Passage Bio Inc (PASG) 2022 Q4 法說會逐字稿

Good morning, and welcome to the Passage Bio Fourth Quarter and Full Year 2022 Financial and Operating Results Conference Call. (Operator Instructions) Please be advised that this call being recorded at the company's request. 

早上好，歡迎參加 Passage Bio 2022 年第四季度和全年財務和運營業績電話會議。 （操作員說明）請注意，本次通話是應公司要求進行錄音的。

Now I'd like to turn it over to Stuart Henderson, Vice President of Corporate Development and Investor Relations. Stuart, please proceed.

現在我想把它交給企業發展和投資者關係副總裁 Stuart Henderson。斯圖爾特，請繼續。

Thank you, operator. This morning, we issued a press release that outlines the topics we plan to discuss today. This release is available on the Passage Bio website under the Press Releases and Statements section of Investors and News. On today's call, Chief Executive Officer, Will Chou, will review our fourth quarter 2022 and recent business highlights. Mark Forman, our Chief Medical Officer, will review our clinical programs; and Simona King, our Chief Financial Officer, will review our fourth quarter and full year 2022 financial results.

謝謝你，接線員。今天早上，我們發布了一份新聞稿，概述了我們今天計劃討論的主題。本新聞稿可在 Passage Bio 網站的投資者和新聞的新聞稿和聲明部分找到。在今天的電話會議上，首席執行官 Will Chou 將回顧我們的 2022 年第四季度和近期業務亮點。我們的首席醫療官 Mark Forman 將審查我們的臨床項目；我們的首席財務官 Simona King 將審查我們第四季度和 2022 年全年的財務業績。

Before we begin, please note that today's call may include a number of forward-looking statements. These forward-looking statements are based on assumptions that are subject to risks and uncertainties that could cause the company's actual results to differ significantly from those suggested by these statements. Given these risks and uncertainties, you should not place undue reliance on these forward-looking statements. Please refer to the company's filings with the SEC for information concerning risk factors that could cause its actual results to differ materially from expectations, including any forward-looking statements made on this call. Except as required by law, the company disclaims any obligation to publicly update or revise any forward-looking statements to the time for or reflect events or circumstances that occur after this call. 

在我們開始之前，請注意，今天的電話會議可能包含一些前瞻性陳述。這些前瞻性陳述基於的假設存在風險和不確定性，這些風險和不確定性可能導致公司的實際結果與這些陳述所建議的結果存在顯著差異。鑑於這些風險和不確定性，您不應過度依賴這些前瞻性陳述。請參閱該公司向美國證券交易委員會提交的文件，了解可能導致其實際結果與預期存在重大差異的風險因素的信息，包括本次電話會議中所做的任何前瞻性聲明。除法律要求外，該公司不承擔公開更新或修改任何前瞻性陳述的義務，或反映本次電話會議後發生的事件或情況。

It is now my pleasure to pass the call over to Will.

現在我很高興將電話轉給威爾。

Thanks, Stuart, and thank you all for joining us this morning. I want to begin today's call by briefly reflecting on this past year. By honing our strategy and operational focus, we ended 2022 in a strong position, and I'm proud of the work the team did to lay the groundwork and build the momentum needed to ensure we can deliver meaningful clinical data from our 2 lead programs in 2023. I'm excited by what 2023 has in store for Passage Bio, and I'm pleased to report that the year is already off to a strong start with the presentation of additional data from Cohorts 1 through 3 of our Imagine-1 clinical trial for GM1 gangliosidosis at the World Symposium last month. The data shared at World continued to demonstrate that PBGM01 administration is well tolerated, has a positive safety profile and exerts a biological effect across all treated infantile GM1 patients. Mark will review these results in more detail shortly. But this data builds upon the information we presented in December and adds to our confidence of the potential benefit that PBGM01 may offer the GM1 patient community. 

謝謝斯圖爾特，也感謝大家今天早上加入我們。我想在今天的電話會議開始時簡要回顧一下過去的一年。通過磨練我們的戰略和運營重點，我們在2022 年結束時處於有利地位，我對團隊所做的工作感到自豪，這些工作奠定了基礎並建立了所需的動力，以確保我們能夠從我們的2 個主導項目中提供有意義的臨床數據2023 年。我對2023 年Passage Bio 的前景感到興奮，我很高興地報告說，隨著我們Imagine-1 臨床隊列1 至3 的其他數據的呈現，這一年已經有了一個良好的開端。上個月在世界研討會上進行的 GM1 神經節苷脂沉積症試驗。 World 上分享的數據繼續表明，PBGM01 給藥具有良好的耐受性，具有積極的安全性，並對所有接受治療的嬰兒 GM1 患者產生生物學效應。馬克很快就會更詳細地審查這些結果。但這些數據建立在我們 12 月提供的信息的基礎上，增強了我們對 PBGM01 可能為 GM1 患者群體帶來的潛在益處的信心。

To date, we've completed dosing of the first 4 cohorts in our Imagine-1 study for a total of 8 patients and look forward to reporting initial data from Cohort 4, which is early infantile patients treated with a high dose by midyear. Based on the encouraging data we have generated thus far and are supporting preclinical data, we are moving forward with plans to treat additional patients with a higher dose than doses administered in Cohorts 1 through 4. We also plan to revise our study inclusion criteria to maximize the benefit risk profile of PBGM01. By treating additional patients at a higher dose, we will generate important clinical data to further inform dose and patient selection as well as discussions with regulatory authorities on the design of the confirmatory study. 

迄今為止，我們已經完成了 Imagine-1 研究中前 4 個隊列的總共 8 名患者的給藥，並期待報告第 4 組的初始數據，該組是在年中接受高劑量治療的早期嬰兒患者。基於我們迄今為止生成的令人鼓舞的數據以及支持臨床前數據，我們正在推進計劃，以比隊列1 至4 中施用的劑量更高的劑量治療更多患者。我們還計劃修改我們的研究納入標準，以最大限度地提高患者的治療效果。 PBGM01 的收益風險概況。通過以更高劑量治療更多患者，我們將生成重要的臨床數據，以進一步告知劑量和患者選擇，以及與監管機構就驗證性研究的設計進行討論。

For our upliFT-D trial for frontotemporal dementia, or FTD, we remain focused on driving patient identification and recruitment initiatives and expanding our global footprint of clinical trial sites. Based on the momentum we are experiencing; we expect to report initial safety and biomarker data from Cohort 1 in the second half of the year. While our primary focus is on generating meaningful clinical data for our GM1 and FTD programs, we also continue to advance our promising preclinical programs in amyotrophic lateral sclerosis, Huntington's disease and temporal lobe epilepsy through our ongoing innovative research partnership with Penn's gene therapy program. 

對於額顳葉癡呆 (FTD) 的 upliFT-D 試驗，我們仍然專注於推動患者識別和招募計劃，並擴大我們的臨床試驗地點的全球覆蓋範圍。基於我們正在經歷的勢頭；我們預計將在今年下半年報告第一組的初步安全性和生物標誌物數據。雖然我們的主要重點是為我們的GM1 和FTD 項目生成有意義的臨床數據，但我們還通過與賓夕法尼亞大學基因治療項目的持續創新研究合作夥伴關係，繼續推進我們在肌萎縮側索硬化症、亨廷頓病和顳葉癲癇方面有前景的臨床前項目。

Moreover, following the prioritization of our research and development efforts announced last November, we remain committed to exploring strategic alternatives to advance our 2 clinical stage programs for Krabbe disease and metachromatic leukodystrophy. In addition, we continue to leverage our strong in-house analytical capabilities at our CMC lab at Princeton West -- as these capabilities provide a competitive advantage and are critical to support ongoing and future clinical development of our programs.

此外，繼去年 11 月宣布的研發工作優先順序之後，我們仍然致力於探索戰略替代方案，以推進我們針對克拉伯病和異染性腦白質營養不良的兩個臨床階段項目。此外，我們繼續利用普林斯頓西 CMC 實驗室強大的內部分析能力，因為這些能力提供了競爭優勢，並且對於支持我們項目的持續和未來臨床開發至關重要。

Lastly, we are supported by a strong balance sheet, providing us with the necessary runway to generate meaningful clinical data for our GM1 and FTD programs. Simona will describe our financials in more detail, but we expect existing cash resources to fund operations into the first half of 2025. 

最後，我們得到了強大的資產負債表的支持，為我們提供了必要的跑道，為我們的 GM1 和 FTD 項目生成有意義的臨床數據。 Simona 將更詳細地描述我們的財務狀況，但我們預計現有現金資源將為 2025 年上半年的運營提供資金。

With that, I will now turn it over to Mark to review our 2 lead clinical programs and the recent GM1 data.

現在，我將把它交給 Mark 來審查我們的 2 個主要臨床項目和最近的 GM1 數據。

Thank you, Will. Let me begin with a brief overview of our lead program, PBGM01, the GM1 gangliosidosis, and then I will review key findings from the interim data shared in December of last year and more recently at the 19th Annual World Symposium. GM1 is a fatal pediatric neurological lysosomal storage disorder caused by a GLB1 gene mutation that results in low activity of the beta-galactosidase enzyme. This leads to rapid neurological decline and in the most severe forms, unfortunately, to mortality within several years. Patients with GM1 are a rare and underserved population, and there are currently no disease-modifying therapies for this disorder. 

謝謝你，威爾。讓我首先簡要概述我們的主導項目 PBGM01（GM1 神經節苷脂沉積症），然後我將回顧去年 12 月和最近在第 19 屆世界研討會上分享的中期數據的主要發現。 GM1 是一種致命的小兒神經性溶酶體貯積症，由 GLB1 基因突變引起，導致 β-半乳糖苷酶活性低下。這會導致神經功能迅速衰退，不幸的是，最嚴重的情況會導致幾年內死亡。 GM1 患者是一個罕見且服務不足的人群，目前還沒有針對這種疾病的疾病緩解療法。

Our Imagine-1 clinical trial focuses on the early and late infantile forms of GM1, which are the most severe forms of (inaudible). The dose escalation portion of this global Phase I/II trial is an open-label study with PBGM01 enrolling 4 distinct cohorts divided by age and dose level. Our approach uses the next-generation proprietary AAVhu68 capsid administered by the cisterna magna to deliver a codon-optimized GLB1 transgene to increase beta-galactosidase enzyme activity in the brain and peripheral tissues. We've experienced strong momentum in our Imagine-1 trial.

我們的 Imagine-1 臨床試驗側重於 GM1 的早期和晚期嬰兒形式，這是最嚴重的形式（聽不清）。這項全球 I/II 期試驗的劑量遞增部分是一項開放標籤研究，PBGM01 招募了 4 個不同的隊列，按年齡和劑量水平劃分。我們的方法使用由大池管理的下一代專有 AAVhu68 衣殼來傳遞密碼子優化的 GLB1 轉基因，以增加大腦和外周組織中的 β-半乳糖苷酶活性。我們在 Imagine-1 試驗中經歷了強勁的勢頭。

To date, we've completed dosing of the first 4 cohorts in the dose escalation portion of the study, representing a total of 8 patients. In December of last year and more recently at the World Symposium, we were excited to share promising interim results from the first 3 cohorts in the study. These cohorts represent the low dose cohorts in both early and late infantile patients and the high dose late infantile cohort for a total of 6 patients. 

迄今為止，我們已經完成了研究劑量遞增部分的前 4 個隊列的給藥，總共 8 名患者。去年 12 月和最近的世界研討會上，我們很高興分享該研究中前 3 個隊列的有希望的中期結果。這些隊列代表早期和晚期嬰兒患者的低劑量隊列以及總共 6 名患者的高劑量晚期嬰兒隊列。

Key findings from these interim data are as follows: first, we're excited to see that PBGM01 continues to be well tolerated and has a favorable safety profile. There have been no treatment-related serious adverse events, no evidence of Dorsal Root Ganglion or DRG toxicity, no immune response requiring adjustment to the immunosuppression and no complications related to the ICM procedure. Second, we observed dose-dependent increases in CSF beta-galactosidase enzyme activity, the enzyme of interest and dose-dependent decreases in CSF GM1 ganglioside levels, a key substrate of beta-galactosidase. Biomarker data also demonstrate that ICM delivery of PBGM01 leads to beta-gal enzyme activity in both the CNS and the periphery. 

這些中期數據的主要發現如下：首先，我們很高興看到 PBGM01 繼續具有良好的耐受性並具有良好的安全性。沒有發生與治療相關的嚴重不良事件，沒有背根神經節或 DRG 毒性的證據，沒有需要調整免疫抑制的免疫反應，也沒有與 ICM 手術相關的並發症。其次，我們觀察到腦脊液β-半乳糖苷酶活性（目標酶）呈劑量依賴性增加，以及腦脊液GM1神經節苷脂水平（β-半乳糖苷酶的關鍵底物）呈劑量依賴性下降。生物標誌物數據還表明，PBGM01 的 ICM 遞送會導致 CNS 和外周中的 β-gal 酶活性。

Third, turning to clinical results. We observed that patients with a lower developmental delay of dosing experienced a better response to treatment on the Vineland and Bayley developmental scales regardless of dose level. We also reported imaging data from the MRI severity score, which can be used to assess treatment effects on brain volume and white matter integrity based on baseline and follow-up MRIs. At this interim analysis, PBGM01 administration was associated with stabilization of MRI severity scores in all treated patients at a follow-up period of 6 to 12 months. In contrast, published natural history data from late infantile GM1 patients showed MRI severity scores increased in the majority of children at a follow-up period of 6 months to 4 years. Overall, the data generated to date give us confidence that PBGM01 is exerting a biological effect in all treated patients with infantile GM1. 

第三，轉向臨床結果。我們觀察到，無論劑量水平如何，給藥發育延遲較低的患者對 Vineland 和 Bayley 發育量表的治療都有更好的反應。我們還報告了 MRI 嚴重程度評分的成像數據，該數據可用於根據基線和後續 MRI 評估對腦容量和白質完整性的治療效果。在此中期分析中，PBGM01 給藥與所有接受治療的患者在 6 至 12 個月的隨訪期間 MRI 嚴重程度評分的穩定相關。相比之下，已發表的晚期嬰兒 GM1 患者的自然史數據顯示，在 6 個月至 4 年的隨訪期間，大多數兒童的 MRI 嚴重程度評分有所增加。總體而言，迄今為止生成的數據讓我們相信 PBGM01 正在對所有接受治療的嬰兒 GM1 患者發揮生物效應。

Based on the favorable safety profile of PBGM01 to date, the observed dose response in key biomarkers and supporting preclinical data, we plan to treat additional patients at a higher dose than has currently been evaluated in the first 4 cohorts. Additionally, we are revising study inclusion criteria to maximize the benefit risk profile of PBGM01. These modifications to the study design will provide us with valuable clinical data to inform dose and patient selection as we seek to optimize the therapeutic benefit of PBGM01. Moreover, these additional data will also allow us to have productive interactions with regulatory authorities on confirmatory study design and the pathway towards a biologics license application. We are excited to continue to advance our Imagine-1 program and expect to dose the first patient at the higher dose in the second half of 2023, following regulatory review. 

基於迄今為止 PBGM01 良好的安全性、在關鍵生物標誌物中觀察到的劑量反應以及支持臨床前數據，我們計劃以比目前在前 4 個隊列中評估的劑量更高的劑量治療更多患者。此外，我們正在修訂研究納入標準，以最大限度地提高 PBGM01 的獲益風險狀況。這些對研究設計的修改將為我們提供有價值的臨床數據，以便在我們尋求優化 PBGM01 的治療效果時為劑量和患者選擇提供信息。此外，這些額外的數據還將使我們能夠與監管機構就驗證性研究設計和生物製劑許可申請途徑進行富有成效的互動。我們很高興能夠繼續推進 Imagine-1 項目，並預計在監管審查後於 2023 年下半年為第一位患者提供更高劑量的劑量。

Next, let me discuss PBFT02 for frontal sample dementia with granular mutations. FTD is a devastating form of early onset dementia affecting patients between the ages of 40 to 65. The form of the disease we are seeking to treat with our therapy is caused by our granulin or GRN gene mutation, which resulted in deficiency of progranulin. It is estimated that about 5% to 10% of FTD is caused by a GRN mutation. We are utilizing the AAV1 capsid to deliver a functional copy of the granulin gene via ICM delivery to the CSF. The goal of this treatment and delivery approach is to potentially provide higher-than-normal levels of the progranulin protein to the CNS to overcome the deficiency in granulin gene mutation carriers. 

接下來，讓我討論 PBFT02 用於治療帶有顆粒突變的額葉樣本癡呆。 FTD 是一種破壞性的早發性癡呆，影響40 至65 歲之間的患者。我們尋求用我們的療法治療的這種疾病是由顆粒蛋白或GRN 基因突變引起的，導致顆粒蛋白前體缺乏。據估計，大約 5% 至 10% 的 FTD 是由 GRN 突變引起的。我們利用 AAV1 衣殼通過 ICM 遞送顆粒蛋白基因的功能副本至 CSF。這種治療和遞送方法的目標是潛在地向中樞神經系統提供高於正常水平的顆粒體蛋白前體蛋白，以克服顆粒體蛋白基因突變攜帶者的缺陷。

Our upliFT-D clinical trial is investigating 2 dose levels of PBFT02 and is sequentially enrolling 2 cohorts. Based on the results of the first 2 cohorts, we have the optionality for a third dose level. The primary endpoint of the study is to evaluate the safety and tolerability of PBFT02, secondary endpoints include disease biomarkers and clinical outcome measures. We continue to focus on activating additional clinical site trial sites around the globe and on driving a variety of initiatives to support patient identification and recruitment. Based on the momentum in these efforts, we expect to share initial safety and biomarker data from Cohort 1 patients in the second half of 2023. These data will focus on safety and CSF levels of program. 

我們的 upliFT-D 臨床試驗正在研究 PBFT02 的 2 個劑量水平，並依次招募 2 個隊列。根據前兩個隊列的結果，我們可以選擇第三個劑量水平。該研究的主要終點是評估 PBFT02 的安全性和耐受性，次要終點包括疾病生物標誌物和臨床結果指標。我們繼續專注於激活全球更多的臨床試驗點，並推動各種舉措來支持患者識別和招募。基於這些努力的勢頭，我們預計在 2023 年下半年分享來自第 1 組患者的初始安全性和生物標誌物數據。這些數據將重點關注項目的安全性和腦脊液水平。

With that, I will now turn the call over to Simona to review our financials.

現在，我將把電話轉給西蒙娜，以審查我們的財務狀況。

Thank you, Mark. As we reported in our press release this morning, cash equivalents and marketable securities were $189.6 million as of December 31, 2022, as compared to $315.8 million as of December 31, 2021. Following the streamlining of our operations and prioritization of our research and development efforts announced last quarter, we expect these existing cash resources to fund operations into the first half of 2025. We will continue to manage our cash form judiciously as we focus on program execution. 

謝謝你，馬克。正如我們今天上午在新聞稿中報導的那樣，截至2022 年12 月31 日，現金等價物和有價證券為1.896 億美元，而截至2021 年12 月31 日為3.158 億美元。在精簡我們的運營並優先考慮我們的研發之後根據上季度宣布的努力，我們預計這些現有現金資源將為 2025 年上半年的運營提供資金。在專注於計劃執行的同時，我們將繼續明智地管理我們的現金形式。

R&D expenses were $17.7 million for the quarter ended December 31, 2022, and $86.1 million for the year ended December 31, 2022, compared to $33 million and $117.7 million for the same quarter and year in 2021. G&A expenses were $10.6 million for the quarter ended December 31, 2022, and $49.3 million for the year ended December 31, 2022, compared to $17.2 million and $60.1 million for the same quarter and year-end 2021. Net loss was $27.1 million for the quarter and $136.1 million for the year ended December 31, 2022, compared to $51.2 million for the quarter and $185.4 million for the year ended December 31, 2021.

截至2022年12月31日的季度研發費用為1770萬美元，截至2022年12月31日的年度研發費用為8610萬美元，而2021年同季度和年度的研發費用為3300萬美元和1.177億美元。該季度的一般管理費用為1060萬美元截至2022年12月31日的淨虧損為4930萬美元，截至2022年12月31日的年度為4930萬美元，而2021年同季度和年底的淨虧損為1720萬美元和6010萬美元。該季度的淨虧損為2710萬美元，截至2021年年底的淨虧損為1.361億美元截至2022 年12 月31 日，相比之下，截至2021 年12 月31 日的季度收入為5120 萬美元，全年收入為1.854 億美元。

Let me now turn it back to Will for closing remarks.

現在讓我轉回威爾做總結髮言。

Thank you, Simona. The primary focus for 2023 is on strong execution and continuing to generate meaningful clinical data from our lead programs in GM1 and FTD. We expect to achieve several program milestones this year. By mid-2023, from our Imagine-1 study, we plan to report initial safety and biomarker data from Cohort 4, which is early infantile patients treated with a high dose. In the second half of 2023, we look forward to dosing the first GM1 patient at a higher dose than those previously evaluated and to reporting initial safety and biomarker data from Cohort 1 of our upliFT-D study.

謝謝你，西蒙娜。 2023 年的主要重點是強有力的執行，並繼續從我們的 GM1 和 FTD 主導項目中生成有意義的臨床數據。我們預計今年將實現多個計劃里程碑。到 2023 年中期，根據我們的 Imagine-1 研究，我們計劃報告第 4 組（接受高劑量治療的早期嬰兒患者）的初始安全性和生物標誌物數據。 2023 年下半年，我們期待以比之前評估的劑量更高的劑量對第一位 GM1 患者進行給藥，並報告我們 upliFT-D 研究第 1 組的初始安全性和生物標誌物數據。

Prior to taking your questions, I would like to thank my colleagues at Passage Bio, who have shown their commitment to the pursuit of our ambitious mission. We also continue to be grateful for the support of the patients, families and clinical trial investigators who have chosen to participate in our studies as well as the support of our partners at the gene therapy program.

在回答您的問題之前，我要感謝 Passage Bio 的同事，他們致力於實現我們雄心勃勃的使命。我們還繼續感謝選擇參與我們研究的患者、家屬和臨床試驗研究人員的支持，以及我們基因治療項目合作夥伴的支持。

With that, I would like to open the call for your questions. Operator?

至此，我想開始詢問大家的問題。操作員？

We will now take any questions you may have. (Operator Instructions) And our first question coming from the line of Yaron Werber with Cowen.

我們現在將回答您可能提出的任何問題。 （操作員說明）我們的第一個問題來自 Yaron Werber 和 Cowen 的線路。

This is Brendan on for Yaron. (inaudible) progress. Maybe just a couple of quick ones from us. In terms of the dose escalation plan, can you actually -- can you confirm whether you've already identified additional patients? It looks like you're going to go both into early analyte infantile for this higher dose? And then really, can you give us a thing, are you -- is there like a particular threshold you're trying to hit in terms of biomarker response or functional improvement? Or are you really just looking to see how much you can maximize the efficacy before transitioning to a pivotal study -- and then just really quickly on a potential pivotal study based on what you know so far with these neurodevelopmental endpoints, can you maybe give us a sense of how long you think you would need to follow patients to support approval in GM1?

這是布倫丹 (Brendan) 替補亞龍 (Yaron)。 （聽不清）進展。也許只是我們的一些快速的。就劑量遞增計劃而言，您能否確認您是否已經確定了其他患者？看起來您將同時進入嬰兒早期分析物以獲得更高的劑量？然後真的，你能給我們一件事嗎？在生物標誌物反應或功能改善方面，你是否想要達到一個特定的閾值？或者您真的只是想看看在過渡到關鍵研究之前可以最大限度地提高功效，然後根據您迄今為止對這些神經發育終點的了解，快速進行潛在的關鍵研究，您能給我們提供一些信息嗎？您認為您需要跟踪患者多長時間才能支持GM1 的批准？

Thanks for the question, Brendan. I'm going to turn that over to Mark. Do you want to answer?

謝謝你的提問，布倫丹。我要把它交給馬克。你想回答嗎？

So yes, thanks. So for the dose escalation (inaudible) cohorts that are currently being considered I mean, over the course of the past few years, we've received a great deal of interest in our trial, and there are -- and inquiries from dozens of families interested in, including both early infantile and late infantile. We've been reviewing these profiles and they have -- and as assessed by the adjudicator, and the majority of these children would meet the revised trial eligibility that we're planning on. Thus, we're confident that we're able to quickly recruit the serve even with the narrowing of the inclusion criteria. 

所以是的，謝謝。因此，對於目前正在考慮的劑量遞增（聽不清）隊列，我的意思是，在過去幾年中，我們對我們的試驗產生了很大的興趣，並且有來自數十個家庭的詢問感興趣，包括早期嬰兒和晚期嬰兒。我們一直在審查這些資料，並且根據裁決員的評估，這些兒童中的大多數將符合我們計劃修訂的試驗資格。因此，我們有信心即使縮小了納入標準，我們也能夠快速招募發球人員。

With regards to the second question with how much beta-galactosidase activity that we need, the amount of beta-galactosidase that is needed to correct the deficits in these patients is not known. What we do know is that in animal models, even modest reductions, and I'm specifically talking about the transgenic mouse knockout model that we used in our preclinical program, even modest increases in beta-galactosidase activity were associated with clinical improvement.

關於第二個問題，即我們需要多少 β-半乳糖苷酶活性，糾正這些患者的缺陷所需的 β-半乳糖苷酶的量尚不清楚。我們所知道的是，在動物模型中，即使是適度的減少，我特別談論的是我們在臨床前計劃中使用的轉基因小鼠敲除模型，即使β-半乳糖苷酶活性的適度增加也與臨床改善相關。

That being said, we're really using the pharmacodynamic marker, the CSF levels of GM1 gangliosides to drive our program. And in the data that we've shared most recently at World, we've shown that at 6 months, at the high dose, we've been able to reduce those levels to 75%. And the goal is to really normalize those levels. And so that is really what we'll be looking for going forward is looking at the levels of reduction of the ganglioside -- GM1 ganglioside levels in conjunction with the clinical outcomes, which we believe will be a lagging indicator.

話雖這麼說，我們實際上是在使用藥效學標記，即 GM1 神經節苷脂的 CSF 水平來驅動我們的計劃。在我們最近在 World 上分享的數據中，我們表明，在高劑量的 6 個月內，我們已經能夠將這些水平降低至 75%。我們的目標是真正使這些水平正常化。因此，我們未來真正要尋找的是觀察神經節苷脂的降低水平——GM1 神經節苷脂水平與臨床結果相結合，我們認為這將是一個滯後指標。

The last question was on follow-up. And so in terms of clinical follow-up, there is a long lead time for seeing developmental changes at a minimum at a minimum, we would at least need to have a follow-up of 6 months.

最後一個問題是關於後續行動。所以在臨床隨訪方面，要看到發育變化至少需要很長的時間，至少需要6個月的隨訪。

And our next question coming from the line of Madhu Kumar with Goldman Sachs.

我們的下一個問題來自高盛的 Madhu Kumar。

This is Omari on for Madhu. So I have 2 questions. First, what are the specific outputs that you're looking for in early infantile high dose cohort for GM1 to pursue registrational studies? And is second, do you have any visibility or registrational endpoint in GM1?

這是奧馬里（Omari）替補馬杜（Madhu）。所以我有兩個問題。首先，您在早期嬰兒高劑量隊列中尋找 GM1 進行註冊研究的具體成果是什麼？第二，您在 GM1 中是否有任何可見性或註冊端點？

Okay. I'll take the first one, and then I'll turn the second question over to Mark. So in terms of specific outputs that we're looking for, it's really 2. We're looking for durable decreases in GM1 ganglioside, as Mark referenced previously, and we're looking for improvement in development. Mark?

好的。我將回答第一個問題，然後將第二個問題交給馬克。因此，就我們正在尋找的具體輸出而言，它實際上是 2。我們正在尋找 GM1 神經節苷脂的持久減少，正如 Mark 之前提到的，我們正在尋求開發方面的改進。標記？

And the second question was regarding the registrational endpoint output. And we will be having ongoing discussions with the health authorities to define the endpoints that will be used for these studies, and we'll certainly provide updates on what those are as they come defined following our discussions with health authorities.

第二個問題是關於註冊端點輸出。我們將與衛生當局進行持續討論，以確定將用於這些研究的終點，並且我們肯定會在與衛生當局討論後提供有關這些終點定義的最新信息。

And our next question coming from the line up Laura Chico with Wedbush.

我們的下一個問題來自勞拉·奇科（Laura Chico）和韋德布什（Wedbush）的陣容。

The first one on GM1, how do the inclusion criteria changes impact potential labeling? I guess what I'm asking is, would this still be something that would be applied more broadly to GM1. And then in terms of perhaps a preclinical question, we're hearing about more constraints on NHP supply chain issues. I'm just curious how that might impact some of the preclinical efforts that you've got going on right now.

第一個關於 GM1，納入標準的變化如何影響潛在的標籤？我想我要問的是，這是否仍然會更廣泛地應用於 GM1。然後，就臨床前問題而言，我們聽說 NHP 供應鏈問題受到更多限制。我只是好奇這可能會如何影響你們目前正在進行的一些臨床前工作。

Okay. Sure. In terms of inclusion criteria, as you know, any protocol amendments we make are subject to regulatory review. So we will be happy to share the details of the inclusion criteria changes after that review is complete. What we have said previously is we're looking to treat patients who are earlier on. And as you know, all GM1 patients pass through earlier stages. And our goal is to identify and find these patients at an earlier stage so we can maximize the risk-benefit of the product. In terms of patient identification, what we do know is from the patients who have been suggested for the trial who have been given to our adjudicator, we know that there are many patients who fit our new recommended inclusion criteria for the protocol. And so we feel confident in our ability to recruit these patients. Mark?

好的。當然。就納入標準而言，如您所知，我們所做的任何協議修訂都需要接受監管審查。因此，我們很樂意在審核完成後分享納入標準變更的詳細信息。我們之前說過，我們正在尋求治療早期患者。如您所知，所有 GM1 患者都會經歷早期階段。我們的目標是在早期階段識別和發現這些患者，以便我們能夠最大限度地提高產品的風險收益。在患者識別方面，我們所知道的是，從推薦參加試驗的患者（已提供給我們的裁決者）中，我們知道有許多患者符合我們新推薦的方案納入標準。因此，我們對招募這些患者的能力充滿信心。標記？

So the second question is around impacts to our preclinical programs in terms of nonhuman primate availability. And our preclinical programs are done in collaboration with the gene therapy program at the University of Pennsylvania. And to date, the availability of [Penn] has not impacted any of the ability of any of our preclinical pipeline to advance. So not an issue right now, but certainly it's something that we're carefully monitoring, and we'll be working closely with our colleagues there to ensure that that doesn't hold things up.

因此，第二個問題是關於非人類靈長類動物可用性方面對我們臨床前計劃的影響。我們的臨床前項目是與賓夕法尼亞大學的基因治療項目合作完成的。迄今為止，[Penn] 的可用性並未影響我們任何臨床前管道的推進能力。所以現在這不是一個問題，但我們肯定正在仔細監控這一問題，我們將與那裡的同事密切合作，以確保這不會阻礙事情的發展。

Our next question coming from the line of Neena Bitritto-Garg with CitiGroup.

我們的下一個問題來自花旗集團的 Neena Bitritto-Garg。

This is (inaudible) on for Neena. Two questions from us. First, being on PBGM01. Can you disclose what the higher dose is? And if not, perhaps how much higher in relation to the current dose that you're looking at? And second, in relation to PBFT02, we recall that you guys had patients in the queue last quarter. Any reason why these patients do not get dosed. And have you guys dosed the second patient yet?

這是 Neena 的（聽不清）。我們提出兩個問題。首先，在 PBGM01 上。您能透露一下較高劑量是多少嗎？如果不是，與您當前正在考慮的劑量相比，也許要高多少？其次，關於 PBFT02，我們記得上個季度你們有病人在排隊。這些患者不接受給藥的任何原因。你們給第二個病人注射了嗎？

Sure. So for -- let me answer the first question. So for GM01, as we mentioned before, the protocol changes are subject to regulatory review. So as soon as that review is complete, we would be happy to share the new dose. In terms of PBFT02, we indeed have patients in the queue. We have GRN positive patients who are at sites who are being queued up for future treatments. In terms of dosing, we are not providing specific details on patient-to-patient dosing within each cohort.

當然。因此，讓我回答第一個問題。因此，對於 GM01，正如我們之前提到的，協議變更需要接受監管部門的審查。因此，一旦審查完成，我們將很樂意分享新劑量。就PBFT02而言，我們確實有患者在排隊。我們有 GRN 陽性患者正在排隊接受未來的治療。在劑量方面，我們沒有提供每個隊列中患者之間劑量的具體細節。

One is our next question. And our next question coming from the line Yun Zhong with BTIG.

這是我們的下一個問題。我們的下一個問題來自 BTIG 的雲鍾專線。

So a follow-up question on dose escalation. Have you got approval on dose escalation itself? Or would that still be dependent on data from Cohort 4? And on patient selection -- sorry, if I missed this, but is the next patient going to be laid on set or early onset? Or are you going to explore both early onset and late onset patient with the high dose? And finally, the -- I think you talked before about the developmental delay as a very critical factor affecting treatment outcome, but the 2 patients in Cohort 4 seem to have very short delay but not by design. So are you going to look for those patients specifically with the short delay?

關於劑量遞增的後續問題。您是否已獲得劑量遞增本身的批准？或者這仍然取決於第 4 組的數據？關於患者選擇——抱歉，如果我錯過了這一點，但是下一個患者是在現場還是提前就診？或者您打算用高劑量探索早發和晚發患者？最後，我想您之前曾談到發育遲緩是影響治療結果的一個非常關鍵的因素，但第 4 組中的 2 名患者似乎有非常短的延遲，但並非有意為之。那麼您會專門尋找那些延誤時間短的患者嗎？

Yes. Thanks for the question. So in terms of dependency on Cohort 4, no, we are increasing the dose right now. We are moving to do that regardless of any results for Cohort 4. For the additional patients that we will treat at dose 3, the higher dose, we are going to be treating both early and late infantile patients. 

是的。謝謝你的提問。因此，就對第 4 組的依賴性而言，不，我們現在正在增加劑量。無論第 4 組的結果如何，我們都將這樣做。對於我們將以劑量 3（較高劑量）治療的其他患者，我們將治療早期和晚期嬰兒患者。

And then I'll turn it over to Mark for the last question.

然後我將把最後一個問題交給馬克。

Right. So can you just remind me again of the last question, make sure I understand it.

正確的。那麼你能再提醒我最後一個問題嗎，確保我理解它。

Yes. It's about developmental delay. And you talked in the past that it seems to be a very critical factor affecting treatment outcome. And both Cohort 4 patients, they have very short delay, but not really the intention -- so not really by design that, it looks like it was accidentally they had a short delay. So are you going to, going forward, look for specifically patients with short delay to improve potential treatment outcomes?

是的。這是關於發育遲緩的問題。您過去曾說過，這似乎是影響治療結果的一個非常關鍵的因素。而第 4 組的兩名患者，他們都有非常短的延遲，但並不是真正的意圖 - 所以不是真正的設計，看起來他們意外地有一個短暫的延遲。那麼，您是否打算在未來專門尋找短期延遲的患者以改善潛在的治療結果？

Yes. So the goal moving forward is we work -- as we're actively working to revise the inclusion criteria is to shift the focus to earlier stages of disease, as Will mentioned earlier, with the goal of identifying patients who have the highest risk benefit risk profile. And with the -- so the current inclusion criteria would certainly not exclude those patients as you pointed out in your comments, but the goal will be to try to enroll more patients with that profile with the shorter delay going forward.

是的。因此，前進的目標是我們的工作 - 正如威爾之前提到的，我們正在積極努力修改納入標準，將重點轉移到疾病的早期階段，目標是識別具有最高風險收益風險的患者輪廓。因此，當前的納入標準肯定不會排除您在評論中指出的那些患者，但目標將是嘗試以更短的延遲招募更多具有該特徵的患者。

Our next question coming from the line of Danielle Brill with Raymond James.

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

This is Alex on for Danielle. Just looking at past notes, I believe that for the GM1 program that the expectation was to have the end of Phase II meeting with the agency somewhere in 2023. But with the added cohorts, when does that -- when do you expect that conversation to take place? Are we looking more like a 2024 event?

這是亞歷克斯為丹妮爾代言。只要看看過去的筆記，我相信對於GM1 計劃，預期是在2023 年某個時候與該機構結束第二階段會議。但是隨著人群的增加，什麼時候會發生——你預計什麼時候會發生這樣的對話？發生？我們看起來更像是 2024 年的活動嗎？

What we plan is to go discuss the registrational pathway with regulatory authorities with data from the additional patients who are being treated at a higher dose. So indeed, that will not be in 2023 as we plan on treating the first patients at this higher dose in the second half of this year.

我們計劃利用更多接受更高劑量治療的患者的數據，與監管機構討論註冊途徑。事實上，這不會是在 2023 年，因為我們計劃在今年下半年以更高的劑量治療第一批患者。

And our next question coming from the line of Whitney Ijem from Canaccord.

我們的下一個問題來自 Canaccord 的 Whitney Ijem。

I guess on FTD, so you mentioned the update later this year will be -- will include safety and biomarker data. Can you remind us for the biomarkers? Is that NFL level? Are there others that we should be thinking about? And how are you thinking about target levels or what would be good in terms of this first dosing cohort in your view?

我想在 FTD 上，你提到今年晚些時候的更新將包括安全性和生物標誌物數據。您能提醒我們生物標誌物嗎？這是NFL級別的嗎？還有其他我們應該考慮的嗎？您如何考慮目標水平，或者您認為第一個劑量組的好處是什麼？

Sure. So let me take that one, Mark. So our initial data from Cohort 1 is going to focus on safety and CSF pro granulin level. So we plan to report per granulin levels at baseline and after 30 days in the CSF. What was the second part of your question?

當然。那麼讓我來吧，馬克。因此，我們第 1 組的初始數據將重點關注安全性和腦脊液顆粒蛋白原水平。因此，我們計劃報告基線時和 30 天后腦脊液中的顆粒蛋白水平。你問題的第二部分是什麼？

So I guess as it relates to CSF progranulin then what are -- is there a target level that you're aiming for? And are you expecting -- or I guess what are your expectations given this is the first dose cohort relative to that potential target?

所以我想，由於它與腦脊液顆粒體蛋白前體相關，那麼您想要達到的目標水平是什麼？你是否期待——或者我猜你的期望是什麼，因為這是與該潛在目標相關的第一個劑量組？

Sure, of course. So based on our preclinical data, what we saw at this current dose level is physiologic levels of CSF program. So our expectations would be to at least see physiologic levels of CSF program. I would like to say that before we discussed the patient recruitment and because of all the patients we have who are identified at sites who are GRN positive, we are confident and looking forward to sharing data from the first cohort of patients in the second half of this year.

當然，當然。因此，根據我們的臨床前數據，我們在當前劑量水平上看到的是腦脊液程序的生理水平。因此，我們的期望是至少看到 CSF 程序的生理水平。我想說的是，在我們討論患者招募之前，由於我們在現場發現的所有患者都是 GRN 陽性，我們有信心並期待在下半年分享第一批患者的數據。今年。

Got it. And then second part of the question, I guess, is, I believe there is targeting enrollment of 3 patients in this first cohort, correct me if I'm wrong, but is the expectation to provide data on a complete cohort? Or will you provide data on if it ends up not being a complete cohort dose in the second half, you'll provide data on whatever patients you have treated?

知道了。我想問題的第二部分是，我相信第一個隊列中的目標是招募 3 名患者，如果我錯了請糾正我，但是是否期望提供完整隊列的數據？或者你會提供數據，如果下半年它最終不是一個完整的隊列劑量，你會提供你治療過的任何患者的數據嗎？

We'll be providing data on multiple patients from the first cohort, and we will be able to give more specific guidance to that later this year.

我們將提供第一批患者的多個患者的數據，並且我們將能夠在今年晚些時候提供更具體的指導。

And I'm showing no further questions in the queue at this time. Ladies and gentlemen, thank you for participating in today's conference. This does conclude your program, and you may now disconnect. Everyone, have a great day.

目前我在隊列中沒有顯示任何其他問題。女士們、先生們，感謝你們參加今天的會議。這確實結束了您的程序，您現在可以斷開連接。大家，祝你有美好的一天。