Rocket Pharmaceuticals Inc (RCKT) 2021 Q2 法說會逐字稿

Welcome to the Rocket Pharmaceuticals Inc. Investor Conference Call. My name is Vanessa, and I will be your operator for today's call. (Operator Instructions).

歡迎參加 Rocket Pharmaceuticals Inc. 投資者電話會議。我叫凡妮莎，我是今天電話的接線生。 （操作員說明）。

I will now turn the call over to your host, Mayur Kasetty, Director of Business Development and Operations.

我現在將把電話轉給主持人、業務開發和營運總監 Mayur Kasetty。

Thank you, Vanessa. Good afternoon, everyone. This is Mayur Kasetty, Director of Business Development and Operations and Investor Relations Lead at Rocket Pharmaceuticals. Thank you for joining us.

謝謝你，凡妮莎。大家下午好。我是 Mayur Kasetty，Rocket Pharmaceuticals 業務開發和營運總監以及投資者關係主管。感謝您加入我們。

The purpose of this call is to share and discuss key updates on our clinical programs. Before we begin, I would like to briefly discuss the use of forward-looking statements on this conference call. Statements we make on this call may include statements which are not historical facts and are considered forward-looking within the meaning of the securities laws and which are usually identified by the use of words such as anticipates, believes, estimates, expects, intends, may, plans, projects, seeks, should, will and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for purposes of complying with those safe harbor provisions.

這次電話會議的目的是分享和討論我們臨床項目的關鍵更新。在我們開始之前，我想先簡單討論一下本次電話會議中前瞻性陳述的使用。我們在本次電話會議上發表的聲明可能包括非歷史事實的聲明，並被視為證券法含義內的前瞻性聲明，並且通常通過使用諸如預期、相信、估計、預期、打算、可能等詞語來識別。我們希望這些前瞻性聲明受到《證券法》第 27A 條和《證券交易法》第 21E 條所載前瞻性陳述的安全港條款的約束，並出於遵守這些安全港條款的目的而做出此聲明。

These forward-looking statements reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects, as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control, including, without limitation, those set forth in our earnings release issued earlier today and in Item 1A, Risk Factors of our annual report on Form 10-K for the year ended December 31, 2020, and as updated by our subsequently filed quarterly reports on Form 10-Q and our other SEC filings. We assume no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise.

這些前瞻性陳述反映了我們目前對我們的計劃、意圖、期望、策略和前景的看法，這些看法是基於我們目前掌握的資訊和我們所做的假設。儘管我們相信這些前瞻性陳述所反映或暗示的我們的計劃、意圖、期望、策略和前景是合理的，但我們不能保證這些計劃、意圖、期望或策略將會實現或實現。此外，實際結果可能與前瞻性聲明中描述的結果有重大差異，並將受到我們無法控制的各種風險和因素的影響，包括但不限於我們今天早些時候發布的收益報告和我們截至2020 年12 月31 日的10-K 表格年度報告的第1A 項“風險因素”，以及我們隨後提交的10-Q 表格季度報告和其他SEC 文件的更新內容。我們不承擔公開更新任何前瞻性陳述的義務，無論是由於新資訊、未來事件或其他原因。

Participating on today's call on behalf of Rocket are Dr. Gaurav Shah, Chief Executive Officer; Dr. Jonathan Schwartz, Chief Medical Officer and Clinical Development Senior Vice President; Dr. Gayatri Rao, Chief Development Officer and Head of Regulatory Policy; Carlos Garcia, Chief Financial Officer; and Claudine Prowse, Senior Vice President of Strategy and Corporate Development. There will be a question-and-answer session at the end of this call in which we will all participate.

代表 Rocket 參加今天電話會議的是執行長 Gaurav Shah 博士； Jonathan Schwartz 博士，首席醫療官兼臨床開發資深副總裁； Gayatri Rao 博士，首席開發長兼監管政策主管；卡洛斯·加西亞，財務長；策略與企業發展資深副總裁 Claudine Prowse。本次電話會議結束時將舉行問答環節，我們都將參加。

I will now turn the call over to Gaurav.

我現在將把電話轉給高拉夫。

Thank you, Mayur. And thank you, everyone, for joining us today. We have several updates to take you through. Let me highlight the 4 key take-homes for today. First, regarding the Danon clinical hold, we are reiterating our previous guidance that based on our most recent FDA interactions and exercising the best of our judgment and estimation, we continue to anticipate resuming the trial this quarter, Q3. Second, for Danon, the low dose is demonstrating increasing and durable benefit. We will go over key data points, including some new ones in a minute. Third, for Danon, we are removing the high dose from future dosing plans. Fourth, Fanconi Anemia, LAD-I and PKD remain on track, and we will provide further clinical updates in Q4. Those are the key takeaways. We will now get to some more details.

謝謝你，馬尤爾。感謝大家今天加入我們。我們有幾項更新可供您參考。讓我重點介紹今天的 4 個關鍵要點。首先，關於達能臨床暫停，我們重申我們先前的指導，根據我們最近與 FDA 的互動，並運用我們最好的判斷和估計，我們繼續預計在本季度（第三季度）恢復試驗。其次，對於達能來說，低劑量顯示出越來越多且持久的益處。我們將在一分鐘內討論關鍵數據點，包括一些新數據點。第三，對於達能，我們正在從未來的劑量計畫中刪除高劑量。第四，範可尼貧血、LAD-I 和 PKD 仍處於正軌，我們將在第四季度提供進一步的臨床更新。這些是關鍵要點。我們現在將了解更多細節。

Starting with Danon. We've been working very closely with the FDA over the last several weeks. And through our discussions, we have agreed to modify our immune suppression and complement inhibition protocols with bolster safety guard rails. In addition to these protocol updates, we've had a chance to review updated low-dose data sets with the FDA that Rocket believes is supportive of its potential as a viable Phase II dose. Notably, photographic evidence for all 3 low-dose patients show improvements, meaning decrease in autophagic vacuoles, a hallmark of Danon disease pathology as assessed by electron microscopy of cardiac tissue via endomyocardial biopsy.

從達能開始。過去幾週我們一直與 FDA 密切合作。透過我們的討論，我們同意修改我們的免疫抑制和補體抑制方案，並加強安全防護。除了這些協議更新之外，我們還有機會與 FDA 一起審查更新的低劑量資料集，Rocket 認為這些資料集支持其作為可行的 II 期劑量的潛力。值得注意的是，所有3 名低劑量患者的照片證據均顯示出改善，這意味著自噬空泡減少，這是達農病病理學的一個標誌，透過心內膜心肌活檢對心臟組織進行電子顯微鏡評估。

Additionally, 2 of the 3 low-dose patients with closely monitored immunosuppressive regimen compliance demonstrated improvements in New York Heart Association Class from 2 to 1, which translates to no comparative dysfunction. These patients also demonstrated substantial improvement of a key marker of heart failure, BNP, which decreased by 75% and 79% versus baseline levels as well as improvements in cardiac output by 35% to 62% compared to baseline as measured by invasive hemodynamics. All 3 treated low-dose patients continue to demonstrate stabilization or improvements in BNP 6-minute walk test as well as New York Heart Association Class. Given the activity observed in patients in the low-dose cohort and importantly, to mitigate associated safety concerns in the E14 range, we have decided to forego pursuit of the higher doses, meaning 1.1e14 vector genomes per kilogram or higher. This is a decision that was made in agreement with the FDA and allows us to focus fully on the low dose moving forward, the 6.7e13, also reduces the total number of patients needed in our Phase I study and potentially allows for more rapid progression to Phase II.

此外，在密切監測免疫抑制方案依從性的 3 名低劑量患者中，有 2 名患者的紐約心臟協會等級從 2 級提高到 1 級，這意味著沒有相對功能障礙。這些患者也表現出心臟衰竭關鍵標記BNP 的顯著改善，與基線水平相比下降了75% 和79%，並且透過有創血流動力學測量，心輸出量比基線水平提高了35% 至62%。所有 3 名接受低劑量治療的患者在 BNP 6 分鐘步行測試以及紐約心臟協會等級測試中繼續表現出穩定或改善。鑑於在低劑量組患者中觀察到的活動，重要的是，為了減輕 E14 範圍內的相關安全問題，我們決定放棄追求更高劑量，即每公斤 1.1e14 個載體基因組或更高。這是與 FDA 達成一致的決定，使我們能夠完全專注於未來的低劑量 6.7e13，也減少了我們 I 期研究所需的患者總數，並可能允許更快地進展到第二階段。

Now as disclosed in December 2020, one patient in the high-dose cohort who is the heaviest patient treated to date and has highly advanced disease developed complement-mediated thrombotic microangiopathy, which resolved fully with transient hemodialysis. This patient continued to have progressive disease considered unrelated to gene therapy by the trial investigator as well as transplant cardiologist and successfully went on to receive a heart transplant. The patient is currently doing well clinically and, of course, resolution of this baseline myopathy that was present prior to treatment. Analysis of the explanted part demonstrates fibrosis that was consistent with end-stage Danon disease.

現在，正如2020 年12 月所披露的那樣，高劑量隊列中的一名患者是迄今為止接受治療的最重的患者，並且患有高度晚期疾病，出現了補體介導的血栓性微血管病，通過短暫性血液透析完全解決了此疾病。試驗研究者和移植心臟科醫生認為該患者仍患有與基因治療無關的進行性疾病，並成功接受了心臟移植。該患者目前臨床狀況良好，當然，治療前存在的基線肌病變也得到了緩解。對外植部分的分析表明，纖維化與終末期 Danon 病一致。

Our belief has always been that the onset of fibrosis in the year or so prior to transplant could diminish the efficacy of gene therapy, and this patient exemplifies the importance of earlier intervention in this disorder. We, at Rocket, do not consider this a safety issue, and it is not considered related to the hold. We believe it does highlight the importance of the right timing in order for gene therapy to be fully effective. In discussions with the FDA on this case, we have refined our eligibility criteria to focus on patients earlier in disease.

我們一直認為，移植前一年左右出現纖維化可能會降低基因治療的功效，而該患者證明了早期幹預這種疾病的重要性。在火箭，我們不認為這是一個安全問題，也不認為它與等待有關。我們相信，它確實強調了正確時機的重要性，以便基因療法充分有效。在與 FDA 就此案例進行討論時，我們完善了資格標準，以關注疾病早期的患者。

Now importantly, as of this past week, we have submitted all requested changes to FDA and have confirmation that we have agreement on the updated program. As mentioned, we expect that we can resume a trial in Q3 with the revised eligibility criteria in place and refined safety measures in place. Moving forward, we have inbound interest for more than 20 patients for participation in the trial, and we look forward to progressing rapidly towards Phase I completion and the Phase II registration trial.

現在重要的是，截至上週，我們已向 FDA 提交了所有要求的變更，並確認我們已就更新計劃達成協議。如前所述，我們預計我們可以在第三季恢復試驗，並制定修訂後的資格標準和完善的安全措施。展望未來，我們有超過 20 名患者有興趣參與試驗，我們期待快速完成 I 期臨床試驗和 II 期註冊試驗。

One final point on Danon. Throughout the duration of this hold, we have had an exceptionally collaborative discussion and dialogue with the agency. And with our confidence in the low dose and modifications to our clinical trial protocol, we are truly excited about the prospects of our Danon program and look forward to presenting longer-term data on both the low- and higher-dose patients in the fourth quarter of this year.

關於達能的最後一點。在整個暫停期間，我們與該機構進行了異常合作的討論和對話。憑藉我們對低劑量和對臨床試驗方案的修改的信心，我們對達能項目的前景感到非常興奮，並期待在第四季度提供低劑量和高劑量患者的長期數據今年的。

Now turning to our lentiviral programs. We provided updates at ASGCT for our Fanconi Anemia, LAD-I and PKD programs and continue our momentum towards regulatory filings. For our final lenti program, we are deeply saddened that the first patient treated in our infatile malignant osteopetrosis Phase I trial has passed away from likely non-gene therapy-related pulmonary complications with autopsy-confirmed evidence of pulmonary hemorrhage that was very likely related to thrombocytopenia following conditioning therapy and also related to underlying osteopetrosis. Of note, pulmonary complications occur more commonly in osteopetrosis patients relative to many other nonmalignant immunologic diseases, especially in those patients who are undergoing a transplant. Consistent with the protocol, we have paused enrollment pending a comprehensive evaluation in collaboration with an independent data monitoring committee. We look forward to providing updates on all of our programs in the fourth quarter of 2021.

現在轉向我們的慢病毒計畫。我們在 ASGCT 上提供了 Fanconi 貧血、LAD-I 和 PKD 項目的最新信息，並繼續推進監管備案。對於我們最後的慢病毒項目，我們深感悲痛的是，在我們的不孕性惡性骨石症I 期試驗中接受治療的第一位患者已經死於可能與非基因治療相關的肺部併發症，屍檢證實的肺出血證據很可能與調理治療後血小板減少症也與潛在的石骨症有關。值得注意的是，相對於許多其他非惡性免疫疾病，肺部併發症在骨石症患者中更常見，特別是在接受移植的患者中。根據協議，我們已暫停招募，等待與獨立數據監測委員會合作進行全面評估。我們期待在 2021 年第四季提供所有計劃的最新資訊。

And finally, as many of you may know, Claudine Prowse will be transitioning out of Rocket to take on the CFO role at another company. Claudine has been with Rocket for 3.5 years and has been an integral part of our growth story from the days of Inotek for those who were there then, we were private to a mid-cap public company. While we are and I personally am sad to see Claudine leave us, we are tremendously excited for her and sincerely thank her for her contributions here at Rocket.

最後，正如你們許多人可能知道的那樣，克勞丁·普勞斯 (Claudine Prowse) 將從 Rocket 離職，在另一家公司擔任財務長。 Claudine 已經在 Rocket 工作了 3.5 年，從 Inotek 時代起，他就一直是我們成長故事中不可或缺的一部分，對於當時在那裡的人來說，我們是一家中型上市公司的私人公司。雖然我們，而且我個人對克勞丁離開我們感到難過，但我們為她感到非常興奮，並真誠地感謝她在火箭隊所做的貢獻。

Now I'll pass it to Claudine.

現在我將其傳遞給克勞丁。

Thank you, Gaurav. Looking back, Rocket has had extraordinary growth since going public. The company has already delivered a lot of value to shareholders. And I look forward to seeing Rocket's continued success in the future over the long term. I am so truly grateful to be part of this journey. Mayur?

謝謝你，高拉夫。回顧過去，Rocket自上市以來取得了非凡的成長。該公司已經為股東創造了許多價值。從長遠來看，我期待看到火箭隊在未來繼續取得成功。我非常感激能夠參與這趟旅程。馬尤爾？

Thank you, Claudine. This concludes our prepared remarks. The Rocket executive team is now happy to address any questions on this update. I'll turn the call back over to the operator for Q&A.

謝謝你，克勞丁。我們準備好的演講到此結束。火箭執行團隊現在很樂意解答有關此更新的任何問題。我會將電話轉回接線生進行問答。

(Operator Instructions) Our first question is from Greg Harrison with Bank of America.

（操作員說明）我們的第一個問題來自美國銀行的格雷格·哈里森。

This is [Ashton] on for Greg. So it seems like you're pretty much aligned with FDA at this point for resuming Danon. I guess is there anything else that needs to be done before getting that study started? And just kind of tack on to that a little bit. With this upcoming AAV gene therapy AdCom (inaudible) running, is there any chance that's a gating factor? And if not, just what are your general expectations for that AdCom?

這是格雷格的[阿什頓]。因此，目前看來您與 FDA 非常同意恢復 Danon 的業務。我想在開始這項研究之前還需要做些什麼嗎？只是稍微強調一點。隨著即將推出的 AAV 基因療法 AdCom（聽不清楚）的運行，這是否有可能成為門控因素？如果沒有，您對 AdCom 的整體期望是什麼？

Gaurav here. Thanks for the question. So as of last week, we have confirmation of no further clinical comments in the protocol. We respect the FDA process, and we're waiting for the FDA to complete this full review. And that's what we can say at the moment.

高拉夫在這裡。謝謝你的提問。因此，截至上週，我們已確認方案中沒有進一步的臨床評論。我們尊重 FDA 的流程，並且正在等待 FDA 完成全面審查。這就是我們現在可以說的。

With regard to the upcoming advisory committee meeting, I will actually pass this over to Dr. Gayatri Rao, who is one of the Rocket executive team members and who actually may know Head of the Office of Orphan Drug Products for 7 years at the FDA and now working with us. Gayatri?

關於即將召開的諮詢委員會會議，我實際上會將其轉交給 Gayatri Rao 博士，他是 Rocket 執行團隊成員之一，實際上可能認識 FDA 孤兒藥產品辦公室主任 7 年，現在與我們合作。加亞特里？

Thanks, Gaurav. This is Gayatri Rao. To answer the specific question related to the Advisory Committee meeting, as far as we know, we -- the -- we really have no reason to believe that there's any sort of relationship between this clinical hold and the timing or the advisory committee meeting, and it's certainly inconsistent with all the communications that we've had with the agency to date. With respect to the meeting itself, we're looking forward to engaging in the meeting and listening and learning from the discussion there.

謝謝，高拉夫。這是加亞特里·拉奧。為了回答與諮詢委員會會議相關的具體問題，據我們所知，我們確實沒有理由相信這次臨床擱置與諮詢委員會會議的時間安排之間存在任何關係，這肯定與我們迄今為止與該機構進行的所有溝通不一致。就會議本身而言，我們期待參與會議並傾聽會議的討論並從中學習。

Our next question is from Dae Gon Ha with Stifel.

我們的下一個問題來自 Dae Gon Ha 和 Stifel。

Great. On the thrombotic microangiography, are you able to discuss the details behind the reclassification of SUSAR? And I guess, does that have anything to do with -- or has that been reflected in the mitigation strategy as you submitted it last week? And I guess a follow-up to that is, in the May call, you talked about 2 buckets as it pertains to the resumption of the trial, that being risk mitigation and eligibility criteria. So has anything changed in your view? Or anything in that proposal changed since that May update?

偉大的。關於血栓微血管造影，您能否討論一下SUSAR重新分類背後的細節？我想，這與您上週提交的緩解策略有關係嗎？我想後續行動是，在五月的電話會議中，您談到了與恢復試驗有關的兩個方面，即風險緩解和資格標準。那麼您的看法有什麼改變嗎？或者自五月更新以來該提案中的任何內容發生了變化？

Absolutely. So the SUSAR reclassification was based on recent guidance that we planned for the agency, and it is reflected in certain protocol changes that will, in the future, define such events as SUSAR. So I think that's the bottom line. So it's really part of the tightening of protocol measures and safety monitoring. And with regards to what we have said in May, it's the same thing. We have defined these monitoring parameters more closely. We've defined handling of SAEs. We've timed some of the safety guardrails around immunosuppression and complement inhibition and slightly refined eligibility criteria to focus slightly earlier treatment and avoid end-stage disease patients. Those are the same points that we had anticipated in May based on the initial FDA call and they remain the exact same.

絕對地。因此，SUSAR 的重新分類是基於我們最近為該機構計劃的指導方針，並且它反映在某些協議更改中，這些更改將在未來將此類事件定義為 SUSAR。所以我認為這是底線。因此，這實際上是加強協議措施和安全監控的一部分。至於我們五月所說的話，也是同樣的事情。我們更嚴格地定義了這些監控參數。我們已經定義了 SAE 的處理。我們圍繞免疫抑制和補體抑制制定了一些安全防護措施，並稍微細化了資格標準，以稍微關注早期治療並避免終末期疾病患者。這些與我們在 5 月根據 FDA 最初電話會議的預期相同，而且仍然完全相同。

Our next question is from Gil Blum with Needham & Company.

我們的下一個問題來自 Needham & Company 的 Gil Blum。

Just about the death that happened on the IMO study, is there really any significant differences between the conditioning regimen seeing in transplant in these patients versus the gene therapy?

就 IMO 研究中發生的死亡而言，這些患者的移植預處理方案與基因療法之間是否真的有顯著差異？

You mean versus other gene therapies?

你的意思是與其他基因療法相比？

No, just versus the hematopoietic stem cell transplant, which is sometimes viewed as the standard of care.

不，只是與造血幹細胞移植相比，造血幹細胞移植有時被視為護理標準。

Got it. Is there any difference between the conditioning used in osteopetrosis gene therapy versus osteopetrosis transplant? That's what you're asking? Correct?

知道了。石骨症基因治療與石骨症移植中使用的調理有什麼不同嗎？這就是你問的？正確的？

Yes.

是的。

Right. I'll pass that over to Dr. Jonathan Schwartz.

正確的。我會將其轉交給喬納森·施瓦茨博士。

This is Jonathan Schwartz. The conditioning regimen that's used in the osteopetrosis gene therapy study is myeloablative busulfan that's governed by pharmacokinetic guidance or TDM therapeutic drug monitoring. In general, this is a less extensive myelosuppressive and less extensive immunomodulatory regimen that would be utilized in an allogeneic transplant for this condition, typically your allogeneic transplant regimens will utilize combinations of myeloablative therapy. Sometimes that's busulfan and cyclophosphamide or total (inaudible) and different chemotherapy regimens. And then they also utilize an immunosuppressive or lymphosuppressive therapies as well. So this is a less extensive but nonetheless myeloablative conditioning regimen that's part of our gene therapy program.

這是喬納森·施瓦茨。骨石症基因治療研究中使用的預處理方案是清髓性白消安，受藥物動力學指導或 TDM 治療藥物監測控制。一般來說，這是一種不太廣泛的骨髓抑制和不太廣泛的免疫調節方案，可用於治療這種情況的同種異體移植，通常您的同種異體移植方案將採用清髓療法的組合。有時是白消安和環磷酰胺或總（聽不清楚）和不同的化療方案。然後他們也使用免疫抑製或淋巴抑制療法。因此，這是一種不太廣泛但仍具有清髓性的預處理方案，是我們基因治療計劃的一部分。

Our next question is from Yaron Werber with Cowen.

我們的下一個問題來自 Yaron Werber 和 Cowen。

Gaurav, I have maybe 2 questions. The first one is when you did your echos, did you see any left ventricular ejection fraction benefits or -- where patient is essentially sort of normal at baseline? And what about stroke volume because it's obviously related to cardiac output? And then any update on 6-minute walk testing with longer follow-up? And with all of that in mind, based on what do you're saying, what do you think might be a primary endpoint for pivotal?

Gaurav，我可能有兩個問題。第一個是當您進行超音波檢查時，您是否看到左心室射血分數有任何改善，或者患者在基線時基本上是正常的？那麼每搏輸出量又如何呢，因為它顯然與心輸出量有關？那麼 6 分鐘步行測試以及更長的追蹤有什麼更新嗎？考慮到所有這些，根據您所說的，您認為關鍵的主要終點是什麼？

So on the echo for ejection fraction, many patients, if not most patients, have preserved ejection fraction until they reach end-stage disease. This was true for most of the patients that had been enrolled in the trial. We have disclosed previously that the exception here was that last patient who did, as I mentioned earlier, move on to have transplant, that patient was starting to lose cardiac function. More on that as we update our criterion. And -- sorry, you have to ask the second one again. There was a couple in there.

因此，就射血分數的回波而言，許多患者（如果不是大多數患者）都保留了射血分數，直到達到終末期疾病。對於大多數參加試驗的患者來說都是如此。我們之前已經透露過，這裡的例外是最後一位患者，正如我之前提到的，繼續進行移植，該患者開始喪失心臟功能。當我們更新我們的標準時，會詳細介紹這一點。而且──抱歉，你得再問第二個問題。那裡有一對夫婦。

Yes. The second one, what about stroke volume because that's obviously a determinant of cardiac output and the 6-minute walk testing?

是的。第二個是每搏輸出量，因為這顯然是心輸出量和 6 分鐘步行測試的決定因素？

Stroke volume and then we'll get to 6-minute walk endpoints. So on cardiac output, the data that was revealed in December, there is the current data set that we're working on that we've also shared with the agency. Some of these patients do start having worsening cardiac output even before there's a loss of ejection fraction. And in 2 of the 3 patients I've mentioned, we have started to see increases in cardiac output as measured by the patient's hemodynamics.

每搏輸出量，然後我們將達到 6 分鐘步行終點。因此，關於心輸出量，即 12 月公佈的數據，我們正在研究當前的數據集，我們也已與該機構共享了該數據集。其中一些患者甚至在射血分數下降之前就開始出現心輸出量惡化。在我提到的 3 名患者中，有 2 名患者的血流動力學測量的心輸出量開始增加。

In terms of 6-minute backcast, we now, and this is new information from before, have demonstrated 6-minute walk test stabilization or improvement in all 3 of the low-dose patients, and that's alongside stabilization or improvements in BNP as well as New York Heart Association Class. So that's new information. And the endpoint, we have cast a wide net in terms of capturing appropriate endpoints to help us guide towards Phase II. These include biomarkers and the kind that we've discussed, BNP, even vacuole clearance and as well as imaging endpoints such as ejection fraction, clinical functional endpoints such as 6-minute walk test or even quality of life endpoints such as NYHA Class. So any of these could be part of the endpoints. We can't speculate on what that -- what those will be until we have an end of Phase I discussion with the FDA. I think the -- there's been about a quarter delay here on the trial right now. At the same time, we've had a collaborative discussion with the FDA. Sometimes you don't have these discussions about endpoints until later in development. And we're hopeful that potentially we could expedite the trial based on the conversations we're having right now with the agency.

就 6 分鐘反向預測而言，我們現在（這是先前的新資訊）已證明所有 3 名低劑量患者的 6 分鐘步行測試穩定或改善，同時 BNP 以及 BNP 也穩定或改善紐約心臟協會課程。這是新資訊。至於終點，我們在捕獲適當的終點方面撒下了廣泛的網，以幫助我們引導第二階段。這些包括生物標記和我們討論過的那種，BNP，甚至液泡清除率，以及射血分數等成像終點、6 分鐘步行測試等臨床功能終點，甚至 NYHA 等級等生活品質終點。因此，其中任何一個都可能是端點的一部分。在我們與 FDA 結束第一階段討論之前，我們無法推測那是什麼——那些將是什麼。我認為目前審判已經推遲了大約四分之一。同時，我們與 FDA 進行了合作討論。有時，直到開發後期才會對端點進行這些討論。我們希望，根據我們目前與該機構的對話，我們有可能加快試驗進程。

And Gaurav, just want to make sure I got that right. The 6-minute walk test -- I'm sorry, if I missed it. You mentioned you saw an improvement in 6-minute walk and New York Heart Class and -- I'm sorry, in BNP and New York Heart Class, but did you also say 6-minute walk, it was stabilized or improved?

Gaurav，只是想確保我做對了。 6 分鐘步行測試——如果我錯過了，我很抱歉。您提到您看到 6 分鐘步行和紐約心臟課程有所改善，並且 - 對不起，在 BNP 和紐約心臟課程中，但您是否也說 6 分鐘步行，它已穩定或改善？

Yes. So I'll go through detail. All 3 patients have stabilization or improvement in BNP, 6-minute walk test and cardiac output. And -- sorry, BNP, 6-minute walk test and heart class. All 3 patients have stabilization or improvement. The 2 patients who had monitored immunosuppression regimen that is closely monitored, those 2 patients specifically had drops in BNP from 75% to 79% versus Phase I. And also, they had improvements in New York Heart Association Class. Those are the 2 patients who had the monitored immunosuppression. But all 3 patients have stabilization across all parameters. 6-minute walk test specifically, we haven't revealed those data, we will in fourth quarter, but it's been stable or improved in all 3 of those patients as well at this point.

是的。所以我會詳細介紹。所有 3 名患者的 BNP、6 分鐘步行測試和心輸出量均穩定或改善。還有——抱歉，BNP，6 分鐘步行測試和心臟課程。所有 3 名患者的病情均已穩定或改善。密切監測免疫抑制方案的 2 名患者，與 I 期相比，這 2 名患者的 BNP 從 75% 下降到 79%。這是 2 名接受監測免疫抑制的患者。但所有 3 名患者的所有參數均穩定。具體來說，6 分鐘步行測試，我們還沒有透露這些數據，我們將在第四季度公佈，但此時所有 3 名患者的情況都已穩定或有所改善。

Our next question is from Mani Foroohar with SVB Leerink.

我們的下一個問題來自 SVB Leerink 的 Mani Foroohar。

My first question is, are there any changes to the protocol for Danon disease that could potentially change the proportion of patients that would be eligible for the trial? Then I have a follow-up.

我的第一個問題是，達農病方案是否有任何變化，可能會改變有資格參加試驗的患者比例？然後我有一個後續行動。

Mani, we are identifying patients that we would consider end-stage disease. We've always said that, in the last year or so prior to transplant, the onset of fibrosis is such that gene therapy probably would not be effective. Those patients were never considered to be part of the treatable population. So overall, the answer is it does not change the treatable or addressable market here.

Mani，我們正在確定我們認為是末期疾病的病人。我們總是說，在移植前的最後一年左右，纖維化開始出現，基因治療可能不會有效。這些患者從未被視為可治療族群的一部分。總的來說，答案是它不會改變這裡的可治療或可尋址市場。

Great. You said you're looking forward to meeting and listening and learning of the September AdCom. Can you confirm whether or not you're invited or will be participating in (inaudible) yourself?

偉大的。您說過您期待與 9 月的 AdCom 會面、聆聽和學習。您能否確認您是否被邀請或將親自參加（聽不清楚）？

Yes. We have had no discussions with the FDA about the AdCom. To date, we have not been invited, and -- but we'll certainly be listening.

是的。我們尚未與 FDA 就 AdCom 進行任何討論。到目前為止，我們還沒有受到邀請，但我們肯定會傾聽。

Our next question is from Raju Prasad with William Blair.

我們的下一個問題來自拉朱·普拉薩德和威廉·布萊爾。

With the agreement with the FDA for not going to the high dose, what should we expect for the clinical progression of this program? Is it the lower dose with more adult patients and then going into a pediatric population? Or do you plan on kind of advancing into the pediatric population once you can reenroll patients into the trial? And then I have a question on the -- in the special regimen.

隨著 FDA 同意不使用高劑量，我們對該計畫的臨床進展有何期待？是用較低的劑量治療較多的成年患者，然後再進入兒童群體嗎？或者，一旦您可以將患者重新納入試驗，您是否計劃進軍兒科族群？然後我有一個關於特殊方案的問題。

Thanks for the question, Raj. Our intent is to move forward right away with the pediatric population low dose, and we'll update as that happens.

謝謝你的提問，拉吉。我們的目的是立即推進兒童低劑量治療，我們將及時更新。

Okay. Great. And maybe if you could just clarify the changes that were made to the immunosuppression regimen as far as complement activation goes, that would be helpful.

好的。偉大的。也許如果您能澄清免疫抑制方案在補體活化方面所做的改變，那將會有所幫助。

We will definitely update as the trial progresses certainly in the fourth quarter. I don't want to provide too many specifics during an active FDA dialogue. But yes, we will definitively update. There's nothing in there that is -- that we would consider major. It's refinements, revisionings, tightening of the protocol and nothing that really affects the types of patients that we can treat other than the eligibility point we made or affects the trial conduct today.

隨著審判的進展，我們肯定會在第四季度進行更新。我不想在與 FDA 的積極對話中提供太多細節。但是，是的，我們一定會更新。那裡沒有什麼是我們認為重要的。它是對方案的改進、修訂和收緊，除了我們制定的資格點或影響今天的試驗進行之外，沒有什麼真正影響我們可以治療的患者類型。

And we have our next question from Esther Rajavelu with UBS.

瑞銀集團的 Esther Rajavelu 提出了下一個問題。

I have just a couple. One is on the patients with the fibrosis. You've kind of defined the market as about 33,000 patients across the U.S. and EU, and does that 33,000 exclude the patients with fibrosis that are in advanced stages? Or how are you kind of whittling down from their tier enrollment criteria?

我只有幾個。一是針對患有纖維化的患者。您將市場定義為美國和歐盟約 33,000 名患者，這 33,000 名患者是否排除了晚期纖維化患者？或者你如何降低他們的等級註冊標準？

Yes, that's a good question. We think that the number of patients with fibrosis that's probably (inaudible) impact of gene therapy is very small. It's really going to be voice in the months and maybe a year or so leading up to the actual heart transplant or an unfortunate case of death. Females, which is a population we haven't really talked about yet and is certainly very viable as we move the program forward, have different sorts of heart disease and certainly would not be affected in the same way. So I think that the -- if you're looking for exact numbers within those 30,000, those numbers are general. There -- we think, if anything, they're -- they've been validated by a third party now. And as we capture even more classifications, there's a possibility that those numbers could expand. So I don't think that, that sliver of sort of patient's baseline characteristics that would eliminate end-stage disease is going to be -- is going to get into that prevalence number too much at this point.

是的，這是一個好問題。我們認為，可能（聽不清楚）基因治療影響的纖維化患者數量非常少。在實際的心臟移植或不幸的死亡病例之前的幾個月甚至一年左右的時間裡，這真的會成為聲音。女性是我們還沒有真正討論過的人群，隨著我們推進該計劃，女性肯定是非常可行的，她們患有不同類型的心臟病，當然不會受到同樣的影響。所以我認為，如果你要尋找這 30,000 人中的確切數字，這些數字都是一般數字。我們認為，如果有的話，它們現在已經得到第三方的驗證。隨著我們捕獲更多的分類，這些數字有可能會擴大。因此，我認為，能夠消除終末期疾病的一小部分患者基線特徵在這一點上不會過多地影響患病率。

And you kind of mentioned females consistently since the start of the trial. What are -- what exactly do you need to see in the current patients that are enrolled to move forward with a girl?

自試驗開始以來，您一直提到女性。您到底需要在目前登記的與女孩繼續治療的患者中看到什麼？

With females?

與女性？

With females. Yes. Sorry.

與女性。是的。對不起。

No, no. We don't really need to see that much. I think we want to get a little bit further into the Phase I and start thinking about what Phase II design would look like in boys first. But there's nothing more we really need to see to start a trial in females. We have not given any guidance on when that trial will start, but it's certainly in the near- to medium-term plans.

不，不。我們其實不需要看那麼多。我認為我們想要進一步了解第一階段，並開始思考第二階段的設計首先會是什麼樣子。但我們真正需要看到的只是在女性中開始試驗。我們尚未就試驗何時開始提供任何指導，但肯定是在中短期計劃中。

Got it. Okay. And just to clarify, the Phase II trial you're planning will be only in boys then?

知道了。好的。澄清一下，您計劃的第二階段試驗將只針對男孩？

The current Phase II would -- not the current. The upcoming Phase II would be based on the current Phase I. And we would want to extrapolate what we've learned from Phase I to apply to Phase II. So that first trial which we hope will be registration in nature would be limited to boys. And in parallel, we would start exploring a trial in females. That would support a separate trial as (inaudible) down the road.

目前的第二階段將是—而不是當前。即將到來的第二階段將基於目前的第一階段。因此，我們希望本質上是註冊的第一次試驗將僅限於男孩。同時，我們將開始探索針對女性的試驗。這將支持今後（聽不清楚）進行單獨的試驗。

Our next question is from Josh Schimmer with Evercore.

我們的下一個問題來自 Evercore 的 Josh Schimmer。

Just continuing on the topic of the Phase II registration study for Danon. What kind of data is it that you are looking to capture from the pediatric patients enrolled in the Phase I study? And how do you think that will ultimately inform the design of the Phase II, what are the different parameters you're considering that are still not yet determined that will be informed by Phase I? And then separately, for the unfortunate patient in past with IMO who passed away, are there any unique features about that patient that might have explained the unfortunate outcome, whether they were older or more advanced disease than patients who might have otherwise gone for a traditional stem cell transplant?

繼續討論達能二期註冊研究的議題。您希望從參與 I 期研究的兒科患者中獲得什麼樣的數據？您認為這最終將如何為第二階段的設計提供資訊？另外，對於過去因 IMO 去世的不幸患者，該患者是否有任何獨特的特徵可以解釋不幸的結果，無論他們比可能接受傳統治療的患者年齡更大或更晚期？

Thanks, Josh. So in terms of what we would need to see in the pediatric Phase I low dose to start a Phase II, I think that's a discussion that obviously we'll have with the agency at the end of Phase I meeting. I think if we see more of what we saw in the low-dose adults and confirmation of potential prospect of direct benefit of pediatrics, if we can confirm that, then we'll be moving towards Phase II relatively rapidly. And in terms of how to define the final endpoint for the Phase II trial, I think that's still a discussion that will be had as soon as possible. I think, the dialogue that we've been having over the last several weeks, hopefully, primes the end of Phase I dialogue and accelerates Phase II development plans for pediatrics as well as adults retention.

謝謝，喬許。因此，就我們需要在兒科第一階段低劑量中看到什麼來開始第二階段而言，我認為這顯然是我們將在第一階段會議結束時與該機構進行的討論。我認為，如果我們在低劑量成人中看到更多的情況，並確認兒科直接受益的潛在前景，如果我們能夠證實這一點，那麼我們將相對較快地邁向第二階段。至於如何定義二期試驗的最終終點，我認為這仍然是一個將盡快進行的討論。我認為，過去幾週我們一直在進行的對話有望為第一階段對話的結束做好準備，並加速兒科和成人保留的第二階段發展計劃。

On the osteopetrosis question, I will defer to Jonathan if there were any differences in that patient versus other osteopetrosis patients that might have been predisposed.

關於石骨症問題，如果該患者與其他可能容易罹患石骨症的患者之間有任何差異，我將聽取喬納森的意見。

Can you repeat the question with respect to the osteopetrosis patient?

您能重複一下關於石骨病患者的問題嗎？

Yes, Jonathan, just wondering if there are any clinical features that might have portended the outcome that they had, whether it was more advanced disease, older patients who maybe have not been eligible for an earlier stem cell transplant that might explain why they had that develop.

是的，喬納森，只是想知道是否有任何臨床特徵可能預示著他們的結果，是否是更晚期的疾病，是否有資格接受早期幹細胞移植的老年患者，這可能可以解釋他們為什麼會出現這種情況發展。

Yes. Yes. So we'll provide a more comprehensive information regarding the specific individual as we disclose clinical data at relevant conferences later this year. I don't think that there was necessarily anything that we would identify in this patient as either low or high risk. One thing that we're very much aware of is that in osteopetrosis, many of these patients do have chronic lung compromise that's related to the bone abnormalities that the ribs caused a restricted lung pattern and some of the sinus abnormalities create sort of a chronic inflammation in the bronchi and pulmonary parencema, which is why -- probably why these patients do have a high degree of pulmonary complications in allogeneic transplant settings. Obviously, our intent is to provide a therapy that's less overall chemo than you would have in an allo transplant. But nonetheless, you're still talking about many of these patients having fairly complex lung environment. I don't think we can comment right now that there was anything specific about this patient that we'd be able to say made him or her different from a typical osteopetrosis patient, all of these kids have pretty severe underlying disorder.

是的。是的。因此，當我們在今年稍後的相關會議上披露臨床數據時，我們將提供有關特定個體的更全面的資訊。我認為我們不一定會在這名患者身上識別出任何低風險或高風險的東西。我們非常清楚的一件事是，在骨石症中，許多患者確實患有慢性肺部損害，這與肋骨導致肺部模式受限和一些鼻竇異常產生某種慢性發炎的骨骼異常有關。和肺實質中，這可能是為什麼這些患者在同種異體移植環境中確實出現高度肺部併發症的原因。顯然，我們的目的是提供一種比同種異體移植所需的整體化療更少的療法。但儘管如此，您仍在談論許多患者的肺部環境相當複雜。我認為我們現在無法評論該患者有任何特殊之處，我們可以說他或她與典型的骨硬化症患者不同，所有這些孩子都有相當嚴重的潛在疾病。

Okay. May I ask one quick follow-up on the Danon pediatric patients and next phase of the trial, if they are younger, are they unlikely then to have baseline abnormalities that would be amenable to improvement? And I guess for older patients, you could see the improvement in BNP and performance status and heart failure. But if you're enrolling younger patients, are you unlikely to see that just because they have not deteriorated to a degree that they would have meaningful baseline abnormalities?

好的。我可以問達能兒科患者的快速追蹤和下一階段的試驗，如果他們更年輕，他們是否不太可能出現可以改善的基線異常？我想對於老年患者，您可以看到 BNP、體能狀態和心臟衰竭的改善。但是，如果您招募年輕患者，您是否不太可能僅僅因為他們的病情尚未惡化到出現有意義的基線異常的程度而看到這一點？

Josh, Gaurav here. There are a number of pediatric patients who have onset of cardiac disease even earlier than the adolescents that have been treated. And remember, the cutoff here is age 15 for young adults/adolescent and below that is considered pediatric. And the disease is although inexorably leads to heart failure around 19 or 20 on average, it is heterogeneous. So there are many pediatric patients who do have some signs or symptoms of cardiac disease. Those are the ones that would be enrolled in the pediatric Phase I. Ultimately, we may want to move the therapy even before onset of cardiac disease as a preventative measure, but that's not what this trial is about. All pediatric patients (inaudible) signs or symptoms, class II heart failure or higher is (inaudible).

喬什，高拉夫在這裡。許多兒科患者的心臟病發病時間甚至早於接受治療的青少年。請記住，這裡的界線是年輕人/青少年的 15 歲，低於該年齡的則被視為兒科。這種疾病雖然不可避免地導致平均 19 或 20 歲左右的心臟衰竭，但它是異質的。因此，有許多兒科患者確實有心臟病的一些徵兆或症狀。這些是將被納入兒科第一階段的藥物。所有兒科患者（聽不清楚）的徵兆或症狀均為 II 級或更高等級的心臟衰竭（聽不清楚）。

And before we move to the next question, Josh, I also wanted to add an IMO that the protocol has defined measures by which we have part of the trial. We have shared this information with the FDA, and we have not been asked to put the trial on hold and (inaudible) self-mandated pause based on the protocol, just leave it there.

在我們進入下一個問題之前，喬什，我還想補充一點，IMO 協議已經定義了我們參與部分試驗的措施。我們已與 FDA 分享了此信息，並且我們沒有被要求暫停試驗並根據方案自行強制暫停（聽不清楚），只是將其留在那裡。

And also, Josh, I know we're spending a lot of time. You had asked about what other information could help us move the trial, the pediatric trial forward into Phase II. We're also developing a final version of our natural history output, and we're learning a lot about how patients decline, especially in the early teenage years. And we hope that, that side-by-side with activity that we're starting to see in the low dose can justify a trial that could potentially be a single-arm trial. So that's the idea here moving to Phase II.

而且，喬什，我知道我們花了很多時間。您曾詢問過哪些其他資訊可以幫助我們將兒科試驗推進到第二階段。我們也正在開發自然史輸出的最終版本，我們正在了解很多關於患者如何衰弱的知識，尤其是在青少年時期。我們希望，我們開始在低劑量下看到的活動能夠證明一項可能是單臂試驗的試驗的合理性。這就是進入第二階段的想法。

Our next question is from David Hoang with SMBC.

我們的下一個問題來自 SMBC 的 David Hoang。

So I wanted to ask about the decision to discontinue the high dose. I mean, clearly, it makes sense for all the reasons we talked about. But I remember you had pursued it in part because you thought there may be some extra cardiac benefits. So without, I guess, maybe capturing those now that have the option of high dose, do you think that, that impacts the overall value proposition of the gene therapy to any significant degree?

所以我想問停止高劑量的決定。我的意思是，顯然，對於我們討論的所有原因來說，這是有道理的。但我記得你追求它的部分原因是你認為它可能對心臟有一些額外的好處。因此，我想，也許如果不捕獲那些現在可以選擇高劑量的人，您認為這會在很大程度上影響基因療法的整體價值主張嗎？

So Danon disease is multi-organ as you say. It would be nice to treat the full spectrum of disease if possible. However, the mortality in this disease is cardiac in origin. So if we're able to address the cardiac aspects of the disease, extending life is in our estimation the ultimate value proposition and especially if we could confirm normal longevity in these patients who would otherwise have to wait to get a heart transplant by age 19 or 20. So it was a strategy that we had in place, but I think we go with what works and what works in a very major way.

所以達農病正如你所說是多器官的。如果可能的話，治療所有疾病就好了。然而，這種疾病的死亡率是心臟病引起的。因此，如果我們能夠解決該疾病的心臟方面問題，那麼延長生命在我們看來就是最終的價值主張，特別是如果我們能夠確認這些患者的正常壽命，否則他們將不得不等到19 歲時才能進行心臟移植或 20. 所以這是我們制定的一項策略，但我認為我們會選擇有效的方法以及在很大程度上有效的方法。

Understood. And then I just was wondering with the -- as you tease out what's the appropriate endpoints for a Phase II in Danon, do you -- is your baseline assumption that the approval that you'll get, would that be an accelerated approval? Or do you think you'd be able to get a full approval (inaudible) basically do you just additional clinical work after the initial approval?

明白了。然後我只是想知道——當你梳理出達能第二階段的適當終點是什麼時，你——你的基準假設是你將獲得的批准，這會是加速批准嗎？或者您認為您能夠獲得完全批准（聽不清楚）基本上您只是在初步批准後進行額外的臨床工作嗎？

Yes. It's hard to speculate at this point. I think that we have a range of biomarkers that could support an accelerated approval plan. At the same time, we also recognize that a mortality benefit and the ultimate marker is clinical success here. So at the moment, we can't really speculate, but we hope to have answers that we start having in the Phase I dialogue with the agency. And I will also ask Jonathan to weigh in here and also comment on some of the other extracardiac manifestation points that were just asked.

是的。目前很難推測。我認為我們擁有一系列可以支持加速批准計劃的生物標記。同時，我們也認識到死亡率的益處和最終標誌是臨床成功。因此，目前我們還不能真正推測，但我們希望在與該機構的第一階段對話中得到答案。我也會請喬納森在這裡發表意見，並對剛剛提出的其他一些心外表現點發表評論。

Thank you, Gaurav. Jonathan Schwartz here again. I think it's important to emphasize that, although obviously, the cardiac disease is what is fatal in essentially all of those male Danon disease patients, and that's where we'll build the endpoint around. I don't think we can yet discount whether the low dose can or can't affect the noncardiac manifestations. Importantly, if you look at Danon female patients, they don't have substantive extracardiac manifestations. So we may well see benefit in neuromuscular or neurocognitive aspects of the disease in these male Danon patients with the levels of transduction that has -- and protein expression that has been seen in the low-dose adults treated to date. Likely, that will take a little bit longer to determine than the cardiac benefits that we believe we have seen to date, but certainly, it's possible that we may also substantively affect the noncardiac elements in these patients just as the females who have likely 30% to 50% of normal (inaudible) expression largely are unaffected by those aspects of this disorder.

謝謝你，高拉夫。喬納森·施瓦茨又來了。我認為有必要強調的是，儘管很明顯，心臟病基本上是所有男性達農病患者的致命疾病，這就是我們將圍繞這一點建立終點的地方。我認為我們還不能忽視低劑量是否會影響非心臟表現。重要的是，如果你觀察達能女性患者，你會發現她們沒有實質的心外表現。因此，我們很可能會看到這些男性 Danon 患者的疾病的神經肌肉或神經認知方面的益處，其轉導水平和迄今為止在低劑量治療的成年人中觀察到的蛋白質表達水平。可能，這需要比我們相信迄今為止所看到的心臟益處更長的時間來確定，但當然，我們也可能對這些患者的非心臟因素產生實質影響，就像可能有 30% 的女性一樣到50% 的正常（聽不清楚）表達很大程度上不受這種疾病這些方面的影響。

Our next question is from Patrick Dolezal with LifeSci Capital.

我們的下一個問題來自 LifeSci Capital 的 Patrick Dolezal。

As it relates to the patient that underwent heart transplant, you mentioned fibrosis was apparent. However, was there any worsening myocarditis observed in the explanted heart or evidence that an immune response contributed to the need for heart transplant? And if so, has there been anything similar observed in biopsies from patients at the low dose?

由於與接受心臟移植的患者有關，您提到纖維化很明顯。然而，在移植的心臟中是否觀察到心肌炎惡化或有證據表明免疫反應導致需要心臟移植？如果是這樣，在低劑量患者的活檢中是否觀察到類似的情況？

All right, Patrick. No, no myocarditis, no inflammatory changes in the explanted heart, and we also didn't see any of those pathologies on the other low-dose patients that we've looked at.

好吧，派崔克。不，沒有心肌炎，移植的心臟沒有發炎變化，而且我們在我們觀察的其他低劑量患者身上也沒有看到任何這些病變。

Our next question is from Eric Joseph with JPMorgan.

我們的下一個問題來自摩根大通的埃里克約瑟夫。

I joined late, so sorry if the question has already been addressed. But maybe just a clarification question as it relates to the potential pivotal Phase II for Danon. Should we be -- are you contemplating a single program that addresses both adolescents and pediatrics? Or would they be programs win in parallel? And I guess, to the extent it's the latter, can you just -- maybe just articulate what some of the gating factors would be to an end of Phase I meeting? Are the data that you have so far in terms of patient numbers and follow-up sufficient? Or would you need to see incremental data with the revised protocol -- or new patient data with the revised protocol?

我加入得很晚，如果問題已經解決，我很抱歉。但也許只是一個澄清問題，因為它涉及達能潛在的關鍵第二階段。我們是否應該—您是否正在考慮制定一個針對青少年和兒科的單一計劃？或者它們會是並行獲勝的程序嗎？我想，就後者而言，您能否——也許只是闡明第一階段會議結束的一些限制因素是什麼？到目前為止，您掌握的患者數量和追蹤數據是否足夠？或者您需要查看修訂後的方案的增量數據，或修訂後的方案的新患者數據？

Yes. So with regard to start of Phase II, what we need to see is, number one, some data in pediatrics for sure, and we need to see the output from a natural history so that we can define the protocol design and also figure out what the right endpoints are going to be in collaboration with the FDA, and those are the things that are gating. We don't think that we need to add more patients to get there, if anything, actually, since we've cut out the high dose now, the number of patients needed to the end of Phase I meeting is likely going to be smaller. So that's one point I want to make. For your first question, we anticipate one trial for pediatrics and adolescents. We don't anticipate 2 separate ones there. So right now, the gating factors are the ones you described, and we hope to move forward pretty rapidly.

是的。因此，關於第二階段的開始，我們首先需要看到的是兒科的一些數據，我們需要看到自然史的輸出，以便我們可以定義方案設計並找出什麼正確的終點將與FDA 合作，而這些都是正在控制的事情。我們認為我們不需要增加更多的患者來達到這一目標，實際上，因為我們現在已經取消了高劑量，所以第一階段會議結束時所需的患者數量可能會更少。這就是我想說的一點。對於你的第一個問題，我們預計將針對兒科和青少年進行一項試驗。我們預計那裡不會有兩個單獨的。所以現在，限制因素就是你所描述的那些，我們希望能夠快速前進。

Thank you, everyone, for participating in today's call, and we look forward to updating you again soon.

感謝大家參加今天的電話會議，我們期待盡快再次向您通報最新情況。

And thank you, ladies and gentlemen. This concludes our conference, and we thank you for your participation. You may now disconnect.

謝謝你們，女士們先生們。我們的會議到此結束，感謝您的參與。您現在可以斷開連線。