Editas Medicine Inc (EDIT) 2024 Q2 法說會逐字稿

Good morning and welcome to the Editas Medicine second quarter 2024 conference call. (Operator Instructions) Please note, this call is being recorded at the company's request. I'd like to turn the call over to Christy Barnhart, Corporate Communications and Investor Relations at Editas Medicine.

早安，歡迎參加 Editas Medicine 2024 年第二季電話會議。（操作員說明）請注意，本次通話是應公司要求進行錄音的。我想將電話轉給 Editas Medicine 企業傳播和投資者關係部門的 Christy Barnhart。

Thank you, Britney. Good morning, everyone, and welcome to our second quarter 2024 conference call. Earlier this morning, we issued a press release providing our financial results and recent corporate updates. A replay of today's call will be available in the Investors section of our website approximately two hours after its completion.

謝謝你，布蘭妮。大家早安，歡迎參加我們的 2024 年第二季電話會議。今天早些時候，我們發布了一份新聞稿，提供了我們的財務表現和最近的公司更新。今天電話會議的重播將在會議結束後大約兩小時在我們網站的投資者部分提供。

After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for the purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995.

在我們準備好發言後，我們將開始問答環節。需要提醒的是，我們在本次電話會議中就公司未來預期、計畫和前景發表的各種言論均構成前瞻性陳述，符合 1995 年《私人證券訴訟改革法案》中的安全港條款。

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC as updated by our subsequent filings.

由於各種重要因素的影響，實際結果可能與這些前瞻性陳述所顯示的結果有重大差異，其中包括我們最新的10-K 表格年度報告的風險因素部分中討論的因素，該報告已向SEC 存檔並更新通過我們隨後的備案。

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements even if our views change.

此外，任何前瞻性陳述僅代表我們今天的觀點，不應被視為代表我們在任何後續日期的觀點。除非法律要求，否則即使我們的觀點發生變化，我們明確不承擔更新或修改任何前瞻性聲明的義務。

Now I will turn the call over to our CEO, Gilmore O'Neill.

現在我將把電話轉給我們的執行長吉爾摩·奧尼爾。

Thanks, Christy, and good morning, everyone. Thank you for joining us today on Editas second quarter of 2024 earnings call. With me today are four other members of the Editas executive team, our Chief Medical Officer, , Baisong Mei; our Chief Financial Officer, Erick Lucera; our Chief Scientific Officer, Linda Burkly; and our Chief Commercial and Strategy Officer, Karen Deardof. Because it is summertime, we're going to keep today's prepared remarks brief and leave more time to take your questions.

謝謝克里斯蒂，大家早安。感謝您今天加入我們的 Editas 2024 年第二季財報電話會議。今天與我在一起的還有 Editas 執行團隊的其他四名成員，我們的首席醫療官 Baisong Mei；我們的財務長 Erick Lucera；我們的首席科學官 Linda Burkly；以及我們的首席商務和策略長 Karen Deardof。由於現在是夏季，我們將保持今天準備好的發言簡短，並留出更多時間來回答你們的問題。

Let me start by saying that we are pleased with Editas's momentum and progress in the second quarter of 2024 as we pursue Editas's goal to deliver life-changing medicines to patients with previously untreatable or undertreated genetic diseases and the position Editas as a leader in in vivo program for gene editing.

首先我要說的是，我們對Editas 在2024 年第二季度的勢頭和進展感到高興，因為我們追求Editas 的目標，即為患有先前無法治療或治療不足的遺傳性疾病的患者提供改變生活的藥物，並將Editas 定位為體內領域的領導者基因編輯程式。

Three Pillars underpin our strategy. The first of those pillars is to drive reni-cel, a gene edited cell therapy for hemoglobinopathies formerly known as EDIT-301 toward BLA and commercialization. Second, to build a differentiated in vivo editing pipeline. And the third, to increase business development activities with a particular focus on monetizing our very strong IP.

三大支柱支撐著我們的策略。第一個支柱是推動 reni-cel（一種治療血紅蛋白病的基因編輯細胞療法，以前稱為 EDIT-301）走向 BLA 和商業化。其次，打造差異化的體內編輯管線。第三，增加業務開發活動，特別著重於將我們強大的智慧財產權貨幣化。

At the start of 2024, we announced the following 2024 objective. For reni-cel, we would provide a clinical update from the RUBY trial for severe sickle cell disease and the EdiTHAL trial for transfusion-dependent beta-thalassemia in mid 2024 and by year end 2024.

2024 年初，我們宣布了以下 2024 年目標。對於 reni-cel，我們將在 2024 年中期和 2024 年底之前提供針對嚴重鐮狀細胞疾病的 RUBY 試驗和針對輸血依賴性β地中海貧血的 EdiTHAL 試驗的臨床更新。

We will complete adult cohort enrollment and initiate the adolescent cohort in RUBY and continue enrollment in EdiTHAL. For our in vivo pipeline, we would establish in vivo preclinical proof-of-concept for an undisclosed indication. And for BD, we would leverage our robust IP portfolio and business development to drive value and complement core gene editing technology capabilities.

我們將在 RUBY 中完成成人隊列入組並啟動青少年隊列，並繼續在 EdiTHAL 中入組。對於我們的體內管道，我們將為未公開的適應症建立體內臨床前概念驗證。對於 BD 來說，我們將利用我們強大的智慧財產權組合和業務開發來推動價值並補充核心基因編輯技術能力。

So how have we executed against this strategy and these objectives in the second quarter? Let's start with reni-cel. First, we shared RUBY and EdiTHAL clinical data in June at EHA 2024, the European Hematology Association Annual Congress. The RUBY dataset included 18 sickle cell patients with 2.4 to 22.8 months of follow-up. And the EdiTHAL dataset included clinical data from seven beta-thalassemia patients of 4.1 to 12.8 months of follow-up.

那麼，我們在第二季如何執行這項策略和這些目標呢？讓我們從 reni-cel 開始。首先，我們在 6 月於歐洲血液學會年會 EHA 2024 上分享了 RUBY 和 EdiTHAL 的臨床數據。RUBY 資料集包括 18 名鐮狀細胞疾病患者，追蹤時間為 2.4 至 22.8 個月。EdiTHAL 資料集包括 7 名 β 地中海型貧血患者追蹤 4.1 至 12.8 個月的臨床數據。

These data from the RUBY trials support our continued belief that reni-cel would be a best-in-class product for sickle cell disease. So why do we think this? All patients treated in the RUBY trial are free from [basil cruise events] post reni-cel infusion. All patients have robust correction of anemia with a mean total hemoglobin level within the normal range for both genders at greater than 14 grams per deciliter.

RUBY 試驗的這些數據支持了我們的持續信念，即 reni-cel 將成為治療鐮狀細胞疾病的最佳產品。那我們為什麼這麼認為呢？RUBY 試驗中接受治療的所有患者在輸注 reni-cel 後均未出現[羅勒巡航事件]。所有患者的貧血均得到了強有力的糾正，男女平均總血紅蛋白水平都在正常範圍內，大於 14 克/分升。

And all patients have high fetal hemoglobin with levels well above 40% from six months onwards. We also demonstrate faster graph with low variability with a mean neutrophil engraftment of 23 days, which may translate to shorten hospital stays for patients. For cell collection, we have a mean up to a series of cycles with a range of one to four per patient.

從 6 個月起，所有患者的胎兒血紅素水平均遠高於 40%。我們還展示了具有低變異性的更快圖表，平均中性粒細胞植入時間為 23 天，這可能會縮短患者的住院時間。對於細胞收集，我們平均有一系列週期，每個患者的週期範圍為一到四個。

Finally, in addition to the clinical data shares at EHA on the manufacturing front for reni-cel, we have a robust manufacturing process with a low failure rate that continues to improve the experience. This low rate of manufacturing failure can decrease patient burden and reduce overall costs as we avoid salary collection and redundant cost of goods sold or COGS. And we're on track to share additional clinical data for both the RUBY and EdiTHAL by the end of this year 2024.

最後，除了在 EHA 共享 reni-cel 製造的臨床數據外，我們還擁有穩健的製造流程，故障率低，可持續改善體驗。這種低製造故障率可以減輕患者負擔並降低整體成本，因為我們避免了工資收取和銷售商品或銷貨成本的多餘成本。我們預計在 2024 年底之前分享 RUBY 和 EdiTHAL 的更多臨床數據。

Second, RUBY enrollment and dosing continues to be strong. Indeed, we have now completed enrollment of the adolescent cohort. As a reminder, we completed the adult cohort enrollment in the first quarter of this year.

其次，RUBY 的註冊和劑量持續強勁。事實上，我們現在已經完成了青少年族群的招募。提醒一下，我們在今年第一季完成了成人隊列的招募。

We are manufacturing drug product and scheduling adolescent and adult dosing concurrently. We also continue to progress EdiTHAL and are pleased to announce completion of the adult cohort enrollment and continue to dose patients.

我們正在生產藥品並同時安排青少年和成人給藥。我們也繼續推進 EdiTHAL 的進展，並很高興地宣布成人隊列入組已完成，並繼續對患者進行給藥。

Finally, based on our continued and collaborative conversations with the FDA, we still expect our future BLA package to be similar in number of patients and duration of follow-up to what we've seen in the gene editing medicine field.

最後，根據我們與 FDA 的持續合作對話，我們仍然期望我們未來的 BLA 方案在患者數量和追蹤持續時間方面與我們在基因編輯醫學領域所看到的相似。

Before I turn to thing to vivo, I'd like to state that we are very focused on the best view for use of capital as we develop reni-cel and map to the future. As part of that focus, we frequently evaluate opportunities, including the potential for partnering reni-cel to most efficiently drive reni-cel towards commercialization ultimately delivered to patients in need.

在談vivo之前，我想聲明一下，我們在開發reni-cel並規劃未來時，非常注重資本利用的最佳視角。作為這一重點的一部分，我們經常評估機會，包括與 reni-cel 合作的潛力，以最有效地推動 reni-cel 商業化，最終交付給有需要的患者。

Now let's turn to our in vivo pipeline where we continue to strengthen our in vivo discovery capabilities and drive lead discovery work on in-vivo therapeutic targets in hematopoietic stem cells of tissue. Importantly, we remain on track to establish in vivo preclinical proof-of-concept for undisclosed indication by the end of the year.

現在讓我們轉向我們的體內管道，我們將繼續加強我們的體內發現能力，並推動組織造血幹細胞體內治療靶點的先導發現工作。重要的是，我們仍有望在今年年底前針對未公開的適應症建立體內臨床前概念驗證。

We want to take a moment, rather I want to take a moment to reiterate our in vivo strategy to develop a pipeline of gene editing medicines for patients with serious genetic disease. As a reminder, our internal development efforts are differentiated from established modalities, and we are not pursuing the same gene editing approaches as others.

我們想花點時間，而不是我想花點時間重申我們的體內策略，為患有嚴重遺傳疾病的患者開發一系列基因編輯藥物。提醒一下，我們的內部開發工作與既定模式不同，我們並沒有追求與其他人相同的基因編輯方法。

First, our strategy is to use our Indel technology for functional upregulation of gene expression to address loss of function or deleterious mutations. Let me be clear, our strategy is not the knockdown strategy that others in gene editing are pursuing. And it is worth highlighting that we have already demonstrated that our Indel technology can drive functional gene upregulation, thus creating differentiated experimental medicines as in our ex vivo development of reni-cel.

首先，我們的策略是使用我們的 Indel 技術對基因表現進行功能性上調，以解決功能喪失或有害突變的問題。讓我明確一點，我們的策略不是其他基因編輯領域所追求的擊倒策略。值得強調的是，我們已經證明我們的 Indel 技術可以驅動功能基因上調，從而創造出差異化的實驗藥物，就像我們的 reni-cel 體外開發一樣。

With reni-cel, we leverage our Indel CRISPR technology to upregulate the expression of the gamma globin gene, a functional Humalog of the beta-globin gene through direct editing of the HBG12 promoter cell. We are now applying the same approach to in vivo therapeutics by using our Indel technology to functionally up-regulate the wild-type allele or functional Humalog of target disease genes as we build our differentiated pipeline.

透過 reni-cel，我們利用 Indel CRISPR 技術透過直接編輯 HBG12 啟動子細胞來上調 γ 珠蛋白基因（β 珠蛋白基因的功能性 Humalog）的表達。我們現在將相同的方法應用於體內治療，在我們建立差異化管道時，使用我們的 Indel 技術在功能上上調野生型等位基因或目標疾病基因的功能 Humalog。

Why does the difference between our functional regulation strategy and the knockdown strategies by other countries matter? Vecause with our in vivo strategy, we are not competing with existing modalities or technologies in development that are based on knockdown strategy.

為什麼我們的功能性監管策略與其他國家的擊倒策略之間的差異很重要？由於我們的體內策略，我們不會與基於擊倒策略的現有模式或正在開發的技術競爭。

Second, our indication selection strategy targets rare and orphan diseases that we believe will allow us to be the first or best in class for a given indication. We expect to move into diseases with larger patient populations in the future. Our latest discovery work is in in vivo therapeutic targets in hematopoietic stem cells and other tissues.

其次，我們的適應症選擇策略針對罕見和孤兒疾病，我們相信這些疾病將使我們成為特定適應症的第一或最好的。我們預計未來將涉足患者人數較多的疾病領域。我們最新的發現工作是造血幹細胞和其他組織的體內治療標靶。

Third, Editas is well positioned to achieve success with our in vivo strategy and pipeline with our established capabilities in four main components of in vivo gene editing medicine. One, our guide RNA modifications that enable high potency gene editing in multiple cell types, including in the liver and improve gene editing outcomes in vivo.

第三，憑藉我們在體內基因編輯醫學四個主要組成部分的既定能力，Editas 完全有能力透過我們的體內策略和管道取得成功。第一，我們的指導RNA修飾能夠在多種細胞類型（包括肝臟）中進行高效基因編輯，並改善體內基因編輯結果。

Two, a superior editing enzyme in AsCas12a. Three, our (inaudible) and four delivery technology where we are currently evaluating lipid nanoparticles for delivery of gene editing cargo into multiple tissue types with multiple companies as well as evaluating additional next-generation delivery technologies. I look forward to sharing more details about our in vivo pipeline later this year and our in vivo proof of concept.

第二，AsCas12a 中的高級編輯酶。第三，我們的（聽不清楚）和第四種遞送技術，我們目前正在與多家公司評估脂質奈米顆粒將基因編輯貨物遞送到多種組織類型中的作用，並評估其他下一代遞送技術。我期待在今年稍後分享有關我們體內管道和體內概念驗證的更多細節。

Finally, I'd like to refer you to our press release issued earlier today for a summary of our financial results for the second quarter of 2024. I take this opportunity to briefly review a few items for the quarter. Our cash, cash equivalents and marketable securities as of June 30 were $318 million compared to $377 million as of March 31, 2024.

最後，我想向您推薦我們今天早些時候發布的新聞稿，以了解我們 2024 年第二季的財務業績摘要。我藉此機會簡要回顧一下本季的一些項目。截至 6 月 30 日，我們的現金、現金等價物和有價證券為 3.18 億美元，截至 2024 年 3 月 31 日為 3.77 億美元。

As you will note, our burn rate was slightly higher this quarter than the past. This higher rate is due to increased external research and development expenses, primarily related to clinical and manufacturing costs related to the accelerated progression of our reni-cel program.

正如您將注意到的，本季我們的資金消耗率略高於過去。這一較高的比率是由於外部研發費用的增加，主要與我們的 reni-cel 項目的加速進展相關的臨床和製造成本有關。

We expect our existing cash, cash equivalents and marketable securities, together with the near-term annual license fees and the contingent upfront payment payable under our license agreement Vertex to fund our operating expenses and capital expenditures into 2026.

我們預計現有的現金、現金等價物和有價證券，加上近期年度許可費和根據我們的許可協議 Vertex 應付的或有預付款，將為我們到 2026 年的營運費用和資本支出提供資金。

Before we turn to Q&A, as always, it must be said that we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, corporate partners and you. We are energized by and proud of our progress and execution this quarter.

在我們像往常一樣進行問答之前，必須要說的是，如果沒有患者、護理人員、研究人員、員工、企業合作夥伴和您的支持，我們就無法實現我們的目標。我們對本季的進展和執行力感到振奮並感到自豪。

With our sharpened strategic focus are world-class scientists and employees are keen in driving execution and strong balance sheet, we continue to progress our strategy to deliver differentiated, adding medicines to patients with serious genetic diseases and evolved from a development stage technology platform company into a commercial stage gene editing company.

隨著我們的策略重點更加明確，世界一流的科學家和員工熱衷於推動執行力和強大的資產負債表，我們繼續推進我們的策略，為患有嚴重遺傳病的患者提供差異化的添加藥物，並從一家處於開發階段的技術平台公司發展成為商業階段的基因編輯公司。

Thank you very much for your interest in Editas. We are happy to answer questions now. Thank you.

非常感謝您對 Editas 的興趣。我們現在很高興回答問題。謝謝。

(Operator Instructions) Jack Allen, Baird.

（操作員說明）Jack Allen、Baird。

Great. Thank you so much for taking the questions and congratulations on all the progress made throughout the quarter. I apologize for any background noise here. I'm traveling today.

偉大的。非常感謝您提出問題，並對整個季度的所有進展表示祝賀。對於這裡的任何背景噪音，我深表歉意。我今天要去旅行。

But I wanted to ask about the preclinical proof of concept from the in vivo program that's expected later this year. I was hoping you could just elaborate a little bit more as it relates to what kind of data you have to put out? Will it be in a large animal model or small animal will model? And how should we think about the potential expansion you're looking at a few to litigate off-target editing profile for this program?

但我想詢問預計今年稍後進行的體內項目的臨床前概念驗證。我希望您能詳細說明一下，因為這與您必須提供什麼樣的數據有關？是大型動物模型還是小型動物模型？我們應該如何考慮您正在考慮的潛在擴展，以對該程序的脫靶編輯配置文件提起訴訟？

So Jack, I think you broke up near the end, but let me just restate the question the way I heard it and then hopefully if you need to correct us, let us know. So essentially, you're just wanted to have an understanding of the data that we will have for our in vivo POC, the size or the species that we will use in vivo.

所以傑克，我認為你們在接近尾聲時分手了，但讓我按照我聽到的方式重述一下這個問題，然後希望如果你需要糾正我們，請告訴我們。因此，本質上，您只是想了解我們將在體內 POC 獲得的數據、我們將在體內使用的大小或物種。

I think you wanted to talk about -- I think I might have heard you talk about indications, I'm not sure. So I'm going to ask Linda maybe to address your question.

我想你想談論——我想我可能聽過你談論適應症，我不確定。所以我想請琳達來回答你的問題。

Yeah. Thank you, Jack. You did break up a little bit. So thanks Gilmore for elaborating there. So we -- yes, we are on track to established preclinical POC in vivo for this undisclosed indication by end of the year. We've not yet disclosed species in which we're working.

是的。謝謝你，傑克。你們確實分手了一點。感謝 Gilmore 的詳細闡述。所以我們——是的，我們預計在今年年底前針對這個未公開的適應症建立臨床前體內 POC。我們尚未透露我們正在研究的物種。

But our evaluation process is going to entail evaluating the biodistribution to the site of interest, the efficiency of editing, the level of target modulation measured for example, biomarker readout and of course, the tolerability. And we'll be sharing more information, the forum and the timing or announcement of that data at a future time.

但我們的評估過程將需要評估感興趣位點的生物分佈、編輯效率、測量的目標調節程度（例如，生物標記讀數，當然還有耐受性）。我們將在未來分享更多資訊、論壇以及該數據的時間或公告。

Samantha Semenkow, Citi.

薩曼莎·塞門科，花旗銀行。

Good morning, and thanks for taking the question. Just building on the prior question, you're using an LNP. What's your strategy in nonviral? Would you expect to have an LNP targeted for the tissue of interest for the proof-of-concept readout indication optimized this year? Or would you need to further optimize after the proof of concept is in hand? Thank you.

早上好，感謝您提出問題。就前一個問題而言，您正在使用 LNP。您在非病毒方面的策略是什麼？您是否期望今年有一個針對感興趣組織的 LNP，以優化概念驗證讀數指示？或者在概念驗證完成後您是否需要進一步優化？謝謝。

So Sam, thank you very much for your question. I'll have Linda take that.

山姆，非常感謝你的提問。我會讓琳達拿走。

Yeah. Thank you, Sam. Thank you for the question. We are evaluating on LNPs with different partners because we are interested in targeting different tissue cell types for different disease areas of interest. We haven't yet disclosed which on tissues we're doing the non-clinical POC targeting in, and we'll be sharing that information at a future time when we disclose the data. So in terms of the targeting aspect that you refer to, we'll share the information in the future.

是的。謝謝你，山姆。謝謝你的提問。我們正在與不同的合作夥伴一起評估 LNP，因為我們有興趣針對不同的疾病領域針對不同的組織細胞類型。我們尚未透露我們正在對哪些組織進行非臨床 POC 靶向，我們將在將來披露數據時分享該資訊。所以關於你提到的定位方面，我們以後會分享這些資訊。

Eric Schmidt, Cantor Fitzgerald.

埃里克·施密特，康托·菲茨傑拉德。

Great. Love the summertime strategy, very efficient. Maybe it'll continue into the fall and winter, we'll see. In terms of my questions. First, with the adolescent reni-cel cohort now completed in terms of enrollment, can you start to estimate your timeline to BLA?

偉大的。喜歡夏季策略，非常有效率。也許它會持續到秋天和冬天，我們拭目以待。就我的問題而言。首先，青少年 reni-cel 隊列現已完成入組，您可以開始估計 BLA 的時間表嗎？

Thank you, Eric. I'm going to have Baisong take that question for you.

謝謝你，埃里克。我將讓白松為你解答這個問題。

Thank you for your question, Eric. We have announced that in June. Wwe have dosed more than 20 patients and we're continuing to dosing patients. So that is moving along very well. And then we continue to consider the CASGEVY approval as our benchmark.

謝謝你的問題，艾瑞克。我們已經在六月宣布了這一點。Wwe 已對 20 多名患者進行了給藥，我們將繼續對患者進行給藥。所以一切進展順利。然後我們繼續將 CASGEVY 的批准作為我們的基準。

So that in terms of a sample size, in terms of efficacy sample size as well as observation duration of 15 to 18 months and the total sample size initial submission with 20 patients and with additional 10 patients during the review. So this is kind of the scope of that.

因此，就樣本量、療效樣本量以及 15 至 18 個月的觀察持續時間而言，以及初始提交的 20 名患者和審查期間額外的 10 名患者的總樣本量。這就是它的範圍。

And we have not shared the specifics of the timeline because we have to get a final alignment with the FDA, but we are very optimistic that we are collecting the data from -- we are dosing closing to the POS data package we are looking for.

我們還沒有分享時間表的具體細節，因為我們必須與 FDA 達成最終一致，但我們非常樂觀地認為我們正在收集數據——我們正在接近我們正在尋找的 POS 數據包。

Thank you, very helpful. And maybe Baisong or Gilmore, can you talk about what we hope to learn at the late 2024 update on the program, but as Gilmore mentioned at this point, we know a fair bit about reni-cel's profile.

謝謝你，非常有幫助。也許 Baisong 或 Gilmore，您能談談我們希望在 2024 年末的程式更新中學到什麼嗎？

So Baisong

蘇柏松

Thanks, Eric. So we expect to have data from longer duration of follow-up for those patients we are present at EHA, which means we're going to have more than 10 patients at one year exposure and additional patient have a different exposure. And now we also at EHA, we present data for 18 patients we have seen in dosing multiple locations.

謝謝，埃里克。因此，我們希望獲得對我們在 EHA 就診的患者進行更長時間追蹤的數據，這意味著我們將有超過 10 名患者進行一年的暴露，並且還有更多患者進行不同的暴露。現在，我們在 EHA 也提供了 18 名患者在多個地點給藥的數據。

So we're going to have more patient data also. So with that, we were very excited for the data end of the year because we're going to have longer duration and we're going to have a data package similar to the CASGEVY BOA. So we are looking forward to share data with you all.

所以我們還將獲得更多的患者數據。因此，我們對今年年底的數據感到非常興奮，因為我們將有更長的持續時間，我們將擁有類似於 CASGEVY BOA 的資料包。因此，我們期待與大家分享數據。

Terence Flynn, Morgan Stanley.

特倫斯‧弗林，摩根士丹利。

Good morning. This is Mia on for Terence. Thanks for taking our question. So recognizing it's still early in the launches of [CASGEVY] and Lyfgenia, but are there any learnings thus far that you hope to utilize for future reni-cel launch? Thanks.

早安.這是特倫斯的米婭。感謝您提出我們的問題。因此，我們認識到 [CASGEVY] 和 Lyfgenia 的發布還處於早期階段，但到目前為止您是否希望將任何經驗教訓用於未來的 reni-cel 發布？謝謝。

Thanks very much, Mia (inaudible) and let me pass you over to Caren Deardorf, our Chief Commercial and Strategy Officer.

非常感謝，米婭（聽不清楚），請讓我將您轉交給我們的首席商業和策略官卡倫·迪爾多夫。

Great. Thanks, Mia, for the question. So we really wanted to say that we're encouraged by the Vertex update of the 20 patients in cell collection, which is a nice bump up from the five in Q1. We really see that as an acceleration that we have anticipated because we understand that there are multiple steps in the process to get a patient dosed.

偉大的。謝謝米婭的提問。因此，我們真的想說，我們對 Vertex 更新的 20 名患者細胞收集感到鼓舞，這比第一季的 5 名患者有了很大的提高。我們確實認為這是我們預期的加速，因為我們知道給患者服藥的過程中有多個步驟。

And we anticipate that they probably have a number of additional patients in the earlier enrollment phase before cell collection, including getting payer reimbursement. We anticipate significantly more uptake over the coming quarters as we look at both companies.

我們預計他們可能在細胞收集之前的早期登記階段有許多額外的患者，包括獲得付款人報銷。當我們研究這兩家公司時，我們預計未來幾季的採用率將顯著提高。

We know from our own enrollment and the excitement in our trial that there is a lot of patient and physician interest. And so, that will continue as there's more exposure to our three therapies. In the US, we also know that payers are doing case-by-case approvals with few rejections. We know that patients are able to get access and that policies will be in place over time.

從我們自己的入組情況和試驗中令人興奮的情況來看，我們知道患者和醫生對此很感興趣。因此，隨著人們更多地接觸我們的三​​種療法，這種情況將繼續下去。在美國，我們也知道付款人正在逐案批准，很少有拒絕的情況。我們知道患者能夠獲得服務，隨著時間的推移，政策將會到位。

As a reminder, we really believe that our fast follower timing is an advantage which gets to your question about the learnings. And that really allows us to be able to optimize our own launch plans. And another key component is that we understand the time it takes for centers to get up to speed for payers to put policies in place.

提醒一下，我們確實相信我們的快速追隨者時機是一個優勢，可以解決您有關學習的問題。這確實使我們能夠優化我們自己的發布計劃。另一個關鍵因素是，我們了解中心需要多長時間才能讓付款人盡快落實政策。

All of that we anticipate will come together around the time that reni-cel might launch. We are already seeing a decrease in the amount of time for onboarding between Bluebird and Vertex and anticipate that onboarding cycle from our own conversations and research will be significantly shorter at the time of our launch.

我們預計所有這些都將在 reni-cel 發佈時完成。我們已經看到 Bluebird 和 Vertex 之間的入職時間有所減少，並預計在我們推出時，我們自己的對話和研究的入職週期將顯著縮短。

So we are really encouraged, and we know how much it takes behind the scenes and we're just really glad to see patients moving closer to dosing. Thank you for the question.

所以我們真的很受鼓舞，我們知道幕後需要付出多少努力，我們很高興看到患者距離給藥越來越近。謝謝你的提問。

Gena Wang, Barclays.

王吉娜，巴克萊銀行。

Thank you. I will ask two questions. First one is what is the average process time from patient enrollment to dose, any differences in adult and adolescent patients?

謝謝。我會問兩個問題。第一個是從病人入組到給藥的平均過程時間是多少，成人和青少年病人有什麼差異？

And the second question regarding your Indel technology, you say you would do up-regulating. Just wanted to make sure that was the knocking down the repressure so that the target gene will be upregulated.

關於你的 Indel 技術的第二個問題，你說你會上調。只是想確保這是消除抑制，從而使目標基因上調。

Thank you very much, Gena. What I'm going to do is have Baisong address your question about the process time or the vein-to-vein time or enrollment to infusion time for adolescents versus adults. And then pass to over to Linda, I'll restate your question, just so we all remember. Baisong?

非常感謝你，吉娜。我要做的是讓 Baisong 回答您關於青少年與成人的處理時間或靜脈間時間或登記至輸注時間的問題。然後交給琳達，我會重申你的問題，好讓我們都記得。白松？

Yeah. Thank you, Gena, for your question. From the enrollment to dosing, it varies quite significantly among patients and some are going to be very short like three or four months and other can be up to 10 months or even longer because some patients have VOE in the middle and during the process before dosing of reni-cel.

是的。謝謝你，吉娜，你的問題。從入組到給藥，患者之間差異很大，有的會很短，例如三、四個月，有的可能長達10個月甚至更長，因為有些患者在中間和給藥前的過程中出現了VOE雷尼塞爾。

From the -- between adult and adolescent and we see now is that we have very robust enrollment that screening process was going faster than we had for adult and the freezes process also going very smoothly. And that's probably also related to that the adolescent patients in a better health condition compared to our older adult patients.

從成人和青少年之間的情況來看，我們現在看到，我們的入學率非常強勁，篩選過程比成人的速度更快，凍結過程也非常順利。這也可能與青少年患者的健康狀況比老年患者更好有關。

Thanks very much, Baisong. And then Gena, you asked a question just to clarify how we're using Indel technology to functionally up-regulate genes and specifically the introduction of the regulator?

非常感謝，白松。然後 Gena，你問了一個問題只是為了澄清我們如何使用 Indel 技術來功能性上調基因，特別是調節劑的引入？

Yeah. Thank you, Gena, for the question. So our functional regulation strategy is not -- it's defferent. It is not a knockdown strategy. So we will -- as per your question, we would not be knocking down the repress or if we use the reni-cel example as a paradigm. In that case, we are creating an indel to disrupt the binding site for the repressor and that way we are upregulating gamma globin expression.

是的。謝謝吉納提出的問題。所以我們的功能調節策略不是──而是不同的。這不是擊倒策略。因此，根據您的問題，我們不會消除鎮壓，或者如果我們使用 reni-cel 範例作為範式。在這種情況下，我們正在創建一個插入缺失來破壞阻遏物的結合位點，這樣我們就可以上調伽馬珠蛋白的表達。

So using that as an example, we could do a similar type of thing for another target of interest. There are other ways that one can create Indel's to upregulate gene expression. This is the approach that we are taking that is differentiated from a knockdown approach. Thank you for the question.

因此，以此為例，我們可以對另一個感興趣的目標執行類似的操作。還有其他方法可以創建插入缺失來上調基因表現。這是我們正在採取的方法，與擊倒方法不同。謝謝你的提問。

Mary Kate Davis, Bank of America.

瑪麗·凱特·戴維斯，美國銀行。

Good morning. Thank you so much for taking my question. I guess looking at your portfolio, how are you looking at the IP licensing opportunities in the future? Thank you.

早安.非常感謝您回答我的問題。我想看看您的投資組合，您如何看待未來的智慧財產權授權機會？謝謝。

Thanks very much, Kate. I'm going to ask our CFO, Erick Lucera to address that.

非常感謝，凱特。我將請我們的財務長埃里克·盧塞拉（Erick Lucera）來解決這個問題。

Yeah, thanks for the question. We believe we have a very strong foundational position with respect to the IP license that we have from Harvard, MIT and abroad. We are very open to having conversations with a range of companies in terms of getting a structure in place that is sort of bespoke and works for both us and them.

是的，謝謝你的提問。我們相信，我們在哈佛、麻省理工學院和國外獲得的智慧財產權授權方面擁有非常強大的基礎地位。我們非常願意與一系列公司進行對話，以建立一個適合我們和他們的客製化結構。

We believe there's a high double-digit number of programs out in development and a good number of those about half are with 8 to 10 different companies. So we look forward to having conversations with folks.

我們相信有大量的項目正在開發中，其中大約一半是由 8 到 10 家不同的公司開發的。因此，我們期待與人們進行對話。

As you can see, we've had some pretty good success in the last few years as evidenced by some of the licenses that we've already put in place. So very excited to have that as a potential source of non-dilutive capital for us for our company.

正如您所看到的，我們在過去幾年中取得了一些相當好的成功，我們已經發放的一些許可證證明了這一點。非常高興能將其作為我們公司非稀釋資本的潛在來源。

Brian Chang, JPMorgan.

布萊恩張，摩根大通。

Hey, guys. Thanks for taking my questions this morning and happy summer. It sounds like you may have had additional discussion of the agency this past quarter. I'm just curious, other than the clinical data, what other additional items have you discussed?

嘿，夥計們。感謝您今天早上回答我的問題，祝夏天快樂。聽起來您在上個季度可能對該機構進行了更多討論。我只是好奇，除了臨床數據之外，你們還討論了哪些其他項目？

And just based on CASGEVY package at the time of the BLA, I would assume that you can potentially file sometime next year. So outside of the clinical package that we're waiting for material data, what other additional data or gating factor do you need to line up between now and then? In other words, any color on your readiness towards filing? Thanks.

僅根據 BLA 時的 CASGEVY 軟體包，我認為您可能會在明年某個時候提交申請。那麼，除了我們正在等待材料資料的臨床套件之外，您還需要從現在到那時排列哪些其他附加資料或門控因素？換句話說，您是否準備好提交申請？謝謝。

Thanks very much, Brian. I think you did sort of a complex question in that you're asking about the multiple data sets that are required to actually go filing? First of all, let me be very clear that we have not actually shared an estimate or given guidance to when we would file the BLA. I think it's very important just to state.

非常感謝，布萊恩。我認為您提出了一個複雜的問題，因為您詢問的是實際歸檔所需的多個資料集？首先，讓我非常明確的是，我們實際上並未分享估算或就何時提交 BLA 提供指導。我認為陳述這一點非常重要。

The second is that we are very happy from the clinical data point of view in the generation, how we're actually progressing towards really meeting or matching up with the benchmark access by the CASGEVY approval with, of course, the additional data that we are generating from a differentiation point of view.

第二個是，從這一代臨床數據的角度來看，我們非常高興，我們實際上是如何在真正達到或匹配 CASGEVY 批准的基準訪問方面取得進展的，當然，還有我們正在提供的附加數據從差異化的角度產生。

The additional data sets obviously include the preclinical, and we know that a key focus of the agency when you consider AdCom was looking at off target editing. We actually were very, how should I say, gratified by the AdCom last December to see that the data set that we have already generated is very robust and probably exceeds -- it was discussed at the AdCom as we feel very good.

額外的數據集顯然包括臨床前數據，我們知道，當您考慮 AdCom 時，該機構的一個重點是專注於脫靶編輯。去年 12 月，我們實際上對 AdCom 感到非常滿意，因為我們已經產生的資料集非常強大，甚至可能超出了 AdCom 上討論的範圍，因為我們感覺非常好。

We're actually also very pleased with the progress of our manufacturing data. And as I said in my earlier prepared remarks, our ongoing discussion with the FDA really gives us confidence about the progress of multiple data sets beyond just the clinical to bring us towards BLA.

事實上，我們對製造數據的進展也非常滿意。正如我在之前準備的演講中所說，我們與 FDA 正在進行的討論確實讓我們對臨床以外的多個數據集的進展充滿信心，從而使我們走向 BLA。

Okay. And maybe just one more follow-up on the in vivo side. Is that going to be first in class or best in class approach. I'm just curious how do you think about balancing the risk and reward for your next assets. Thank you.

好的。也許只是體內方面的一個後續行動。這將是同類第一還是同類最佳方法。我只是好奇你如何考慮平衡下一個資產的風險和回報。謝謝。

Thank you very much, Brian, I'm going to have Linda address that.

非常感謝你，布萊恩，我會讓琳達解決這個問題。

Yeah. Thanks, Brian, for the approach on that question. I think the differentiated approach is for going after frontal regulation is really important. I think from an indication standpoint, because of the fact that we can go after targets that others may not be able to go after using a knockdown strategy and that is established modalities or other technologies in development can't go after that target.

是的。謝謝布萊恩對這個問題的回答。我認為差異化的方法對於追求正面調節非常重要。我認為從指示的角度來看，因為我們可以追求其他人可能無法使用擊倒策略來追求的目標，並且已建立的模式或正在開發的其​​他技術無法追求該目標。

That really gives us the ability to be first in class. We can also envision editing strategies that would yield a better outcome than other approaches that are going after that particular indication, giving us best in class. So we can either have first-in-class or best-in-class opportunities here.

這確實讓我們有能力成為班級第一。我們還可以設想編輯策略，這些策略將比其他針對該特定指示的方法產生更好的結果，從而為我們帶來一流的結果。因此，我們在這裡要么擁有一流的機會，要么擁有一流的機會。

Joon Lee, Truist Securities.

李俊，Truist 證券公司。

Good morning. This is [Mady] on for Joon. Congrats on the progress and thanks for taking our question. So maybe a two-part question. Could you please provide any additional color on your in vivo editing approach, as you previously talked about (inaudible) and they usually require a landing site insertion first. So any color there would be appreciated.

早安.這是為 Joon 準備的 [Mady]。恭喜您的進展，並感謝您提出我們的問題。所以也許是一個由兩個部分組成的問題。正如您之前談到的（聽不清楚），您能否提供有關您的體內編輯方法的任何其他顏色，它們通常需要先插入登陸位點。所以任何顏色都會受到讚賞。

And then to follow on Gena's question, how many disease you see being amenable to Indel mediated functional upregulation. Thank you.

然後繼續回答 Gena 的問題，您認為有多少疾病適合 Indel 介導的功能上調。謝謝。

Thanks, Mady, for your questions. Let me start -- I'll have Linda address both questions and I'll restate the second question. Obviously your first question was as we talk about our Indel function upregulation, how is that distinguished from the use LSRs? So Lina?

謝謝麥迪提出的問題。讓我開始——我將讓琳達回答這兩個問題，然後我將重申第二個問題。顯然，你的第一個問題是當我們談論我們的 Indel 功能上調時，它與使用 LSR 有何不同？那麼莉娜？

Yes. Thank you for the question. Yeah, the LSR technology that we disclosed at ASGCT. We're very excited about that. That is a technology that may enable us in the future to have large gene insertions and so this would be a gene replacement approach. This is something that we're working towards.

是的。謝謝你的提問。是的，就是我們在ASGCT上揭露的LSR技術。我們對此感到非常興奮。這項技術可能使我們在未來能夠進行大量基因插入，因此這將是一種基因替代方法。這是我們正在努力的方向。

What we're doing in the shorter term now is functional upregulation of gene expression and this is increasing the expression of a gene in order to compensate for a loss of function or a deleterious mutation in a patient with a serious genetic disease. So if that answers your first question.

我們現在在短期內所做的是基因表達的功能上調，這是增加基因的表達，以補償患有嚴重遺傳疾病的患者的功能喪失或有害突變。如果這回答了你的第一個問題。

I think then you asked a question about how many diseases are amenable to Indel and there are many, obviously, there are many genetic diseases caused by loss of function or deleterious mutations. And there are many ways in this in which they're regulated by various regulatory elements. And so, there should be many opportunities here for functional upregulation of those targets.

我想你問了一個問題，有多少種疾病會受到 Indel 影響，顯然，有許多遺傳性疾病是由功能喪失或有害突變引起的。它們透過多種方式受到各種監管要素的監管。因此，這些目標的功能上調應該有很多機會。

If I may -- thank you very much, Linda. I think one of the key things is that as we know from the human genome, only a small quantity of the genome actually encodes protein. There's a large amount. The vast majority of the genome actually is non-coding. And much of that comprises of regulatory elements that actually control the expression of genes.

如果可以的話——非常感謝你，琳達。我認為關鍵的事情之一是，正如我們從人類基因組中所知，只有一小部分基因組實際上編碼蛋白質。數量很大。基因組的絕大多數其實是非編碼的。其中大部分由實際控制基因表現的調控元件組成。

And as Linda very elegantly put it, this is what we're actually trying to target and just to be absolutely clear, we are talking about Indel using our CRISPR technology general and very specifically in the very near term, leveraging our ASCas12a, which as we highlight is we believe one of the key differentiation tools in our toolbox as we believe it is superior editing CRISPR enzyme because of its high efficacy and its high fidelity.

正如 Linda 非常優雅地指出的那樣，這就是我們實際上想要瞄準的目標，而且要絕對清楚，我們正在談論 Indel 使用我們的 CRISPR 技術，特別是在不久的將來，利用我們的 ASCas12a，我們強調的是，我們相信我們工具箱中的關鍵分化工具之一，因為我們相信它是卓越的編輯CRISPR 酶，因為它的高效性和高保真度。

Dae Gon Ha, Stifel.

大貢河，斯蒂菲爾。

Hey, good morning, guys. Thanks for taking our questions and congrats on the progress as well. Maybe first question for Linda, going back to the in vivo, recognizing you're going to be disclosing.

嘿，早上好，夥計們。感謝您提出我們的問題，也祝賀我們的進展。也許琳達的第一個問題，回到體內，認清你將要揭露。

So I don't want to probe too much, but at least help us appreciate it a little bit more is this -- are you guys kind of driven by the limitations of LNP mediated delivery in terms of what cell types and what organ types you can go into? Or it is more dependent on how big of a size market you have a potential of first indication as well as the potential subsequent indications that can come after this first one?

所以我不想探究太多，但至少可以幫助我們更多地理解這一點——你們是否受到 LNP 介導的傳遞在細胞類型和器官類型方面的限制所驅動？或者它更取決於您擁有第一個跡象的潛力以及第一個跡象之後可能出現的潛在後續跡像有多大的市場規模？

And then second question, maybe high-level, Gilmore and Baisong, year-end, we're also expecting Beam's first data set coming out of BEAM-101. You talk about reni-cel being best in class. So I was just wondering what kind of data set would keep you more confident about that notion going into that ASH presentation. Thanks so much.

然後是第二個問題，也許是高層，Gilmore 和 Baisong，年底，我們也期待 Beam 的第一個資料集來自 BEAM-101。你說雷尼塞爾是班上最好的。所以我只是想知道什麼樣的資料集會讓您對 ASH 演示中的概念更有信心。非常感謝。

Thanks very much, Dae Gon. So Linda?

非常感謝，大坤。那麼琳達？

Thank you, Dae Gon. So to your first question, yes, in terms of the LNP, the delivery, obviously is critical for getting POC. So we've shared our interest in targeting hematopoietic stem cells. And this is obviously to translate this remarkable success we're having with our reni-cel asset. So we are obviously trying to target hematopoietic stem cells.

謝謝你，大袞。所以對於你的第一個問題，是的，就 LNP 而言，交付顯然對於獲得 POC 至關重要。因此，我們對標靶造血幹細胞有著共同的興趣。這顯然是為了反映我們在 reni-cel 資產上所取得的巨大成功。所以我們顯然正在嘗試針對造血幹細胞。

In vivo, we've also -- so we haven't disclosed all of the disease areas that we're interested in. And other than HSCs, we have mentioned that we are interested in targeting the liver. And so, there are validated LNPs for targeting liver. So there is a pragmatic approach here based on delivery.

在體內，我們也——所以我們還沒有透露我們感興趣的所有疾病領域。除了 HSC 之外，我們還提到我們對靶向肝臟感興趣。因此，有針對肝臟的經過驗證的 LNP。所以這裡有一個基於交付的務實方法。

And if I may add, Linda, thank you. It's not just the delivery tool that we are leading with an LNP that actually determines how we select our targets. Obviously, delivery is an important element. Obviously, amenability to functional regulation is important. We're actually selecting diseases based on their clinical translatability and that we want to be ensure that we can actually get obvious clinical signals in our human proof of concept.

如果我可以補充一下，琳達，謝謝你。實際上決定我們如何選擇目標的不僅僅是我們以 LNP 為主導的交付工具。顯然，交付是一個重要因素。顯然，服從功能調節很重要。我們實際上是根據疾病的臨床可轉化性來選擇疾病，我們希望確保我們能夠在人類概念驗證中真正獲得明顯的臨床訊號。

And obviously then -- obviously, we also further filter that by ensuring that we are truly differentiated to ensure maximize probability, not just a technical clinical regulatory, but actually also commercial success.

顯然，我們還進一步過濾這一點，確保我們真正與眾不同，以確保最大化機率，不僅是技術臨床監管，而且實際上也是商業成功。

And then with regard to your second question, what we expect to see from the Beam data set, frankly, obviously, we're looking forward to seeing it. It is always good to see a continued pursuit of therapeutics within a clinical space for which there is an enormous, enormous unmet need in the context of sickle cell disease and transfusion dependent thalassemia.

然後關於你的第二個問題，我們期望從 Beam 資料集中看到什麼，坦白說，顯然，我們期待看到它。很高興看到臨床領域對治療方法的持續追求，在鐮狀細胞疾病和輸血依賴性地中海型貧血的背景下，存在著巨大的未滿足的需求。

It's very hard -- I can't speculate on what Beam will show. I look forward to hearing it and we all look forward to hearing it. But I will tell you that we are very happy with the differentiated profile that we are developing for at reni-cel. And it's important to point out that we are very happy with the biological profile, the hematological profile, the clinical profile, all of which are very strong.

這非常困難——我無法推測 Beam 會展示什麼。我期待聽到它，我們都期待聽到它。但我要告訴你的是，我們對 reni-cel 正在開發的差異化形象非常滿意。需要指出的是，我們對生物學特徵、血液學特徵、臨床特徵非常滿意，所有這些都非常強大。

And in addition, as we've alluded to, we are confident in the evolution in the current state of and the continued evolution of our manufacturing from the success rates is very gratifying. So overall, we actually feel very good.

此外，正如我們所提到的，我們對當前狀態的發展充滿信心，並且從成功率來看，我們製造業的持續發展是非常令人滿意的。所以總的來說，我們實際上感覺非常好。

And of course, it's important, though, to remember, as I said earlier, that an additional piece of the data includes our nonclinical, including our off-target editing, which is a very robust. As I said in the package we've generated. And of course, some of that robustness stems from us using ASCas12a as opposed Cas9 with its differentiated high efficacy, high fidelity characteristic.

當然，重要的是要記住，正如我之前所說，額外的數據包括我們的非臨床數據，包括我們的脫靶編輯，這是非常可靠的。正如我在我們生成的包中所說的。當然，這種穩健性部分源自於我們使用 ASCas12a，而不是 Cas9，其具有差異化的高效能、高保真特性。

Luca Issi, RBC Capital.

盧卡·伊西，加拿大皇家銀行資本。

Well, great. Thanks so much for taking my question and congrats on the progress. I have two quick ones. Maybe on sickle cell disease. We have seen the US Health and Human Service issuing a negative opinion here on covering fertility preservation for federally insured patients who received gene therapy for sickle cell disease. So just wondering what is your take on that?

嗯，太好了。非常感謝您提出我的問題並祝賀我的進展。我有兩個快的。也許是鐮狀細胞疾病。我們看到美國衛生與公眾服務部對接受鐮狀細胞疾病基因治療的聯邦保險患者的生育力保留保險發表了負面意見。所以只是想知道你對此有何看法？

And then maybe second, Gilmore, bigger picture, you seem very excited about the in vivo up-regulation strategy here. Is there a version of the world where you just partner reni-cel both US and ex US instead of building a commercial infrastructure and just focused on your in vivo strategy. Any thoughts there? Much appreciated. Thanks so much.

然後也許第二，吉爾摩，從更大的角度來看，你似乎對這裡的體內上調策略感到非常興奮。世界上有沒有一個版本，您只需與美國和美國以外的 reni-cel 合作，而不是建立商業基礎設施，而只專注於您的體內策略。有什麼想法嗎？非常感謝。非常感謝。

Thanks very much, Luca. So I'm going to pass your first question to Caren around the HHS decision.

非常感謝，盧卡。因此，我將把你關於 HHS 決定的第一個問題轉給卡倫。

Lucas, thank you for calling that out. We are deeply disappointed by this decision, and we join the voices of Vertex, Bluebird, really the whole field in this decision, which seem very out of touch with the severity of sickle cell and the unmet need. And it just continues to drive the discrepancy between the commercial patients' ability to access therapies and have companies cover the fertility preservation as you know, and Medicaid patients. So we are very disheartened.

盧卡斯，謝謝你指出這一點。我們對這個決定深感失望，我們加入了福泰(Vertex)、藍鳥(Bluebird) 的聲音，實際上是整個領域的決定，這似乎與鐮狀細胞病的嚴重性和未滿足的需求非常脫節。如你所知，它只會繼續拉大商業患者獲得治療和讓公司承擔生育保留費用的能力與醫療補助患者之間的差異。所以我們非常灰心。

We also know that there are a lot of voices who are within Congress and within the industry and other organizations, including the patient advocacy groups who have a very strong voice. And our hope is that all of us together will be able to really raise this issue and have it reversed in the coming time.

我們也知道，國會內部、產業內和其他組織內有很多聲音，包括擁有非常強烈聲音的病患倡議團體。我們希望我們所有人一起能夠真正提出這個問題並在未來扭轉局面。

We believe that things will sort themselves out. We are disappointed for the patients who are seeking treatment today. Our belief in our own timing as fast follower is a lot of these unfortunate decisions will be figured out at the time that we're ready to come to market. But thank you for calling it out. It is really an out of touch decision and we will hope for the best into your part.

我們相信事情會自行解決。我們對今天尋求治療的患者感到失望。我們相信，作為快速追隨者，我們自己的時機是，許多不幸的決定將在我們準備好進入市場時解決。但謝謝你把它叫出來。這確實是一個脫離實際的決定，我們希望您能做到最好。

Thanks very much, Caren. And then look at your second question around, I think it stems from our prepared remarks how -- why we're extraordinarily excited by our reni-cel, our in vivo progress. We're also very conscious of how we deploy our capital, and I'm going to ask Erick to address that.

非常感謝，卡倫。然後看看你的第二個問題，我認為這源自於我們準備好的評論——為什麼我們對我們的 reni-cel，我們體內的進展感到非常興奮。我們也非常清楚如何部署我們的資本，我將請艾瑞克解決這個問題。

Luca, I just following up. As we've said for many years, our intention was to look for partners outside of the US and I can tell you as someone who invested in biotech for 15 years and has been doing business development and CFO for about 15 years. You never know where those discussions may go.

盧卡，我剛剛跟進。正如我們多年來所說，我們的目的是尋找美國以外的合作夥伴，作為一個投資生物技術 15 年、從事業務開發和首席財務官大約 15 年的人，我可以告訴你。你永遠不知道這些討論會走向何方。

But what we can assure you is that we're going to do that right thing in terms of what's in the best interest for getting our products to as many patients as possible and driving shareholder returns to the best level possible.

但我們可以向您保證的是，我們將採取最符合最佳利益的正確做法，將我們的產品帶給盡可能多的患者，並推動股東回報達到最佳水平。

Phil Nadeau, TD Cowen.

菲爾·納多，TD·考恩。

Good morning. Thanks for taking our questions. Two from us. First on reni-cel and the prospects for clinical differentiation. We're curious what your most recent thoughts on the time to see that clinical differentiation on things like end-organ damage. It's possible that we could start to see strong signals of that in the ASH presentation.

早安.感謝您回答我們的問題。我們兩個。首先介紹 reni-cel 和臨床分化的前景。我們很好奇您最近對終末器官損傷等臨床分化有何看法。我們可能會開始在 ASH 演示中看到強烈的訊號。

And then second on the in vivo development program. Gilmore, I think you said the initial indication will be orphan, then there will be larger indications perhaps later. Can you give us some sense of what size patient population you think is necessary for a good return on an investment? What's too small? Kind of what's the sweet spot for an orphan population?

其次是體內開發計劃。吉爾摩，我想你說過最初的適應症將是孤兒，然後也許以後會有更大的適應症。您能否告訴我們您認為需要多少患者群體才能獲得良好的投資回報？什麼太小了？對孤兒群體來說，什麼是最有利的地方？

Thanks very much, Phil. So I'll have Baisong talk about the differentiation and how we see that evolving. And then I will take your question on how we think about the size of the population?

非常感謝，菲爾。因此，我將請拜松談談差異化以及我們如何看待這種差異化的演變。然後我會回答你的問題，我們要如何看待人口規模？

Thanks for the question. As we have stated before, in clinical trial, we're looking at three categories of evidence about differentiation and including hematological parameters and organ function and the patient reported outcome. And then the -- in terms of the timing of those endpoints.

謝謝你的提問。正如我們之前所說，在臨床試驗中，我們正在研究有關分化的三類證據，包括血液學參數和器官功能以及患者報告的結果。然後是——就這些端點的時間而言。

And when we see that change and -- so for the organ function, you specifically mentioned that it is relatively new field. But fortunately, we already see more publications in allogenic transplants for treating sickle cell disease. They have presented encouraging data that after allergenic transplant, you can see the end organ function improvement, including cardiovascular, central nervous system and so on so forth.

當我們看到這種變化時——對於器官功能，您特別提到這是一個相對較新的領域。但幸運的是，我們已經看到更多關於同種異體移植治療鐮狀細胞疾病的出版物。他們提供了令人鼓舞的數據，即過敏性移植後，可以看到終末器官功能的改善，包括心血管、中樞神經系統等。

In our clinical trial, we monitor multiple organ and organ functions, including pulmonary cardiovascular, liver, renal and that. And so, based on the publication, some of reporting that when you see some improvement already. So we are very encouraged by that.

在我們的臨床試驗中，我們監測多個器官和器官功能，包括肺心血管、肝臟、腎臟等等。因此，根據該出版物，一些報告稱，當您已經看到一些改進時。所以我們對此感到非常鼓舞。

But other parameters, for example, the hematological parameter will give us more opportunity to directly measure that change. For example, we're talking about the correction in [Libya]. And then the third category is patient report outcome. And we are also very encouraged by the reports and the publishing this field that we will be able to see and the quality-of-life change after the treatment.

但其他參數，例如血液學參數，將使我們有更多機會直接測量這種變化。例如，我們正在討論的修正[利比亞]。第三類是患者報告結果。我們也對這一領域的報告和出版以及治療後生活品質的變化感到非常鼓舞。

So we're looking forward to see even more data. And we are very excited to see that our -- the data from all our patients are very consistent. Now we reported 18 patient data. We see that the same direction and the same trajectory in terms of our patient data wise. We're looking forward to share more data to end the year.

因此，我們期待看到更多數據。我們非常高興地看到我們所有患者的數據都非常一致。現在我們報告了18名患者的數據。就我們的患者數據而言，我們看到相同的方向和相同的軌跡。我們期待在年底分享更多數據。

Thanks very much, Baisong. And then Phil, regards your second question, which is around where do we think that a population size for an orphan indication where we're sort of focusing our initial foray in vivo lines up for optimal ROI.

非常感謝，白松。然後菲爾，關於你的第二個問題，即我們認為孤兒適應症的群體規模在哪裡，我們在體內的初步嘗試是否符合最佳投資回報率。

A couple of things, first of all, the reason that we're actually focusing on rare orphan, main reason, obviously, is that as we bring in new technology to patients, we want to actually maximize the probability of technical and regulatory success. While we at the field and agencies characterize and learn the long-term risk benefits associated with this technology.

有幾件事，首先，我們實際上關注罕見孤兒的原因，顯然，主要原因是，當我們為患者引入新技術時，我們希望實際上最大限度地提高技術和監管成功的可能性。我們在現場和機構中描述並了解與該技術相關的長期風險效益。

More importantly, that when I turn or not more important, but then I turn to market size, the market size talk about is really based on patients, the patient numbers with indication versus the price and obviously price will be determined by a number of factors, including the amount saved by what we're talking about are potentially or largely curative therapies with high potency.

更重要的是，當我轉向或不更重要時，但後來我轉向市場規模，所談論的市場規模實際上是基於患者，有適應症的患者數量與價格，顯然價格將由多種因素決定，包括我們所談論的潛在或很大程度上具有高效力的治療方法所節省的金額。

I mean, this will be one of the things we're really excited about our technology is we're talking about using this technology, not just because it's new and cool, but because it has the potential to deliver high potency, large effect sizes in patients.

我的意思是，這將是我們對我們的技術真正感到興奮的事情之一，我們正在談論使用這項技術，不僅因為它是新的、很酷的，而且因為它有潛力提供高效、大的效應量在患者中。

And so, when you actually consider those elements, our current estimates that a range of about [400 million to 500 million] is about the market size that would be meaningful and enable us to drive growth. And as we grow and evolve into treating larger populations as we build that safety characterization in a number of a smaller orphan size populations.

因此，當您實際考慮這些因素時，我們目前估計大約 [4 億至 5 億] 的市場規模是有意義的，使我們能夠推動成長。隨著我們的成長和發展，我們會在一些較小的孤兒群體中建立安全特徵，以治療更大的群體。

Jay Olson, Oppenheimer.

傑·奧爾森，奧本海默。

Hey, this is [Rishi] on the line for Jason. Thanks for taking the question. First, maybe on reni-cell. By the time you filed a BRA. I'm just curious, do you think the follow-up in the adolescent cohort is long enough, so the label may cover both adult and adolescent patients? Thank you.

嘿，這是傑森的[Rishi]。感謝您提出問題。首先，也許是腎細胞。當您提交 BRA 時。我只是很好奇，您認為青少年群組的追蹤時間足夠長，因此該標籤可能涵蓋成人和青少年患者嗎？謝謝。

Thank you, Rishi. I would just recap state your question because I was a little muffled on the line. I think you were asking was will the adolescent cohort be followed for long enough to be part of the label (multiple speakers)

謝謝你，里希。我只想重述一下你的問題，因為我在電話中有點悶悶不樂。我想你問的是青少年群體是否會被追蹤足夠長的時間以成為標籤的一部分（多個發言者）

We are very pleased with the progress of adolescent cohort, and we started enrollment of this year and we already completed enrollment in a matter of months. So very pleased with that. We certainly wanted to seek a far broader indication of all age cohorts. And we already have alignment with FDA about the clinical trial for the older age cohorts. So that's where we are very much looking forward to that.

我們對青少年隊列的進展感到非常滿意，我們今年開始招生，幾個月後就已經完成了招生。對此非常滿意。我們當然希望尋找更廣泛的所有年齡層的指標。我們已經與 FDA 就老年族群的臨床試驗達成一致。這就是我們非常期待的地方。

Yanan Zhu, Wells Fargo Securities.

朱亞楠，富國銀行證券。

Great. Thanks for taking our questions. So for the in vivo program, are you trying to up-regulate the gene -- the disease-causing gene itself? Or are you trying to up-regulate a different gene to compensate for the loss of the disease-causing genes.

偉大的。感謝您回答我們的問題。那麼對於體內程序，你是否試圖上調基因──致病基因本身？或者您是否試圖上調不同的基因以補償致病基因的損失。

In other words, are we talking about a haplo insufficiency type of indication or are we talking about recessive gene -- recessive gene defect here? Secondarily, I wanted to ask about any updated timing for the CAFC patent dispute process. Thank you.

換句話說，我們是在談論單倍體不足類型的適應症還是在談論隱性基因——這裡的隱性基因缺陷？其次，我想詢問 CAFC 專利糾紛程序的最新時間表。謝謝。

Thanks very much, Yanan. So with the first question I'm going to start by saying that you have actually described -- you've actually -- you nailed both elements of the operating strategy, but I'll let Linda just expand on that and then I will restate the second question, and we address that.

非常感謝，亞南。因此，對於第一個問題，我首先要說的是，您實際上已經描述了——您實際上已經——確定了營運策略的兩個要素，但我將讓琳達對此進行擴展，然後我將重申第二個問題，我們解決這個問題。

Yeah. Thanks very much for your question. So the two scenarios that you described, like both are possible approaches. One can imagine in lots of function, homozygous recessive states upregulating a pathway gene that can compensate for the loss of being mutated gene. So that's the case with the reni-cel example, where beta globin in TDT is -- there is no expression of beta-globin or in sickle cell disease, it's a deleterious mutation.

是的。非常感謝你的提問。因此，您描述的兩種情況都是可能的方法。人們可以想像在許多功能中，純合隱性狀態上調一種途徑基因，可以補償突變基因的損失。腎細胞疾病的例子就是這種情況，TDT 中的 β 珠蛋白是－沒有 β 珠蛋白的表達，或在鐮狀細胞疾病中，這是一種有害的突變。

And so, it's not functioning properly. And we upregulate gamma globin to compensate in both of those cases. One can also imagine a scenario of [homozygous] efficiency where you have one of the yield has a mutation, pathogenic mutation, but there's a wild type of deal that can be upregulated to compensate for the loss of function of the mutated allele. So either scenario is a potential target for us.

因此，它無法正常運作。我們上調伽馬珠蛋白來補償這兩種情況。人們也可以想像一種[純合]效率的場景，其中一個產量有突變，致病性突變，但有一種野生類型的交易可以被上調以補償突變等位基因的功能喪失。因此，這兩種情況都是我們的潛在目標。

Thank you very much, Linda. And I think, Yanan, you asked a second question about an update on the CAFC timings. Obviously, the oral presentations occurred in the last quarter in May, and we anticipate a decision probably for the end of the year.

非常感謝你，琳達。我想，亞南，你問了第二個問題，關於 CAFC 時間的更新。顯然，口頭陳述是在五月的最後一個季度進行的，我們預計可能會在今年年底做出決定。

I was just wondering if I could translate haplo insufficiency into late terms for those who might not have done molecular biology or genetics. By haplo insufficiency, everyone carries two copies, most copies -- two copies of the gene and the context of haplo insufficiency, one gene is not functioning, which results in a reduction in the total dose of protein that's available to the person resulting in disease, so-called insufficiency or haplo insufficiency.

我只是想知道對於那些可能沒有做過分子生物學或遺傳學的人來說，我是否可以將單倍體不足轉化為後期術語。透過單倍體不足，每個人都攜帶兩個拷貝，大多數拷貝——基因的兩個拷貝，而單倍體不足的情況下，一個基因無法發揮作用，這會導致人可用的蛋白質總劑量減少，從而導致疾病，所謂的不足或單倍體不足。

And the strategy that Linda is describing that we're pursuing to manage that is that you drive up expression of the normal copy to actually approach or get to the same dose of overall protein that would be required for normal health.

琳達描述的我們正在追求的策略是，提高正常副本的表達，以實際接近或達到正常健康所需的相同劑量的整體蛋白質。

Steve Seedhouse, Raymond James.

史蒂夫席德豪斯，雷蒙德詹姆斯。

Hi, good morning and thank you for the question. This is Nick on for Steve. Had a quick follow-up to Luca's first question actually. Are you able to speak to the importance and demand for fertility support in your own clinical trials experience for SCD? Also curious of your thoughts on the potential market impact if you're not able to provide the support once approved. Thank you.

你好，早安，謝謝你的提問。這是尼克替史蒂夫發言。實際上對盧卡的第一個問題進行了快速跟進。您能否在您自己的 SCD 臨床試驗經驗中講述生育支持的重要性和需求？如果您在獲得批准後無法提供支持，也想知道您對潛在市場影響的想法。謝謝。

So I'm going to split that question into two parts. I'm going to ask Baisong to talk about our experience in our clinical trials. And then I'll have Caren to talk about the impact and very importantly, how we anticipate mitigating or ensuring that impact is not going to be there.

所以我會把這個問題分成兩部分。我想請白松談談我們臨床試驗的經驗。然後我將請卡倫談談影響，非常重要的是，我們預計如何減輕或確保影響不會出現。

Yeah. Thank you for the question, Nick. We in clinical trial setting, we do provide fertility support, which is critical for patient, especially in this patient population that it is important for them to have that support to be able to go through the chemotherapy and conditioning process. I will let Caren to emphasize the importance of that in the commercial setting.

是的。謝謝你的提問，尼克。我們在臨床試驗環境中，確實提供生育支持，這對患者至關重要，特別是在這個患者群體中，獲得這種支持以完成化療和調理過程對他們來說非常重要。我會讓卡倫強調這一點在商業環境中的重要性。

Yeah. Thanks for the question. So we do see this as a very important component of support to six locations in the context of the gene-editing transplant. In terms of impact on the market, what I will say is that for the Medicaid population within the CMMI model that we've all discussed, and we hope and anticipate we'll get started sometime in 2025. There actually is a carve out there.

是的。謝謝你的提問。因此，我們確實認為這是在基因編輯移植背景下支持六個地點的非常重要的組成部分。就對市場的影響而言，我要說的是，對於我們都討論過的 CMMI 模型中的醫療補助人群，我們希望並預計我們將在 2025 年的某個時候開始。那裡實際上有一個雕刻。

So that within the model, which we don't know how many seats will be included, but that does cover Medicaid patients and the fertility preservation is unable to be included in that and then in the commercial setting, it's fine. So the decision that HHS or the IG made does not affect commercial and also again, CMMI, which we are encouraged and very hopeful that will move quickly.

因此，在該模型中，我們不知道將包含多少個席位，但它確實涵蓋了醫療補助患者，並且生育力保存無法包含在其中，然後在商業環境中，這很好。因此，HHS 或 IG 做出的決定不會影響商業，也不會影響 CMMI，我們對此感到鼓舞，並非常希望它能夠迅速採取行動。

And I am hopeful that there will be enough pressure and enough parties that will move to eventually change this. So by the time we're launching, I can't promise, but I don't anticipate it will be a huge market impact. And even in the coming years, I think that there are other opportunities for patients to be able to receive the gene editing therapies and the fertility preservation.

我希望會有足夠的壓力和足夠的政黨採取行動，最終改變這一現狀。因此，當我們推出時，我無法保證，但我預計這不會產生巨大的市場影響。即使在未來幾年，我認為患者還有其他機會接受基因編輯療法和保留生育能力。

It might be worth just pausing for a second and just take people through the acronyms and the sort of the structure of (multiple speakers)

也許值得暫停一下，讓人們了解縮寫詞和結構類型（多個發言者）

So [CMS] has a section on -- It's the CMMI model, which is created to be able to explore and launch pilot programs to patients to different areas of need. There are a number that have been done in oncology over the last years, and they created a specific cell and gene therapy program of which the sickle cell disease area was highlighted, and the program was initiated earlier this year kicked off, and it is voluntary for both manufacturers and for states.

因此，[CMS] 有一個章節是關於 CMMI 模型，該模型的創建是為了能夠為不同需求領域的患者探索和啟動試點計畫。過去幾年在腫瘤學方面做了很多工作，他們創建了一個特定的細胞和基因治療計劃，其中重點強調了鐮狀細胞病領域，該計劃於今年早些時候啟動，並且是自願的對於製造商和國家來說。

So TBD on exactly who is involved in it, but the opportunity is there with a lot of funding for federal CMS through the CMMI model to be able to negotiate with manufacturers on behalf of a lot of states. So it takes out some of that work and that variability.

因此，具體誰參與其中尚待確定，但聯邦 CMS 有機會透過 CMMI 模式獲得大量資金，以便能夠代表許多州與製造商進行談判。因此它消除了一些工作和可變性。

Again, it is a promising program that needs to be moved forward quickly. But within it, there was a waiver on the Anti-Kickback Statute around providing as a fertility preservation. So hopefully that gives a little bit better context.

同樣，這是一個有前途的計劃，需要迅速推進。但在其中，關於提供生育力保護的反回扣法規有一項豁免。所以希望這能提供更好的背景。

Thanks very much, Caren.

非常感謝，卡倫。

Liisa Bayko, Evercore ISI.

莉莎·貝科，Evercore ISI。

Hi, this is [Dring] on for Liisa. Thanks for taking our questions. So there's large number of patients in the Middle East. And can you please comment on how you plan to target this region? Do you plan to execute global launch yourself? Or will you need a partner to come during the construct of these? Thank you.

大家好，我是 Liisa 的 [Dring]。感謝您回答我們的問題。所以中東地區有大量的患者。您能否評論一下您計劃如何瞄準該地區？您打算自己進行全球發布嗎？或者您需要一個合作夥伴來參與這些專案的建設嗎？謝謝。

Thanks very much, Dring. I'm going to have Caren address that question.

非常感謝，德林。我將請卡倫回答這個問題。

Yeah. Great. Thank you. And we agree in the Middle East and there are other geographies where there is a significant unmet need. As we've said, and as was stated earlier, we continue to consider partnering for anything outside of the United States and any way that we can improve and accelerate access of therapies like reni-cel to patients in need. So we continue to maintain that sub-strategy and we'll update as appropriate.

是的。偉大的。謝謝。我們同意中東和其他地區存在大量未滿足的需求。正如我們已經說過的，以及之前所說的，我們繼續考慮在美國以外的任何領域進行合作，以及任何可以改善和加速有需要的患者獲得像 reni-cel 這樣的療法的方式。因此，我們將繼續維持該子策略，並將視情況進行更新。

Thank you very much, Caren.

非常感謝你，卡倫。

Thank you. Ladies and gentlemen, this concludes today's call. Thank you once again for your participation. You may now disconnect.

謝謝。女士們、先生們，今天的電話會議到此結束。再次感謝您的參與。您現在可以斷開連線。