients in the European study have been enrolled in the higher-dose cohort. Before I hand the call over to Ricardo, I want to stress that patient safety and well-being will always be uniQure's top priority, and we are committed to working with the DSMB to complete our investigation as soon as possible. Now let me turn the call over to Ricardo.

而歐洲Ib期研究－Ib/II期研究中，6名患者的低劑量組已經全部入組，公司繼續預計在2023年呈現1年的追蹤資料。在將電話交給里卡多之前，我想強調的是，患者的安全和健康永遠是 uniQure 的首要任務，我們致力於與 DSMB 合作，盡快完成調查。現在讓我把電話轉給里卡多。

Thanks, Matt, and good morning.

謝謝，馬特，早安。

In mid-July, uniQure notified the health authorities of serious unexpected suspected adverse events related to 2 subjects in Europe treated with the higher dose of AMT-130 at a single clinical site. The first patient experienced onset of motor and other striatal symptoms within 12 days after the procedure, following admissions of a hospital and MRI, which showed enhanced T2-weighted MRI signal along the tracks of the infusion in the striatum caudate, consistent with edema or swelling in the brain. Treatment with steroids was initiated and tapered through a final dose of 10 days later.

7 月中旬，uniQure 向衛生當局通報了與歐洲單一臨床地點接受高劑量 AMT-130 治療的 2 名受試者有關的嚴重意外疑似不良事件。第一位患者在手術後 12 天內出現運動症狀和其他紋狀體症狀，隨後入院接受 MRI 檢查，MRI 顯示沿紋狀體尾部輸注軌蹟的 T2 加權 MRI 訊號增強，與腦水腫或腫脹一致。開始使用類固醇治療，並在 10 天後逐漸減少劑量，直到使用最後一劑。

The subject is now fully oriented and has a nonclinical neurological exam, but still have couple deficits in terms of fluency, memory and attention relative to its pre-automated state.

該對象現已完全恢復定向並進行了非臨床神經系統檢查，但與自動化之前的狀態相比，在流暢性、記憶力和注意力方面仍然存在一些缺陷。

The second patient experienced vomiting and raised intracranial pressure as presented 12 days after the procedure. Following admission to the hospital (technical difficulty)

第二名患者在手術後 12 天出現嘔吐和顱壓升高。入院後（技術困難）

I'm sorry, if you don't mind going back in your remarks just a little bit because we were losing you on the audio just a bit. You were fading out. So I apologize interrupting you. But if you can go back a little bit to reiterate and just for real clarity.

很抱歉，如果您不介意的話，我們稍微回顧一下您的發言，因為我們剛剛聽不清楚您的聲音。你漸漸消失了。所以我很抱歉打擾你。但如果您可以稍微回顧一下以重申一下，只是為了真正清楚。

Absolutely. So I apologize. Let me start again. So in mid-July, uniQure notified the health authorities of serious unexpected suspect adverse events related to 2 subjects in Europe treated with a higher dose of AMT-130 at a single clinical site. The first patient experienced onset of motor and other striatal symptoms within 12 days after the procedure. Following addition to the hospitals and MRI was performed that showed an enhanced T2-weighted MRI signal along the track of the infusion and in the striatum and in the caudate consistent with edema or swelling in the brain. Treatments with steroids was initiated and tapered through a final dose 10 days later. The subject is now fully oriented and has nonclinical neurological exam, but still has several deficits in terms of fluency, memory and attention motive to its pre-automated state.

絕對地。所以我很抱歉。讓我重新開始。因此，7 月中旬，uniQure 向衛生當局通報了與歐洲單一臨床地點接受高劑量 AMT-130 治療的 2 名受試者有關的嚴重意外疑似不良事件。第一位患者在手術後 12 天內出現運動症狀和其他紋狀體症狀。隨後，醫生前往醫院進行了 MRI 檢查，結果顯示沿著輸液軌跡、紋狀體和尾狀體中的 T2 加權 MRI 訊號增強，與腦部水腫或腫脹一致。開始使用類固醇治療，並在 10 天後逐漸減少劑量，直到最後一次劑量。該對象現已完全恢復定向並進行了非臨床神經系統檢查，但在流暢性、記憶力和注意力動機方面與自動化前狀態相比仍然存在一些缺陷。

The second patient experienced vomiting and raised intracranial pressure that presented 12 days after the receiver. Following admission to the hospital, the patient was found to have papilledema or optic disc swelling, but the MRI did not show any evidence of edema in the striatum or longer-tract infusion. A lumbar puncture to remove 20 ccs of cerebral spinal fluid was performed and the symptoms fully resolved...

第二名患者在接受治療 12 天後出現嘔吐和顱壓升高症狀。入院後發現患者出現視乳頭水腫或視乳頭腫脹，但MRI未顯示紋狀體水腫或長束灌注的證據。進行了腰椎穿刺以取出 20 cc 的腦脊髓液，症狀完全消失...

Yes. I'm sorry, you were cutting out again, and I just feel for the benefit of all of those listening into the call, the content of what you're sharing is so important that it may be better to have Matt provide your remarks, and then we'll go to you in the Q&A session. Again, I think that, that matters for everyone listening in. Thank you. So we'll have Matt pickup from that.

是的。很抱歉，您又打斷我了，我只是覺得，為了所有收聽電話會議的人的利益，您所分享的內容非常重要，最好讓馬特先發表您的意見，然後我們再在問答環節找您。我再說一遍，我認為這對所有聽眾都很重要。因此我們將讓馬特 (Matt) 從那裡接手。

Okay. Yes, Matt Kapusta, everybody. So let me start off with the second patient experience, vomiting and raised intracranial pressure around 12 days after the procedure. Following admission to the hospital, the patient was found to have papilledema or optic disc swelling, but the MRI did not show any evidence of edema in the striatum or longer tracts. A lumbar puncture to remove 20 ccs of cerebral spinal fluid was performed and the symptoms fully resolved leading to discharge. The subject also received prophylactic antibiotics.

好的。是的，馬特‧卡普斯塔 (Matt Kapusta)，大家好。那麼讓我先來介紹一下第二位患者的經歷，手術後大約 12 天出現嘔吐和顱壓升高。入院後，發現患者出現視乳頭水腫或視神經乳頭腫脹，但MRI未顯示紋狀體或較長束水腫的證據。進行了腰椎穿刺以取出 20 cc 腦脊髓液，症狀完全消失並出院。該受試者也接受了預防性抗生素治療。

A subsequent review of the safety data from the previous treated patients identified a third patient who received a higher dose of AMT-130 in March of this year and U.S. segments. This patient had a serious adverse event that was initially deemed by the investigator to be related to the procedure and not AMT-130.

隨後對先前接受治療的患者的安全性數據進行審查，發現第三名患者在今年 3 月接受了更高劑量的 AMT-130 治療，且在美國有分部。該患者發生了嚴重不良事件，研究人員最初認為該事件與手術有關，而與 AMT-130 無關。

The patient was admitted to the hospital 7 days after the procedure with severe headache and vomiting. The patient was treated with analgesics and discharge from the hospital, but returned to the hospital 2 days later with the recurring headache, this time contributed to a CSF leak from a diagnostic lumbar puncture conducted at the prior visit.

患者手術後 7 天因嚴重頭痛和嘔吐入院。患者接受止痛藥治療後出院，但 2 天後因反覆頭痛再次返回醫院，這次頭痛是由於上次就診時進行的診斷性腰椎穿刺導致的腦脊髓液漏。

The patient was treated with a blood patch, which is the procedure by which blood is injected into the spinal canal to patch a hole through which cerebral spinal fluid is leaking. The patient was then discharged from the hospital and is now fully recovered. While the CAT scan taken on day 7 did not reveal any abnormalities, MRI taken on the patient's 14-day follow-up visit showed some edema or swelling in the striatum and the infusion tracks, which largely resolved by the patient's 30-day follow-up visit.

該患者接受了血液修補治療，即將血液注入椎管修補腦脊髓液漏出的孔洞。患者隨後出院，目前已完全康復。雖然第 7 天進行的 CAT 掃描未發現任何異常，但在患者第 14 天的隨訪中進行的 MRI 顯示紋狀體和輸液軌道出現一些水腫或腫脹，這些症狀在患者第 30 天的隨訪中基本上得到解決。

Upon discussion with the DSMB following the events observed in European study, we have reclassified and reported this patient event as a SUSAR and reported to the authorities in mid-July. In compliance with our study protocols, uniQure has reported these events in the appropriate regulatory agencies, review them in detail with our DSMB and initiated a comprehensive investigation. While our investigation is not yet complete, we have thus far found no evidence that these events are related to quality of the clinical loss of AMT-130 or the shipping and handling of the drug or we haven't found any evidence that they were related to a non-lease and pharmaceutical preparation for the surgical procedures.

根據歐洲研究中觀察到的事件，在與 DSMB 進行討論後，我們已將此病患事件重新歸類並報告為 SUSAR，並於 7 月中旬向當局報告。按照我們的研究協議，uniQure 已向適當的監管機構報告了這些事件，與我們的 DSMB 一起詳細審查了它們，並啟動了全面調查。雖然我們的調查尚未完成，但迄今為止我們尚未發現任何證據表明這些事件與 AMT-130 的臨床損失或藥物的運輸和處理品質有關，也沒有發現任何證據表明它們與外科手術的非租賃和藥物製備有關。

As part of our investigation, we are also evaluating if there's any evidence that medical history or genetic predisposition may make some patients more susceptible to acute inflammation. We will share the results of our investigation in a timely manner with regulators and with the medical and scientific community when possible. As all 3 events occurred within the first 1 to 2 weeks after the procedure, we believe that enhanced patient monitoring during this period has the potential to satisfactorily address any patient risk.

作為調查的一部分，我們也正在評估是否有證據表明病史或遺傳傾向可能會使某些患者更容易患急性發炎。我們將盡可能及時與監管機構以及醫學界和科學界分享我們的調查結果。由於所有 3 起事件均發生在手術後的 1 至 2 週內，我們認為在此期間加強對患者的監測有可能令人滿意地解決任何患者風險。

We have developed additional risk mitigation protocols, including closer patient monitoring procedures and treatments, which we are currently discussing with our DSMB. The DSMB does not view these events as a dose-limiting toxicity. However, we and our DSMB believe it's prudent to temporarily pause additional patient dosing with a higher dose until we complete our safety review and investigation and has put the observation and risk mitigation plans in place.

我們已經制定了額外的風險緩解協議，包括更密切的患者監測程序和治療方法，目前正在與我們的 DSMB 進行討論。 DSMB 不認為這些事件是劑量限制性毒性。然而，我們和我們的 DSMB 認為，暫停以更高劑量給額外患者用藥是明智之舉，直到我們完成安全審查和調查並製定觀察和風險緩解計劃。

We expect this will occur sometime in the early fourth quarter. It's important to note that the delay does not apply to any future administration of the low dose of AMT-130. Thus far, no significant adverse events related to AMT-130 have been reported by any of the 12 patients treated with a lower dose, who have now been followed up for up to 2 years. The DSMB has allowed us to continue enrolling at the lower dose of AMT-130 for patients crossing over from the placebo group in the U.S. study, which is expected to take place in the third quarter.

我們預計這將在第四季度初的某個時候發生。值得注意的是，這種延遲並不適用於未來任何低劑量的 AMT-130 的給藥。迄今為止，接受較低劑量治療的 12 名患者中均未報告與 AMT-130 相關的重大不良事件，這些患者的追蹤時間現已長達 2 年。 DSMB 讓我們繼續在美國研究中招募從安慰劑組交叉接受較低劑量 AMT-130 的患者，預計將於第三季度進行。

We are optimistic this matter to be resolved in a timely manner and dosing of the 5 remaining patients in the European higher-dose cohort can be resumed. I want to reiterate, we do not expect that this will have any impact on previously guided data readouts in 2023.

我們樂觀地認為這一問題將得到及時解決，並且可以恢復對歐洲高劑量組剩餘 5 名患者的給藥。我想重申，我們預計這不會對 2023 年之前指導的數據讀數產生任何影響。

With 36 patients enrolled to across both clinical trials, we expect to have sufficient data to maintain our time lines for regulatory discussions and decisions regarding potential registrational pathway. We also continue to be very encouraged by the 12-month update we provided in June on the patients in the lower-dose cohort of the U.S. study. These data show neurofilament light chain levels in your baseline and lowering a mutant Huntington protein levels suggested a meaningful target engagement. We believe this notes has the potential to provide benefits to patients suffering from Huntington's disease and we look forward to working with the HD community to develop a treatment for this devastating disease.

兩項臨床試驗共招募了 36 名患者，我們預計將擁有足夠的數據來維持有關潛在註冊途徑的監管討論和決策的時間表。我們六月提供的美國研究中低劑量組患者的 12 個月更新情況也讓我們感到非常鼓舞。這些數據顯示，您的基線中的神經絲輕鏈水平和降低突變亨廷頓蛋白水平表明有意義的目標參與。我們相信這份報告有可能為亨廷頓舞蹈症患者帶來益處，我們期待與亨廷頓舞蹈症社群合作，研發出治療這種毀滅性疾病的方法。

Now I'd like to open up the call for analyst questions, operator. Thank you.

接線員，現在我想開始分析師提問環節。謝謝。

(Operator Instructions)

（操作員指令）

Our first question will come from Paul Matteis of Stifel.

我們的第一個問題來自 Stifel 的 Paul Matteis。

This is Alex on for Paul. I just wanted to ask, have you share these updates with the FDA yet? What has your dialogue been and is there any risk to be placed on a clinical hold?

這是亞歷克斯 (Alex) 代替保羅 (Paul)。我只是想問一下，你已經與 FDA 分享這些更新資訊了嗎？你們的對話內容是什麼？

Right. This is Ricardo. So absolutely. So right after we brought these reports from the sites, we shared them with both the EMA and the FDA. And so far, we have heard nothing. (technical difficulty)

正確的。這是里卡多。絕對是這樣。因此，我們從這些站點獲得這些報告後，立即與 EMA 和 FDA 分享了這些報告。到目前為止，我們還沒有聽到任何消息。 （技術難度）

Yes, I think your audio is still muffled. But just to repeat it, all of these events have been shared with the appropriate regulatory agencies in accordance with our protocols and regulations and we have not had any specific dialogue with them or outreach that we received.

是的，我認為您的音訊仍然很模糊。但需要重申的是，所有這些事件都已根據我們的協議和規定與相應的監管機構共享，我們尚未與他們進行任何具體對話或進行任何外聯。

Our next question will come from Joe Schwartz of SVB Securities.

我們的下一個問題來自 SVB 證券的 Joe Schwartz。

This is Beth on for Joe. So I know you said that no clear root cause of these serious adverse events have been identified yet, but just curious what your initial hypothesis is on what could be driving it? Is there any sort of reason to believe that it could be associated with the degree of wild-type Huntington's protein knockdown? And just in the serious adverse events occurred so closely to the administration period, curious if that could be playing any sort of role as well?

這是貝絲為喬表演的。所以我知道您說過尚未確定這些嚴重不良事件的明確根本原因，但我好奇您對於導致這些事件的原因的初步假設是什麼？有什麼理由相信它可能與野生型亨廷頓蛋白敲除的程度有關？且嚴重不良事件發生的時間與用藥期間如此接近，好奇這是否也會起到某種作用？

Yes. I think that obviously, we need to complete our investigation before we weigh in specifically on the hypothesis. But I will say that the proximity of these events, which have happened within days of the procedure lead us to believe that it's probably unlikely that it's a mechanism of action related and that it is probably something related to either the immune response or inflammation associated with the product or the procedure itself.

是的。我認為，顯然，我們需要先完成調查，然後才能具體評估這個假設。但我要說的是，這些事件發生的時間都很接近，都在手術後的幾天內發生，這使我們相信，這不太可能與作用機制有關，而可能與產品或手術本身相關的免疫反應或發炎有關。

Got it. And I guess just as a quick follow-up for the 3 patients who appears as serious adverse events, how are they doing now? And just in terms of their NfL signal, have you been monitoring that and notice any sort of differences in how it's maybe the time it takes return to baseline compared to others?

知道了。我想只需對出現嚴重不良事件的 3 名患者進行快速跟踪，他們現在的情況如何？就他們的 NfL 訊號而言，您是否一直在監控它，並注意到與其他人相比，它恢復到基線所需的時間有何差異？

Yes. The 3 patients are no longer hospitalized. 2 of the 3 patients have fully recovered. One of the patients have substantially recovered. I think there's some subtle deficits that are continuing to be monitored. And we have been doing the battery of follow-up tests, including neurofilament light. All of that information is going to be shared or is being shared with the data safety monitoring board in part of the comprehensive investigation.

是的。這3名患者均不再住院。 3名患者中，2名已完全康復。其中一名病人已基本康復。我認為存在一些細微的缺陷，需要繼續監測。我們一直在進行一系列後續測試，包括神經絲光。作為全面調查的一部分，所有這些資訊都將被共享或正在與資料安全監控委員會共享。

Our next question will come from Debjit Chattopadhyay of Guggenheim Partners.

我們的下一個問題來自古根漢合夥人公司的 Debjit Chattopadhyay。

Just a couple of clarifications. What was the volume of administration between the low and the high dose? And is there any difference in the rate of infusion between the 2 doses?

只需澄清幾點。低劑量和高劑量之間的給藥量是多少？這兩種劑量的輸注速度有何不同？

The volume, I think, is roughly the same. I think it's just the concentration that is different. I don't know, Ricardo, if you have changed your audio. But I believe that's the case. And the rate of infusion, I think, is consistent with the low-dose procedure as well.

我認為，音量大致相同。我認為只是濃度不同。里卡多，我不知道您是否改變了您的音訊。但我相信事實確實如此。我認為輸注的速度也與低劑量程序一致。

So yes, so the volume is exactly the same at the low dose and the high dose. It's basically a total of 3 mills in -- for both. And the data input is exactly the same.

是的，低劑量和高劑量的體積完全相同。基本上，兩者合計投入了 3 千萬。且資料輸入也完全相同。

And did you measure neutralizing antibodies at baseline?

你在基線測量過中和抗體嗎？

Yes, and none of the patients have neutralizing antibodies.

是的，並且沒有一個病人具有中和抗體。

Our next question will come from Joseph Thome of Cowen.

我們的下一個問題來自 Cowen 公司的 Joseph Thome。

It seems like the disease course or the response course is a little bit different in the European patients than the U.S. and then that U.S. patient had the CSF issue. So have you ruled out that this is a potential physician or administration error versus something like AMT-130? And then second, what do you expect to learn, I guess, between now and that Q4 safety review?

看起來歐洲患者的病程或反應過程與美國患者略有不同，而那位美國患者出現了腦脊髓液問題。那麼，您是否排除了這是由 AMT-130 之類的藥物引起的潛在醫生或管理人員失誤？第二，從現在到第四季安全審查期間，您希望了解什麼？

So we -- until we finish our investigation, it's probably difficult to rule anything out at this juncture. Having said that, there's been no specific evidence that we have found that's directly implicated the procedure or the way that the procedure has been done. And it's not clear if that's something that we'll be able to identify. But it is true that 2 of these particular SUSARs happened at 1 clinical site and they were the first 2 procedures that were performed at that clinical site. So we'll continue to investigate that, but as I said, we know there's no evidence that supports that thesis right now.

因此，在我們完成調查之前，目前可能很難排除任何可能性。話雖如此，我們還沒有發現任何與該手術或手術方式直接相關的具體證據。目前還不清楚我們是否能夠識別這一點。但確實有 2 例特定的 SUSAR 發生在 1 個臨床地點，並且它們是該臨床地點執行的前 2 例程序。因此我們會繼續調查此事，但正如我所說，我們知道目前沒有證據支持這個論點。

Between now and the next Data Safety Monitoring Board meeting, we're going to complete our investigation associated with reviewing all different aspects and factors that could contribute to the root cause. And we will, in addition, have some further follow-up associated with the 14 patients in the high-dose cohort. I'll just remind everybody that we have treated 14 patients in the high-dose cohort and one of those 14 patients have not reported any significant adverse events related to AMT-130 to follow-up up to 1 year.

從現在到下一次資料安全監測委員會會議期間，我們將完成與審查可能導致根本原因的所有不同面向和因素相關的調查。此外，我們還將對高劑量組的 14 名患者進行進一步追蹤。我只想提醒大家，我們已經治療了 14 名高劑量組患者，其中一名患者在長達 1 年的追蹤中沒有報告與 AMT-130 相關的任何重大不良事件。

So all of that information will be compiled and pulled together for the DSMB as part of the review that we expect to have next month.

因此，所有這些資訊都將被彙編並匯總到 DSMB，作為我們預計下個月進行的審查的一部分。

Our next question shall come from Salveen Richter of Goldman Sachs.

我們的下一個問題來自高盛的 Salveen Richter。

This is Elizabeth on for Salveen. A few from us. So have any more procedures being performed at that same site in the EU where the first 2 procedures were performed?

這是代表薩爾文 (Salveen) 的伊麗莎白 (Elizabeth)。我們中的一些人。那麼，在歐盟內進行前兩次手術的同一地點是否還有其他手術在進行？

And then do you intend to message to the Street after the safety review in 4Q? And then what are kind of the exact evaluations that are going to be performed during safety investigation? And if you could give more color on some of the specific things you're going to be looking at?

那麼，您打算在第四季的安全審查之後向華爾街傳達什麼訊息嗎？那麼安全調查期間具體要進行哪些評估呢？您能否更詳細地介紹一下您將要關注的一些具體事項？

Okay. So the answer to your first question is no, there's been no additional procedures that have been performed at that particular site or any site for that matter. So just to make that clear.

好的。因此，對於您的第一個問題，答案是否定的，在該特定站點或任何站點都沒有執行任何額外的程序。只是為了把這一點說清楚。

Second is that we will provide an update after we complete our review with the Data Safety Monitoring Board. And then third, as I mentioned, there's various different factors and analysis that we'll be looking at. One is that we're going to continue to complete our investigation of the critical quality attributes to the product. As I said, there's nothing thus far that suggests that there's any CMC-related issues or critical quality attributes, but we want to finalize that analysis. We will continue to review the pharmaceutical preparation and shipping and handling associated with the product.

第二，我們將在與資料安全監測委員會完成審查後提供最新消息。第三，正如我所提到的，我們將研究各種不同的因素和分析。一是我們將繼續完成對產品關鍵品質屬性的調查。正如我所說，到目前為止還沒有任何跡象表明存在任何與 CMC 相關的問題或關鍵品質屬性，但我們希望完成該分析。我們將繼續審查與該產品相關的藥品製備、運輸和處理。

Again, there's no evidence that suggests that. There's additional data that will be approved on follow-up visits. Again, remember that we have 26 patients that have been treated thus far that are doing quarterly follow-up visits. And in particular, in the high-dose cohort, a number of those analysis are batched. So we will aggregate that data and review that data with the DSMB, and we expect to do that over the course of the next 60 to 90 days.

再說一遍，沒有證據顯示這一點。還有一些其他數據將在後續訪問中獲得批准。再次提醒，請記住，迄今為止我們已經治療了 26 名患者，並且每季都會進行一次隨訪。特別是在高劑量組中，許多分析都是分批進行的。因此，我們將匯總這些數據，並與 DSMB 一起審查這些數據，我們預計在接下來的 60 到 90 天內完成這項工作。

Our next question shall come from Eliana Merle of UBS.

我們的下一個問題來自瑞銀的 Eliana Merle。

This is Sara Khan on for Eliana. As you're thinking about building out the pipeline beyond hemophilia and Huntington's, how are you thinking about potential business development there?

這是 Sara Khan 為 Eliana 表演的。當您考慮拓展血友病和亨丁頓舞蹈症以外的治療領域時，您如何看待這些領域潛在的業務發展？

So the pipeline beyond Huntington's disease. I mean, we're always looking at business development. Business development is something that is going to be part of our strategy. I think what we're committed to is being disciplined about business development and making sure that any transaction that we might consider is strategic and that we believe can drive value for our shareholders. So beyond that, it's not something that I can really comment on.

因此，該管道不僅限於亨廷頓氏舞蹈症。我的意思是，我們一直在關注業務發展。業務發展將成為我們策略的一部分。我認為，我們致力於嚴守業務發展準則，確保我們考慮的任何交易都是策略性的，並且我們相信這些交易能夠為股東帶來價值。除此之外，我很難對此發表評論。

Our next question will come from Danielle Brill of Raymond James.

我們的下一個問題來自 Raymond James 的 Danielle Brill。

This is Alex on for Danielle. Is there any way this could be related to the duration of the surgery? We're just kind of curious if there's any way that this could be rectified by the planned shortened surgical procedure. And then a quick follow-up or a separate question on the control crossover. Was it ever an option for the patients or for you as a company to provide the low-versus-high dose for the placebo crossover patients who chose to crossover?

這是亞歷克斯 (Alex) 為丹妮爾 (Danielle) 表演的。這與手術持續時間有關係嗎？我們只是有點好奇是否有辦法透過計劃中的縮短手術來糾正這個問題。然後對控制交叉進行快速跟進或單獨提問。對於選擇交叉治療的安慰劑交叉患者，患者或貴公司可以選擇提供低劑量或高劑量的藥物？

Yes. In relation to that question with respect to duration, again, our investigation isn't complete yet, but I'll just remind, I mean, we've done 26 procedures that have been generally consistent in terms of duration. And this is the first 3 SUSARs or events like this that we've seen. So it's -- our thesis is that it's probably not related to the duration of the procedure, but it's something that we'll continue to look at.

是的。關於持續時間的問題，我們的調查尚未完成，但我要提醒一下，我們已經完成了 26 項程序，這些程序的持續時間基本上一致。這是我們見過的前 3 次 SUSAR 或類似事件。所以，我們的論點是，這可能與手術持續時間無關，但我們會繼續關注。

With respect to the crossover, listen, it's difficult to enroll patients in the first-in-man study where they have the possibility of sham control unless they have the potential to crossover to treatment. So I think that, that was always something that I think, was an option that was less open. Of course, it became something that we have to establish safety.

關於交叉，聽著，很難讓患者參與首次人體試驗，因為他們有可能進行假對照，除非他們有潛力進行交叉治療。所以我認為，這始終是一個不太開放的選擇。當然，這已經成為我們必須確保安全的事情。

So I think that now we can offer that the DSMB has evaluated the information and believe that, that's something that we should provide to the patients that had a control.

因此我認為現在我們可以提供 DSMB 已評估的信息，並且相信這是我們應該向接受對照的患者提供的信息。

If I could follow up though. In terms of the crossover, I understand they could crossover. But in terms of -- was that always an option of that they could receive the high dose and now that's off the table, or was that going to be determined after the normal safety and advocacy data?

如果我可以跟進的話。關於交叉，我的理解是他們可以交叉。但就——他們是否一直都可以接受高劑量治療，而現在卻無法再接受了，還是要在正常的安全和宣傳數據之後再決定？

I don't think there was any specificity about exactly which dose they got. I think that, that was something that would be determined based on the information that the DSMB had at the current time. So the bottom line is there is an option for crossover patients to get the high-dose cohort, but it will depend.

我認為沒有具體說明他們服用了哪種劑量。我認為，這是根據 DSMB 目前掌握的資訊來確定的。因此，底線是交叉患者可以選擇高劑量組，但這也取決於具體情況。

Our next question shall come from Sami Corwin of William Blair.

我們的下一個問題來自 William Blair 的 Sami Corwin。

Based on the biomarker data from the low-dose cohort and now the 2 stars in the high-dose cohort, are you guys rethinking your development strategy for AMT-130 at all? And like in particular, are you reevaluating possibly expanding the low-dose cohort?

根據低劑量組的生物標記數據以及現在高劑量組的 2 位明星，你們是否正在重新考慮 AMT-130 的開發策略？具體來說，您是否正在重新評估擴大低劑量組的可能性？

We have not made any decisions yet. It's a little too early for that. I think we want to complete our investigation and have our review with the DSMB. And at that point in time, we'll be better reformed to weigh in on how we might bring forward the product and how that might impact the dose that we move forward.

我們尚未做出任何決定。現在說這個還太早。我認為我們希望完成調查並與 DSMB 進行審查。到那時，我們將進行更好的改革，權衡如何推出產品以及這將如何影響我們未來的劑量。

Okay. And then are there any changes in the time line for conducting the procedures with the new surgical procedure?

好的。那麼，新手術程序實施的時間表有什麼改變嗎？

Well, we wanted to complete dosing of the higher-dose cohort. So that was something that we messaged in the June call. That was really what we're focused on. So we're probably not going to be moving forward with the third-dose cohort until we complete the enrollment of these remaining 5 patients. We think, again, this is something that's a decision that we'll be able to make in the next 60 to 90 days. So we think any impact on the third-dose cohort will be minimal.

嗯，我們想要完成高劑量組的給藥。這就是我們在六月電話會議上傳達的訊息。這確實是我們關注的重點。因此，在完成剩餘 5 名患者的招募之前，我們可能不會繼續進行第三劑接種。我們再次認為，這是我們能在未來 60 到 90 天內做出的決定。因此我們認為對第三劑疫苗的影響將是微乎其微的。

The other part that I'll mention is that, again, the third-dose cohort, it's not really a dose cohort, it's a surgical-adaptive cohort, where we're going to be mostly focused on understanding the feasibility and CP, the procedure. So we don't think that, that impact is going to impact late-stage development in a material way at this juncture.

我要提到的另一部分是，第三劑量隊列實際上並不是一個劑量隊列，而是一個手術適應性隊列，我們將主要專注於了解可行性和 CP 以及程序。因此，我們認為，這種影響不會對後期開發產生實質影響。

Our next question will come from Robyn Karnauskas (inaudible) of Truist.

我們的下一個問題來自 Truist 的 Robyn Karnauskas（聽不清楚）。

This is Alex on for Robyn. I just wanted to clarify, if the DSMB concludes that the SAEs observed were procedure-related, would this third-dose cohort with a different procedure to qualified to establish a new procedure that might be better? Or would you need additional clinical trials? And would you apply that to the low-dose cohort if you wanted to expand that trial and carry that forward?

這是 Alex 為 Robyn 表演的。我只是想澄清一下，如果 DSMB 得出結論認為觀察到的 SAE 與程序有關，那麼採用不同程序的第三劑量組是否有資格建立可能更好的新程序？還是您需要額外的臨床試驗？如果您想擴大該試驗並繼續進行，您會將其應用於低劑量組嗎？

Yes. Again, it's going to be difficult to hypothesize or conjecture about what might happen. I would say again that it's probably unlikely that it's generic procedure-related. We haven't seen any significant adverse events related to AMT-130 or the procedure and the entire low-dose cohort of 12 patients, and there's 11 of the 14 in the high-dose cohort where we haven't seen it as well. It might be something related to the specific procedure right, of that particular patient. But I think it's unlikely that there's some generic issue with the procedure itself, given the safety track record that we have over the last 2 years. But any learnings that we get from this to the extent that they're applicable across the board, they certainly will be applied for the benefit of all patients. And that would include risk mitigation or closer-patient monitoring procedures.

是的。再次，假設或推測會發生什麼將會非常困難。我想再說一遍，這不太可能與通用程式有關。我們沒有發現與 AMT-130 或該程序以及整個 12 名低劑量組患者相關的任何重大不良事件，而在 14 名高劑量組中，也有 11 名患者沒有發現此類事件。這可能與特定患者的特定手術程序有關。但考慮到我們過去兩年的安全記錄，我認為該程序本身不太可能存在一些一般問題。但是，我們從中獲得的任何經驗如果能夠適用於所有領域，就肯定會造福所有患者。這包括降低風險或更密切的患者監測程序。

Up next, we have Luca Issi of RBC Capital Markets.

接下來我們請到的是 RBC Capital Markets 的 Luca Issi。

I know this was discussed a little bit earlier, but can you just help us understand how adverse events are dichotomized as related to the procedure versus related to the actual drug, is that a pretty clear cut? Or is this more like a fine line that comes down to clinical judgment? So again, any color there would be great.

我知道之前已經討論過這個問題，但您能否幫助我們理解不良事件是如何分為與手術相關的不良事件和與實際藥物相關的不良事件的，這樣劃分是否比較明確？或者這更像是一條取決於臨床判斷的細線？所以再說一次，任何顏色都可以。

And then in terms of resuming the dose, what are your options here that you're contemplating in order to resolve the issue at a high dose in addition to more frequent monitoring, what are the other levers that you can pull? How you're thinking about potentially refining inclusion-exclusion criteria? Are you considering maybe putting all patients on stereo-prophylactically? Any additional color there would be great.

那麼就恢復劑量而言，除了更頻繁的監測之外，您正在考慮採取哪些選擇來解決高劑量的問題，您還可以採取哪些其他措施？您如何考慮改進納入-排除標準？您是否考慮讓所有患者都接受立體預防治療？任何額外的顏色都很棒。

Yes. So adverse events are really characterized by the investigator. So those events are documented and the specific investigator that is managing that patient really weighs in and attribute that to either the procedure or the product or unrelated to the best of their ability. So it's really a judgment call that is really clinician-directed. It's also something that we would review with our Data Safety Monitoring Board and to take into opinion their evaluation and recommendations as well.

是的。因此不良事件實際上是由研究人員描述的。因此，這些事件都被記錄下來，負責管理該患者的具體研究人員會認真考慮，並盡其所能將其歸因於手術、產品或無關因素。因此，這實際上是由臨床醫生做出的判斷。我們也會與資料安全監控委員會一起審查此事，並考慮他們的評估和建議。

And then just remind me your second question?

然後提醒我你的第二個問題？

Yes, what are your options going forward here to kind of solve the issues? You obviously talked about more frequent monitoring, but I was wondering if there's any other components here that you're contemplating?

是的，您接下來有什麼選擇來解決這些問題？您顯然談到了更頻繁的監控，但我想知道您是否正在考慮其他組件？

Yes. No, it's really -- I mean just as to remind you -- all of these really happened in the first 1 to 2 weeks, right? So these are things that we can check in with patients on a daily basis. Before they're discharged from the hospital, we can do specific evaluations to make sure that they are meeting certain standards for discharge. There's a possibility that we could do, if there's anything we have normal or unusual, we can do an additional MRI procedure. And then if there are any symptoms of edema or inflammation, we can much more rapidly bring them in for suppression or steroid treatment. So that's really what it is that we're focused on. If there's any reactions that happen quickly, we can identify those reactions and then get the patient treated. And with that, we think we can substantially mitigate any risk to the patients.

是的。不，真的——我只是想提醒你——所有這些都確實發生在前 1 到 2 週，對嗎？這些是我們可以每天與患者檢查的事情。在他們出院之前，我們可以做具體的評估，以確保他們符合一定的出院標準。如果發現任何正常或不正常的情況，我們可以進行額外的 MRI 檢查。如果出現任何水腫或發炎症狀，我們可以更快地進行抑製或類固醇治療。所以這確實就是我們關注的重點。如果出現任何快速發生的反應，我們可以識別這些反應，然後對患者進行治療。有了它，我們認為我們可以大大減輕患者的風險。

Our next question will come from Kristen Kluska of Cantor Fitzgerald.

我們的下一個問題來自 Cantor Fitzgerald 的 Kristen Kluska。

Just to switch gears on hemophilia B. Is there any color behind the decision that the review could not be done in Europe on an accelerated basis? And when in the U.S. and Europe and CSL bearing expect approval decisions to take place at this time? And then can you remind us of the near-term milestone payments you are eligible for?

只是為了換個話題討論血友病 B。那麼美國、歐洲和 CSL 預計何時會做出批准決定？然後您能提醒我們您有資格獲得的近期里程碑付款嗎？

Yes, sure. So with respect to the interactions with EMA that is being handled completely by CSL. What we have heard from CSL is that there was no specific issue that was identified in the review that led to the switching from accelerated-to-standard review that this is simply just a bandwidth issue and for EMA and as a result, that they needed some additional time for the review, but there was nothing specific.

是的，當然。因此，與 EMA 的互動完全由 CSL 處理。我們從 CSL 獲悉，審查中並未發現導致從加速審查轉為標準審查的具體問題，這只是 EMA 的頻寬問題，因此他們需要一些額外時間進行審查，但並未發現具體問題。

With respect to the timing of approval, I think that again is something that CSL will have to provide. I think what we've said is that we would now expect approval probably early next year, early in the first quarter of next year. That's based on the standard review. So that's what we would (technical difficulty) With respect to milestones, we have stated that there's $175 million that would be received upon commercial launch of the product in the United States and Europe. And then there's additional milestones that are commercial related to certain net sales thresholds as well as commercial launch in Japan.

關於批准時間，我認為這是 CSL 必須提供的。我想我們已經說過，我們現在預計批准可能在明年年初，即明年第一季初。這是基於標準審查。所以這就是我們要做的（技術難度）關於里程碑，我們已經聲明，在美國和歐洲商業推出該產品時將收到 1.75 億美元。然後還有一些與某些淨銷售額門檻以及在日本的商業發布相關的其他里程碑。

Our next question will come from Judah Frommer of Credit Suisse.

我們的下一個問題來自瑞士信貸的 Judah Frommer。

First, maybe just following up on kind of the hypothesis that CMC or quality control and handling our product could have potentially been an issue here. Would those have been the same for the EU and the U.S. product, where those have come from the same batch or potentially been handled the same way just by being conducted at different sites?

首先，也許只是追蹤某種假設，即 CMC 或品質控制和處理我們的產品可能是一個問題。對於歐盟和美國的產品來說，這些產品是否來自同一批產品，或者可能只是在不同的地點以相同的方式處理？

Precisely the analysis that we do, right? We just look to see if there's any loss, a lot of differences in any of the critical quality attributes. And based on that assessment, we do not believe that the -- that this is likely to be anything related to CMC.

這正是我們所做的分析，對嗎？我們只是看看是否有任何損失，以及任何關鍵品質屬性是否存在很大差異。基於該評估，我們認為這不太可能與 CMC 有關。

Okay. And then just if we do end up in a situation where there was a dose-limiting toxicity here, kind of -- can you assess kind of how that would affect your confidence in the program, if you were maybe only going forward with the low dose? Maybe just remind us of your preclinical work and how the potentially confer functional benefit if we are going to be in a functional study at some point ideally with that least or low dose?

好的。那麼，如果我們最終確實面臨出現劑量限制性毒性的情況，您是否可以評估如果您只繼續使用低劑量，這會如何影響您對該計劃的信心？也許只是提醒我們您的臨床前工作，以及如果我們要在某個時間點以最少或低劑量進行功能研究，它如何可能帶來功能性益處？

Yes. This doesn't impact my confidence in the program, honestly. I mean the purpose of a dose-finding study is exactly that to find the right dose. We are really pleased with the data that we presented thus far from the first 10 patients in the U.S. study. We haven't seen any significant adverse events related to the low dose. We saw suppression of mutant protein and through the spinal fluid that, quite frankly, was more meaningful than what we saw in the preclinical work. So that was over 50% depression mutant protein. At 12 months, we've seen neurofilament light levels near baseline. So we're really encouraged by that data. And even if there is a dose-limiting toxicity, we'll have to obviously continue to follow patients that received the low-dose cohort, but we continue to be really pleased and encouraged about that dose.

是的。說實話，這並沒有影響我對該計劃的信心。我的意思是劑量探索研究的目的正是找到正確的劑量。我們對迄今為止從美國研究中獲得的前 10 位患者獲得的數據感到非常滿意。我們尚未發現任何與低劑量有關的重大不良事件。我們看到突變蛋白的抑制，並透過脊髓液，坦白說，這比我們在臨床前工作中看到的更有意義。因此，憂鬱症突變蛋白的比例超過50％。在 12 個月時，我們看到神經絲光水平接近基線。因此這些數據確實讓我們感到鼓舞。即使存在劑量限制性毒性，我們顯然也必須繼續追蹤接受低劑量治療的患者，但我們對該劑量仍然感到非常高興和鼓舞。

Our next question shall come from Yanan Zhu of Wells Fargo.

我們的下一個問題來自富國銀行的朱亞南。

So I think in 2021, FDA convened an Advisory Committee meeting reviewing AAV gene therapy safety. And one of the topics was MRI abnormalities arising in patients who received intra-parenchymal injections of AAV. So I'm wondering, based on those, the information presented there, how do you feel your -- the cases you have been seeing similar or different from those cases, for example, in terms of timing of onset and whether patients are symptomatic or not?

因此我認為 2021 年 FDA 召開了一次諮詢委員會會議，以審查 AAV 基因治療的安全性。其中一個主題是接受 AAV 腦實質內注射的患者出現的 MRI 異常。所以我想知道，基於這些所提供的信息，您認為您所看到的病例與這些病例有何相似或不同之處，例如在發病時間以及患者是否有症狀方面？

Yes. It's hard for me to compare it against what was presented at the panel, but as I say, these are pretty acute cases. All the patients have been treated, have either fully recovered or substantially recovered. The most important thing is, obviously, the clinical prognosis for these patients. We're still learning a lot around what we're actually seeing in the MRI. What is this related to? In some cases, it's the drug working, and it's not a best thing. But what is the best thing, obviously, if there's any safety implications for the patients, but the most important thing is that these patients can be treated, they can be monitored more closely and that they can recover, right? So that's really the most important thing that we're focused on. And so we're pleased in that regard.

是的。我很難將其與小組討論中提出的情況進行比較，但正如我所說，這些都是非常嚴重的案例。所有患者均已治療，或完全康復或基本康復。顯然，最重要的是這些患者的臨床預後。我們仍在學習大量有關 MRI 中實際看到的內容。這和什麼有關？在某些情況下，這是藥物起作用了，但這並不是最好的事情。但顯然，如果對患者有任何安全隱患，那最好的事情是什麼呢？所以這確實是我們關注的最重要的事情。我們對此感到高興。

Got it. If I may have a quick follow-up. In the low-dose patients, have any of them been followed up with MRI? And whether are there any MRI findings in those patients, of course, those will be nonsymptomatic.

知道了。如果我可以快速跟進的話。在低劑量患者中，有沒有接受過 MRI 追蹤？這些患者是否有任何 MRI 發現，當然，這些都是無症狀的。

All of them, every simulation is followed up with an MRI. Those MRIs happen, I believe, quarterly. And the -- I think what we've reported at the time that we presented this data on the low-dose cohort patients is that there were no structural abnormalities on the MRI, but a full safety update will be provided when we present comprehensive data next year.

所有這些，每次模擬都會透過 MRI 進行追蹤。我相信這些 MRI 檢查每季進行一次。而且——我認為我們在展示低劑量組患者的數據時報告稱，MRI 上沒有結構異常，但明年我們展示全面數據時將提供完整的安全更新。

Our next question will come from Yun Zhong of BTIG.

我們的下一個問題來自BTIG的Yun Zhong。

This is a follow-up question on the low dose. Given the data, like you said, Matt, expect -- exceeded our expectations. So I wonder how much effort and time would you like to spend to figure out the high dose before deciding maybe low dose is the optimal dose to move forward?

這是關於低劑量的後續問題。從數據來看，就像馬特所說的那樣，預計超出了我們的預期。所以我想知道，在決定低劑量可能是最佳劑量之前，您願意花多少精力和時間來確定高劑量？

Yes. I mean I'll remind everybody. So we have 14 patients that have received treatment with the high dose. So -- and there's remaining 5 patients in the European study that have not been treated thus far. This is in the first 2 dose cohorts. So I mean, we can follow the 14 patients that we've treated and have very robust data to, I think, evaluate the high dose and the low dose next year. So I'm not sure we concerned that we'll be spending a lot of energy or a lot of time evaluating this.

是的。我的意思是我會提醒大家。因此，我們有 14 名患者接受了高劑量治療。所以——歐洲研究中還有 5 名患者迄今尚未接受治療。這是前兩劑。所以我的意思是，我們可以追蹤我們治療過的 14 名患者，並且擁有非常可靠的數據，我認為，可以在明年評估高劑量和低劑量。所以我不確定我們是否擔心會花費大量精力或時間來評估這一點。

I think to the extent that the DSMB continues to have pause when we do our safety review, we always have the possibility of contemplating, treating those remaining patients with a low dose. But as I said, we'll cross that bridge when we have that discussion and provide an update after that time.

我認為，只要 DSMB 在我們進行安全審查時繼續暫停，我們總是有可能考慮用低劑量治療剩下的患者。但正如我所說的，當我們進行討論時，我們會解決這個問題，並在那之後提供最新消息。

And we have a follow-up question from Debjit of Guggenheim Partners.

古根漢合夥人公司的 Debjit 也提出了後續問題。

A clarification. Is the EU segment enrolling subjects with similar disease stage and caudate putamen volume as the United States?

澄清一下。歐盟部分是否招募與美國具有相似疾病分期和尾殼核體積的受試者？

Yes.

是的。

Got it. And do you have a sense where the NfL lines up in these patients? I know it's early, but given the U.S. patient who had SAE back in March, do you have a sense of where NfL lines up in these patients with SAEs versus those who have not experienced an SAE?

知道了。您是否知道這些患者中的 NfL 群組情況如何？我知道現在還為時過早，但考慮到 3 月美國出現 SAE 的患者，您是否知道 NfL 在這些出現 SAE 的患者和未出現 SAE 的患者中處於什麼位置？

Yes. What I'll say is that we're not providing any of that specific details, but the information is being reviewed by the Data Safety Monitoring Board.

是的。我要說的是，我們不會提供任何具體的細節，但這些資訊正在接受資料安全監控委員會的審查。

And we have a follow-up from Luca of RBC Capital Markets.

我們也收到了 RBC Capital Markets 的 Luca 的後續提問。

Great. I'll be quick. Just circling back on the hemophilia B delay in Europe. Is this related to the companion diagnostic? Or how should we think about that?

偉大的。我會很快的。剛剛回顧了歐洲血友病 B 的延遲情況。這與伴隨診斷有關嗎？或者說我們該如何思考這個問題？

No. I answered that part before. There's no specific issue that was cited by the European authorities related to it at all. So this is not like there's a specific issue that they've identified and feel they need more time to review that specific issue with just a bandwidth issue with the agency that they feel they just need more time to complete the review.

沒有，我之前回答過這個部分。歐洲當局根本沒有提到與此相關的具體問題。因此，這並不像他們發現了一個特定問題並覺得他們需要更多時間去審查該特定問題，而只是機構的頻寬問題，他們覺得他們只是需要更多時間來完成審查。

And I'm seeing no further questions in the queue. I would now like to turn the conference back to Matthew Kapusta for closing remarks.

我發現隊列中沒有其他問題。現在，我想請馬修·卡普斯塔致閉幕詞。

Thank you, operator. In summary, we remain confident in the potential of AMT-130 in Huntington's disease, continue to be very encouraged by the data we recently presented. We hope to resume higher-dose enrollment with minimal delay. We do not expect any impact to the previously guided data readouts for next year. As mentioned earlier, patient safety will always be our top priority, and I'd like to express my gratitude for patients, their families and physicians who have been part of our clinical trial to date for their trust in us and their dedication to pursuing new treatment options. Thank you for attending this call, and we look forward to providing further update as soon as possible. Thank you.

謝謝您，接線生。總之，我們仍然對 AMT-130 在治療亨廷頓舞蹈症的潛力充滿信心，我們最近呈現的數據繼續讓我們感到鼓舞。我們希望盡快恢復更高劑量的招募。我們預計這不會對明年先前指導的數據讀數產生任何影響。如前所述，病人安全永遠是我們的首要任務，我要向迄今為止參與我們臨床試驗的患者、他們的家人和醫生表示感謝，感謝他們對我們的信任以及他們致力於尋求新的治療方案。感謝您參加本次電話會議，我們期待盡快提供進一步的更新。謝謝。

Thank you. This concludes today's conference call. Thank you all for participating. You may now disconnect, and have a pleasant day.

謝謝。今天的電話會議到此結束。感謝大家的參與。現在您可以斷開連接並享受愉快的一天。