Freeline Therapeutics Holdings PLC (FRLN) 2023 Q2 法說會逐字稿

Good morning, everyone, and welcome to the Freeline's second-quarter 2023 financial and business update conference call. (Operator Instructions) Please also note today's event is being recorded. At this time, I'd like to turn the floor over to Naomi Aoki, SVP of Investor Relations and Corporate Communications. Ma'am, you may begin.

大家早上好，歡迎參加 Freeline 2023 年第二季度財務和業務更新電話會議。 （操作員說明）另請注意今天的活動正在錄製中。現在，我想請投資者關係和企業傳播高級副總裁 Naomi Aoki 發言。女士，您可以開始了。

Thank you, operator, and thanks to everyone for joining us on the call. Earlier today, we issued a press release and filed our quarterly reports on Form 6-K with our second quarter 2023 financial results and business updates. The release and 6-K are both available on the Investors section of our website.

謝謝接線員，也感謝大家加入我們的通話。今天早些時候，我們發布了一份新聞稿，並以 6-K 表格形式提交了季度報告，其中包含 2023 年第二季度的財務業績和業務更新。該新聞稿和 6-K 均可在我們網站的投資者部分獲取。

We'll begin the call with prepared remarks by Michael Parini, our Chief Executive Officer; Pamela Foulds, our Chief Medical Officer; and Paul Schneider, our Chief Financial Officer; Rose Sheridan, our SVP of Research is also on the call and will be available for Q&A. Before we begin, I would like to remind everyone that we will be making forward-looking statements, which may include our plans and expectations with respect to our research and development pipeline, clinical trials, and financial projections, all of which involve certain assumptions and risks beyond our control that could cause our actual developments and results to differ materially from those statements.

我們將首先由我們的首席執行官邁克爾·帕里尼 (Michael Parini) 準備好講話； Pamela Foulds，我們的首席醫療官；和我們的首席財務官 Paul Schneider；我們的研究高級副總裁 Rose Sheridan 也將接聽電話並接受問答。在開始之前，我想提醒大家，我們將做出前瞻性陳述，其中可能包括我們對研發管線、臨床試驗和財務預測的計劃和預期，所有這些都涉及某些假設和我們無法控制的風險可能導致我們的實際發展和結果與這些陳述存在重大差異。

A description of these risks is in our most recent annual report on Form 20-F and other periodic reports filed with the SEC. Freeline does not undertake any obligation to update any forward-looking statements made during this call. I'd now like to turn the call over to Michael.

這些風險的描述參見我們向 SEC 提交的最新 20-F 表格年度報告和其他定期報告。 Freeline 不承擔更新本次電話會議期間所做的任何前瞻性陳述的義務。我現在想把電話轉給邁克爾。

Thanks, Naomi, and thank you, everyone, for joining us today. At Freeline, our goal is to bring life-changing gene therapies to people with chronic debilitating diseases. We strive to do this by optimizing all components of our gene therapy candidates to truly unlock the great potential of this modality.

謝謝內奧米，也謝謝大家今天加入我們。在 Freeline，我們的目標是為患有慢性衰弱性疾病的人們提供改變生活的基因療法。我們努力通過優化基因治療候選藥物的所有成分來實現這一目標，以真正釋放這種模式的巨大潛力。

We have taken important steps towards that goal with the dosing of the first two patients ever treated with FLT201, our AAV gene therapy for Gaucher disease. The dosing of these patients represents a significant milestone for FLT201 for Freeline and most importantly, for Gaucher patients who need and deserve better treatment options.

我們為實現這一目標邁出了重要的一步，對前兩名接受 FLT201（我們針對戈謝病的 AAV 基因療法）治療的患者進行了給藥。這些患者的用藥劑量代表了 FLT201 for Freeline 的一個重要里程碑，最重要的是，對於需要並值得更好治療選擇的戈謝患者而言。

As previously announced, we dosed the first patient in our GALILEO-1 Phase 1/2 trial, FLT201 in late June. Following the stagger between patients that is built into the trial protocol, we dosed the second patient in the trial last week, marking the completion of dosing in the first cohort and putting us squarely on track to report initial clinical data this quarter. This initial data will focus on assessments of safety and enzyme activity in these first two patients. I will have more data on the first patient in the second.

正如之前宣布的，我們於 6 月下旬對 GALILEO-1 1/2 期試驗 FLT201 中的第一位患者進行了給藥。按照試驗方案中規定的患者之間的交錯，我們上週對試驗中的第二名患者進行了給藥，標誌著第一組的給藥完成，並使我們完全步入本季度報告初步臨床數據的軌道。該初始數據將重點評估前兩名患者的安全性和酶活性。我將在第二個患者中獲得有關第一個患者的更多數據。

We expect to have enough data on both patients to provide meaningful insights into safety and enzyme activity to help and form FLT201's emerging product profile as a potential best-in-class therapy. FLT201 is a highly differentiated gene-therapy candidate that delivers a novel transgene developed by our scientists for a rationally engineered, longer-acting variant of GCase, the enzyme deficient in people with Gaucher. We believe FLT201 has the potential to be life-changing for people with Gaucher disease Type 1, which is the most common type of Gaucher with approximately 18,000 patients in the US, UK, EU4, and Israel.

我們希望獲得關於這兩名患者的足夠數據，以提供有關安全性和酶活性的有意義的見解，以幫助形成 FLT201 的新興產品概況，使其成為潛在的同類最佳療法。 FLT201是一種高度差異化的基因治療候選藥物，它提供了我們的科學家針對GCase（戈謝病患者缺乏的酶）合理設計、長效的變體開發的新型轉基因。我們相信 FLT201 有可能改變 1 型戈謝病患者的生活，這是最常見的戈謝病類型，在美國、英國、歐盟四國和以色列約有 18,000 名患者。

Many Gaucher patients continue to experience serious symptoms despite treatment with currently approved therapies. Current therapies also carry a heavy lifelong treatment burden. Earlier this month, we hosted a virtual KOL with Dr. Reena Sharma, a Gaucher Disease specialist at the Salford Royal Hospital in the UK. Dr. Sharma highlighted the ongoing unmet need in Gaucher disease, the rationale for gene therapy in Gaucher, and the opportunity to dramatically reduce both the disease and treatment burden.

儘管採用目前批准的療法進行治療，許多戈謝病患者仍然出現嚴重症狀。目前的療法還帶來沉重的終生治療負擔。本月早些時候，我們與英國索爾福德皇家醫院的戈謝病專家 Reena Sharma 博士舉辦了一場虛擬 KOL。 Sharma 博士強調了戈謝病持續未得到滿足的需求、戈謝病基因治療的基本原理，以及大幅減輕疾病和治療負擔的機會。

We believe that FLT201 has the potential to adjust that. That provide better efficacy than current treatments with a onetime therapy. Furthermore, we believe FLT201 has the opportunity to be first to market gene therapy for Gaucher Disease Type 1 with a best-in-class profile compared to other gene therapies in development. Advancing FLT201 for clinical development is our greatest strategic priority, and we are extremely pleased with our progress, with the momentum we are seeing in the trial.

我們相信 FLT201 有潛力調整這一點。這比目前的一次性治療提供了更好的療效。此外，我們相信 FLT201 有機會率先上市針對 1 型戈謝病的基因療法，與正在開發的其他基因療法相比，FLT201 具有同類最佳的特點。推進 FLT201 的臨床開發是我們最大的戰略重點，我們對我們在試驗中看到的進展和勢頭感到非常滿意。

Turning now to our early-stage pipeline. We are building on our work for Gaucher disease to extend the impact of our innovation around the longer-acting GCase variant into GBA1-linked Parkinsons disease. As negotiated, GBA1 mutations lead to a deficiency of the GCase enzyme. GBA1 mutations are present in 5% to 15% of Parkinson's disease patients making them the most common genetic risk factor for developing Parkinson's, and they're associated with earlier onset and more severe disease.

現在轉向我們的早期管道。我們正在戈謝病工作的基礎上，將我們圍繞長效 GCase 變體的創新的影響擴展到 GBA1 相關的帕金森病。根據協商，GBA1 突變會導致 GCase 酶缺乏。 GBA1 突變存在於 5% 至 15% 的帕金森病患者中，使其成為患帕金森病最常見的遺傳風險因素，並且與較早發病和更嚴重的疾病相關。

The early preclinical data looks promising with our GCase variant demonstrating almost 20-fold greater activity with wild type enzyme in various cell lines, including brain and neuroblastoma cells. We are now optimizing the GCase variant for distribution in the brain and conducting in vivo studies. And we aim to move this program forward expeditiously. The GBA1-linked Parkinson's disease program also represents our first step toward our broader research strategy of moving gene therapy into larger disease areas.

早期的臨床前數據看起來很有希望，我們的 GCase 變體顯示野生型酶在各種細胞系（包括腦細胞和神經母細胞瘤細胞）中的活性幾乎提高了 20 倍。我們現在正在優化 GCase 變體在大腦中的分佈並進行體內研究。我們的目標是迅速推進該計劃。 GBA1 相關帕金森病項目也代表了我們朝著將基因治療轉移到更大疾病領域的更廣泛研究戰略邁出了第一步。

We have made tremendous progress this year. We are focused and working on programs that we believe are highly differentiated with the potential to address serious ongoing unmet needs for patients and drives significant value for shareholders. With the momentum in the GALILEO-1 trial of FLT201, initial clinical data this quarter and the natural extension of our work into Parkinson's disease, I firmly believe that Freeline is poised for both near- and long-term success. I will now turn the call over to Pam to provide in more detailed overview of FLT201.

今年我們取得了巨大進步。我們專注於並致力於我們認為具有高度差異化的項目，這些項目有可能解決患者持續未得到滿足的嚴重需求，並為股東帶來巨大價值。憑藉 FLT201 GALILEO-1 試驗的勢頭、本季度的初步臨床數據以及我們的工作自然延伸到帕金森病領域，我堅信 Freeline 已做好了近期和長期成功的準備。我現在將把電話轉給 Pam，以提供 FLT201 的更詳細概述。

Thanks, Michael. We're very proud of the progress we're making in the GALILEO-1 trial of FLT201. As many of you know, we spent the last year-and-a-half laying strong foundations for the trial, opening up 15 sites across the US, UK, Europe, Latin America, and Israel. And we are seeing that investment payoff in the current pace of enrollment.

謝謝，邁克爾。我們對 FLT201 的 GALILEO-1 試驗所取得的進展感到非常自豪。正如你們許多人所知，我們在過去一年半的時間里為試驗奠定了堅實的基礎，在美國、英國、歐洲、拉丁美洲和以色列開設了 15 個站點。我們正在以目前的招生速度看到投資回報。

Investigator and patient interest are strong. We have line of sight into multiple additional patients, and we're executing against our timeline to deliver meaningful initial data this quarter and continue to efficiently advance the trial. As we look ahead the initial clinical data readout, I wanted to take this opportunity to help set the stage by highlighting the rationale for gene therapy in Gaucher disease, reviewing the compelling preclinical data, supporting FLT201, and explaining why we believe these initial data will provide important insights into safety and potential efficacy.

研究人員和患者的興趣都很濃厚。我們已經了解了更多患者，並且正在按照時間表執行，以在本季度提供有意義的初始數據，並繼續有效地推進試驗。當我們展望最初的臨床數據讀出時，我想藉此機會強調戈謝病基因治療的基本原理，回顧令人信服的臨床前數據，支持FLT201，並解釋為什麼我們相信這些初始數據將有助於奠定基礎。提供有關安全性和潛在功效的重要見解。

Gaucher disease is a rare genetic disorder characterized by a deficiency of glucocerebrosidase or GCase, an enzyme needed to metabolize a certain type of lipids. As a result, complex substrates known as Gb1 and lyso-Gb1 build up in multiple organs, including the spleen, liver, bone and lung. Enzyme replacement therapy is the standard of care and has made a significant impact on the disease. Despite treatment with ERT, however, many patients continue to have symptoms, particularly those associated with deeper tissues, including bone and lung.

戈謝病是一種罕見的遺傳性疾病，其特徵是缺乏葡萄糖腦苷脂酶或 GCase（一種代謝某種脂質所需的酶）。結果，稱為 Gb1 和 lyso-Gb1 的複雜底物在多個器官中積聚，包括脾、肝、骨和肺。酶替代療法是標準治療方法，對該疾病產生了重大影響。然而，儘管接受了 ERT 治療，許多患者仍然有症狀，特別是與深層組織（包括骨和肺）相關的症狀。

ERT also carries a heavy lifelong treatment burden requiring lengthy biweekly infusions, impacting decisions about work, where to live, ability to travel, and overall quality of life. Additionally, the wild-type GCase delivered by ERT has a short half-life. Meaning patients experience troughs in enzyme levels in between infusions, giving harmful substrates the opportunity to build back up, potentially contributing to disease progression.

ERT 還帶來沉重的終生治療負擔，需要每兩週一次的長時間輸液，影響有關工作、居住地點、旅行能力和整體生活質量的決策。此外，ERT 傳遞的野生型 GCase 半衰期短。這意味著患者在兩次輸注之間會經歷酶水平的低谷，使有害底物有機會積聚，可能導致疾病進展。

As Dr. Sharma outlined during our KOL event, both the success and shortcomings of ERT, support the rationale for gene therapy in Gaucher disease. ERT has shown that introducing GCase into the bloodstream leads to efficacy, supporting the case for gene therapy that does the same. Unlike ERT, however, a gene therapy has the opportunity to deliver a continuous level enzyme with a onetime infusion.

正如 Sharma 博士在我們的 KOL 活動中概述的那樣，ERT 的成功和缺點都支持戈謝病基因治療的基本原理。 ERT 表明，將 GCase 引入血液中會產生療效，這支持了具有相同作用的基因療法。然而，與 ERT 不同的是，基因療法有機會通過一次性輸注提供連續水平的酶。

In addition to potentially delivering continuous enzyme, FLT201 delivers a longer-acting GCase variant. Because the variant is more stable than wild type, we believe it has the potential to reach the deeper tissues that ERT poorly addresses and to stay in tissues longer, more effectively clearing harmful substrates, and improving clinical outcomes. This potential is borne out in our preclinical data, which show that FLT201 induce high GCase expression at low doses, increase uptake of GCase in disease affected organs including bone and lung in Gaucher mice compared to ERT, and reduce pathological substrates in disease affected organs, again, including bone and lung in Gaucher mice compared to ERT.

除了可能提供連續酶外，FLT201 還提供長效 GCase 變體。由於該變體比野生型更穩定，我們相信它有可能到達 ERT 難以處理的深層組織，並在組織中停留更長時間，更有效地清除有害底物，並改善臨床結果。這種潛力在我們的臨床前數據中得到了證實，這些數據表明，與ERT 相比，FLT201 在低劑量下誘導高GCase 表達，增加戈謝小鼠受疾病影響的器官（包括骨和肺）對GCase 的攝取，並減少受疾病影響的器官中的病理底物。再次，包括與 ERT 相比，戈謝小鼠的骨骼和肺。

The initial data readout this quarter will focus on safety and plasma GCase levels from the first cohort of GALILEO-1, which is assessing a dose of 4.5e11 with later data readouts, looking at substrate reduction and various clinical parameters. As a reminder, GALILEO-1 is a dose-finding, multi-center international study assessing the safety and efficacy of a single dose of FLT201 in adults with Gaucher disease Type 1.

本季度的初始數據讀出將重點關注第一批GALILEO-1 的安全性和血漿GCase 水平，該隊列正在評估4.5e11 的劑量以及稍後的數據讀出，著眼於底物減少和各種臨床參數。需要提醒的是，GALILEO-1 是一項劑量探索、多中心國際研究，評估單劑量 FLT201 在成人 1 型戈謝病患者中的安全性和有效性。

Each dosed cohort has two patients with a stagger between patients and the flexibility to expand the number of patients in any dose cohorts. While the initial clinical data are in early look, we believe they will provide important insights not only into safety but also into potential efficacy. We are using the same capsid we used in our earlier programs, and based on our experience in nearly 20 patients, we would expect meaningful increases in plasma GCase levels within four to six weeks of dosing.

每個劑量組有兩名患者，患者之間的時間錯開，並且可以靈活地擴大任何劑量組中的患者數量。雖然初始臨床數據還處於早期階段，但我們相信它們不僅將為安全性而且為潛在功效提供重要見解。我們使用的衣殼與我們早期項目中使用的衣殼相同，根據我們對近 20 名患者的經驗，我們預計在給藥後 4 至 6 週內血漿 GCase 水平會出現有意義的增加。

Based on what we see preclinically with FLT201 as well as what we know from ERT, there's a strong correlation between plasma GCase levels and substrate clearance and subsequently, between substrate clearance and clinical outcomes. As we look toward these initial data, we believe that a good safety profile and plasma GCase above the normal level would constitute a positive early clinical signal of FLT201's potential. With that, I'll turn the call over to Paul to review our financial results.

根據我們對 FLT201 的臨床前觀察以及我們從 ERT 中了解到的情況，血漿 GCase 水平和底物清除率之間以及隨後的底物清除率和臨床結果之間存在很強的相關性。當我們研究這些初始數據時，我們相信良好的安全性和高於正常水平的血漿 GCase 將構成 FLT201 潛力的積極早期臨床信號。這樣，我會將電話轉給保羅，以審查我們的財務業績。

Thank you, Pam. In addition to our clinical and research progress, we have also made significant stride to build a leaner, more focused, and sustainable organization. We'll review operating costs on an ongoing basis to ensure all spending is focused on high-priority activities aligned to our strategic focus. Our six-month results of operations and cash flows reflect the actions taken to prioritize the portfolio, downsize the organization, finalize the sale of our German subsidiary, settled the arbitration with Brammer, and execute the ADS ratio change to regain Nasdaq compliance.

謝謝你，帕姆。除了我們的臨床和研究進展之外，我們還在建立一個更精簡、更專注和可持續的組織方面取得了重大進展。我們將持續審查運營成本，以確保所有支出都集中在與我們的戰略重點相一致的高優先級活動上。我們六個月的運營業績和現金流反映了我們為優先考慮投資組合、縮小組織規模、完成德國子公司的出售、與布拉默解決仲裁以及執行美國存託股比率變更以重新獲得納斯達克合規性而採取的行動。

Even with one-time charges related to these actions, our total operating expenses decreased 34% in the first half of 2023 compared to the same period last year. With that, I'll turn to an update on our cash position and runway guidance, all figures reported in US dollars. In the second quarter, our cash and cash equivalents totaled $38.8 million compared to $55.4 million as of March 31, 2023. We expect our current cash and cash equivalents to enable us to fund our planned operations into the second quarter of 2024.

即使算上與這些行動相關的一次性費用，2023 年上半年我們的總運營費用仍比去年同期下降了 34%。接下來，我將介紹我們現金狀況和跑道指導的最新情況，所有數據均以美元報告。第二季度，我們的現金和現金等價物總計為3880 萬美元，而截至2023 年3 月31 日為5540 萬美元。我們預計當前的現金和現金等價物將使我們能夠為2024 年第二季度的計劃運營提供資金。

Our R&D expenses for the six months ended June 30, 2023, was $19.7 million compared to $38.8 million for the same period in 2022. The 49% decrease was primarily attributable to decrease in expenditures related to the company's de-prioritized FLT180a and FLT190 programs, including CMC costs and related capacity fees and reduced head count related cost.

截至2023 年6 月30 日的六個月，我們的研發費用為1,970 萬美元，而2022 年同期為3,880 萬美元。減少49% 的主要原因是與公司取消優先級的FLT180a 和FLT190 項目相關的支出減少，包括 CMC 成本和相關容量費用以及減少人員數量相關成本。

Our G&A expenses for the six months ended June 30, 2023, was $17.6 million compared to $16.3 million for the same period in 2022. The increase was primarily attributed to $2.2 million in costs associated with the sale of our German subsidiary and $2 million associated with depository fees paid in connection with the ADS ratio change. These increases were offset primarily by reduced G&A headcount related costs.

截至2023 年6 月30 日的六個月，我們的一般管理費用為1,760 萬美元，而2022 年同期為1,630 萬美元。這一增長主要歸因於與出售我們的德國子公司相關的220 萬美元成本和與與 ADS 比率變化相關的存託費。這些增長主要被一般與行政人員相關成本的減少所抵消。

The company also recorded a gain of $2.2 million due to the mutual release and settlement agreement with Brammer Bio announced in May. This agreement resulted in the release of approximately $4.5 million of discharged net liabilities offset by a settlement payment of approximately $2.3 million. Our net loss was $14.8 million, or $0.23 per ordinary share for the six months ended June 30, 2023, compared to a net loss of $51.1 million or $0.95 per ordinary share in the same period in 2022. With that, I'll now turn the call over to the operator for Q&A.

由於 5 月份宣布與 Brammer Bio 達成相互釋放和和解協議，該公司還錄得 220 萬美元的收益。該協議導致約 450 萬美元的已解除淨負債被釋放，並被約 230 萬美元的和解付款所抵消。截至 2023 年 6 月 30 日的六個月，我們的淨虧損為 1,480 萬美元，即每股普通股 0.23 美元，而 2022 年同期的淨虧損為 5,110 萬美元，即每股普通股 0.95 美元。致電接線員進行問答。

(Operator Instructions) Patrick Trucchio, H.C. Wainwright.

（操作員說明）Patrick Trucchio, H.C.溫賴特。

Good morning. This is Luis Santos for Patrick and thank you for taking our questions. We are curious about little bit more detail on the baseline characteristics of the patients in the first cohort and which data can we expect from that first data cut?

早上好。我是帕特里克的路易斯·桑托斯，感謝您回答我們的問題。我們很好奇第一組患者的基線特徵的更多細節，以及我們可以從第一次數據切割中期待哪些數據？

Hey, Luis, thank you. It's Michael Parini. Appreciate the question. Maybe we'll take the second part first, and I can take that. And then I'll turn it over to Pam to talk about patient entry criteria and baseline characteristics.

嘿，路易斯，謝謝你。我是邁克爾·帕里尼。感謝這個問題。也許我們會先進行第二部分，我可以接受。然後我會將其交給 Pam 討論患者進入標準和基線特徵。

In terms of data expectations, as we mentioned in our release, we've dosed the second patient to complete the first cohort for the GALILEO-1 trial that was in early August. We previously reported that we dosed the first patient back in late June. So we're really excited about the opportunity to generate and share some data later this quarter on both patients.

就數據預期而言，正如我們在新聞稿中提到的，我們已經對第二名患者進行了給藥，以完成 8 月初的 GALILEO-1 試驗的第一個隊列。我們之前報導過，我們在六月下旬給第一位患者註射了藥物。因此，我們非常高興有機會在本季度晚些時候生成和共享這兩名患者的一些數據。

We expect to share, obviously, safety data for both patients, and we'll have more on patient one and patient two, but also enzyme activity levels, given our experience with the AAVS3 capsid from prior programs. We do expect to see enzyme activity improvements during this early phase of the trial, and this should be meaningful as we look to see what's the future development plans for the program in terms of dosing.

顯然，我們希望分享這兩名患者的安全數據，並且考慮到我們在之前項目中對 AAVS3 衣殼的經驗，我們將獲得更多關於患者 1 和患者 2 的信息，還有酶活性水平。我們確實希望在試驗的早期階段看到酶活性的改善，這應該是有意義的，因為我們希望了解該項目在劑量方面的未來發展計劃。

And ultimately, the goal was to really find the Phase 3 dose for FLT201. And so we should have meaningful insights on those questions as a result of this first data cohort. In terms of the patients already enrolled in the trial, maybe, Pam, you want to talk a little bit about generally speaking, the entry criteria and the baseline characteristics of the patients.

最終，我們的目標是真正找到 FLT201 的 3 期劑量。因此，通過第一個數據隊列，我們​​應該對這些問題有有意義的見解。就已經入組試驗的患者而言，帕姆，您也許想談談一般情況、患者的進入標準和基線特徵。

Sure, happy to. So while we haven't announced specifics about the individual patients, I can share the entry criteria. And so for the trial, it is for Gaucher disease Type 1 only. Males and females above the age of 18, no upper age limit.

當然，很高興。因此，雖然我們還沒有公佈個別患者的具體情況，但我可以分享進入標準。因此，該試驗僅針對 1 型戈謝病。 18歲以上男女不限，年齡不限。

Patients do come in on stable doses of ERT or SRT coming in. And they can clearly have also the confirmed diagnosis of Gaucher. There's multiple other inclusion-exclusion, but those are the key criteria for entry.

患者確實接受了穩定劑量的 ERT 或 SRT。而且他們也可以清楚地得到戈謝病的確診。還有多種其他包含-排除，但這些是進入的關鍵標準。

And what would you like to see in the safety and tolerability perspective. In this gene therapy space, it's differentiated. And so are we expecting that the doses that were required to get to that normal range of GCA's expression are going to reach any toxicity?

從安全性和耐受性的角度來看，您希望看到什麼？在這個基因治療領域，它是與眾不同的。那麼我們是否期望達到 GCA 表達正常範圍所需的劑量會達到任何毒性？

Yeah, thanks for the follow-up, Luis. Maybe, Pam, you want to talk a little bit about what our expectations are for data from this cohort, including a bit about the normal range for GCase levels in Gaucher patients.

是的，謝謝您的跟進，路易斯。 Pam，也許您想談談我們對該隊列數據的期望，包括戈謝病患者 GCase 水平的正常範圍。

Sure. Off course. So first off, this is predominantly a safety study. So that's going to be a major component of our assessment as we go along within this cohort and with any subsequent cohorts that we have. We will only be speaking to the safety of these two patients when we have the data. So we can't say about future doses, but we can talk about these here.

當然。當然。首先，這主要是一項安全研究。因此，當我們在這個隊列以及我們擁有的任何後續隊列中進行評估時，這將成為我們評估的主要組成部分。只有當我們掌握了數據後，我們才會談論這兩名患者的安全。所以我們不能說未來的劑量，但我們可以在這裡討論這些。

Importantly, we'll be looking not only at general safety like you would in any clinical trials, but clearly also those that are relevant within the gene therapy spacing, especially with AAV, long-term safety, whether that's any change in liver, liver enzymes. We'll be assessing all of that. And we hope to have -- we'll certainly have some safety data when we present in end of Q3.

重要的是，我們不僅會像在任何臨床試驗中那樣關註一般安全性，而且還會關注與基因治療間隔相關的安全性，尤其是AAV 的長期安全性，無論是肝臟、肝臟等方面有任何變化嗎？酶。我們將評估所有這些。我們希望在第三季度末提供一些安全數據。

In terms of expectations, again, hard to say, we'll follow the data. But importantly, when we look at GCase levels, plasma GCase levels specifically are a marker for us for how our liver is expression the gene basically that we have given. So that's going to be a really important and key component of our endpoints, and we'll be sharing that data.

就預期而言，再次很難說，我們將跟踪數據。但重要的是，當我們觀察 GCase 水平時，血漿 GCase 水平特別是我們的肝臟如何表達我們所賦予的基因的一個標記。因此，這將成為我們端點的一個非常重要和關鍵的組成部分，我們將共享這些數據。

The normal range for plasma GCase is about 1[nM], if you will. It depends on the different labs. It can be between 1[nM] and 1.5[nM]. So we'll be looking at those levels compared to what would be normal within our labs as well. So we will be presenting all that data.

如果您願意的話，血漿 GCase 的正常範圍約為 1[nM]。這取決於不同的實驗室。它可以在 1[nM] 和 1.5[nM] 之間。因此，我們將把這些水平與我們實驗室內的正常水平進行比較。所以我們將展示所有這些數據。

(Operator Instructions) Dae Gon Ha, Stifel.

（操作員指示）Dae Gon Ha，Stifel。

This is Benazir here for Dae Gon. Thanks for taking our questions. One of the key advantages of FLT201 was really the expression in key unmet tissues like the lung and the bone marrow. Can you speak to any measurements that you're taking, maybe not even in this next readout but just going forward that will help further build on preclinical findings that show that there was expression in these other tissues?

我是貝娜齊爾，前往大貢。感謝您回答我們的問題。 FLT201 的主要優勢之一實際上是在肺和骨髓等關鍵未滿足的組織中表達。您能否談談您正在進行的任何測量，甚至可能不在下一個讀數中，但只是繼續前進，這將有助於進一步建立表明在這些其他組織中存在表達的臨床前發現？

Thank you. Thanks for the question. Maybe, Pam, you want to talk a little bit about what data will be collecting during the trial. Obviously, it's early days in this first cohort, and I think there is a very strong correlation between plasma GCase activity and clinical outcomes. I think your question's a bit more specific about other parameters of efficacy. And so Pam, maybe you could shed a little bit of light on that question.

謝謝。謝謝你的提問。帕姆，也許您想談談試驗期間將收集哪些數據。顯然，第一組研究還處於早期階段，我認為血漿 GCase 活性與臨床結果之間存在非常強的相關性。我認為你的問題對於其他功效參數更加具體。帕姆，也許你可以對這個問題做出一些解釋。

Sure. Off course. So as Michael mentioned, we have strong nonclinical data, demonstrating the correlation to plasma GCase and lyso-Gb1 reduction. Lyso-Gb1 is a toxic substrate, which has a very clear correlation inherent to clinical outcomes. In terms of what data we will be collecting or we are collecting in this study, not only are we collecting, if you will, the usual suspects of hemoglobin and platelets, we'll be looking at liver and spleen size.

當然。當然。正如 Michael 提到的，我們有強有力的非臨床數據，證明了與血漿 GCase 和 lyso-Gb1 減少的相關性。 Lyso-Gb1 是一種有毒底物，與臨床結果具有非常明顯的內在相關性。就我們將要收集的數據或我們在這項研究中收集的數據而言，如果您願意的話，我們不僅會收集血紅蛋白和血小板的常見數據，我們還將研究肝臟和脾臟的大小。

Getting a sense of expression or activity in those deeper tissues like lung and bone marrow, we have multiple assessments planned. We will be looking at pulmonary function tests; we'll be looking at chest x-rays as well; we will be assessing bone density; we'll be looking at bone density; we will be looking at MRIs. And so those are some of the key components.

為了了解肺和骨髓等深層組織的表達或活動，我們計劃進行多項評估。我們將進行肺功能測試；我們也會檢查胸部 X 光檢查；我們將評估骨密度；我們將關注骨密度；我們將查看核磁共振成像。這些是一些關鍵組成部分。

We'll be also assessing things such as fatigue, pain, quality of life. There's Gaucher disease severity scale that we will be assessing as well. So we'll be utilizing multiple clinical outcomes to get some picture of efficaciousness of our product over the longer term.

我們還將評估疲勞、疼痛、生活質量等因素。我們還將評估戈謝病嚴重程度量表。因此，我們將利用多種臨床結果來了解我們產品的長期有效性。

Okay, excellent. Thank you so much.

好的，非常好。太感謝了。

And ladies and gentlemen, at this time, it's showing no additional questions. I'd like to end today's question-and-answer session and turn the floor back over to Michael Parini for any closing remarks.

女士們先生們，此時，它沒有顯示任何其他問題。我想結束今天的問答環節，並將發言權交回邁克爾·帕里尼 (Michael Parini) 進行結束語。

Thanks and thank you all for your time and participation in today's call. With the momentum we have going in GALILEO-1 for FLT201, the exciting initial clinical data readout later this quarter and the promising research projects that we've announced in particular the GBA1-linked Parkinson's disease, I truly believe we are well positioned for near- and long-term success. But before closing, I did want to thank the Freeline team for all their hard work as well as our study investigators and the patients who are participating in our trials. Thank you all and have a good day.

感謝大家抽出寶貴時間參加今天的電話會議。憑藉我們在GALILEO-1 上針對FLT201 的發展勢頭、本季度晚些時候公佈的令人興奮的初始臨床數據以及我們宣布的有前景的研究項目，特別是與GBA1 相關的帕金森氏病，我堅信我們已做好準備，在不久的將來能夠實現這一目標。 - 以及長期的成功。但在結束之前，我確實想感謝 Freeline 團隊的辛勤工作以及我們的研究人員和參與我們試驗的患者。謝謝大家，祝您有美好的一天。

Ladies and gentlemen, with that, we'll be concluding today's conference call and presentation. We thank you for joining. You may now disconnect your lines.

女士們、先生們，我們今天的電話會議和演示就到此結束。我們感謝您的加入。您現在可以斷開線路。