Editas Medicine Inc (EDIT) 2023 Q3 法說會逐字稿

Good morning, and welcome to Editas Medicine's Third Quarter Conference Call. (Operator Instructions) Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Cristi Barnett, Corporate Communications and Investor Relations at Editas Medicine.

早上好，歡迎參加 Editas Medicine 第三季電話會議。 （操作員說明）請注意，本次通話是應公司要求進行錄音的。我現在想將電話轉給 Editas Medicine 企業傳播和投資者關係部門的 Cristi Barnett。

Thank you, Rob. Good morning, everyone, and welcome to our third quarter 2023 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 2 hours after its completion. 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. 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.

謝謝你，羅布。大家早上好，歡迎參加我們的 2023 年第三季電話會議。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於會議結束後約 2 小時在我們網站的投資者部分提供。在我們準備好發言後，我們將開始問答環節。謹此提醒，我們在本次電話會議中就公司未來預期、計劃和前景發表的各種言論構成前瞻性陳述，以符合1995 年《私人證券訴訟改革法案》中的安全港條款。實際結果可能與實際結果存在重大差異。這些前瞻性陳述中指出的因素是由於各種重要因素造成的，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 備案，並透過我們後續的文件進行了更新。

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

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。現在，我將把電話轉給我們的執行長吉爾摩·奧尼爾。

Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas Medicine's Third Quarter Earnings Call. I'm joined today by 4 other members of the Editas executive team, Baisong Mei, our Chief Medical Officer; Erick Lucera, our Chief Financial Officer; Linda Burkly, our Chief Scientific Officer; and Caren Deardorf, our new Chief Commercial and Strategy Officer. We are pleased with Editas' momentum and progress in the third quarter, and I look forward to sharing these details. Before that, however, let's take a quick step back to provide perspective.

謝謝克里斯蒂，大家早安。感謝您今天參加 Editas Medicine 第三季財報電話會議。今天加入我的還有 Editas 執行團隊的其他 4 名成員：我們的首席醫療官 Baisong Mei； Erick Lucera，我們的財務長； Linda Burkly，我們的首席科學官；以及我們新任首席商務和策略長 Caren Deardorf。我們對 Editas 第三季的勢頭和進展感到滿意，我期待分享這些細節。然而，在此之前，讓我們快速退後一步來提供觀點。

Editas' goal is to deliver life-changing medicines to patients with previously untreatable or untreated diseases. I joined Editas in June 2022 to help realize this goal tasked with guiding the company's evolution from a platform development company to a commercial therapeutics company. As many of you know, in January of this year, we shared Editas' vision and strategy to position Editas as a leader in programmable gene editing. As a reminder, 3 pillars underpin our strategy. First, to accelerate the clinical development of EDIT-301, our autologous ex vivo gene-edited medicine for severe sickle cell disease and transfusion-dependent beta-thalassemia and drive it towards approval and launch.

Editas 的目標是為患有先前無法治療或未經治療的疾病的患者提供改變生活的藥物。我於 2022 年 6 月加入 Editas，幫助實現這一目標，其任務是引導公司從平台開發公司發展為商業治療公司。正如你們許多人所知，今年 1 月，我們分享了 Editas 的願景和策略，將 Editas 定位為可程式基因編輯領域的領導者。提醒一下，我們的策略有三大支柱支撐。首先，加速我們用於治療嚴重鐮狀細胞疾病和輸血依賴性β地中海貧血的自體離體基因編輯藥物EDIT-301的臨床開發，並推動其獲得批准和上市。

Second, to sharpen our discovery focus to in vivo editing therapies; and third, expand our business development activities to partner complementary technological capabilities that can advance our in vivo pipeline development in addition to out-licensing our robust IP and know-how to maximize the use of CRISPR-based medicines. At the start of 2023, we outlined the following 2023 objectives. For EDIT-301, to provide a clinical update from the EDIT-301 RUBY trial for severe sickle cell disease or SCD, by the end of 2023. To provide a clinical data update for EDIT-301 EDITHAL trial for transfusion-dependent beta-thalassemia or TDT by the end of 2023. And to have dosed 20 total patients in the RUBY trial by the end of 2023.

其次，將我們的發現重點集中在體內編輯療法上；第三，擴大我們的業務開發活動，與互補的技術能力合作，除了授權我們強大的智慧財產權和專業知識以最大限度地利用基於 CRISPR 的藥物之外，這些能力還可以推進我們的體內管道開發。 2023 年初，我們概述了以下 2023 年目標。對於 EDIT-301，到 2023 年底提供針對嚴重鐮狀細胞病或 SCD 的 EDIT-301 RUBY 試驗的臨床更新。為輸血依賴性β地中海貧血的 EDIT-301 EDITHAL 試驗提供臨床數據更新或TDT 到2023 年底。並在2023 年底之前為RUBY 試驗中的總共20 名患者進行了給藥。

For in vivo medicine development, to hire a new Chief Scientific Officer with specific expertise aligns to our vision and to advance the discovery of in vivo editing of hematopoietic stem cells or HSCs and other tissues. And for business development, to leverage our robust IP portfolio and business development capabilities to drive value and to complement our core gene editing technology capabilities. So how have we executed against this strategy and these objectives in the third quarter.

對於體內藥物開發，聘請一位具有特定專業知識的新首席科學官符合我們的願景，並推動造血幹細胞或造血幹細胞和其他組織的體內編輯的發現。對於業務發展，利用我們強大的智慧財產權組合和業務開發能力來推動價值並補充我們的核心基因編輯技術能力。那麼，我們在第三季如何執行這項策略和這些目標。

Let's start with EDIT-301. First, on clinical data. We will present a company-sponsored webinar in tandem with a poster presentation at ASH, both on December 11. That is next month. We plan to share clinical data from 11 sickle cell patients in the RUBY trial and 6 beta-thalassemia patients in the EDITHAL trial. Baisong will share more details about our presentation later on the call.

讓我們從 EDIT-301 開始。首先，關於臨床數據。我們將於 12 月 11 日在 ASH 上舉辦由公司贊助的網路研討會和海報展示。也就是下個月。我們計劃分享 RUBY 試驗中 11 名鐮狀細胞疾病患者和 EDITHAL 試驗中 6 名β地中海貧血患者的臨床數據。 Baisong 將在稍後的電話會議上分享有關我們演示的更多詳細資訊。

Second, on enrollment. We have enrolled 27 sickle cell and 8 beta-thalassemia patients into our RUBY and EDITHAL studies, respectively, and screening continues at a good pace. Third, on dosing, we now expect to dose the 20th patient in the RUBY trial in the January 2024 timeframe due to individual patient schedules. And finally, for 2024 data disclosures, we remain on track to present a substantial clinical data set of sickle cell patients with considerable clinical follow-up in the RUBY study in the middle of 2024. Baisong will share further details regarding our December data readout and clinical progress of EDIT-301 in his remarks.

二是關於招生。我們已分別將 27 名鐮狀細胞疾病患者和 8 名 β 地中海貧血患者納入我們的 RUBY 和 EDITHAL 研究，且篩檢工作仍在順利進行中。第三，在給藥方面，根據個別患者的時間表，我們現在預計在 2024 年 1 月的時間範圍內對 RUBY 試驗中的第 20 名患者進行給藥。最後，對於2024 年的數據揭露，我們仍有望在2024 年中期的RUBY 研究中提供大量鐮狀細胞患者的臨床數據集，並進行大量臨床隨訪。Baisong 將分享有關我們12 月數據讀出的更多詳細信息，以及他在演講中介紹了 EDIT-301 的臨床進展。

On the regulatory front, we are also pleased at just 2 weeks ago, the FDA recently or granted us their Regenerative Medicine Advanced Therapy or RMAT designation to EDIT-301 for the treatment of severe sickle cell disease. Advantages of the RMAT designation include all the benefits of the Fast Track and breakthrough therapy designation programs, including, but not limited to, intensive FDA guidance on efficient and expedited drug development possible rolling review and priority review of the BLA. With respect to commercial plans, as we previously shared, we made another important hire as we continue to gain momentum in pursuing a leadership position in hematopoietic stem cell medicines for hemoglobinopathies.

在監管方面，我們也很高興在兩週前，FDA 最近授予我們 EDIT-301 再生醫學高級療法或 RMAT 稱號，用於治療嚴重鐮狀細胞疾病。 RMAT 指定的優點包括快速通道和突破性治療指定計劃的所有好處，包括但不限於 FDA 對高效和快速藥物開發的深入指導、可能的滾動審查和 BLA 的優先審查。關於商業計劃，正如我們之前分享的那樣，隨著我們在血紅蛋白病造血幹細胞藥物領域繼續獲得領導地位，我們又進行了一項重要的聘用。

In late September, we announced that Caren Deardorf, a highly experienced and successful therapeutics commercial leader has joined Editas as our new Chief Commercial and Strategy Officer. Caren has a proven ability to translate early discovery and clinical assets into robust business strategies with disciplined portfolio prioritization and value creation. Additionally, she has led multiple successful U.S. and global product launches. Caren's expertise and track record make her the ideal leader to help Editas reach this goal for patients. To further enable commercialization, as previously shared in July, we will increase our clean room capacity when we move our CMC team into the new Azzur Devens facility in early 2024.

9 月下旬，我們宣布，經驗豐富且成功的治療商業領袖 Caren Deardorf 已加入 Editas，擔任我們新的商業和策略長。 Caren 擁有公認的能力，能夠將早期發現和臨床資產轉化為穩健的業務策略，並具有嚴格的投資組合優先順序和價值創造。此外，她還領導了許多成功的美國和全球產品發布。 Caren 的專業知識和業績記錄使她成為幫助 Editas 為患者實現這一目標的理想領導者。為了進一步實現商業化，正如先前在 7 月分享的那樣，我們將在 2024 年初將 CMC 團隊遷入新的 Azzur Devens 工廠時增加無塵室容量。

With this increased capacity, we ensure our ability to scale EDIT-301 manufacturing, both for clinical supply for our RUBY and EDITHAL trials as well as to prepare for commercial readiness. In a step forward for the gene editing industry and patients alike, we were delighted to see the recent exa-cel AdCom. The very focused review by FDA and the AdCom confirmed our confidence in the robust nature of our own off-target assessments. The patient testimonies in addition were incredibly moving and powerful and demonstrate the significant need for new and transformative medicines for the treatment of sickle cell disease.

隨著產能的增加，我們確保了擴大 EDIT-301 生產規模的能力，既可以用於 RUBY 和 EDITHAL 試驗的臨床供應，也可以為商業準備做好準備。我們很高興看到最近的 exa-cel AdCom，這對於基因編輯行業和患者來說向前邁出了一步。 FDA 和 AdCom 的非常集中的審查證實了我們對我們自己的脫靶評估的穩健性的信心。此外，患者的證詞非常感人且有力，證明了對治療鐮狀細胞疾病的新的變革性藥物的巨大需求。

Turning now to in vivo and our pipeline development. As stated earlier this year, our Drug Discovery Group began lead discovery work on in vivo therapeutic targets in hematopoietic stem cells and other tissues. And in July, we hired Linda Burkly as our Chief Scientific Officer to Spirit head these efforts. Linda looks forward to sharing more at the appropriate time. As a reminder, under our new target selection criteria, we will select therapeutic targets that will allow our genome editing approach to differentiate maximally from the current standard of care for serious diseases. The target selection criteria will work to identify targets that maximize the probability of technical, regulatory and commercial success.

現在轉向體內和我們的管道開發。正如今年稍早所述，我們的藥物發現小組開始主導造血幹細胞和其他組織體內治療標靶的發現工作。 7 月，我們聘請 Linda Burkly 擔任首席科學官，負責 Spirit 領導這些工作。琳達期待在適當的時候分享更多。提醒一下，根據我們新的標靶選擇標準，我們將選擇治療靶點，使我們的基因組編輯方法能夠最大程度地區別於當前嚴重疾病的治療標準。目標選擇標準將致力於確定能夠最大限度地提高技術、監管和商業成功可能性的目標。

Now let's turn to business development. In August, we shared that we entered into an agreement with Vor Bio, providing a nonexclusive license for ex vivo Cas9 gene edit HSC therapies for the treatment and/or prevention of hematological malignancies. Under this agreement, Editas received an upfront payment and will be eligible for future development, regulatory and commercial milestone payments as well as royalties on medicines utilizing the related intellectual property. Turning to our intellectual property position, as a reminder, Editas holds a large portfolio of foundational U.S. and international patents and is the exclusive licensee of Harvard University and the Broad Institute Cas9 patent estates covering Cas9 use in developing human medicines. Only a small fraction of these patents are involved in the ongoing USPTO interference proceedings. As the exclusive licensee we are uniquely positioned to issue exclusive and nonexclusive sublicenses for Cas9 to any company seeking to use these enzymes to make human medicines, including in vivo and ex vivo users.

現在讓我們轉向業務發展。 8 月，我們宣布與 Vor Bio 達成協議，為用於治療和/或預防血液惡性腫瘤的離體 Cas9 基因編輯 HSC 療法提供非獨家許可。根據該協議，Editas 收到了預付款，並將有資格獲得未來的開發、監管和商業里程碑付款以及利用相關智慧財產權的藥品特許權使用費。談到我們的智慧財產權地位，需要提醒的是，Editas 擁有大量美國和國際基礎專利，並且是哈佛大學和 Broad Institute Cas9 專利財產的獨家被授權人，涵蓋 Cas9 在開發人類藥物中的用途。這些專利中只有一小部分涉及正在進行的美國專利商標局干涉訴訟。作為獨家被授權人，我們擁有獨特的優勢，可以向任何尋求使用這些酵素製造人類藥物的公司（包括體內和離體用戶）頒發 Cas9 的獨家和非獨家再授權。

Our recently announced licensing deal with Vor Bio further bolsters our confidence that our IP portfolio provides meaningful value now and in the future. To conclude my remarks, we are energized by the promising efficacy and safety data we shared in June, signaling that EDIT-301 may be a clinically differentiated onetime durable medicine that can provide life-changing clinical benefits to patients with sickle cell disease and beta-thalassemia in the long-term, specifically driving early and robust correction of anemia and sustained increases in fetal hemoglobin. With our sharpened strategic focus, our world-class scientists and employees and our keen drive in execution, we continue to build momentum to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases. I will now turn the call over to Baisong, our Chief Medical Officer.

我們最近宣布與 Vor Bio 達成的授權協議進一步增強了我們的信心，即我們的智慧財產權組合在現在和未來都能提供有意義的價值。最後，我們對6 月分享的有希望的療效和安全性數據感到振奮，這表明EDIT-301 可能是一種臨床差異化的一次性耐用藥物，可以為鐮狀細胞病和β-細胞病患者提供改變生活的臨床益處。從長遠來看，地中海貧血，特別是推動貧血的早期和強有力的糾正以及胎兒血紅蛋白的持續增加。憑藉我們更明確的策略重點、世界一流的科學家和員工以及我們敏銳的執行力，我們將繼續積蓄動力推進我們的策略，為患有嚴重遺傳疾病的患者提供差異化的編輯藥物。我現在將電話轉給我們的首席醫療官拜松。

Thank you, Gilmore. Good morning, everyone. Let's start with EDIT-301 in development of severe sickle cell disease and transfusion dependent beta-thalassemia. As Gilmore mentioned in his remarks, we continue to enroll and dose patients in the RUBY trial for severe sickle cell disease and in the EDITHAL trial for transfusion-dependent beta-thalassemia. As of today, in the RUBY trial, we have enrolled 27 patients and the 20 patients in the RUBY trial is expected to be dosed in the January 2024 timeframe.

謝謝你，吉爾摩。大家，早安。讓我們從嚴重鐮狀細胞疾病和輸血依賴性β-地中海貧血的發展中的 EDIT-301 開始。正如 Gilmore 在他的演講中所提到的，我們繼續在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 試驗中招募患者並給予患者劑量。截至今天，在 RUBY 試驗中，我們已經入組了 27 名患者，RUBY 試驗中的 20 名患者預計將在 2024 年 1 月的時間範圍內接受給藥。

In the EDITHAL trial for transfusion-dependent beta-thalassemia to date, we have enrolled 8 patients. As I shared earlier this year, I have been visiting and continue to visit our RUBY and EDITHAL clinical trial sites, continuously speaking with our investigators, and I appreciate the enthusiasm and the support from the investigator at study sites. I'm pleased with the momentum of EDIT-301 in patient recruitment, (inaudible) editing and dosing in both studies. I'm excited to hear from the investigators that patients dosed with EDIT-301 have already seen positive changes in their lives. As we have previously shared, we will engage with the FDA in the second half of the year.

迄今為止，在針對輸血依賴性β地中海貧血的 EDITHAL 試驗中，我們已招募了 8 名患者。正如我今年早些時候分享的那樣，我一直在訪問並將繼續訪問我們的 RUBY 和 EDITHAL 臨床試驗中心，不斷與我們的研究人員交談，我感謝研究中心研究人員的熱情和支持。我對兩項研究中 EDIT-301 在病患招募、（聽不清楚）編輯和劑量方面的勢頭感到滿意。我很高興從研究人員那裡得知，服用 EDIT-301 的患者的生活已經發生了積極的變化。正如我們之前所分享的，我們將在今年下半年與 FDA 接觸。

On a related note, we found the recent exa-cel AdCom recycle, and it has reaffirmed the power and potential of this gene editing technology. As a physician, I'm excited for patients living with serious diseases that gene editing has the potential to transform the treatment of the diseases and ultimately, patient lives. As a drug developer, I'm eager to see the first medicine approved and swiftly followed by more medicine from other companies, including Editas. More importantly, I'm excited to announce that we will share RUBY and EDITHAL clinical data in a poster presentation at ASH as well as in the company-sponsored webinar both on Monday, December 11.

與此相關的是，我們發現了最近的 exa-cel AdCom 回收，它再次證實了這種基因編輯技術的力量和潛力。作為一名醫生，我為患有嚴重疾病的患者感到興奮，因為基因編輯有可能改變疾病的治療方法，並最終改變患者的生活。作為一名藥物開發商，我渴望看到第一種藥物獲得批准，並迅速跟進包括 Editas 在內的其他公司的更多藥物。更重要的是，我很高興地宣布，我們將在 ASH 的海報展示以及公司主辦的 12 月 11 日星期一的網路研討會上分享 RUBY 和 EDITHAL 的臨床數據。

So what we will show. The RUBY data set, we're including clinical data from 11 patients. We will present efficacy data, including total hemoglobin, fetal hemoglobin and vaso-occlusive events or VOE and safety data, including neutrophil and platelet engraftment. The follow-up period of these 11 patients includes 2 patients with at least 12 months follow-up and an additional 4 patients with at least 5 months follow-up. The other patients will have a 1- to 4-month follow-up period. The EDITHAL data set will include clinical data from 6 patients. We will present efficacy data including total hemoglobin and fetal hemoglobin and safety data, including neutrophil and platelet engraftment. The follow-on period after EDIT-301 treatment includes at least 5 months data from the first 2 patients treated. The other patient will have 1 to 4 months follow-up period.

那麼我們將展示什麼。 RUBY 資料集包含 11 名患者的臨床資料。我們將提供療效數據，包括總血紅蛋白、胎兒血紅蛋白和血管閉塞事件或 VOE 以及安全性數據，包括嗜中性球和血小板植入。這11名患者的追蹤期包括2名患者至少追蹤12個月，另外4名患者至少追蹤5個月。其他患者將有1至4個月的追蹤期。 EDITHAL 資料集將包括 6 名患者的臨床數據。我們將提供包括總血紅素和胎兒血紅蛋白在內的療效數據以及包括嗜中性球和血小板植入在內的安全性數據。 EDIT-301 治療後的追蹤期包括前 2 名接受治療的患者的至少 5 個月的數據。另一名患者將有1至4個月的追蹤期。

As a reminder, this past June, we shared promising RUBY clinical data in an oral presentation at the European Hematology Association Congress or EHA followed by our company-sponsored webinar, we also presented possible initial data from the first patient treated in the EDITHAL trial. The RUBY dataset covers safety and efficacy data from the first 4 patients including 10 month data from the first patient treated and 6-month data from the second patient treated, including total hemoglobin and fetal hemoglobin, demonstrating EDIT-301 drives early robust correction of anemia to a normal physiological range of total hemoglobin in as early as 4 months after EDIT-301 treatment. EDIT-301 drives robust and sustained increase in fetal hemoglobin in excess of 40%. All 4 of those RUBY sickle cell patients remained free of vaso-occlusive events since EDIT-301 treatment.

提醒一下，今年6 月，我們在歐洲血液學協會大會或EHA 的口頭報告中分享了有希望的RUBY 臨床數據，隨後我們公司主辦了網絡研討會，我們還提供了EDITHAL 試驗中第一位接受治療的患者的可能的初始數據。 RUBY 數據集涵蓋了前4 名患者的安全性和有效性數據，包括第一位接受治療的患者的10 個月數據和第二位接受治療的患者的6 個月數據，包括總血紅蛋白和胎兒血紅蛋白，證明EDIT-301 推動了貧血的早期穩健糾正EDIT-301 治療後 4 個月內，總血紅蛋白就達到正常生理範圍。 EDIT-301 使胎兒血紅素強勁持續增加超過 40%。自 EDIT-301 治療以來，所有 4 名 RUBY 鐮狀細胞患者均未出現血管閉塞事件。

Additionally, all those participants including 4 RUBY patients and 1 EDITHAL patient to a successful engraftment within 1 month of dosing and has stopped red blood cell transfusion. EDIT-301 was well tolerated by patients, and the safety profile for EDIT-301 was consistent with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. And the trajectory of correction of anemia and expression of fetal hemoglobin was consistent across EDIT-301 when treated sickle cell patient and beta-thalassemia patient at the same follow-up time zone. We continue to believe that EDIT-301 can potentially provide robust clinical benefit to patients with severe sickle cell disease and transfusion-dependent beta-thalassemia, potentially provide clinical differentiation in the long-term.

此外，所有參與者（包括 4 名 RUBY 患者和 1 名 EDITHAL 患者）在給藥後 1 個月內成功植入，並停止了紅血球輸注。患者對 EDIT-301 的耐受性良好，EDIT-301 的安全性與清髓性白消安預處理和自體造血幹細胞移植一致。當在同一追蹤時間區治療鐮狀細胞疾病患者和β-地中海貧血患者時，EDIT-301 中貧血校正和胎兒血紅蛋白表達的軌跡是一致的。我們仍然相信 EDIT-301 可以為患有嚴重鐮狀細胞疾病和輸血依賴性β地中海貧血的患者提供強大的臨床益處，並有可能提供長期的臨床分化。

We look forward to our presentation of additional clinical data and a longer follow-up in December. As we have previously stated, the choice of CRISPR enzyme and the target to edit to switch on fetal hemoglobin expression matters. EDIT-301 used our proprietary AsCas12a enzyme to edit HBG1/2 promoter. AsCas12a increases the efficiency of editing and significantly reduce off-target editing when compared to other critical enzyme including Cas9. Editing HBG1 promoter -- HBG1/2 promoter in human CD34 positive cells, resulting in greater red blood cell production and normal proliferative capacity and improve red blood cell health when compared to editing of BCL11A.

我們期待在 12 月提供更多臨床數據和更長的追蹤時間。正如我們之前所說，CRISPR 酶的選擇和編輯目標以開啟胎兒血紅蛋白表達很重要。 EDIT-301 使用我們專有的 AsCas12a 酵素來編輯 HBG1/2 啟動子。與 Cas9 等其他關鍵酶相比，AsCas12a 提高了編輯效率並顯著減少脫靶編輯。與編輯 BCL11A 相比，編輯 HBG1 啟動子——人類 CD34 陽性細胞中的 HBG1/2 啟動子，可產生更大的紅血球產量和正常的增殖能力，並改善紅血球健康。

We look at the differentiation in 3 categories of endpoints in clinical trials. Hematological parameters and organ function and patient reported outcome quality of life. Based on the clinical data so far, we believe that sustained normal level of hemoglobin could be a potential point of differentiation for EDIT-301. As a reminder, a sustained normal total hemoglobin level is an important clinical outcome for patients as the correction of anemia can significantly improve quality of life and ameliorate the end organ damage. We look forward to sharing additional data including RUBY and EDITHAL clinical data next month.

我們研究了臨床試驗中三類終點的差異。血液學參數和器官功能以及患者報告的生活品質結果。根據迄今為止的臨床數據，我們認為持續正常的血紅蛋白水平可能是 EDIT-301 的潛在分化點。提醒一下，持續正常的總血紅素水平對於患者來說是一個重要的臨床結果，因為糾正貧血可以顯著提高生活品質並減輕終末器官損傷。我們期待下個月分享更多數據，包括 RUBY 和 EDITHAL 臨床數據。

Now I will turn the call over to Erick, our Chief Financial Officer.

現在我將把電話轉給我們的財務長埃里克。

Thank you, Baisong, and, good morning, everyone. I'm happy to be speaking with you today and with 1 quarter under my belt at Editas, I'm even more impressed by the quality of our science, our leadership in the gene editing field, the strong intellectual property portfolio and our highly differentiated work from other players in the field. I was excited to join this summer, and I continue to be impressed with what I see. With that, I'd like to refer you to our press release issued earlier today for a summary of our financial results for the third quarter 2023, and I'll take this opportunity to briefly review a few items. Our cash, cash equivalents and marketable securities as of September 30 were $446 million compared to $480 million at June 30, 2023. We expect our existing cash, cash equivalents and marketable equity securities to fund our operating expenses and capital expenditures into the third quarter of 2025. Revenue for the third quarter of 2023 was $5.3 million, which primarily relates to the upfront payment under the nonexclusive Cas9 license to Vor Bio in August 2023.

謝謝白松，大家早安。我很高興今天能與您交談，在 Editas 工作了 1 季度，我對我們的科學品質、我們在基因編輯領域的領導地位、強大的知識產權組合以及我們高度差異化的產品印象更加深刻來自該領域其他參與者的工作。我很高興今年夏天加入，我所看到的仍然給我留下了深刻的印象。在此，我想向您推薦我們今天早些時候發布的新聞稿，了解我們 2023 年第三季度的財務業績摘要，我將藉此機會簡要回顧一些項目。截至9 月30 日，我們的現金、現金等價物和有價證券為4.46 億美元，而2023 年6 月30 日為4.8 億美元。我們預計現有現金、現金等價物和有價證券將為我們第三季度的營運費用和資本支出提供資金。2025年。2023年第三季的收入為530萬美元，主要與2023年8月向Vor Bio授予非獨家Cas9許可的預付款有關。

R&D expenses this quarter were $41 million, essentially flat from the third quarter of 2022, which reflects various offsetting expenses, including decreases in R&D spend related to our reprioritization and targeted focus on our EDIT-301 program, offset by increased spending in pre-commercialization efforts, including medical affairs and patient advocacy. G&A expenses for the third quarter of 2023 were $15 million, which decreased from $16 million for the third quarter of 2022. The decrease in expense is primarily attributable to decreased head count expenses, including stock compensation and reduced legal costs. Overall, Editas remains in strong financial position, bolstered by our sharpened discovery focus, June capital raise recent out-licensing deal.

本季的研發費用為4,100 萬美元，與2022 年第三季基本持平，這反映了各種抵銷費用，包括與我們重新確定優先順序和有針對性地關注EDIT-301 計劃相關的研發支出減少，但被預商業化支出的增加所抵消努力，包括醫療事務和病人宣傳。 2023 年第三季的一般管理費用為 1,500 萬美元，低於 2022 年第三季的 1,600 萬美元。費用減少主要歸因於人員費用減少，包括股票薪資和法律費用減少。總體而言，Editas 的財務狀況仍然強勁，這得益於我們加強對發現的關注以及 6 月份最近的對外許可交易的融資。

Our cash runway into the third quarter of 2025 provides ample resources to support our continued progress in the RUBY and EDITHAL trials of EDIT-301 and continued commercial manufacturing preparation and advance our discovery and research efforts. As I've shared before, I'm a former buy-side investor, and I know the value of buy-side and sell-side knowledge. I look forward to hearing from our shareholders as we work to advance our gene editing medicine. We value your feedback. And with that, I'll hand the call back to Gilmore.

我們到 2025 年第三季的現金跑道提供了充足的資源，以支持我們在 EDIT-301 的 RUBY 和 EDITHAL 試驗中持續取得進展，並繼續進行商業製造準備，並推進我們的發現和研究工作。正如我之前分享的，我是前買方投資者，我知道買方和賣方知識的價值。在我們努力推進基因編輯醫學的過程中，我期待收到股東的來信。我們重視您的回饋。然後我會把電話轉給吉爾摩。

Thank you, Erick. As we continue our momentum and the execution of our goals, it remains an exciting year for Editas. We look forward to continuing our transformation and sharing our progress with you. 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, investment community. Thanks very much for your interest in Editas, and we're happy to answer questions. Thank you.

謝謝你，埃里克。隨著我們繼續保持勢頭並執行我們的目標，對於 Editas 來說，今年仍然是激動人心的一年。我們期待繼續轉型並與您分享我們的進步。像往常一樣，必須說，如果沒有患者、照護者、研究人員、員工、企業合作夥伴以及您、投資界的支持，我們就無法實現我們的目標。非常感謝您對 Editas 的興趣，我們很樂意回答問題。謝謝。

(Operator Instructions) Our first question comes from the line of Brian Chan with JPMorgan.

（操作員指示）我們的第一個問題來自摩根大通的布萊恩陳（Brian Chan）。

(inaudible) And any other insights that you potentially read through to your path to approval.

（聽不清楚）以及您可能閱讀並獲得批准的任何其他見解。

Brian, thanks very much. I'm afraid it was incredibly difficult to hear you with the background noise, and I know you're suffering from some connection problems there. I think I heard you talk about or off-targeting. So I'm assuming you're referring to (inaudible) front. Yes. And so let me just go with that and then we can follow if it's incorrect. But I think you referred to the AdCom. I have to say is that the AdCom represents an incredibly and drove a great excitement for this week. It was a great day for sickle cell warriors, where patients now can think about not battling a disease, but actually living a life, it was a significant milestone for CRISPR genome editing as that AdCom represents almost a notable step towards approval for the first CRISPR-based medicine.

布萊恩，非常感謝。恐怕在背景噪音中聽清你的聲音非常困難，而且我知道你遇到了一些連接問題。我想我聽到你談論或偏離目標。所以我假設你指的是（聽不清楚）前面。是的。因此，讓我繼續說下去，如果它不正確，我們可以遵循。但我認為你提到了 AdCom。我不得不說的是，AdCom 代表了本周令人難以置信的興奮。對於鐮狀細胞戰士來說，這是偉大的一天，患者現在可以考慮不再與疾病作鬥爭，而是真正過上自己的生活，這是CRISPR 基因組編輯的一個重要里程碑，因為AdCom 幾乎代表著第一個CRISPR 獲得批准的重要一步為基礎的醫學。

What struck us in the very focused discussion of the AdCom was the positive tone. But actually also, as we listen to the commentary, it really substantially strengthened our confidence in the very robust data package that we've generated about off-target editing. I hope I've answered your question because with off-target editing what I heard. I think the only other thing I want to emphasize, of course, is that we have chosen to advance our proprietary-owned AsCas12a enzyme, which indeed has higher fidelity and a significant reduction in off-target edits when compared to Cas9.

AdCom 的討論非常集中，讓我們印象深刻的是積極的基調。但實際上，當我們聽到評論時，它確實大大增強了我們對我們生成的有關脫靶編輯的非常強大的資料包的信心。我希望我已經回答了你的問題，因為我聽到的內容經過了脫靶編輯。當然，我想我想強調的另一件事是，我們選擇推進我們專有的 AsCas12a 酶，與 Cas9 相比，它確實具有更高的保真度，並且脫靶編輯顯著減少。

I'm just wondering if there were a lot of focus specifically on off-target effects. So I'm just wondering if there is any work that you're doing now that is different than the gene editors players that are in the market that are different to make sure that the regulators will be happy with the way that you're monitoring these off-target effects.

我只是想知道是否有很多專門關注脫靶效應。所以我只是想知道您現在正在做的工作是否與市場上的基因編輯玩家不同，以確保監管機構對您的監控方式感到滿意這些脫靶效應。

I mean without going into details, I don't think it's appropriate at this time to go into details. We are doing more than was discussed at the AdCom. And that's where our confidence about the robustness of our data package comes from. I hope that was the question.

我的意思是，在不討論細節的情況下，我認為現在不適合討論細節。我們正在做的事情比 AdCom 上討論的還要多。這就是我們對資料包的穩健性充滿信心的來源。我希望這就是問題所在。

Our next question comes from the line of Samantha Semenkow with Citi.

我們的下一個問題來自花旗銀行的 Samantha Semenkow。

Just a follow up on the last question, Gilmore, and you sort of touched on this, the difference between Cas12a and Cas9. Can you just talk a little bit more in detail about what you're seeing as the different off-target risk? And how you'd be able to show that to regulators when you get to that step?

Gilmore，只是對最後一個問題的跟進，您談到了 Cas12a 和 Cas9 之間的差異。您能否更詳細地談談您所看到的不同的脫靶風險？當你到達這一步時，你如何能夠向監管機構展示這一點？

Indeed happy to. Let me just preface again with the sort of high-level labs in published data. We have and others have shown a substantial reduction in off-target editing when comparing AsCas12a versus the Cas9 enzyme. With regard to the data package that we have generated and continue to generate off-target, it is substantial. I'm not sure that we are in place to share more details. I don't know, Linda, if you have anything to add.

確實很高興。讓我再次以已發布數據中的高級實驗室作為序言。我們和其他人已經證明，在比較 AsCas12a 與 Cas9 酶時，脫靶編輯顯著減少。就我們已經產生並繼續產生的脫靶資料包而言，這是相當可觀的。我不確定我們是否可以分享更多細節。琳達，我不知道你還有什麼要補充的嗎？

Yes, I would just add -- this is Linda Burkly, CFO. Yes, I would just add and echo what Gilmore just said that we're using multiple orthogonal methods additional method as compared -- additional methods as compared to what we heard at the AdCom. And -- and so we're very confident in our package as we proceed in our path to the BLA and yes, we -- in our preclinical data, we are not seeing off-target editing in our preclinical experiments. So we're very confident in our package going forward.

是的，我想補充一下——我是財務長 Linda Burkly。是的，我只是補充並呼應 Gilmore 剛才所說的，我們正在使用多種正交方法和其他方法進行比較——與我們在 AdCom 聽到的方法相比的其他方法。因此，當我們繼續走向 BLA 的道路時，我們對我們的方案非常有信心，是的，我們 - 在我們的臨床前數據中，我們在臨床前實驗中沒有看到脫靶編輯。因此，我們對我們的一攬子計劃的未來非常有信心。

The next question is from the line of Joon Lee with Tui Securities.

下一個問題來自途易證券的 Joon Lee。

Thanks for the update. Based on all that's been presented during the AdCom, where do you see room for clinical differentiation? And is that something that we can expect to see at ASH. Specifically, can you comment on your platelet engraftment reticulocyte count and markers of hemolysis?

感謝更新。根據 AdCom 期間提出的所有內容，您認為臨床差異化的空間在哪裡？這是我們可以在 ASH 上看到的東西嗎？具體來說，您能評論一下您的血小板植入網織紅血球計數和溶血標記嗎？

So I think the key thing is that we are very excited already, the clinical data that we have presented and what we see as a competitive fast follower with potential for differentiation and what we've seen to date was a consistent highest level correction of anemia to the normal physiological range, which is by design in our choosing of AsCas12a to edit gamma-globin promoter. I'm going to ask Baisong just to tell you a little more about what we can about what we're going to share at ASH on December 11.

所以我認為關鍵是我們已經非常興奮，我們提供的臨床數據以及我們認為具有分化潛力的有競爭力的快速追隨者以及我們迄今為止看到的一致的最高水平的貧血糾正正常生理範圍，這是我們選擇AsCas12a 來編輯γ-珠蛋白啟動子時的設計。我想請 Baisong 告訴您更多關於我們將在 12 月 11 日在 ASH 上分享的內容。

Thanks for the question, Joon. So -- as I mentioned that in the ASH presentation, we'll have data from 11 RUBY patients and 6 EDITHAL patients, and we will have a longer follow-up period with 2 patients in the RUBY trial with at least 12 months, and then we have additional data from 5 months for the RUBY trial. And go back to your question also on the AdCom in there. And we are very actually pleased to see, as -- Gilmore mentioned, the very successful AdCom and reaffirm, I believe, the technology and also the MOA of using fetal hemoglobin as a target to treat sickle disease and beta-thalassemia. And we -- for differentiation, we are confident that we are a fast follower, we differentiate molecule -- and we are very pleased to see that we presented data that we'll be able to correct the anemia. And in our case, the normal total hemoglobin for female with 12 to 16 gram per deciliter and for male is 13.8 to 18-gram per deciliter, and we're pleased to see our patients going to the normal range and we are pleased to share more data during the ASH and webinar presentation data next month.

謝謝你的提問，瓊。因此，正如我在ASH 演示中提到的，我們將獲得11 名RUBY 患者和6 名EDITHAL 患者的數據，並且我們將對RUBY 試驗中的2 名患者進行更長的隨訪期，至少12 個月，並且然後我們獲得了 RUBY 試驗 5 個月的額外數據。回到你關於 AdCom 的問題。正如 Gilmore 所提到的，我們非常高興地看到 AdCom 非常成功，我相信，我們重申了使用胎兒血紅蛋白作為治療鐮狀病和 β 地中海貧血的目標的技術和 MOA。對於差異化，我們有信心我們是一個快速追隨者，我們區分分子，我們很高興看到我們提供的數據將能夠糾正貧血。在我們的病例中，女性正常總血紅蛋白為 12 至 16 克每分升，男性為 13.8 至 18 克每分升，我們很高興看到我們的患者恢復到正常範圍，我們很高興與大家分享下一個月ASH 和網路研討會演示期間的更多數據。

I think the only other thing is it's -- we do note that we've had very successful engraftment timelines. It's too early to say more than that in the space. And I think we're also very happy with where our hemolytic markers are.

我認為唯一的另一件事是——我們確實注意到我們的植入時間表非常成功。現在談更多還為時過早。我認為我們對溶血標記物的位置也非常滿意。

Our next question is from the line of Greg Harrison with Bank of America.

我們的下一個問題來自美國銀行的格雷格·哈里森。

Just thinking when should we expect an update on the in vivo editing efforts? And how do you think the commercial opportunity is there relative to ex vivo in sickle cell and then what other indications or tissues do you think are attractive candidates for your in vivo technology?

只是想一下我們什麼時候該期待體內編輯工作的更新？您認為鐮狀細胞相對於體外的商業機會如何？您認為還有哪些其他適應症或組織對您的體內技術有吸引力？

Thanks very much, Greg. With regard to future updates, this is a company who philosophically wants to make promises and make discussions that we believe that we can absolutely deliver on. We have been doing work over the last year. Linda has already been here about 3 months. We want to ensure that she has the time to, again, engaging with our medical and commercial team now led by our new Chief Commercial and Strategic Officer, the ability to make sure that we choose and progress against high conviction targets based on our selection criteria.

非常感謝，格雷格。關於未來的更新，這是一家從哲學上希望做出承諾並進行討論的公司，我們相信我們絕對可以兌現。去年我們一直在做工作。琳達已經來這裡大約三個月了。我們希望確保她有時間再次與我們的醫療和商業團隊合作，現在由我們新任首席商務和策略官領導，能夠確保我們根據我們的選擇標準選擇高信念目標並取得進展。

With regard to your second question, let's just remind me again targeted tissues. Yes, forgive me. So we have actually advanced for -- in fact Linda. I might ask you talk about target tissues.

關於你的第二個問題，我們再次提醒目標組織。是的，請原諒我。所以我們實際上已經為琳達取得了進展。我可能會問你談談靶組織。

Yes. Yes, thank you for the question. So of course, we're very excited to develop an in vivo HSC program based on the success of the -- our targeting approach for sickle cell disease and TDT and so moving the targeting of the HBG1/2 locus to an in vivo approach and so we're very well positioned for that, considering the emerging success that we're seeing in the clinic that Baisong has described. And so we're working very hard to come up with the delivery strategy for in vivo HSC and we're doing that both internally and through potential external partners. And so that's -- we're very excited about that avenue. And then in terms of other tissues of interest, we'll be talking about those in the future. We are interested in the liver, but I'll be talking about other tissues as well in the future.

是的。是的，謝謝你的提問。當然，我們非常高興能夠基於我們針對鐮狀細胞病和 TDT 的靶向方法的成功開發體內 HSC 計劃，因此將 HBG1/2 基因座的靶向轉移到體內方法，並且因此，考慮到我們在拜松在所描述的診所中看到的新興成功，我們已經做好了充分的準備。因此，我們正在非常努力地制定體內 HSC 的交付策略，我們正在內部和透過潛在的外部合作夥伴這樣做。所以，我們對這條路感到非常興奮。然後就其他有興趣的組織而言，我們將在未來討論這些組織。我們對肝臟有興趣，但我將來也會討論其他組織。

Thanks very much, Linda. And then with regard to the third part of your question, you asked about the commercial opportunity for in vivo. Essentially, what you can actually see is a strategy that we're driving, which progressively expands the number of patients and the fraction or proportion of the patient population that can actually use the tissue or use these treatments. Allogeneic opened the door to therapeutics, but the substantial issue there was finding matched donors. We're about only about 1/10 of patients can find a matched donor by going to autologous ex vivo, we've increased that tenfold.

非常感謝，琳達。然後關於你問題的第三部分，你問了vivo的商業機會。從本質上講，您實際上可以看到的是我們正在推動的策略，該策略逐漸擴大患者數量以及可以實際使用組織或使用這些治療的患者群體的分數或比例。同種異體打開了治療的大門，但重要的問題是尋找匹配的捐贈者。我們大約只有 1/10 的患者可以透過離體自體移植找到匹配的捐贈者，我們已經將這個數字增加了十倍。

By going to in vivo and thus eliminating the risks and burdens of conditioning, we can actually further expand the patient population and address the unmet need that extends into patients who are not described as severe, it's worth remembering that the median survival for this disease in a developed healthcare system like that of the United States is about 45 to 50 as again, was impressed upon us at the AdCom by those incredibly moving testimonies from patients and their parents and family members. And indeed, in economies with no healthcare system it's an 80% mortality about 5 years of age. So there is a substantial unmet need and in vivo will massively increase the commercial -- the eligible patient population.

透過進入體內，從而消除調理的風險和負擔，我們實際上可以進一步擴大患者群體，並解決延伸至不被描述為嚴重的患者的未滿足的需求，值得記住的是，這種疾病的中位生存期像美國這樣發達的醫療保健系統大約有 45 到 50 個，AdCom 的患者及其父母和家人的令人難以置信的感人證詞再次給我們留下了深刻的印象。事實上，在沒有醫療保健系統的經濟體中，5 歲左右的死亡率為 80%。因此，存在大量未滿足的需求，並且體內將大量增加商業-合格的患者群體。

Our next question is from the line of Huidong Wang with Barclays.

我們的下一個問題來自巴克萊銀行的王惠東。

I think a lot of questions asked about the differentiating profile for your the EDIT-101. So maybe I wanted to ask, in a way, actually, there was surprising, we saw VOE events happened so early during exa-cel AdCom. I'm wondering what is your thoughts there? And then for your efficacy clinical profile, what kind of say factors you can pay attention to in order to monitor these events and try to develop differentiated profile versus exa-cel.

我認為很多問題都是關於 EDIT-101 的差異化設定檔。所以也許我想問，在某種程度上，實際上，令人驚訝的是，我們在 exa-cel AdCom 期間看到 VOE 活動發生得這麼早。我想知道你有什麼想法？然後，對於您的療效臨床概況，您可以關注哪些因素，以便監測這些事件並嘗試開發與 exa-cel 不同的概況。

Thank you very much, Gena. So doesn't want to just recapitulate your questions, be sure I get it all. You want to talk about the differentiation of our EDIT-301 product for as we're focusing on severe sickle cell disease, you were interested in or surprised to see VOEs reported in some patients post treatment at the AdCom. And I think your recent also understanding what are the elements that we're monitoring for, for differentiation in our efficacy profile. Well, I will start and then pass -- I can start and then I'll have Baisong comment on the differentiation of our efficacy profile.

非常感謝你，吉娜。因此，我不想只是重述您的問題，請確保我明白了全部內容。您想談談我們的 EDIT-301 產品的差異化，因為我們專注於嚴重鐮狀細胞疾病，您對 AdCom 治療後一些患者報告的 VOE 感興趣或感到驚訝。我認為您最近也了解了我們正在監控哪些要素，以實現我們功效概況的差異化。好吧，我會開始，然後通過——我可以開始，然後我會讓拜松評論我們功效概況的差異。

With regard to the VOEs, I think understanding a full explanation will be hard for us at this point. There were many elements of the data that were not presented, which is not surprising in a very truncated presentation. But obviously, looking at the correlation of fetal hemoglobin expression, the other factors that can drive VOEs, et cetera, is something that we obviously look forward to get with more data being able to understand. I think what does stand and remains true is that the upregulation of fetal hemoglobin actually has a substantive impact on controlling VOEs. Now as we look to differentiation for EDIT-301, we're looking beyond not just the control of VOEs, but actually correcting other elements of the disease. And with that and with a particular focus on the correction of anemia to a normal physiologic range and its impact, I ask Baisong to talk more about that.

關於 VOE，我認為目前我們很難理解完整的解釋。有許多數據元素沒有呈現，這在一個非常簡短的演示中並不奇怪。但顯然，我們顯然希望透過了解更多數據來了解胎兒血紅素表現的相關性、其他可能驅動 VOE 的因素等。我認為，胎兒血紅素的上調實際上對控制 VOE 有實質影響。現在，當我們尋找 EDIT-301 的差異化時，我們不僅關注 VOE 的控制，而且實際上糾正疾病的其他因素。有鑑於此，特別關注將貧血糾正到正常生理範圍及其影響，我請白鬆多談談這一點。

Yes. Thanks, Gilmore. Absolutely, we are still very confident that we believe that EDIT-301 is a differentiated molecule. Given that what we've seen so far, we have to see that we can actually correcting up with anemia to physiological range of total hemoglobin. And with that, we look into that not only hematological parameters, but end organ function and as well as patient reported outcome. So we continue to be that direction will allow us to demonstrate differentiation.

是的。謝謝，吉爾摩。當然，我們仍然非常有信心相信 EDIT-301 是一個差異化的分子。鑑於到目前為止我們所看到的情況，我們必須看到我們實際上可以將貧血糾正到總血紅蛋白的生理範圍。這樣，我們不僅研究血液學參數，還研究終末器官功能以及患者報告的結果。因此，我們繼續朝這個方向發展，這將使我們能夠展現差異化。

One key thing I think it's worth highlighting when we talk about patient reported outcomes is that fatigue is a significant complaint. In fact, again, we heard of the patient testimonials. Lack of energy, fatigue, not just the hospitalizations and pain, but fatigue and loss of energy. And so these are important elements or specific subdomains of the patient for outcomes that we're paying attention to.

當我們談論患者報告的結果時，我認為值得強調的關鍵事情是疲勞是一個重要的抱怨。事實上，我們再次聽到了患者的感言。缺乏精力、疲勞，不只是住院和疼痛，而是疲勞和精力喪失。因此，這些是我們關注的患者結果的重要元素或特定子領域。

Our next question comes from the line of Jack Allen with Baird.

我們的下一個問題來自傑克艾倫和貝爾德的對話。

Congratulations to the team on the progress made throughout the quarter. I wanted to ask a little bit about the RMAT discussions. To what degree was the differentiation on total hemoglobin discussed in RMAT? And then are we -- during the prepared remarks, you mentioned a more substantial data set expected in mid '24. During the RMAT discussions, did you have any conversations around what could be viewed to the pivotal data set here and love to hear any thoughts if so?

恭喜團隊在整個季度取得的進展。我想問一些有關 RMAT 討論的問題。 RMAT 中討論的總血紅素的差異程度如何？然後我們 - 在準備好的發言中，您提到預計將在 24 年中期提供更豐富的數據集。在 RMAT 討論期間，您是否就可以查看此處的關鍵資料集進行過任何對話，並希望聽到任何想法（如果有）？

Thanks very much, Jack, for your question. I think the first thing is it's premature to go into the details of discussions about the FDA. However, I am glad that you highlighted RMAT because indeed, the FDA does and did review clinical data, including hematologic parameters, which as you quite correctly pointed out, include the correction of anemia. And as we said, we also included the nonclinical package to demonstrate how that happened by design. I think the other point about the RMAT, obviously, as we said in the prepared remarks, is that it essentially increases our confidence in the timeless review through the various mechanisms that are available to us, both with high-frequency engagement with the agency going forward as well as the possibility of our priority review and rolling submission.

非常感謝，傑克，你的問題。我認為首先，現在討論有關 FDA 的細節還為時過早。然而，我很高興您強調了 RMAT，因為 FDA 確實並且確實審查了臨床數據，包括血液學參數，正如您非常正確地指出的那樣，包括貧血的糾正。正如我們所說，我們還包含了非臨床套件來演示這是如何透過設計發生的。我認為關於RMAT 的另一點，顯然，正如我們在準備好的發言中所說，它從本質上增強了我們對透過我們可用的各種機制進行永恆審查的信心，這兩種機制都與該機構進行了高頻次接觸。以及我們優先審查和滾動提交的可能性。

You asked about the substantive data set. And I think what I would say is that if you look to exa-cel as a benchmark, we've actually seen that the original exa-cel BLA accepted by the FDA included an efficacy data set of 20 patients with 16-month follow-up. An additional efficacy data set of 10 patients was added to that during the review period. What that actually tells us when you look at our being on track to dose our 20th patient by January -- in the January '24 timeframe and the continuing robust enrollment that we're seeing in a RUBY study, it really validates our line of sight to creating or generating and present -- being able to present in the middle of 2024 a substantive data set with robust follow-up around a period that shows the correction of anemia and fetal hemoglobin expression and validates line of sight to a BLA into 2025.

你問的是實質資料集。我想我想說的是，如果你以 exa-cel 作為基準，我們實際上已經看到 FDA 接受的原始 exa-cel BLA 包括 20 名患者隨訪 16 個月的療效數據集 -向上。在審查期間，另外增加了 10 名患者的療效資料集。當您看到我們預計在1 月之前為第20 名患者進行給藥時，這實際上告訴了我們什麼——在24 年1 月的時間範圍內，以及我們在RUBY 研究中看到的持續強勁的入組情況，它確實驗證了我們的視線創建或生成並呈現——能夠在2024 年中期呈現實質性數據集，並在一段時期內進行強有力的後續行動，顯示貧血和胎兒血紅蛋白表達的糾正情況，並驗證2025 年BLA 的視線。

Our next question is from the line of Dae Gon Ha with Stifel.

我們的下一個問題來自 Dae Gon Ha 和 Stifel。

Maybe, I'll briefly go back to the off-target editing and then BD 1 for Caren. On the off-target editing, I guess, Gilmore, you talked a lot about the differentiation of AsCas12a versus the Cas9 BUs. Just curious, does that, in your view, I think you need a little bit more characterization work on the molecular side given that Cas9 is being a little bit more prevalently used on the CRISPR-Cas based medicine field. And maybe as an offshoot of that, I think there were also discussions around how exa-cel ran all these analyses in a more theoretical manner, but didn't really test the treated patients, blood samples pre and post. So can you confirm if you guys are doing the pre and post testing of the blood samples to see if off-target editing is actually happening or not?

也許，我會簡單地回到脫靶編輯，然後是 Caren 的 BD 1。關於脫靶編輯，我想，Gilmore，您談論了很多關於 AsCas12a 與 Cas9 BU 的差異。只是好奇，在您看來，鑑於 Cas9 在基於 CRISPR-Cas 的醫學領域中的使用更加普遍，我認為您需要在分子方面進行更多的表徵工作。也許作為其中的一個分支，我認為還討論了 exa-cel 如何以更理論的方式進行所有這些分析，但並沒有真正測試接受治療的患者、治療前和治療後的血液樣本。那麼，您能否確認一下您是否正在對血液樣本進行前後測試，看看是否確實發生了脫靶編輯？

And then a question for Caren, to an earlier question about BD and expansion opportunity, you talked about the in vivo HSC delivery, but I don't know if that was intentional or not, but I didn't hear you talk about non-genotoxic conditioning. So I don't know if you can comment on a little bit more on that. Do you see that as part of your armamentarium going forward? Perhaps your Magenta experience can speak to that.

然後是 Caren 的問題，對於之前關於 BD 和擴展機會的問題，您談到了體內 HSC 交付，但我不知道這是有意還是無意，但我沒有聽到您談論非-遺傳毒性調理。所以我不知道你是否可以對此發表更多評論。您認為這是您未來軍備庫的一部分嗎？也許你的 Magenta 經歷可以說明這一點。

So thanks very much, Dae Gon. With regard to the AsCas12a versus Cas9, I think the first takeaway is that we have published -- we have published data from ourselves and other labs showing that there is a differentiated significant reduction in off-targets with AsCas12a. Secondly, we have a very -- we don't actually believe that the prevalence of Cas9 would change the requirements for off-target data package generation. Third, our data package that we've generated to date is very robust. And as Linda said, we're using multiple orthogonal both in silico and in vitro evaluations also including, by the way, our nonclinical tox in vivo, but at evaluations that go beyond what we saw presented and discussed at the AdCom. So again, all of that adds to our confidence. And then finally, we are actually testing the drug product. So that's kind of the off-target.

非常感謝，大坤。關於 AsCas12a 與 Cas9，我認為第一個要點是我們已經發布了——我們已經發布了我們自己和其他實驗室的數據，表明 AsCas12a 的脫靶率有顯著降低。其次，我們實際上並不相信 Cas9 的流行會改變脫靶資料包產生的要求。第三，我們迄今為止產生的資料包非常可靠。正如 Linda 所說，我們在電腦和體外評估中使用了多重正交評估，順便說一句，還包括我們的體內非臨床毒性，但評估超出了我們在 AdCom 上看到和討論的範圍。再說一次，所有這些都增強了我們的信心。最後，我們實際上正在測試藥品。所以這有點偏離目標。

If I could then turn to your question around or non-genotoxic conditioning. This is an area that remains of interest to us. We have done internal work. We're also monitoring the external landscape. One of the things, one of the additional benefits of having Caren join us is that she knows, as you quite correctly pointed out, that stays very well. So Caren, I don't know if you want to add further commentary.

那我可以談談你關於非基因毒性調節的問題嗎？這是我們仍然感興趣的領域。我們已經做好了內部工作。我們也在監測外部情勢。其中一件事，讓卡倫加入我們的額外好處之一是，她知道，正如您非常正確地指出的那樣，這種情況會保持得很好。 Caren，我不知道你是否想補充更多評論。

Yes. Thank you. Thanks for the question. And I just want to comment how excited I am to be here with the Editas team to help move these therapies forward. Now you bring up a really important point, something that's important to all of us and will absolutely be part of the evolution of this market space and treatment modality. I think the benefit today is that the risk benefit for severe sickle cell and TDT does remain very strong with the current offering, but we take it very seriously, and we're doing a lot of important work to try to make sure we are part of moving forward to evolve this to be an overall better treatment.

是的。謝謝。謝謝你的提問。我只想評論一下，我很高興能與 Editas 團隊一起幫助推動這些療法的發展。現在你提出了一個非常重要的觀點，這對我們所有人來說都很重要，並且絕對會成為這個市場空間和治療方式演變的一部分。我認為今天的好處是，目前的產品對嚴重鐮狀細胞和 TDT 的風險益處仍然非常強大，但我們非常認真地對待它，我們正在做很多重要的工作來努力確保我們是其中的一部分繼續將其發展為一種整體更好的治療方法。

I just wanted to add to what Gilmore had said, like to affirm that we do test -- we have tested drug [product lots] from a larger number of sickle cell disease patients to confirm the -- and have not detected off-target editing in that larger number of sickle cell disease patients with samples.

我只是想補充吉爾摩所說的內容，想確認我們確實進行了測試——我們已經測試了來自大量鐮狀細胞病患者的藥物[產品批次]以確認——並且沒有檢測到脫靶編輯其中有數量較多的鐮狀細胞疾病患者樣本。

Our next question is from the line of Phil Nadeau with TD Cowen.

我們的下一個問題來自 Phil Nadeau 和 TD Cowen。

Congrats on progress -- And thanks for taking our questions. 2 from us. First, in terms of continued recruitment in the clinical trials. Do you assume any change in the rate that you'll be able to recruit patients following what seems likely to be the approvals of the first 2 genomic medicines for sickle cell disease by the end of the year? That's the first question. And then second, a follow-up on differentiation. How long a follow-up do you think you'll need to determine whether fatigue or the hemoglobin levels are truly differentiated. Is that something that you'll know kind of relatively quickly? Or will that take months if not years of follow-up to determine?

恭喜取得的進展—並感謝您提出我們的問題。 2 來自我們。首先，在臨床試驗的持續招募方面。您認為，在今年年底前兩種治療鐮狀細胞疾病的基因組藥物可能獲得批准後，您招募患者的速度是否會發生任何變化？這是第一個問題。其次，差異化的後續行動。您認為需要追蹤多長時間才能確定疲勞或血紅素水平是否真正有所區別。這是你很快就會知道的事情嗎？或需要幾個月甚至幾年的追蹤才能確定？

Thanks very much, Phil. With regard to recruitment, no, we do not expect any change. We believe that our enrollment will continue to robust. I'll pass that to Baisong, who can tell you about his personal experience and conversations with sites and investigators.

非常感謝，菲爾。關於招聘，不，我們預計不會有任何變化。我們相信，我們的入學人數將持續強勁。我會將其轉交給白松，他可以告訴您他的個人經歷以及與網站和調查人員的對話。

Thanks, Phil, for your question. Really that -- I have been continuously visiting study site, I see really very strong momentum and feedback about it. And we actually have many patients on our list for this trial. So we actually do not see the impact. So we continue to see the possible momentum. And not only now, but we'll see it for next year, and we will continue to see the momentum on that.

謝謝菲爾的提問。確實如此——我一直在不斷訪問研究網站，我看到了非常強勁的勢頭和反饋。事實上，我們的試驗名單上有許多患者。所以我們實際上看不到影響。因此，我們繼續看到可能的勢頭。不僅是現在，我們明年也會看到這一點，而且我們將繼續看到這方面的勢頭。

So indeed, the investigator said that notwithstanding approvals, this is still an area that they are particularly interested in with regard to our therapy and the trials. You asked another question about differentiation and with regard to the time to actually see differences in total hemoglobin. And then some of the more downstream clinical impacts would be around fatigue or other outcomes. And I've got to ask Baisong to talk about that.

事實上，研究人員表示，儘管獲得了批准，但這仍然是他們對我們的治療和試驗特別感興趣的領域。您問了另一個關於分化和實際看到總血紅蛋白差異的時間的問題。然後一些更下游的臨床影響將圍繞疲勞或其他結果。我得請白松談談這件事。

Yes, yes. Yes. So this is actually a very important question. We are looking into that as we -- as I mentioned, we're looking to 3 categories of clinical end points for the differentiation. Certainly, that for hematological parameter, you will be taking shorter time to see. And for the patient reported outcome, for example, you specifically mentioned the fatigue usually, based on my experience in other studies that when you kind of -- when you kind of see this patient recorded outcome usually takes 6 months and for the [TDT], you see something that usually takes 1 year, you see some kind of improvement. But you more longer, you will see much more impact for compared to the baseline.

是的是的。是的。所以這其實是一個非常重要的問題。正如我所提到的，我們正在研究這一點，我們正在尋找 3 類臨床終點來進行區分。當然，對於血液學參數，你需要更短的時間才能看到。例如，對於患者報告的結果，您通常特別提到疲勞，根據我在其他研究中的經驗，當您看到該患者記錄的結果通常需要 6 個月的時間，並且 [TDT] ，您看到通常需要一年時間的事情，你看到某種改進。但時間越長，與基線相比，您會看到更多的影響。

So we are very optimistic and confident that we'll be able to see something in that direction for patient reported outcome on that. And the other category I mentioned is also for the end organ damage, and we actually look into the cardiac, pulmonary, liver, and CNS and as well as the kidney. So we'll also see that looking forward to see the improvement. These areas are quite relatively new, but there are publications for allogeneic bone marrow transplant for sickle cell patients, for example, in the brand, blood vessel or plus the vascular system in brands and also the in cardiac system. There are some reports relatively limited, see that allogeneic transplant for sickle cell patients could potentially actually improve the improve organ function. So we're looking forward to that direction.

因此，我們非常樂觀和有信心，我們將能夠看到患者報告的結果朝這個方向發展。我提到的另一類也是針對終末器官損傷，我們實際上研究了心臟、肺部、肝臟、中樞神經系統以及腎臟。所以我們也會期待看到改進。這些領域相對較新，但有針對鐮狀細胞患者的同種異體骨髓移植的出版物，例如，在品牌、血管或品牌中的血管系統以及心臟系統中。有一些報導相對有限，認為鐮狀細胞患者的同種異體移植實際上可能會改善器官功能。所以我們期待這個方向。

Yes. And Phil, one of the things I would say is that Baisong and I have been around the block long enough as drug developers to know that when you are start applying new outcomes measures in clinical trials using potent new medicines that have sort of have an unprecedented potency in disease, you're ability to absolutely firmly predict the absolute time point, the number of patients, et cetera, are needed to actually demonstrate that benefit can be and vary and require additional work. So while we are very enthusiastic about the work that we're doing here, we also are pragmatic and experienced enough to know that we will see hematologic parameters quickly. We may see end organ functional physiologic parameters in a slightly longer-term. And then with regard to other outcomes, some of that will be, as I say, we're optimistic, but we have to just temper that with the realism that it may take somewhat longer.

是的。菲爾，我要說的一件事是，拜松和我作為藥物開發人員已經在這個領域工作了足夠長的時間，知道當你開始在臨床試驗中使用有效的新藥物來應用新的結果措施時，這些藥物具有前所未有的效果疾病的效力，您能夠絕對準確地預測絕對時間點、患者數量等，需要實際證明益處可能會有所不同，並且需要額外的工作。因此，雖然我們對在這裡所做的工作非常熱情，但我們也很務實且經驗豐富，知道我們很快就會看到血液學參數。我們可能會在稍長的時間內看到終末器官功能生理參數。然後關於其他結果，正如我所說，其中一些結果我們是樂觀的，但我們必須以可能需要更長時間的現實來調整這一點。

Our next question is from the line of Yanan Zhu with Wells Fargo.

我們的下一個問題來自富國銀行朱亞楠的電話。

Thanks for taking my questions. So I was wondering, a focus at the AdCom was the adequacy of the number of patient samples tested for off-target and whether that's enough to characterize the risk in certain patients with genetic variants. I think I was wondering in your off-target analysis work, are you targeting, again, single-digit sample numbers? Or are you targeting a number significantly higher than that. The next question is about percent fetal hemoglobin as a differentiator. I think you talked a lot about total hemoglobin. But I was wondering, based on your -- on the data you have reported so far and also in abstract at ASH -- it seems like you had 3 patients of your first 4 patients who had greater than 50% fetal hemoglobin. I was wondering about your confidence of that being replicated in additional patients and also that being a differentiator.

感謝您回答我的問題。所以我想知道，AdCom 的重點是測試脫靶的患者樣本數量是否充足，以及這是否足以描述某些具有遺傳變異的患者的風險。我想我想知道在您的脫靶分析工作中，您的目標是否是單位數樣本數？或者您的目標數字明顯高於該數字。下一個問題是關於胎兒血紅素百分比作為區分因子。我認為您談論了很多關於總血紅蛋白的內容。但我想知道，根據您迄今為止報告的數據以及 ASH 的摘要數據，您的前 4 名患者中似乎有 3 名患者的胎兒血紅蛋白超過 50%。我想知道您是否有信心在更多患者中複製這一點，並成為差異化因素。

And lastly, I was wondering about your thoughts on whether there is a correlation between total hemoglobin and hemolytic markers and whether you can comment on your thoughts there, i.e. higher maybe at a patient level, whether a higher total hemoglobin is correlated with better hemolytic marker observations.

最後，我想知道您對總血紅蛋白和溶血標記之間是否存在相關性的想法，以及您是否可以評論您的想法，即可能在患者水平較高，較高的總血紅蛋白是否與更好的溶血標誌物相關觀察。

Thanks very much, Yanan. So I'm going to try and choreograph a set of answers to a complex set of questions, if you will, or quite diversity question. So -- with regard to the adequacy sample, I think the first thing we should do is just remind ourselves that the discussion -- the very -- so what I would say, the informed discussion at the AdCom demonstrated that a robust evaluation of at risk really shows that from an off-target point of view, the risk management, even with the data set presented to the AdCom was actually very good. I will say that we are using additional (inaudible) or orthogonal in silico and vitro, and I need some in vivo, that's on the (inaudible) in silico and in vitro assessments which go well beyond what was shown at the AdCom in our data package.

非常感謝，亞南。因此，如果你願意的話，我將嘗試為一組複雜的問題或相當多樣化的問題設計一組答案。因此，關於充分性樣本，我認為我們應該做的第一件事就是提醒自己，討論——非常——所以我想說的是，AdCom 的知情討論表明，對風險確實表明，從偏離目標的角度來看，即使向AdCom 提供的資料集，風險管理實際上也非常好。我想說的是，我們正在使用額外的（聽不清楚）或正交的電腦和體外評估，我需要一些體內評估，即（聽不清楚）電腦和體外評估，這遠遠超出了AdCom 在我們的數據中顯示的內容包裹。

I'm not going to go into the specifics of the numbers of patients, just to say it's more. And obviously, we'll share more detail about that in -- at an appropriate time in the future. I think the other thing about the variance, again, I just want to reaffirm that I thought actually that the discussion by the geneticists at the AdCom was very illuminating. I thought both parties, the experts on the panel as well as in the sponsor really articulated very clearly how the nature of variation, the nature of common ancestry for all humanity and how we can really manage and identify variants and the risks associated with that. I think it was a very robust discussion. And again, it gave us great confidence in our management of risk and the data package that we're generating there. Linda, I don't know if you want to add to that.

我不會詳細說明患者數量，只是說更多。顯然，我們將在未來適當的時候分享更多相關細節。我認為關於方差的另一件事，我只是想重申，我認為實際上 AdCom 遺傳學家的討論非常有啟發性。我認為雙方、小組專家以及贊助商都非常清楚地闡明了變異的本質、全人類共同祖先的本質，以及我們如何真正管理和識別變異以及與之相關的風險。我認為這是一次非常熱烈的討論。再次，它讓我們對風險管理和我們在那裡產生的資料包充滿信心。琳達，我不知道你是否想補充這一點。

No, I think that was a very good summary. I think that there was -- yes, I think that was a very good summary Gilmore was going to add.

不，我認為這是一個非常好的總結。我認為——是的，我認為這是吉爾摩要補充的一個非常好的總結。

Thanks very much, Linda. With regards to the percentage of fetal hemoglobin is a differentiator, obviously, very excited about the data we show. It's early days yet. And what is clear from the experience described for people who have coincident inheritance of hereditary persistence of fetal hemoglobin with sickle cell disease or indeed thalassemia is that the higher the level of fetal hemoglobin percentage or [fracturing] fetal hemoglobin, the greater the band certainly for sickle cell disease. I'd say it's early days for us. But Baisong, do you want to add to that?

非常感謝，琳達。關於胎兒血紅蛋白的百分比是一個區分因素，顯然，我們對顯示的數據感到非常興奮。現在還為時過早。 And what is clear from the experience described for people who have coincident inheritance of hereditary persistence of fetal hemoglobin with sickle cell disease or indeed thalassemia is that the higher the level of fetal hemoglobin percentage or [fracturing] fetal hemoglobin, the greater the band certainly for鐮形血球貧血症.我想說這對我們來說還為時過早。但是白松，你想補充一下嗎？

Yes. Yes. Thank you, , for this question. As Gilmore mentioned, we are very pleased to see the fetal hemoglobin data, as you referred to, actually see patients over 50%. And this is -- we are excited on that. It's also because this is a rational design approach for EDIT-301. We compare that this approach of targeting the HBG1/2 promoter -- with HBG1/2 promoter versus BCL11A, we found that we have better fetal hemoglobin expression. But we are in the early stage. We actually want to see more data to disease, and we're looking forward to see more data (inaudible) on that.

是的。是的。謝謝你提出這個問題。正如 Gilmore 所提到的，我們很高興看到胎兒血紅蛋白數據，正如您所提到的，實際上看到的患者超過 50%。我們對此感到興奮。也因為這是 EDIT-301 的合理設計方法。我們比較了這種針對 HBG1/2 啟動子的方法—使用 HBG1/2 啟動子與 BCL11A，我們發現我們有更好的胎兒血紅素表現。但我們還處於早期階段。我們實際上希望看到更多有關疾病的數據，並且我們期待看到更多這方面的數據（聽不清楚）。

Thanks very much, Baisong. I think your final question was around the correlation between total hemoglobin and hemolytic markers. I think that, that is an interesting question before handing to Baisong, I'll just remind 1 thing. While hemolytic -- hemolysis is a critical part of sickle cell disease. The key driver we believe for driving total hemoglobin by design is enhanced erythroid production. Baisong, I don't know if you want to add anything.

非常感謝，白松。我認為你的最後一個問題是關於總血紅素和溶血標記之間的相關性。我認為，這是一個有趣的問題，在交給白松之前，我只想提醒一件事。雖然溶血－溶血是鐮狀細胞疾病的重要組成部分。我們認為，透過設計驅動總血紅蛋白的關鍵驅動因素是增強紅血球生成。白松，不知道你還有什麼要補充的嗎？

Yes, that's exactly right, Gilmore, -- that's what we're going to say. I think what I want to mention that we are very positive about our hemolytic marker data on that. And then the -- so the total hemoglobin level is related 2 aspects of that. One is hemolysis, one is erythropoiesis. So we -- I think in our design, we designed to have this molecule have fetal hemoglobin expression. And also with the targeting of the HBG1/2 promoter we have better erythropoiesis and better red blood cell production. So we are looking forward to see more data on that, but we are very pleased with our hemolytic biomarkers.

是的，完全正確，吉爾摩——這就是我們要說的。我想我想說的是，我們對這方面的溶血標記數據非常樂觀。然後，總血紅蛋白水平與這兩個方面有關。一種是溶血，一種是紅血球生成。所以我們——我認為在我們的設計中，我們設計讓這種分子具有胎兒血紅蛋白表達。而且透過 HBG1/2 啟動子的靶向，我們可以實現更好的紅血球生成和紅血球生成。因此，我們期待看到更多這方面的數據，但我們對我們的溶血生物標記非常滿意。

Our next question is from the line of Eric Schmidt with Cantor Fitzgerald.

我們的下一個問題來自埃里克·施密特和坎托·菲茨杰拉德。

Congrats on the progress. Maybe the first, the HBF production levels are obviously quite impressive. Is there a total hemoglobin above which you start to grow concerned in sickle cell disease that patients have too much hemoglobin? And if so, what might be -- and then maybe a follow-up for Caren. We saw a couple of large pharma gene editing deals this week. Perhaps you could comment on the overall level of interest in potential platform-type collaborations.

祝賀取得的進展。也許第一，HBF 的生產水準顯然相當令人印象深刻。血紅素總量是否超過這個數值，您會開始擔心鐮狀細胞疾病患者的血紅素過多？如果是這樣，可能會是什麼——然後可能是卡倫的後續行動。本週我們看到了幾筆大型製藥基因編輯交易。也許您可以評論一下對潛在平台類型合作的整體興趣程度。

Thanks very much, Eric. With regard to the total hemoglobin, we believe that correcting and that's what we've seen, hemoglobin physiologic range is of substantial benefit. I think it's -- we haven't -- we're not going to -- it's hard to speculate about a level that is too high. Indeed, there has been an experience in general with polycythemia in sort of a broader patient population with some conflicting data about the risks of same. But as I say, we feel very confident about the data we're getting in regard to our total hemoglobin and the way that we are correcting it to normal physiological ranges. I think you asked a question about some recent gene editing deals just this week that are announced. What I would say is that what is striking about it is it is great to see pharma, I say big pharma now in a period where we've seen some (inaudible) up deals leaning in and increasing their excitement around the genome editing space.

非常感謝，埃里克。關於總血紅素，我們相信，糾正血紅蛋白生理範圍是有很大好處的，這就是我們所看到的。我認為——我們沒有——我們不會——很難推測過高的水平。事實上，在更廣泛的患者群體中普遍存在紅血球增多症的經驗，但關於其風險的一些相互矛盾的數據。但正如我所說，我們對所獲得的總血紅蛋白數據以及將其校正到正常生理範圍的方式非常有信心。我想你問的問題是關於本週剛宣布的一些最近的基因編輯交易。我想說的是，令人震驚的是，很高興看到製藥公司，我說的是大型製藥公司，現在我們已經看到一些（聽不清）的上升交易傾斜並增加了他們對基因組編輯領域的興奮。

In other words, what I would say is this has been a very good week for CRISPR genome editing space with both that sort of critical near to final step towards approval for our first CRISPR-based therapy and to see now pharma actually looking essentially to the lens of substantial derisking of their view of the value of genome editing as they look to grow their portfolios.

換句話說，我想說的是，對於CRISPR 基因組編輯領域來說，這是非常好的一周，我們的第一個基於CRISPR 的療法的批准已接近最後一步，並且看到現在製藥公司實際上主要關注的是當他們尋求擴大投資組合時，他們對基因組編輯價值的看法大大降低了。

Yes. Thanks, Eric. It's Caren. What I would add is I think Editas is so well positioned right now, having refocused the portfolio. We are in a great place to be able to move our own programs forward and are very excited by the continued interest, and it opens the door for partnering, should that be the right path for us.

是的。謝謝，埃里克。是卡倫。我要補充的是，我認為 Editas 現在的定位非常好，已經重新調整了產品組合的重點。我們處於一個很好的位置，能夠推進我們自己的項目，並且對持續的興趣感到非常興奮，並且它為合作打開了大門，如果這對我們來說是正確的道路的話。

Our next question comes from the line of Steve Seedhouse with Raymond James.

我們的下一個問題來自 Steve Seedhouse 和 Raymond James 的對話。

Two quick ones. First, our lymphocyte and neutrophil counts at baseline and post-transplant, something that you are going to share in either the poster or the associated presentation at ASH. And then separately, is your intent at Editas to commercialize EDIT-301 on your own?

兩個快的。首先，我們在基線和移植後進行淋巴細胞和嗜中性球計數，您將在 ASH 的海報或相關演示中分享這些內容。另外，您在 Editas 是否打算自行將 EDIT-301 商業化？

Thanks very much for that question. With regard to neutrophil engraftment data, that is something that we actually did present at EHA -- and it would comprise or could be summarized in our presentations at the end of the year because it's actually a measure of -- engraftment is part of the safety monitoring that we do in our studies. And then with regard to your second question, which was around commercializing 301 on our own. Well, we actually look to commercializing 301. We're actually building towards that because that we believe that's important. We have indicated previously that we're interested in an ex U.S. partner with a large footprint. Obviously, the details of any such partnership and how that might expand would really depend very much in those negotiations. It was something that we would share upon any kind of agreement, but only then.

非常感謝你提出這個問題。關於中性粒細胞植入數據，這是我們在EHA 上實際展示的內容，它將包含或可以在我們年底的演示中進行總結，因為它實際上是一種衡量標準——植入是安全性的一部分監控我們在研究中所做的事情。然後關於你的第二個問題，這是關於我們自己將 301 商業化的問題。嗯，我們實際上希望將 301 商業化。我們實際上正在朝這個方向努力，因為我們相信這很重要。我們之前曾表示，我們對一家規模較大的前美國合作夥伴感興趣。顯然，任何此類夥伴關係的細節以及如何擴大夥伴關係實際上很大程度上取決於這些談判。這是我們在任何形式的協議下都會分享的東西，但只有那時。

Gilmore, just to clarify, I was asking about lymphocyte and neutrophil counts like longitudinally post-transplant, just because in the exa-cel data, they don't recover to baseline. So I'm just curious if that's something you plan to share and it'd be interesting to know whether it's different or the same given the different genomic target and different editor.

Gilmore，只是為了澄清一下，我問的是淋巴細胞和嗜中性球計數，例如移植後的縱向計數，只是因為在 exa-cel 數據中，它們沒有恢復到基線。所以我只是好奇這是否是你打算分享的東西，並且考慮到不同的基因組目標和不同的編輯器，知道它是否不同或相同會很有趣。

So well, we have not seen -- we've been actually very happy with our accounts. We're actually very happy with our accounts to date, but what I can follow up on that.

好吧，我們還沒有看到——我們實際上對我們的帳戶非常滿意。事實上，我們對迄今為止的帳目非常滿意，但我可以對此進行跟進。

Our next question is from the line of Luca Issi with RBC.

我們的下一個問題來自 RBC 的 Luca Issi。

Great. Two quick ones here. Maybe based on -- it sounds like you're obviously on track in those 20 patients by January 2024. Are you enrolling any adolescent -- just trying to understand if there is a scenario where your initial label will just include adults versus some of your peers who also get a broad label that also include adolescent -- so again, any color there, much appreciated. And maybe a second one, quick 1 for Linda here. I think during the AdCom earlier this week acquired a potential suggestion to further characterize off-target editing risk was to actually do whole genome sequencing in 20 patients before and after the genetic manipulation. So I just wonder if that's something that you're contemplating to do. Thanks so much.

偉大的。這裡有兩個快速的。也許是基於——聽起來你顯然在2024 年1 月之前就已經在這20 名患者中步入正軌了。你是否招募了任何青少年——只是想了解是否存在一種情況，即你的初始標籤只包括成年人而不是你的一些患者同齡人也得到了一個廣泛的標籤，其中還包括青少年——所以再說一次，任何顏色都非常受歡迎。也許還有第二個，快給琳達 1。我認為在本週早些時候的 AdCom 會議上獲得了一項進一步表徵脫靶編輯風險的潛在建議，即在基因操作前後對 20 名患者進行全基因組測序。所以我只是想知道這是否是您正在考慮做的事情。非常感謝。

Yes. Thank you for your question. I'll take your first question, and I'll pass that. I think we have a plan to dosing adolescent patient. And also for the general clinical program, we are intended to go to all -- that patients of all ages. So that's kind of -- because this disease is essentially starting with genetic disease start from very young age so we intended to actually be able to have this model to be able to benefit patient from all ages. So that's kind of our intention. I mean, all those things, of course, the label you mentioned will have further discussion and alignment with FDA.

是的。謝謝你的問題。我會回答你的第一個問題，然後我會通過它。我認為我們有一個給青少年患者用藥的計劃。對於一般臨床計劃，我們的目標是針對所有年齡層的患者。所以這就是——因為這種疾病本質上是從很小的時候開始的遺傳疾病，所以我們打算實際上能夠讓這個模型能夠使所有年齡層的患者受益。這就是我們的意圖。我的意思是，所有這些事情，當然，你提到的標籤將與 FDA 進行進一步的討論和協調。

Yes. Thank you for your question. Yes, that was a very interesting conversation at the AdCom. One of our orthogonal methods and this also came up at the AdCom was the method of using a biochemical method applied to make a DNA. And this is a method -- one of the methods that we use, which is unbiased method in which the naked DNA is taken from cells and subjected to cutting with your (inaudible) -- and then you do a whole genome sequencing basically to look for off-target editing. And so this is called Digenome. And so this is one of our methods that we use and look at with our drug product before putting the drug product to patients.

是的。謝謝你的問題。是的，這是 AdCom 上一次非常有趣的對話。我們的正交方法之一（AdCom 也提出了這種方法）是使用生化方法製造 DNA 的方法。這是一種方法——我們使用的方法之一，這是一種無偏見的方法，從細胞中取出裸露的DNA並用你的（聽不清楚）進行切割——然後你進行全基因組測序，基本上是為了看看用於脫靶編輯。所以這被稱為 Digenome。因此，這是我們在將藥物用於患者之前使用和研究的方法之一。

So -- so I think this is one of the robust criteria that we -- one of the robust methods that we use in our approach. So I think that's basically one of the reasons that we are confident in our approach to -- in addition to the other methods that we use in silico and (inaudible) that were described I guess that's basically what I'm prepared to share at this moment, but there are many other aspects to our approach that were also make us very confident to -- about our approach to the off-target editing package that we're preparing.

所以——所以我認為這是我們的穩健標準之一——我們在我們的方法中使用的穩健方法之一。所以我認為這基本上是我們對我們的方法充滿信心的原因之一- 除了我們在計算機中使用的其他方法以及所描述的（聽不清）我想這基本上就是我準備在本次分享的內容但我們的方法還有許多其他方面也讓我們非常有信心——關於我們正在準備的脫靶編輯包的方法。

Our next question is from the line of Jay Olson with Oppenheimer.

我們的下一個問題來自傑·奧爾森和奧本海默的對話。

Congrats on the progress. Maybe just another question on read across from the exa-cel AdCom since there was some discussion about long-term monitoring and surveillance of these patients. Can you just share your thoughts and plans to follow EDIT-301 patients long-term in a post-approval setting?

祝賀取得的進展。也許只是 exa-cel AdCom 上的另一個問題，因為有一些關於這些患者的長期監測和監測的討論。您能否分享一下您在批准後環境中長期追蹤 EDIT-301 患者的想法和計劃？

Thanks for the question, Jay. So -- we certainly will have a long-term fallout for patients. And so that study is designed to actually follow the patient up to 15 years for anybody who actually dosed with EDIT-301 and that's also consistent with the regulatory requirements. So that's absolutely our plan.

謝謝你的提問，傑伊。因此，我們肯定會對患者產生長期影響。因此，這項研究的目的是對任何實際服用 EDIT-301 的患者進行長達 15 年的跟踪，這也符合監管要求。所以這絕對是我們的計劃。

The next question is from the line of Liisa Bayko with Evercore ISI.

下一個問題來自 Evercore ISI 的 Liisa Bayko。

This is Julien on for Lisa. So we have 3 questions. First, we know that CEC has filed an appeal to the Court of Appeals -- when do we expect to hear the decision for that? And then second, as I know you mentioned that more substantial data set for sickle cell is coming in the middle of 2024. I'm just wondering when should we expect more substantial dataset for the TDT patients? And then the third is you mentioned that in the second half, you plan to engage with the FDA to seek alignment or regulatory path for 301. We're wondering will you inform the Street on the results of the discussion? And if so, what's the timing for that?

這是朱利安為麗莎代言的。所以我們有 3 個問題。首先，我們知道 CEC 已向上訴法院提出上訴——我們預計什麼時候能聽到裁決？其次，據我所知，您提到鐮狀細胞病的更豐富的數據集將於 2024 年中期發布。我只是想知道我們什麼時候應該期待 TDT 患者的更豐富的數據集？第三，您提到下半年您計劃與 FDA 合作，尋求 301 的協調或監管路徑。我們想知道您是否會向華爾街通報討論結果？如果是的話，時間是什麼時候？

This is Eric. Just with respect to any courses in front of -- court cases in front of the CVC or anything like that. We don't really want to comment on those until the final decision is actually rendered. So we'll just be anxiously awaiting for all of that just like you.

這是埃里克。就 CVC 面前的法庭案件或類似的任何課程而言。在最終決定真正做出之前，我們不想對這些發表評論。因此，我們將像您一樣焦急地等待這一切。

Yes. So based on -- for your second question about the mid of next year for the program. And as 2 part of that, one is, as we just shared that we will have 20 patients dosed by a January timeframe next year. Then by middle of next year, we will have substantial follow-up for those 20 patients, and we also have continued dosing patients over the course. So we have a lot of data over the middle of next year for sickle cell disease.

是的。因此，基於您關於明年中期該計劃的第二個問題。其中第二部分是，正如我們剛剛分享的那樣，我們將在明年 1 月的時間範圍內為 20 名患者接受給藥。然後到明年年中，我們將對這 20 名患者進行大量隨訪，並且在整個過程中我們將繼續給患者用藥。因此，我們將在明年年中獲得大量有關鐮狀細胞疾病的數據。

What about for the beta-thalassemia.

那麼β-地中海型貧血呢？

Yes. Yes, absolutely. Yes, because I saw your question probably cover both, but I'd just make sure that we cover on that. And the -- we actually have a very strong momentum for EDITHAL study also and that we just shared, we actually already have 8 patients enrolled, and we continue to enroll in dosing patients. And but we have not shared what is the goal for next year, how many patients -- EDITHAL patient with dose. We will share that in an appropriate time.

是的。是的，一點沒錯。是的，因為我看到你的問題可能涵蓋了這兩個問題，但我只是確保我們涵蓋了這一點。事實上，我們對 EDITHAL 研究也有非常強勁的勢頭，我們剛剛分享過，我們實際上已經招募了 8 名患者，並且我們將繼續招募給藥患者。但我們還沒有透露明年的目標是什麼，有多少患者——EDITHAL 患者的劑量。我們將在適當的時候分享這一點。

And your third part of your question is about FDA engagement and outcome. And so we're well engaged with the FDA, and we continue to have engagement with the FDA as we just mentioned that we actually have these unmet designation allows us a lot more frac prevent interaction with the agency, including senior management of the agency. But we have not shared -- have a timeline to share the outcome yet. We'll share that in appropriate time.

你問題的第三部分是關於 FDA 的參與和結果。因此，我們與FDA 進行了良好的合作，並且我們將繼續與FDA 進行合作，正如我們剛才提到的，我們實際上擁有這些未滿足的指定，這使我們能夠更多地阻止與該機構的互動，包括與該機構的高階管理層的互動。但我們還沒有分享——還沒有分享結果的時間表。我們將在適當的時候分享這一點。

Our next question is from the line of Mani Foroohar with Leerink.

我們的下一個問題來自 Mani Foroohar 和 Leerink。

This is Lillian on line for Mani. I just wanted to ask if you could potentially give us an update on the progress of the manufacturing scaling for 301, both for clinical development and for potential commercialization. And then on the other side, second question, in terms of the package for BLA. So with the timing, I think you had mentioned potential package readiness by 2025, but then we might have a post-marketing data from potentially to gene therapy program. I was wondering if you -- and how you would see that impacting potential pivotal design?

我是莉蓮 (Lillian)，正在為瑪尼 (Mani) 在線。我只是想問您是否可以向我們介紹 301 生產規模的最新進展，包括臨床開發和潛在商業化。另一方面，第二個問題，關於 BLA 的一攬子計劃。因此，就時間安排而言，我認為您已經提到了到 2025 年潛在的一攬子準備就緒，但隨後我們可能會獲得從潛在的基因治療計劃的上市後數據。我想知道您是否以及您如何看待這對潛在關鍵設計的影響？

This is Eric. I'll take the first question with respect to the manufacturing scaling and timing. As a reminder, we're very confident in what we're doing and making the investments in manufacturing for the commercial launch. We haven't specifically commented on the scale or timing, but just reiterate our confidence in everything we're doing on a manufacturing standpoint.

這是埃里克。我將回答有關製造規模和時間安排的第一個問題。提醒一下，我們對我們正在做的事情以及為商業發布而進行的製造投資非常有信心。我們沒有具體評論規模或時間安排，但只是重申我們對從製造角度所做的一切充滿信心。

This is Baisong. Your second part of your question. As we shared that we will have 20 patients dosed by January time from next year and by middle of next middle of next -- middle of 2025, then we will have substantial data packages probably equivalent to the access BLA filing, which is accepted by FDA, which have like 20 patients in the efficacy data cohort. So they subsequently added additional 10 patients in the addendum with 4 months additional 4 months data upwards. So we expect that we will be able to file the FDA equipment package to -- we will have equivalent data package by the middle of next year.

這是白松。你問題的第二部分。正如我們所說，從明年 1 月開始，到明年中旬（2025 年中旬），我們將有 20 名患者接受給藥，然後我們將擁有大量數據包，可能相當於 FDA 接受的訪問 BLA 備案，其療效數據隊列中有大約20 名患者。因此，他們隨後在附錄中增加了另外 10 名患者，並提供了 4 個月以上的額外 4 個月數據。因此，我們預計我們將能夠向 FDA 提交設備包——到明年年中我們將擁有同等的資料包。

But what exactly the -- exactly the only data package when you align with the FDA so that we are -- that will have the agreement with the FDA on that, too. And you mentioned about post-marketing or the commercialization of these 2 molecules. And as I shared earlier that we do not see that recruitment in momentum perspective, and you mentioned about data package -- and we're actually very excited about the AdCom discussion. And we feel that this AdCom have further validation of CRISPR technology, further validation of the fetal hemoglobin as a mechanism of action to treat sickle cell and beta-thalassemia. So we actually see all those work have a positive impact to EDIT-301.

但是，當您與 FDA 保持一致時，唯一的資料包到底是什麼，以便我們在這方面也將與 FDA 達成協議。您提到了這兩種分子的上市後或商業化。正如我之前分享的那樣，我們沒有從勢頭的角度來看招聘，並且您提到了數據包 - 我們實際上對 AdCom 討論感到非常興奮。我們認為AdCom進一步驗證了CRISPR技術，進一步驗證了胎兒血紅素作為治療鐮狀細胞和β地中海貧血的作用機轉。所以我們實際上看到所有這些工作都對 EDIT-301 產生積極影響。

Our final question comes from the line of Terence Flynn with Morgan Stanley.

我們的最後一個問題來自特倫斯·弗林與摩根士丹利的對話。

This is Matt Score on for Terence Flynn. So looking to the future a bit, can you expand on your approach to target selection, how we should think about your pipeline evolving going forward? Also, as you think about tissue-specific delivery for your future in vivo programs, how are you thinking about the advantages and disadvantages to investing in AAV and/or LNP?

我是特倫斯·弗林的馬特·斯科科。因此，展望未來，您能否擴展一下您的目標選擇方法，我們應該如何考慮您的管道未來的發展？此外，當您考慮未來體內專案的組織特異性遞送時，您如何考慮投資 AAV 和/或 LNP 的優點和缺點？

Yes. Thank you very much for your question. So as far as target selection, our approach is really to apply criteria so that we are well differentiated from standard of care. Very important that we're delivering medicines that are meeting needs that the patients have that are not already met by existing therapeutic. And so we are going to look for targets in which we have high conviction as well as targets that have high profitability for technical as well as clinical and commercial success. And so I'm very excited here to have Caren having joined so that I can partner with her as well as Baisong and triangulating this to very much select our targets. I think we're really well positioned now to be selecting these where, as I said before, I think we're very excited about the in vivo sickle cell disease TDT target. Because we already have emerging data supporting that target and getting to your question about delivery.

是的。非常感謝您的提問。因此，就目標選擇而言，我們的方法實際上是應用標準，以便我們與護理標準區分開來。非常重要的是，我們提供的藥物能夠滿足患者現有治療方法尚未滿足的需求。因此，我們將尋找我們有高度信念的目標，以及在技術、臨床和商業成功方面具有高獲利能力的目標。因此，我很高興 Caren 加入，這樣我就可以與她以及 Baisong 合作，並透過三角測量來選擇我們的目標。我認為我們現在確實處於有利位置，可以選擇這些藥物，正如我之前所說，我認為我們對體內鐮狀細胞疾病 TDT 標靶感到非常興奮。因為我們已經有新的數據來支持該目標並解決您有關交付的問題。

Where our strategy, which Gilmore described in January is nonviral delivery. And so we are prioritizing LNP delivery amongst the nonviral deliveries and working internally as well as through external partners to drive an approach for in vivo HSC targeting for our HBG1/2 promoter with an LNP strategy. As far as other targets and tissues, of course, LNPs are validated for delivery to liver. So we're interested in that. And I think we're well positioned there as well with our technology and especially with the recent deal that we saw announced and just showing the interest -- continuing interest in form in this space. And -- but we're also interested in other tissues. And so there are many targets out there amenable to Editas technology, and we're excited to move forward, and we'll certainly be sharing information with you as we -- as it emerges in the future at an appropriate time. Thank you.

吉爾摩在一月描述的我們的策略是非病毒傳播。因此，我們在非病毒遞送中優先考慮 LNP 遞送，並在內部以及透過外部合作夥伴開展工作，以推動一種透過 LNP 策略針對我們的 HBG1/2 啟動子的體內 HSC 靶向方法。當然，就其他標靶和組織而言，LNP 已被驗證可輸送至肝臟。所以我們對此很感興趣。我認為我們在技術上也處於有利地位，特別是最近我們宣布的交易，並且只是表現出興趣——對這個領域的形式的持續興趣。而且——但我們也對其他組織感興趣。因此，有許多目標適合 Editas 技術，我們很高興能夠向前邁進，並且我們一定會與您分享訊息，因為它在未來適當的時間出現。謝謝。

Thank you, everyone. This will conclude today's conference. You may disconnect your lines at this time. We thank you for your participation.

謝謝大家。今天的會議到此結束。此時您可以斷開線路。我們感謝您的參與。