Alector Inc (ALEC) 2023 Q4 法說會逐字稿

Good day, and thank you for standing by, and welcome to Elekta's Q4 2023 earnings conference call. At this time, all participants are in listen only mode after the speakers' presentation, there will be a question and answer session to ask a question. (Operator Instructions) Again, please be advised that today's conference is being recorded. I would now like to turn the conference over your speaker for today, Katie Hogan. Please go ahead.

美好的一天，感謝您的耐心等待，歡迎參加 Elekta 的 2023 年第四季財報電話會議。此時，所有參與者都處於只聽模式，在演講者演講後，將有一個問答環節來提問。（操作員指示）再次請注意，今天的會議正在錄製中。現在我想把會議交給今天的發言人凱蒂·霍根 (Katie Hogan)。請繼續。

Thank you, operator, and hello, everyone. Earlier this afternoon we released our financial results for the fourth quarter and full year 2023 press release is available on our website at www.alector.com, and our 10-K was filed with the Securities and Exchange Commission this afternoon, and joining me on the call today are Dr. Arnon Rosenthal, Co-Founder and CEO; Dr. Sara Kenkare-Mitra, President and Head of Research and Development; Dr. Gary Romano, Chief Medical Officer; and Dr. Marc Grasso, Chief Financial Officer. After our formal remarks, we'll open the call for Q&A.

謝謝接線員，大家好。今天下午早些時候，我們發布了第四季度的財務業績，並在我們的網站www.alector.com 上發布了2023 年全年新聞稿，我們的10-K 已於今天下午向美國證券交易委員會提交，請與我一起閱讀今天的電話會議是聯合創始人兼首席執行官 Arnon Rosenthal 博士； Sara Kenkare-Mitra 博士，總裁兼研發主管；加里·羅馬諾博士，首席醫療官；財務長 Marc Grasso 博士。正式發言後，我們將開始問答環節。

I'd like to note that during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide on the webcast, which contains our forward-looking statement disclosure, and we also encourage you to review our SEC filings for more information. I would now like to turn the call over to Arnon Rosenthal, Chief Executive Officer. Arnon?

我想指出的是，在這次電話會議中，我們將做出一些前瞻性聲明。請花點時間查看我們在網路廣播中的幻燈片，其中包含我們披露的前瞻性聲明，我們也鼓勵您查看我們向 SEC 提交的文件以獲取更多資訊。我現在想將電話轉給執行長 Arnon Rosenthal。阿農？

Thank you, Katie, and good afternoon, everyone, and thank you for joining Alector for our fourth quarter and full year 2023 financial results conference call. I'll begin by highlighting the broad mechanistic potential of our immuno-oncology candidate or candidates recruit microglia, the brain's primary immune cells to combat neurodegeneration by containing multiple classes of misfolded protein, maintaining brain health and organ function and supporting the maintenance of healthy synapses astrocytes oligodendrocytes, the blood-brain barrier and the vasculature by harnessing microglia are candidates aim to comprehensively address the complex pathology of neurodegenerative diseases, potentially providing long-lasting clinical benefit across multiple disease stages.

謝謝凱蒂，大家下午好，謝謝您加入 Alector 參加我們的 2023 年第四季和全年財務業績電話會議。首先，我將強調我們的免疫腫瘤學候選者或候選者招募小膠質細胞（大腦的主要免疫細胞）的廣泛機制潛力，透過含有多種錯誤折疊蛋白質來對抗神經退化，維持大腦健康和器官功能並支持健康突觸的維護星狀細胞、少突膠質細胞、血腦屏障和利用小膠質細胞的脈管系統都是候選者，旨在全面解決神經退化性疾病的複雜病理學，有可能在多個疾病階段提供長期的臨床益處。

Our investigational drug candidates have the potential to be effective as stand-alone therapies or in combination with other treatments, particularly those targeting misfolded proteins, the broad disease fighting mechanism that our drugs that activate as well as the potential synergy between our immuno-oncology candidates and therapies directed against misfolded proteins has the potential to elicit a more potent therapeutic benefit with longer durability and better efficacy at multiple disease stages compared to current therapies against misfolded proteins.

我們的研究候選藥物有可能作為獨立療法或與其他治療組合有效，特別是那些針對錯誤折疊蛋白的治療、我們的藥物激活的廣泛抗病機制以及我們的免疫腫瘤學候選藥物之間的潛在協同作用與目前針對錯誤折疊蛋白的療法相比，針對錯誤折疊蛋白的療法有可能帶來更有效的治療益處，在多個疾病階段具有更長的持久性和更好的療效。

As I reflect on the past year, I am pleased to highlight that 2023 was marked by successful clinical execution and clarity around time lines for our advanced clinical development programs. We achieved significant milestones in our late-stage program, reinforcing a lactose standing as a pioneer in immuno-oncology. Importantly, we completed trial enrollment for our two lead programs include the pivotal in front to a Phase three trial for of our progranulin elevating candidate at that cinema in frontotemporal dementia with progranulin gene mutation or STBGRAN. and invoke to Phase two trial of our term to candidate AL. zero zero two in early Alzheimer's disease in partnership with GSK.

當我回顧過去的一年時，我很高興地強調，2023 年是我們先進臨床開發計畫的成功臨床執行和明確的時間表的標誌。我們在後期專案中取得了重要的里程碑，鞏固了乳糖作為免疫腫瘤學先驅的地位。重要的是，我們完成了兩個主要項目的試驗註冊，包括在該電影院針對顆粒體蛋白前體基因突變或STBGRAN 的額顳葉癡呆患者進行顆粒體蛋白前體提升候選藥物的第三階段試驗的關鍵。並援引候選人 AL 的任期第二階段審判。與葛蘭素史克 (GSK) 合作治療早期阿茲海默症零零二。

We also risen recently dosed the first participant in progress, A. B, the Phase two clinical trial of AL. one one in early Alzheimer's disease. Furthermore, in February 2020 for the FDA granted breakthrough therapy designation to Ratos avelumab for FTVGRN., marking another significant achievement. It is worth noting that although to be the complex disease clinically, we have developed a straightforward approach to correcting progranulin deficiency, the underlying cause of the disease. Collectively, these advancements move us closer to potential meaningful data readout this year and next in January, we also further strengthened our balance sheet with the completion of $75 million of follow-on financing, which Mark will touch on further later in this call. Sarah will provide insight in our early research and development efforts, including a lack of brain carrier technology platform.

我們最近也對正在進行的第一個參與者進行了給藥，A.B，AL 的二期臨床試驗。早期阿茲海默症的一一。此外，2020 年 2 月，FDA 授予 Ratos avelumab 治療 FTVGRN 的突破性療法稱號，標誌著另一項重大成就。值得注意的是，儘管該疾病在臨床上是一種複雜的疾病，但我們開發了一種簡單的方法來糾正顆粒體蛋白前體缺乏（該疾病的根本原因）。總的來說，這些進步使我們更接近今年和明年1 月份潛在的有意義的數據讀數，我們還通過完成7500 萬美元的後續融資進一步加強了我們的資產負債表，馬克將在本次電話會議稍後進一步談到這一點。莎拉將提供有關我們早期研發工作的見解，包括缺乏腦載體技術平台。

Our commitment to addressing all the generation remains unwavering and with our advanced pipeline strong cash position, we are well-equipped for meaningful value creation in the next phase of our growth this year, we'll continue to focus on delivering and translation and translating our progress into meaningful impact. An important event will be the anticipated data readout from Embark to Phase two trial of L. zero zero during the fourth quarter. This will potentially be a major step forward in elucidating our immune-oncology hypothesis together with the support from our partners.

我們對滿足所有一代需求的承諾仍然堅定不移，憑藉我們先進的管道和強大的現金狀況，我們已做好充分準備，在今年下一階段的增長中創造有意義的價值，我們將繼續專注於交付和翻譯以及翻譯我們的產品取得有意義的影響。一個重要事件將是第四季度從 Embark 到 L.零零第二階段試驗的預期數據讀出。在我們合作夥伴的支持下，這可能會成為闡明我們的免疫腫瘤學假設的重要一步。

We are committed to advancing neurodegenerative disease research, reflecting our firm belief in immuno-oncology in the non-oncology potential. With that, I will turn it it over to Gary to talk about our goals and expectations for our clinical development program. Gary?

我們致力於推動神經退化性疾病研究，反映了我們對免疫腫瘤學在非腫瘤學潛力方面的堅定信念。接下來，我將把它交給加里，談談我們對臨床開發計劃的目標和期望。加里？

Thank you, Ana. And I'll begin with our LCS here to program the most advanced cancer program in clinical development for Alzheimer's disease. Algiers here too is a novel investigational humanized monoclonal antibody that binds to and activates trend to a key microglial receptor that senses pathological changes in the brain binding of LTROs here too, that the trend to receptor triggers microglial signaling pathways, which increased microglial proliferation, survival and function, enhancing the effectiveness of microglia for protect the brand against insults, including age related neuro degenerative disease.

謝謝你，安娜。我將從我們的 LCS 開始，為阿茲海默症的臨床開發制定最先進的癌症計劃。Algiers 也是一種新型研究中的人源化單株抗體，它能結合並激活關鍵小膠質細胞受體的趨勢，該受體能夠感知大腦中與LTRO 結合的病理變化，該受體的趨勢會觸發小膠質細胞訊號傳導途徑，從而增加小膠質細胞的增殖和存活和功能，增強小膠質細胞保護品牌免受侮辱的有效性，包括與年齡相關的神經退化性疾病。

We completed our Phase one trial of AL. two years or two in healthy volunteers, which demonstrated both dose-dependent target engagement and activation of microglia in the trial. ALCOCO. two was also shown to be well tolerated. Our ongoing invoke two Phase IIb study of AL. zero zero two is a randomized, double-blind, placebo-controlled common close designed study of up to 96 weeks of treatment with LCOs here too, in which 381 participants with early Alzheimer's disease were randomized.

我們完成了 AL 的第一階段試驗。在健康志願者中進行了兩年或兩年，這表明試驗中小膠質細胞的劑量依賴性標靶參與和活化。阿爾科科。這兩種也被證明具有良好的耐受性。我們正在進行兩項 AL IIb 期研究。零零二是一項隨機、雙盲、安慰劑對照的共同封閉設計研究，該研究也採用LCO 治療長達96 週，其中381 名患有早期阿茲海默症的參與者被隨機分組。

The study includes three doses of Algiers here too, that demonstrated robust target engagement and increased microglial signaling in phase one in both to completed enrollment ahead of schedule. In September of last year. The primary clinical outcome measure for the study is the CDR sum of boxes. We're also collecting secondary clinical and functional outcome assessments, including the ADAS-Cog 13 and ADCSADLMCI., from which we will derive treatment effects and the integrated Alzheimer's Rating Scale or high interest.

該研究還包括三劑阿爾及爾疫苗，在第一階段中表現出強大的目標參與和增加的小膠質細胞信號傳導，從而提前完成了入組。去年九月的時候。研究的主要臨床結果指標是 CDR 框架總和。我們還收集二次臨床和功能結果評估，包括 ADAS-Cog 13 和 ADCSADLMCI。，我們將從中得出治療效果和綜合阿茲海默症評估量表或高興趣。

The trial will also deliver a robust biomarker package, reflecting target engagement as well as treatment effects on microglial activity and Alzheimer's passive physiology treatment effects on Alzheimer's path physiology will be assessed with CSF and plasma biomarkers of A-beta and tau as well as both amyloid and tau PET and will also have biomarkers of Astra closest neuroinflammation. And that's the Chemicon neurodegeneration.

該試驗還將提供一個強大的生物標記包，反映目標參與以及對小膠質細胞活性和阿茲海默症被動生理學的治療效果。治療對阿茲海默症路徑生理學的影響將使用腦脊髓液和A-β 和tau 以及澱粉樣蛋白的血漿生物標記進行評估和 tau PET，還將具有與 Astra 最接近的神經發炎的生物標記。這就是 Chemicon 神經退化。

We intend to use a proportional analysis approach with this study, which will enable us to use all of the data collected in this common close design trial, meaning that it will include data from all participants out to 48 weeks and also include additional longer-term follow-up from those participants who were in the study for up to 96 weeks. We also have a long term extension will remain blinded to treatment assignment and thus can provide additional information on long-term safety and also on treatment effects on clinical outcome measures and biomarkers.

我們打算在這項研究中使用比例分析方法，這將使我們能夠使用在這項共同封閉設計試驗中收集的所有數據，這意味著它將包括所有參與者長達48 週的數據，還包括額外的長期數據對參與研究長達 96 週的參與者進行追蹤。我們還有一個長期延期，將對治療分配保持不知情，因此可以提供有關長期安全性以及對臨床結果指標和生物標誌物的治療效果的更多資訊。

As we reported last year at a I see a subset of participants in the ongoing Phase two trial have had treatment emergent MRI findings that resembles the analog aggregated imaging abnormalities or area that has been observed with anti amyloid therapies. These MRI findings are indistinguishable from area with regard to the MRI features, incidence, timing of onset and resolution relatedness to the number of APOE four wheels as well as to the frequency and spectrum of associated clinical manifestations in the current trial population that includes equally for heterozygous and APOE4 noncarriers analysis of the still blinded data shows an incidence of ARIA in our age of approximately 20% of those with RUE.

正如我們去年報導的那樣，我看到正在進行的第二階段試驗的一部分參與者的治療中出現的 MRI 結果類似於抗澱粉樣蛋白治療中觀察到的模擬聚合成像異常或區域。這些 MRI 發現與 MRI 特徵、發生率、發作時間和分辨率相關性與 APOE 四輪數量以及當前試驗人群中相關臨床表現的頻率和頻譜等方面無法區分。對仍然盲法數據的雜合子和APOE4 非帶因者分析顯示，我們這個年齡的ARIA 發生率約為RUE 患者的20%。

Approximately 90% have been asymptomatic and most symptomatic participants have had mild and self-limited presentations most relevant from a clinical perspective, the incidence of clinically serious area that is those with ARIA related SAE.s, it's just under 1% of all participants that have been dosed an independent data monitoring committee reviews data from this trial regularly and continues to recommend that the trial proceed our goals for invoke to trial and for the LTOs here too in the long term are to slow the progression of Alzheimer's disease by therapeutic restoration of microglial function. While one of the potential effects of trim to agonism may be to increase the clearance of misfolded proteins, including amyloid. We expect ALTRC. or to also amplify the broader beneficial effects of healthy microglia on the brain.

大約90% 的人沒有症狀，大多數有症狀的參與者有輕微和自限性的表現，從臨床角度來看，最相關的臨床嚴重區域的發生率是ARIA 相關的SAE，僅不到所有參與者的1%已接受劑量的獨立數據監測委員會定期審查該試驗的數據，並繼續建議該試驗繼續進行。我們的目標是調用試驗，並且長期目標是透過治療性恢復來減緩阿茲海默症的進展。小膠質細胞功能。而修剪對激動作用的潛在影響之一可能是增加錯誤折疊蛋白質（包括澱粉樣蛋白）的清除。我們預計 ALTRC。或者還可以放大健康小膠質細胞對大腦的更廣泛的有益影響。

This includes maintaining synaptic connections supporting astrocytes and oligodendrocytes function for serving the blood-brain barrier and vasculature and upholding immune tolerance. Thus, our expectation as the risk is that the restoration of microglial function by LCOs here to reduce the brain's vulnerability to neurodegenerative disease and that the ENVISION trial will demonstrate treatment related slowing of Alzheimer's disease progression as demonstrated by a combination of clinical functional and biomarker readout, given the multiple mechanisms by which healthy microbial protect the brain against neurodegenerative disease.

這包括維持支持星狀細胞和少突膠質細胞功能的突觸連接，以服務血腦屏障和脈管系統並維持免疫耐受性。因此，我們的風險預期是LCO 恢復小膠質細胞功能，以降低大腦對神經退化性疾病的脆弱性，並且ENVISION 試驗將證明治療相關的阿茲海默症進展減緩，如臨床功能和生物標記讀數相結合所證明的那樣考慮到健康微生物通過多種機制保護大腦免受神經退化性疾病的侵害。

We hypothesized that by the end of development, ALCRC. or two may ultimately displace stronger efficacy than current therapies to target individual misfolded proteins through its novel and complementary mechanism of action. We expect LTOs or two to be effective either as a stand-alone therapy or in combination with anti-amyloid therapies. Given that agonism of trend two has the potential to reduce the brain's vulnerability to neurodegenerative disease through these multiple downstream mechanisms, we believe that treatment of benefits of LTOs here to may manifest differently from what we have seen in the anti amyloid antibody trials.

我們假設到開發結束時，ALCRC。或兩種最終可能會透過其新穎且互補的作用機制取代比目前針對個體錯誤摺疊蛋白質的療法更強的功效。我們預期 LTO 或兩種 LTO 作為獨立療法或與抗澱粉樣蛋白療法聯合使用都會有效。鑑於趨勢二的激動作用有可能透過這些多種下游機制降低大腦對神經退化性疾病的脆弱性，我們認為 LTO 的治療效果可能與我們在抗澱粉樣蛋白抗體試驗中看到的不同。

For example, with regard to biomarker responses, lowering cerebral amyloid PET signal to the 20 to 30 Centroid threshold, which for anti-amyloid antibodies appears to be a necessary condition for clinical efficacy. It may not be relevant to this mechanism of action that goes beyond amyloid clearance. Additionally, optimal disease stages for intervention may be broader. Unlike therapeutics targeting amyloid or tau, we do not expect the beneficial effects of healthy microglia to be limited to specific parts of physiological stages of disease and thus, sales yields here too as potential to benefit patients from preclinical Alzheimer's disease through advanced dementia.

例如，就生物標記反應而言，將腦澱粉樣蛋白 PET 訊號降低至 20 至 30 個質心閾值，這對於抗澱粉樣蛋白抗體來說似乎是臨床療效的必要條件。它可能與這種超越澱粉樣蛋白清除的作用機轉無關。此外，介入的最佳疾病階段可能更廣泛。與針對澱粉樣蛋白或tau 蛋白的療法不同，我們預計健康小膠質細胞的有益作用不會僅限於疾病生理階段的特定部分，因此，這裡的銷售收益也有可能使臨床前阿茲海默症到晚期癡呆的患者受益。

I'll now turn to lead us into Matt for novel first-in-class progranulin, elevating candidate and the most advanced therapeutic and clinical development for the treatment of frontotemporal dementia. You may recall that legacy Nomad has previously received both orphan drug designations for FTD and Fast Track designation for FTD granulin from FDA. We are pleased to share that in February, FDA granted listen, I-Mab Breakthrough Therapy Designation for FTD granulin based on our INFRONT two Phase two clinical trial data, FDA's breakthrough therapy designation is granted to expedite the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on clinically significant endpoints.

現在我將帶領我們進入馬特（Matt）的新型首創顆粒蛋白前體，提升候選者以及治療額顳葉失智症的最先進的治療和臨床開發。您可能還記得，傳統 Nomad 先前已獲得 FDA 的 FTD 孤兒藥物指定和 FTD 顆粒蛋白快速通道指定。我們很高興與大家分享，根據我們的 INFRONT 二期臨床試驗數據，2 月份 FDA 授予 I-Mab 針對 FTD 顆粒蛋白的突破性療法指定，FDA 授予突破性療法指定是為了加快預期藥物的開發和審查當初步臨床證據顯示該藥物可能在臨床顯著終點上比現有療法有實質改善時，用於治療嚴重疾病。

With this designation, we look forward to continued productive conversations with the FDA recognizing the unmet need for people living with FTD granulin, a serious condition for which there are no FDA approved treatment options available in October 2023, we achieved target enrollment of the pivotal randomized, double-blind, placebo-controlled in front three Phase three clinical trial of Leidos Intermat randomizing 103 participants with symptomatic FTD granulin and 16 participants who are presymptomatic at risk for FTD granulin.

憑藉這一稱號，我們期待與FDA 繼續進行富有成效的對話，認識到FTD 顆粒蛋白患者未得到滿足的需求，這是一種嚴重疾病，目前尚無FDA 批准的治療方案可供選擇，到2023 年10 月，我們實現了關鍵隨機試驗的目標入組Leidos Intermat 的前三期雙盲、安慰劑對照三期臨床試驗隨機分組了103 名有症狀的FTD 顆粒蛋白參與者和16 名症狀前有FTD 顆粒蛋白風險的參與者。

Our goal is to enroll 90 to 100 symptomatic participants, supported by feedback from FDA and EMA. We are actively progressing the Infront three trial in partnership with GSK and look forward to the pivotal Phase three data readout following the 96 week treatment period. I'd like to now turn to a oh one oh one. Our second product candidate in our progranulin portfolio that we are developing in partnership with GSK.

我們的目標是在 FDA 和 EMA 的回饋支持下招募 90 至 100 名有症狀的參與者。我們正在與 GSK 合作積極推進 Infront 三期試驗，並期待 96 週治療期後關鍵的三期數據讀出。我現在想談談喔一哦一。我們正在與 GSK 合作開發顆粒蛋白前驅產品組合中的第二個候選產品。

Michael Harrison, I-Mab. A wonderful one is a monoclonal antibody that blocks sortilin to elevate progranulin levels. Its distinct pharmacokinetic and pharmacodynamic properties have potential to enable dosing regimens that may be more suitable for use in the treatment of larger indications such as Alzheimer's disease. Our Phase one study in healthy volunteers demonstrated that a oh one oh one was well tolerated and increased progranulin levels in plasma and CSF in a dose-dependent manner in August 2023, Alector and GSK received FDA clearance of its IND application for a oh one oh one in the treatment of early Alzheimer's disease.

邁克爾·哈里森，I-Mab。一種很棒的抗體是一種單株抗體，它可以阻斷分類蛋白以提高顆粒體蛋白前體的水平。其獨特的藥物動力學和藥效學特性有可能使給藥方案更適合用於治療阿茲海默症等更大的適應症。我們在健康志願者中進行的一期研究表明，oh one oh one 具有良好的耐受性，並以劑量依賴性方式增加血漿和腦脊髓液中的顆粒體蛋白前體水平，2023 年8 月， Alector 和葛蘭素史克(GSK) 獲得了FDA 批准其oh one oh 的IND 申請。一種治療早期阿茲海默症的藥物。

The rationale for treatment of Alzheimer's disease is that genetic variants that result in modest reductions of progranulin levels are associated with an increased risk of developing Alzheimer's disease. Conversely, in animal models of Alzheimer's disease, elevation of progranulin has been shown to be protective in February of this year. The first participant was dosed in the progress AD. study of AL001 oh one, which is being operationalized by our partner, GSK progress AD. is a randomized, double-blind, placebo-controlled Phase two clinical trial of A. oh one oh one, enrolling approximately 282 patients with early Alzheimer's disease at multiple sites globally.

治療阿茲海默症的基本原理是，導致顆粒體蛋白前體水平適度降低的遺傳變異與阿茲海默症的風險增加有關。相反，在阿茲海默症的動物模型中，顆粒體蛋白前體的升高在今年二月已被證明具有保護作用。第一個參與者在 AD 過程中接受給藥。對 AL001 的研究哦，我們的合作夥伴葛蘭素史克進展 AD 正在實施該研究。是 A. oh one oh one 的一項隨機、雙盲、安慰劑對照的二期臨床試驗，在全球多個地點招募了大約 282 名早期阿茲海默症患者。

The 36 week study is designed to assess the safety and efficacy of two dose levels available to one compared to placebo participants randomized to one of three dose groups receiving a oh one oh one or placebo intravenously. The primary endpoint of the study is disease progression as measured by the CDR sum of boxes. The trial also employs other clinical and functional outcome assessments and biomarkers. We look forward to sharing additional information on progress AT. as the trial advances. With that overview, I'll now turn the call over to Sarah to provide an update on our early research pipeline. Sarah?

這項為期36 週的研究旨在評估與安慰劑參與者相比，兩種劑量水平的安全性和有效性，參與者被隨機分配到三個劑量組之一，接受靜脈注射「哦一哦一”或安慰劑。研究的主要終點是透過 CDR 框架總和來衡量的疾病進展。該試驗還採用了其他臨床和功能結果評估和生物標記。我們期待分享更多有關 AT 進展的資訊。隨著審判的進展。有了這個概述，我現在將把電話轉給莎拉，以提供我們早期研究管道的最新資訊。莎拉？

Clearly, we are making meaningful strides in progressing our research portfolio to fuel our development pipeline and set the stage for our long-term growth. Our drug discovery engine is fine tune through a decade of deep biological exploration and experience and expertise in neuroscience as well as strong expertise and experience in antibody protein engineering and preclinical development. We have also developed a modular and scalable target discovery platform, which seamlessly integrates genetics, multi-omics and in-house generated VetLab data to uncover novel targets.

顯然，我們在推進我們的研究組合方面正在取得有意義的進展，以推動我們的開發管道並為我們的長期成長奠定基礎。我們的藥物發現引擎經過十年的深入生物探索、神經科學方面的經驗和專業知識以及抗體蛋白質工程和臨床前開發方面的強大專業知識和經驗進行了微調。我們還開發了一個模組化且可擴展的目標發現平台，該平台無縫整合遺傳學、多組學和內部生成的 VetLab 數據，以發現新的目標。

The system further improved predictions through machine learning based target identification, multidimensional functional validation and data integration with AI based analysis, our overall integrated approach allows us to move swiftly from target identification to the development of late-stage first-in-class immuno neurology drug candidates. In addition to our target and drug discovery engine, we have also made progress on our proprietary blood-brain barrier technology. While our late-stage clinical candidates show brain penetration and target engagement.

該系統透過基於機器學習的目標識別、多維功能驗證以及基於人工智慧分析的數據整合進一步改進了預測，我們的整體整合方法使我們能夠迅速從目標識別到後期一流免疫神經藥物的開發候選人。除了我們的標靶和藥物發現引擎外，我們在專有的血腦屏障技術上也取得了進展。而我們的後期臨床候選者則表現出腦部穿透力和目標參與度。

We are developing a proprietary versatile blood-brain barrier technology called electro brain carrier or ABC, to strive to lower efficacious doses with favorable safety and efficacy and enable delivery of additional novel drugs into the CNS. We intend to selectively deploy our technology in a fit-for-purpose manner on our next generation program that are currently in our early portfolio, ABC technologies that toolbox approach incorporating a suite of single-chain variable fragments, antigen binding fragments or variable heavy chain domains that bind to targets at the blood-brain barrier, such as transparent and CTE98 heavy chain with railing affinity.

我們正在開發一種專有的多功能血腦屏障技術，稱為電腦載體或ABC，以努力降低有效劑量，同時具有良好的安全性和有效性，並能夠將更多的新藥物輸送到中樞神經系統。我們打算以適合目的的方式選擇性地將我們的技術部署在我們的下一代項目上，該項目目前屬於我們的早期產品組合，ABC 技術是工具箱方法，包含一套單鏈可變片段、抗原結合片段或可變重鏈與血腦障壁標靶結合的結構域，例如具有欄桿親和力的透明重鏈和 CTE98 重鏈。

We have been able to achieve greater than tenfold increase in vein concentrations of multiple cargoes and demonstrated deep brain penetration to cell types of interest like neuron and microglia. The modular nature of this technology allows the affinity vibrancy and format of the final therapeutic to be harmonized with the mechanism of action and sell that specificity of the associated cargo. We are also leveraging our ABC technology to advance the development of protein replacement therapies for neurodegenerative diseases, which align with our focus on genetic risk factors our technology's adaptability is demonstrated through versatile bispecific formats, complemented by customizable Fc adaptations for optimized effector function half-life and single chain configuration.

我們已經能夠將多種貨物的靜脈濃度增加十倍以上，並證明了對神經元和小膠質細胞等感興趣的細胞類型的深層大腦滲透。該技術的模組化性質允許最終治療劑的親和力和形式與作用機制相協調，並銷售相關貨物的特異性。我們也利用我們的ABC 技術來推進神經退化性疾病蛋白質替代療法的開發，這與我們對遺傳風險因素的關注相一致，我們的技術的適應性透過多功能雙特異性格式得到證明，並輔以可自訂的Fc 適應，以優化效應器功能半衰期和單鏈配置。

Based on the translatability of preclinical safety and efficacy studies, our technology appears to exhibit a favorable safety profile even when actively engaging with EPSi. We look forward to sharing more details about our innovative research portfolio, including our electro brain carrier technology during a virtual event later this year. I'll now turn it over to Marc to provide an update on our financial results. Marc?

基於臨床前安全性和有效性研究的可轉化性，即使在積極參與 EPSi 時，我們的技術似乎也表現出良好的安全性。我們期待在今年稍後的虛擬活動中分享有關我們創新研究組合的更多細節，包括我們的電腦載體技術。現在我將把它交給馬克，以提供我們財務業績的最新資訊。馬克？

Try to summarize in our fourth quarter and full year 2023 financial results, which we made available after the market close today, we are in a strong cash position to deliver against our strategic objectives. We continue to focus on fiscal management and program prioritization. And as of December 31st, 2023, our cash, cash equivalents and short-term investments totaled $548.9 million, strengthening our financial position. We completed a follow-on financing in January of this year, raising $75 million in gross proceeds. Inclusive of this raise, our cash runway is now through 2026, approximately a full year beyond the expected FTVGR. and pivotal Phase three in front three data readout in approximately two years beyond our trend to Phase two in both to data readout further, we are now also in a position to selectively accelerate investment in our innovative proprietary portfolio, including programs enhanced by our proprietary electro brain carrier technology platform. We appreciate the support of significant new investors as well as participation from our existing shareholders.

今天收盤後我們發布了 2023 年第四季和全年財務業績，總結一下，我們擁有充足的現金狀況來實現我們的策略目標。我們繼續專注於財務管理和計劃優先順序。截至 2023 年 12 月 31 日，我們的現金、現金等價物和短期投資總計 5.489 億美元，增強了我們的財務狀況。我們於今年 1 月完成了後續融資，籌集了 7,500 萬美元的總收益。包括本次融資在內，我們的現金跑道現在一直持續到 2026 年，比預期的 FTVGR 大約整整一年。和關鍵的第三階段在大約兩年內完成前三數據讀出，超越我們在數據讀出方面進一步進入第二階段的趨勢，我們現在還能夠有選擇地加速對我們創新的專有投資組合的投資，包括由我們專有的電子增強的項目腦載體技術平台。我們感謝重要新投資者的支持以及現有股東的參與。

Now turning to our operating results. Collaboration revenue for the fourth quarter was $15.2 million compared to $14.4 million for the same period in 2022. Collaboration revenue for the year was $97.1 million compared to $133.6 million in 2022. Total research and development expenses for the fourth quarter were $47.7 million compared to $54.5 million for the same period in 2022. Total research and development expenses for the year were $192.1 million compared to $210.4 million in 2022.

現在轉向我們的經營業績。第四季的協作收入為 1,520 萬美元，而 2022 年同期為 1,440 萬美元。2022 年的協作收入為 9,710 萬美元，而 2022 年為 1.336 億美元。第四季的研發總費用為 4,770 萬美元，而 2022 年同期為 5,450 萬美元。全年研發費用總額為 1.921 億美元，而 2022 年為 2.104 億美元。

Total general and administrative expenses for the quarter were $14.9 million compared to $15.4 million for the same period in 2022. Total general and administrative expenses for the year were $56.7 million compared to $61 million in 2022 for 2024 we estimate our collaboration revenue to be between $60 million and $70 million are anticipated. Total research and development expenses are estimated to be between $210 million and $230 million and total anticipated general and administrative expenses are estimated to be between $60 million and $70 million in December. Electric Costa to virtual research and development events discussing our trim two and progranulin programs in detail.

本季的一般和管理費用總額為 1,490 萬美元，而 2022 年同期為 1,540 萬美元。今年的一般和管理費用總額為 5,670 萬美元，而 2022 年為 6,100 萬美元，我們預計 2024 年的合作收入將在 6,000 萬美元至 7,000 萬美元之間。12 月的研發費用總額預計在 2.1 億美元至 2.3 億美元之間，預計一般和管理費用總額預計在 6,000 萬美元至 7,000 萬美元之間。Electric Costa 參加虛擬研發活動，詳細討論我們的修剪二和顆粒蛋白前驅計畫。

The events included presentations from leading scientific and clinical experts who encourage those who didn't have an opportunity to participate in the live events to watch the replays located under the Investor Events and Presentations section of our website. We remain focused on advancing our novel portfolio and electro bringing care technology to treat neurodegenerative diseases. We look forward to providing additional updates as we advance our work. That concludes our prepared comments for today's call. Operator, you may now open the line for Chris.

這些活動包括領先的科學和臨床專家的演講，他們鼓勵那些沒有機會參加現場活動的人觀看我們網站投資者活動和演講部分下的重播。我們仍然專注於推進我們的新型產品組合和電子護理技術來治療神經退化性疾病。我們期待在推進工作時提供更多更新。我們為今天的電話會議所準備的評論到此結束。接線員，您現在可以為克里斯接通電話。

(Operator Instructions) Yaron Werber, TD Cowen.

（操作員說明）Yaron Werber，TD Cowen。

This is Brendan on for your own. Thanks very much for taking the question.

這是布倫丹為你自己做的。非常感謝您提出問題。

Just a couple of quick ones from us actually.

實際上只是我們的一些快速的。

First on the brain carrier program, just wondering if you might be able to give us a little bit more color on kind of just the broad approach to the platform.

首先是關於大腦載體計劃，只是想知道您是否能夠為我們提供更多有關該平台的廣泛方法的資訊。

I mean, you mentioned transparent and CTE 98. Are you kind of at this point planning to kind of choose one and use that across the board for all the VC programs, are you going to get to go indication by indication basis? And then I guess really on the ADP. zero to seven asset that you called out in the press release. And kind of just wondering what drove the decision to target gpNMB and maybe how applicable that target would be kind of to the broader Parkinson's population.

我的意思是，您提到了透明和 CTE 98。您現在是否打算選擇一個並將其全面用於所有風險投資項目，您是否打算逐一指示地進行？然後我想真的是在 ADP 上。您在新聞稿中提到的零到七個資產。只是想知道是什麼促使我們決定以 gpNMB 為目標，也許該目標對更廣泛的帕金森氏症族群有何適用性。

Thanks very much.

非常感謝。

And I'll just address the question about the blood-brain barrier technology, and then I'll pass it to Harlan to to answer your question on GPNMB briefly, you know our blood-brain barrier approach, as we said in place of a versatile, big main carrier technology, and we are targeting our blood-brain barrier proteins, both TFR. and CD. 90 heavy chain. But at this moment, we are going after both these targets and applying them across both our second generation second-generation efforts for our current on late-stage programs as well as our new novel sort of target molecules in research and certainly do not have any intent initially to choose one or the other we will, depending on on the best, the best approach for each target and each molecule. And again, we're using a very adaptable technology, which allows us to customize for therapeutic affinity Valence, et cetera. We've got our bispecific formats and customizable FC. adaptations that allow us to tweak effector function as well as optimize half-life of the molecule. So our approach currently is to drive both these both these approaches targeting approaches trafficking approaches both for our late-stage programs as well as for our novel targets. Maybe Arne can share his thoughts on our 80 people to seven program that you can?

我將只解決有關血腦屏障技術的問題，然後我會將其傳遞給 Harlan，以簡要回答您在 GPNMB 上的問題，您知道我們的血腦屏障方法，正如我們所說的那樣多功能、大型主要載體技術，我們的目標是血腦屏障蛋白，即TFR。和CD。 90重鏈。但目前，我們正在追求這兩個目標，並將它們應用於我們當前後期專案的第二代第二代努力以及我們正在研究的新型目標分子，當然沒有任何我們最初打算根據每個目標和每個分子的最佳方法來選擇其中一個。再說一次，我們使用的是一種適應性很強的技術，它使我們能夠客製化治療親和力效價等。我們擁有雙特異性格式和可自訂的 FC。適應性使我們能夠調整效應器功能並優化分子的半衰期。因此，我們目前的方法是為我們的後期專案以及我們的新目標推動這兩種目標方法和販運方法。也許阿恩可以分享他對我們的 80 人到 7 人計劃的想法，您可以嗎？

Yes. So yes, we do think that gpNMB targeting will be applicable for sporadic Parkinson's disease. Gpnmb is the lysosomal regulator or it's a risk gene for Parkinson's disease. There are both risk and protective barrier islands, and we developed a drug that may meet and exceed the protective variant. And we think that sort of fair lysosomal pathology is a general feature in Parkinson's disease and gpNMB is interacting with the lock to interacting with Jacada to other risk genes for Parkinson's disease. It's up-regulated in multiple types of sporadic PBC. So we do think that it will be applicable before for any type of Parkinson's disease.

是的。所以，是的，我們確實認為 gpNMB 標靶將適用於散發性帕金森氏症。Gpnmb 是一種溶小體調節因子，也是帕金森氏症的風險基因。屏障島既有風險，也有保護性，我們開發了一種藥物，可能達到並超越保護性變異。我們認為這種公平的溶酶體病理學是帕金森氏症的普遍特徵，並且 gpNMB 與 Jacada 與帕金森氏症其他風險基因的鎖相互作用。它在多種類型的散發性 PBC 中表達上調。所以我們確實認為它以前適用於任何類型的帕金森氏症。

All right.

好的。

Thanks very much.

非常感謝。

Paul Matteis, Stifel.

保羅馬蒂斯，斯蒂菲爾。

Hi, this is Julian on for Paul. Thanks so much for taking our question. I guess on L. zero zero to the trend to program some with the readout expected towards the end of the year, the trials and anticipated to run for about a year, at least for at least at a minimum. In terms of follow-up, I guess what gives you guys confidence that this will be long enough separate from placebo? And do you anticipate at all that there will be a significant group of patients out to two years.

大家好，我是保羅的朱利安。非常感謝您提出我們的問題。我猜L.零零的趨勢是對一些預計在今年年底的讀數進行編程，試驗並預計運行大約一年，至少至少持續一年。在後續行動方面，我想是什麼讓你們有信心相信這將與安慰劑分開足夠長的時間？您是否預計兩年內將會出現大量患者？

And any other color on how the overall data will be analyzed or shared and a top line would be super helpful.

關於如何分析或共享整體數據的任何其他顏色以及頂線都會非常有幫助。

Thank you.

謝謝。

Yes, hi. Thanks for the question. This is Gary. So the study, as you heard, was a common close sites in which all patients will stay in the trial. We're up to 96 weeks and then roll over into long-term extension. And that is until the last patient out reaches 48 weeks at which time all patients will roll over into the long-term extension. And so we will have data not only of what we have paid out the 48 weeks on everybody, but we'll also have data out to two will have, for example, clinical outcome assessments out to 96 weeks on a good subset of patients. We're planning to use in an analysis method called a proportional analysis method or proportional MMRM, for example, which uses all of the data. So it's not just the time to event at one time point, but it includes data at all from all time points as a way of getting the most out of your data by by using all of the data. And that's our plan for the analysis for the primary analysis we asked the question about do we think this is enough time to see treatment effect. We're looking at treatment effect in this study as happy and and ELEKTRA designed the study in order to be a biomarker study, and that will look at the totality of the data. So looking to see that we can slow Alzheimer's disease through a combination of clinical functional and biomarker readouts. And we're going to have a very robust biomarker package that includes not only what we originally intended, which would be amyloid and tau PET study sub-studies, but also now with the acceleration in validation of phospho-tau assays, we'll be looking at future on seven and tau aggregates in plasma on all patients. So we feel confident that we are going to through this totality of this data, the able to determine whether we're slowing the progression of Alzheimer's disease, which is what the original our design was intended to do.

是的，嗨。謝謝你的提問。這是加里。因此，正如您所聽到的，該研究是一個常見的封閉場所，所有患者都將留在其中進行試驗。我們的期限最長為 96 週，然後會轉為長期延期。直到最後一名患者出院的時間達到 48 週，屆時所有患者都將轉入長期延期。因此，我們不僅將獲得 48 週內為每個人支付的費用的數據，還將獲得兩個患者的數據，例如，對一部分患者進行 96 週的臨床結果評估。例如，我們計劃使用一種稱為比例分析方法或比例 MMRM 的分析方法，該方法使用所有資料。因此，它不僅僅是一個時間點的事件發生時間，還包括所有時間點的數據，作為使用所有數據充分利用數據的一種方式。這就是我們對主要分析的分析計劃，我們提出了這樣的問題：我們認為現在是否有足夠的時間來觀察治療效果。我們正在研究這項研究中的治療效果，而 ELEKTRA 設計研究是為了成為生物標記研究，這將著眼於數據的整體性。因此，我們希望透過臨床功能和生物標記讀數的結合來減緩阿茲海默症的發展。我們將擁有一個非常強大的生物標記包，其中不僅包括我們最初的預期，即澱粉樣蛋白和 tau PET 研究子研究，而且現在隨著磷酸 tau 測定驗證的加速，我們將未來著眼於所有患者血漿中的七聚體和tau 蛋白聚集體。因此，我們有信心透過這些全部數據，能夠確定我們是否正在減緩阿茲海默症的進展，這正是我們最初設計的目的。

Excellent.

出色的。

Thanks for the color.

謝謝你的顏色。

Jeffrey Hung, Morgan Stanley.

傑弗裡洪，摩根士丹利。

Hi, Steve.

嗨，史蒂夫。

Hi.

你好。

This is Michael Yang on for Geoff, and thank you for taking our question. Um, for Rinvoq, how do you expect levels a sizable chunk to account for patients at baseline was preclinical AD versus maybe a little bit more progress. Dementia like does a higher baseline valuable time to like imply higher chances for it's a pharmacodynamic effect.

我是邁克爾楊 (Michael Yang) 為傑夫 (Geoff) 發言，感謝您回答我們的問題。嗯，對於 Rinvoq 來說，您如何期望水平相當大的部分能夠解釋基線時處於臨床前 AD 的患者與可能有更多進展的患者。癡呆症的基線值越高，代表其產生藥效作用的可能性就越大。

So first, let me just add this is Gary again, just to clarify, we are enrolling patients, as you said, with early Alzheimer's disease. We are not enrolling enrolling, for example, just those with genetic variants like the R4 37 H. variant. You know, we don't believe that the baseline levels of sizable chunk to necessarily we don't really know whether that's going to predict a pharmacological effect, but we what we would expect in our study is that and the binding of the of sales here as we are to trend to causes internalization of the receptor and this actually causes a reduction in soluble trend, too, because what we're basically doing is is reducing by binding and internalizing receptor. We're lowering the levels of and microglial membrane trend to which are and that reduces the amount of the cleavage product, sizable chunk to which is consistently cleaved in from time to right. So we plant we will see as we saw, we intend to see as we did in Phase one, a reduction in cycle time, too. And we again, there's different ideas about cycle time to what its role is. We believe that primarily it's just it's a really a marker of membrane trim two and three, there have been and there's a fair amount of data out there that suggests that cyclical trend to levels, which are again, are reflecting the amounts of trend to in the membrane correlate as they are higher. They correlate with with better outcomes or progression of disease of Alzheimer's disease or slower conversion from MCI to Alzheimer's disease, slower progression of brain volume loss. So again, but that is a function basically of having greater trend to activity. And our antibody A. increases jumped to signaling.

首先，讓我再次補充一下，我是加里，只是為了澄清一下，正如您所說，我們正在招募患有早期阿茲海默症的患者。例如，我們不招收那些具有 R4 37 H. 變異體等遺傳變異的人。你知道，我們不相信相當大的區塊的基線水平一定是我們真的不知道這是否會預測藥理作用，但我們在我們的研究中期望的是這一點以及銷售的約束力在這裡，我們要趨向於導致受體的內化，這實際上也會導致可溶性趨勢的減少，因為我們基本上所做的是透過結合和內化受體來減少。我們正在降低小膠質細胞膜的水平，從而減少裂解產物的量，相當大的塊會不斷地裂解。因此，我們工廠將看到我們所看到的，我們打算看到我們在第一階段所做的那樣，週期時間也縮短了。我們再說一遍，關於週期時間及其作用有不同的想法。我們認為，這主要是膜修剪二號和三號的一個真正標誌，已經有相當多的數據表明，水平的周期性趨勢，這再次反映了趨勢的數量。膜相關性越高。它們與阿茲海默症的更好結果或疾病進展或從 MCI 到阿茲海默症的較慢轉化、腦容量損失的較慢進展有關。再說一遍，但這基本上是具有更大活動趨勢的函數。我們的抗體 A. 增加跳躍到訊號傳導。

Thank you so much, really helpful.

非常感謝，真的很有幫助。

Yes.

是的。

Pete Stavropoulos, Cantor Fitzgerald.

皮特·斯塔夫羅普洛斯，康托·菲茨傑拉德。

I are on the team.

我在團隊中。

Thank you for taking my questions on. So first, wondering, I believe that for the invoke two study of the placebo rolls over, you will start, you will be starting them at a lower dose than those in the original randomized to active arm and then titrating them upwards.

感謝您回答我的問題。因此，首先，我想知道，對於安慰劑滾動的調用兩項研究，您將開始，您將以比最初隨機分配到活性組中的劑量更低的劑量開始，然後向上滴定它們。

Can you just discuss the timeline for the titration and though will you be able to capture any data points, you know, especially biomarker wise, that could suggest that the starting dose is therapeutically active?

您能否討論一下滴定的時間表，儘管您是否能夠捕獲任何數據點，您知道，尤其是生物標記方面，這可能表明起始劑量具有治療活性？

And if so, what would be the key biomarker or biomarkers you believe may be informative at that time point?

如果是這樣，您認為在那個時間點可能提供資訊的關鍵生物標記是什麼？

Yes.

是的。

Thanks, Pete.

謝謝，皮特。

Good question. So that you're right where we are. So just to clarify in the long-term extension, all patients that were on active doses in the double-blind will roll over to the same dose and continue in the long-term extension. Those that were originally randomized to placebo will be rolled out and the titrated up started on active beginning with a tight with a at a lower dose. That's right, six milligrams per kilogram and increase, and they will they will be dose escalated every two months. And the reason and one reason for doing this is to learn more about the potential mitigations for the Ariol like signal that we're seeing, as you know, and but some of the anti amyloid therapeutics, there's been some data that suggests that starting at a lower dose and or titrating more slowly than we did in this double-blind study could be mitigate. So that's one advantage. We do believe that this slow titration that was actually going to help us in another way and not only to learn about mitigation for area, but also help us to in a sense it will this is a long-term extension, which by the way, we invested with AbbVie to keep this blinded to the original treatment assignment. This will give us an opportunity to continue to follow patients beyond the double blind into the long-term extension to us to look for not only for safety, but also to look for treatment effects on biomarkers and most importantly, on clinical outcome measures. So fortunately, for example, with the common close design, some of the patients will have nearly a year of data follow-up data on clinical outcomes. But in the long-term extension, which really essentially be a randomized start design, we'll be able to look for support for differences between the original placebo group and the and the of the active dose groups in the long-term extension, we'll be able to look at those clinical outcome assessments and differences from the between the placebo and active in that long-term extension.

好問題。這樣您就在我們身邊。因此，為了澄清長期延期，所有在雙盲中服用活性劑量的患者將轉至相同劑量並繼續長期延期。那些最初隨機接受安慰劑的患者將被推出，並從活性藥物開始滴定，並以較低劑量開始。沒錯，每公斤六毫克並增加，他們將每兩個月增加一次劑量。這樣做的原因之一是為了更多地了解我們所看到的 Ariol 樣信號的潛在緩解作用，如您所知，但在一些抗澱粉樣蛋白治療藥物中，有一些數據表明從比我們在這在雙盲研究中所做的較低的劑量和/或更慢的滴定速度可以緩解這種情況。這是一個優勢。我們確實相信，這種緩慢的滴定實際上會以另一種方式幫助我們，不僅可以了解區域的緩解措施，而且在某種意義上也可以幫助我們，這是一個長期的延伸，順便說一句，我們與艾伯維（AbbVie）進行了投資，以使其對最初的治療分配不知情。這將使我們有機會繼續追蹤雙盲之後的患者，進入長期延伸，我們不僅要尋找安全性，還要尋找對生物標記的治療效果，最重要的是，對臨床結果指標的治療效果。所以幸運的是，例如透過共同封閉設計，一些患者將擁有近一年的臨床結果的數據追蹤數據。但在長期擴展中，這實際上本質上是一個隨機開始設計，我們將能夠在長期擴展中尋找原始安慰劑組與活性劑量組之間差異的支持，我們將能夠在長期擴展中查看這些臨床結果評估以及安慰劑和活性藥物之間的差異。

Right.

正確的。

Thank you for that. One question on the on the Phase two for AL. one zero one was originally initiated with GSK.

謝謝你。關於 AL 第二階段的一個問題。 「一零一」最初是由葛蘭素史克發起的。

Just on looking at the study design, I see that there are two undisclosed doses are being evaluated. How did you select those doses, as you know, if you can tell us, I know was it based on a certain level of PRGPGPRGNI. increase in the Phase one? Are you trying to keep it above a certain threshold or below a certain level?

只要看看研究設計，我就發現有兩種未公開的劑量正在接受評估。如您所知，您是如何選擇這些劑量的，如果您能告訴我們，我知道它是基於一定程度的 PRGPGPRGNI。第一階段增加？您是否試圖將其保持在某個閾值以上或低於某個水平？

Yes, Sarah, I'll start. Maybe, Sarah, do you want to chime in on the on the PK here that the behavior?

是的，莎拉，我要開始了。也許，莎拉，你想插話這裡的 PK 行為嗎？

Yes, these. So we have two doses. We have a maximal dose that gives us maximal elevations of progranulin, and we also chose a somewhat lower dose. And those the I'm not sure how much of this we've disclosed in terms of the actual doses and the and the randomization ratio. So I mean, I have to defer to Mark or Sarah as to whether we were a special event in Spain.

是的，這些。所以我們有兩劑。我們有一個最大劑量，可以最大程度地提高顆粒體蛋白前體，我們也選擇了稍低的劑量。我不確定我們在實際劑量和隨機比率方面披露了多少。所以我的意思是，關於我們在西班牙是否是一個特殊的活動，我必須聽從馬克或莎拉的意見。

Thanks, Gary. I agreed, Pete. We haven't disclosed the actual doses or the selection, but mostly that the doses were selected based on the PK and PD data that was generated in our Phase one single and multiple ascending dose study and based on progranulin levels, of course, on. So it was the elevation of progranulin in plasma and CSF that was modeled. And based on this, the two doses were selected, we haven't really shared the exact doses or the exact criteria for the selection of the dose Okay.

謝謝，加里。我同意了，皮特。我們還沒有透露實際劑量或選擇，但主要是根據我們的第一階段單次和多次遞增劑量研究中生成的 PK 和 PD 數據以及當然基於顆粒體蛋白前體水平來選擇劑量。因此，我們模擬的是血漿和腦脊髓液中顆粒體蛋白前驅物的升高。基於此，選擇了兩個劑量，我們還沒有真正分享確切的劑量或選擇劑量的確切標準。

Thank you for taking my questions.

感謝您回答我的問題。

Greg Harrison, Bank of America.

格雷格·哈里森，美國銀行。

Your line is open and good afternoon and thanks for taking the question of what endpoints that you'll report from the book to trial, do you think will be key to understanding the benefit of LO. twos various mechanisms beyond annualized reduction and potentially showing differentiation versus anti-amyloid antibodies?

您的熱線已開通，下午好，感謝您提出問題，即您將從書中報告的試驗終點是什麼，您認為這將是理解 LO 益處的關鍵。除了年化減少之外，還有其他多種機制可能與抗澱粉樣蛋白抗體相比表現出差異化嗎？

Yes.

是的。

Thank you for that question, Greg, on. So just to remind everyone, the mechanism here is that we believe the steric therapeutic restoration of microglial function that will slow disease progression. And as you mentioned, that includes may include enhanced clearance of misfolded proteins like amyloid, which we know is one of the important functions of microglia. But there are also a number of other beneficial effects of microglia that they do in normal maintenance to preserve brain health, reduce vulnerability of the brain to two insults, including age-related neurodegenerative diseases. And I think we mentioned this a couple of times in the presentation. So the euro and in this study, therefore, we are and again, this is a novel mechanism, and we think that it's important to to realize that the and that through these various downstream mechanisms that help of healthy that are in play because of healthy microglia that there are there are a number of things we can measure and we're going to be measuring in the study, including outside the typical Alzheimer's biomarkers and we mentioned A-beta and tau, both in plasma and on PET scans will also be measuring astrocytes effects on astrocytes and synapses and and then just a function, et cetera. I think the totality, really what the decision is going to be based on the whether or not we're slowing the progression of Alzheimer's disease. And so all of those mechanisms to be meaningful have to add up to a slowing in the progression of disease. And that will probably be best measured by a clinical outcome measures and also by biomarkers and of those biomarkers not only a beta, but very importantly, the tau biomarkers because we know that tau changes and talent, how aggregates travel or correlate most closely and with disease progression in a day and so we'll be looking at the clinical outcome measures of the looking at the Alzheimer's biomarkers, particularly, for example, a plasma P. two and seven and also looking at how aggregates with other other tau possible assays like the microtubule binding region assay, I want to emphasize, you know, the study is powered for and for clinical effect of about 40%. That's a big effect. So we we may or we may not see a clinically significant effect that that size in this relatively small Phase two study. But again, the original design was intended, not not to not to be a decision made on the primary clinical endpoint, but on the totality of the data, particularly the biomarker data that I mentioned.

謝謝你提出這個問題，格雷格。所以提醒大家，這裡的機制是我們相信小膠質細胞功能的立體治療恢復將減緩疾病進展。正如您所提到的，這可能包括增強對澱粉樣蛋白等錯誤折疊蛋白質的清除，我們知道這是小膠質細胞的重要功能之一。但小膠質細胞還有許多其他有益作用，它們在正常維護中可以起到保護大腦健康的作用，減少大腦對兩種損傷的脆弱性，包括與年齡相關的神經退化性疾病。我想我們在演示中多次提到這一點。因此，在這項研究中，我們再次強調，這是一種新穎的機制，我們認為重要的是要認識到，透過這些有助於健康的各種下游機制，這些機制正在發揮作用，因為健康小膠質細胞，我們可以測量很多東西，我們將在研究中測量，包括典型的阿茲海默症生物標記之外，我們提到的A-β 和tau 蛋白，在血漿和PET 掃描中也將被測量測量星狀細胞對星狀細胞和突觸的影響，然後只是測量功能，等等。我認為總體而言，真正的決定將取決於我們是否正在減緩阿茲海默症的進展。因此，所有這些機制要有意義，就必須加起來減緩疾病的進展。這可能最好透過臨床結果測量和生物標記來衡量，這些生物標記不僅是beta，而且非常重要的是tau 生物標記物，因為我們知道tau 蛋白的變化和能力，聚合體如何移動或與最密切相關。一天內疾病進展，因此我們將研究阿茲海默症生物標記的臨床結果測量，特別是血漿 P.2 和 7，並研究如何與其他 tau 可能的檢測方法聚合，例如微管結合區測定，我想強調一下，你知道，這項研究的動力是針對40%左右的臨床效果。這是一個很大的影響。因此，在這項相對較小的二期研究中，我們可能會也可能看不到如此規模的臨床顯著效果。但同樣，最初的設計並不是不根據主要臨床終點做出決定，而是根據數據的整體，特別是我提到的生物標記數據做出決定。

Got it.

知道了。

That's that's really helpful.

這真的很有幫助。

Thanks.

謝謝。

Thank you, Greg. One moment.

謝謝你，格雷格。一會兒。

Corinne Johnson, Goldman Sachs.

科琳·約翰遜，高盛。

And just one follow-up. Could you please share what's embedded in the cash runway guidance with respect to clinical activities more so beyond the near term to make commitments?

只有一個後續行動。您能否分享一下現金跑道指引中有關臨床活動的內容，以便在短期內做出承諾？

Yes, thanks. For the questions.

對了謝謝。對於問題。

I think the question was around what's included in the cash runway guidance. So the cash runway guidance, as noted is now through 2026 months, about two years post the expanded trend to data and also of approximately full year beyond the anticipated FTDGR. and Phase three data and also allows us to accelerate our investment in our blood-brain barrier technology platform and also our proprietary early-stage pipeline. Importantly, it's conservative in the sense that we're not including any milestones from partners, including the potential significant opt-in from AbbVie at the end of the completion of the Phase two. And it doesn't include a full spend on oh two through the Phase two completion. Also continued spend on that program for the extension study and spend on the FTDGR. and Phase three and also spend on the recently commenced on a scale of one Tier one Phase two for Alzheimer's disease. Those are those are the major components in addition to continuing to progress our blood-brain barrier platform and early pipeline.

我認為問題在於現金跑道指南中包含哪些內容。因此，正如所指出的，現金跑道指導現在到 2026 個月，即數據擴大趨勢後大約兩年，也是超出預期 FTDGR 的大約全年。和第三階段數據，也使我們能夠加快對血腦屏障技術平台以及我們專有的早期管道的投資。重要的是，它是保守的，因為我們沒有包括合作夥伴的任何里程碑，包括艾伯維在第二階段完成結束時潛在的重大選擇。而且它不包括第二階段完成期間的全部支出。也繼續在該計劃上進行擴展研究並在 FTDGR 上進行支出。第三階段，也花費在最近開始的針對阿茲海默症的第一階段第二階段的規模。這些是除了繼續發展我們的血腦屏障平台和早期管道之外的主要組成部分。

I'm just thinking through thanks for the questions.

我只是在考慮謝謝你的問題。

Carter Gould, Barclays.

卡特·古爾德，巴克萊銀行。

This is Leon on for Carter. Thanks for taking my question.

這是卡特的萊昂。感謝您提出我的問題。

So we have two on invoke oh two.

所以我們有兩個調用哦兩個。

So at this point, do you have alignment or understanding with AbbVie on what a potentially good proof profile can look like on the readout and in terms of your update on achieving 90% enrollment in the OE. from Invokana to now, that's against the backdrop of having the REO like effects you've seen. So we want to get your thoughts here on the implication of getting and with 90% enrollment into OLE., is there some nuance that we're missing or anything that you'd like to highlight in terms of what this could tell you about the safety and tolerability profile?

因此，在這一點上，您是否與艾伯維（AbbVie）一致或理解，在讀數上以及在 OE 中實現 90% 註冊率的更新方面，潛在的良好校樣配置文件會是什麼樣子？從 Invokana 到現在，這是在您所見過的類似 REO 效果的背景下實現的。因此，我們希望了解您對獲得 OLE 的影響有何想法，並且 90% 的學生入學 OLE。我們是否遺漏了一些細微差別，或者您想強調什麼，這可以告訴您有關 OLE 的信息。安全性和耐受性概況？

Thank you.

謝謝。

Yes.

是的。

Well, to the latter question, it's just that that's 90% of those those that were eligible to roll over out of the kind of the 90 60 common close designed study. And um, and I mean, I think that we believe that reflects an interest in patients to continue. There are increasingly other other options like they can start taking account of that, but most like to see it here or 90% or so or a rolling over and staying in touch in the long-term extension, which we interpret positively in terms of tolerability and potentially other effects of the drug. But we can't specify we really can't no speculate on this point.

嗯，對於後一個問題，這只是那些有資格從 90 60 共同封閉設計研究中轉出的人中的 90%。嗯，我的意思是，我認為我們相信這反映了患者對繼續治療的興趣。越來越多的其他選擇，例如他們可以開始考慮這一點，但大多數人喜歡在這裡看到它或 90% 左右，或者在長期擴展中滾動並保持聯繫，我們從容忍度方面積極解釋這一點以及藥物的潛在其他影響。但我們不能具體說明，我們真的不能對此進行推測。

I'm blanking on your first question, our tests, can you just remind me at the beginning, I'm sure of the number you're asking you're asking about why November now about the readout, right. So yes. So I'm sorry, I'm sorry, I blanked out there. So.

我對你的第一個問題空白，我們的測試，你能在一開始就提醒我嗎，我確定你問的數字你問的是為什麼十一月現在關於讀數，對吧。所以是的。所以，對不起，對不起，我當時腦子一片空白。所以。

Yes. So as I mentioned, we've been aligned with AbbVie, really from the start on on how we designed this study that we're really looking at the totality of the data to tell us whether we're slowing the progression of Alzheimer's disease, which would switch to make a decision on what happens next with this compound, whether it progresses. So that includes that includes, as I said, no clinical out clinical outcome measures, and it includes some functional measures, and it includes a lot of biomarkers. So and particularly, we're thinking that we'll be really focusing on those Alzheimer's biomarkers of Alzheimer's type physiology to tell us that we are seeing some slowing of the disease.

是的。正如我所提到的，我們一直與艾伯維保持一致，從一開始我們就如何設計這項研究，我們確實在研究全部數據，以告訴我們是否正在減緩阿茲海默症的進展，這將轉而決定化合物接下來會發生什麼，是否有進展。正如我所說，這包括沒有臨床結果測量，它包括一些功能測量，它包括許多生物標記。因此，特別是，我們認為我們將真正關注阿茲海默症類型生理學的阿茲海默症生物標誌物，以告訴我們，我們正在看到這種疾病的某些減緩。

Yes.

是的。

No, I think you answered your question.

不，我想你已經回答你的問題了。

Myles Minter, William Blair.

邁爾斯·明特，威廉·布萊爾。

I just a couple on impact to any sort of material differences that you're seeing in the ARIA incidence rates between the double-blind portion of inferred to the long-term open-label extension.

我只是想談談對雙盲部分與長期開放標籤延伸之間的 ARIA 發生率所看到的任何實質差異的影響。

I would assume that REO goes up if you're having placebo switched to active drug in that arm. That's the first question. The second one is you're measuring tallying all of those patients as you got to do a primary analysis by which you stratify by Talbot and similar to what Eli Lilly did and others have done in a post hoc setting.

我認為如果您將該手臂中的安慰劑改為活性藥物，REO 就會上升。這是第一個問題。第二個是你要測量統計所有這些患者，因為你必須進行初步分析，透過塔爾博特進行分層，類似於禮來公司和其他人在事後環境中所做的事情。

Thanks.

謝謝。

Yes, thank you.

是的，謝謝。

On to the second question, we will we will have the capability of doing that post we didn't we didn't we have stratify the part that the patient, the study based on tau, but we will be able to look with possibly the plasma Pito on measures in order to in order to see whether there are differential effects based on baseline tau tau are not the baseline tau apathy now. And then I guess you do see other there are other good actually. And your first the first question was around the area cycle.

關於第二個問題，我們將有能力做那篇文章，我們沒有，我們沒有對患者的部分進行分層，基於 tau 的研究，但我們將能夠用可能的方式來看待對血漿Pito 進行測量，以了解是否存在基於基線tau 的差異效應，而不是現在的基線tau 冷漠。然後我猜你確實看到了其他實際上還有其他好的東西。你的第一個問題是圍繞著地區週期的。

Yes.

是的。

So on we've shown we've shared this data, the MIT imaging MRIs and the MRIs themselves the clinical vignettes these patients and truly this looks indistinguishable from the area that is described with anti-amyloid antibodies. And with every regard with regard to timing of onset, for example, we see this early in treatment and then it really tapers off and the the time to onset and resolution of the related as equal to number of HB4 wheels, the MRI features themselves and the clinical manifestation. So it really we really we don't we don't see any differences and we've shown it to a number of the area experts who have also said that this is really indistinguishable.

因此，我們已經證明我們已經共享了這些數據，麻省理工學院的成像 MRI 和 MRI 本身就是這些患者的臨床片段，實際上，這看起來與抗澱粉樣蛋白抗體所描述的區域沒有區別。例如，就發病時間而言，我們在治療早期就看到了這一點，然後它確實逐漸減少，相關的發病時間和分辨率等於 HB4 輪的數量、MRI 特徵本身和臨床表現。所以我們真的沒有看到任何差異，我們已經向一些領域專家展示了它，他們也說這確實無法區分。

And I think we see any differences between the main study and the extension study there.

我認為我們看到了主要研究和擴展研究之間的任何差異。

Myles, to your Sure question, I see the RDR difference from the 19% to 23% that you reported yesterday after you're much?

邁爾斯，對於你的問題，我看到 RDR 與你昨天報告的 19% 到 23% 之間存在差異，之後你的情況是多少？

Yes, no, sorry. Sorry, we were blinded to the Who's Who in the study, but no thought so far we have seen very little area in the in the long-term extension study.

是的，不，抱歉。抱歉，我們對研究中的名人錄一無所知，但沒想到到目前為止我們在長期擴展研究中看到的領域很少。

Would that be an accountant earlier days with the extension of 30 miles?

這會是早些時候的會計師延長 30 英里的里程嗎？

So to Trident interop inferences from those percentages would be, you know, difficult.

因此，對於 Trident 互通來說，從這些百分比推斷會很困難。

Colby. Thanks for the questions yet.

科爾比。感謝您的提問。

Neena Bitritto-Garg, Deutsche Bank.

Neena Bitritto-Garg，德意志銀行。

It's David Novak on the line for any and I thank you for taking our questions. So on the ABCI. technology, can you discuss how your transferrin approach differs from other transferrin base delivery platforms? And then also on invoke to on given what you know about the ALO. two mechanism, which biomarkers do you see as being most likely be correlated with improvement on CDR sum of boxes or any other clinical end points?

我是大衛諾瓦克（David Novak），感謝您回答我們的問題。ABCI 也是如此。技術，您能否討論一下您的轉鐵蛋白方法與其他轉鐵蛋白基礎遞送平台有何不同？然後根據您對 ALO 的了解，請呼叫 on 。兩種機制，您認為哪些生物標記最有可能與 CDR 框架總和或任何其他臨床終點的改善有關？

Maybe I can start with the ADC technology and then Gary can address your second question.

也許我可以從 ADC 技術開始，然後 Gary 可以回答你的第二個問題。

So on in terms of our BBB. approach, it employs a versatile blood brain barrier carrier technology, which uses a suite of fragments that target, both TFR. and CD. 98 heavy chain. What we found is that thus far we're getting about tenfold increases in brain concentrations utilizing these of these multiple cargoes. I think what's unique about our technology is that it is an adaptable technology and it's sort of modular and is customizable based on the sort of the requirements of therapeutic affinity, bale and C and format, and we can match that to a variety of cargoes. We use bispecific formats and we are also able to customize and make adaptations to the Fc portion and have been able to sort of tweak a variety of ranges of effector function as well as our half-life. As we said in the call, in our safety and efficacy studies in nonhuman primates thus far suggest a favorable safety and efficacy profile even when we have FC engagement.

就我們的 BBB 而言，如此。該方法採用了多功能血腦屏障載體技術，該技術使用一套針對 TFR 的片段。和CD。 98重鏈。我們發現，到目前為止，利用這些多種貨物，我們的大腦濃度增加了約十倍。我認為我們技術的獨特之處在於它是一種適應性強的技術，它是一種模組化的，可以根據治療親和力、捆包和C 以及格式的要求進行定制，我們可以將其與各種貨物相符。我們使用雙特異性格式，我們還能夠自訂和適應 Fc 部分，並且能夠調整各種範圍的效應器功能以及我們的半衰期。正如我們在電話會議中所說，迄今為止，我們對非人類靈長類動物的安全性和有效性研究表明，即使我們參與 FC，也具有良好的安全性和有效性。

Yes.

是的。

And we will be, by the way, we will have a webinar on. So I don't the dates are set, but sometime this summer, of which we will go into a lot more detail on our technology. So please to join at that time, and I'll pass it to Gary, what was the lowest that question?

順便說一句，我們將舉辦一個網路研討會。所以我還沒有確定日期，但在今年夏天的某個時候，我們將更詳細地介紹我們的技術。那麼請當時加入，我會將其傳遞給Gary，這個問題的最低限度是多少？

I'm sorry, I didn't hear.

抱歉，我沒聽到。

Yes.

是的。

So sense for invoke to know, given what we know about the ALO. two mechanism, which biomarkers do you see as being most likely to be correlated with improvement in CDR sum of boxes or more generally our outlook?

鑑於我們對 ALO 的了解，調用知道是有意義的。兩種機制，您認為哪些生物標記最有可能與 CDR 框架總和或更普遍的我們的前景的改善相關？

Yes, sure.

是的，當然。

Well, again, that would be the out biomarkers of Alzheimer's type physiology. Most most importantly, I think the on the tau biomarkers, both we'll we will we will have tau PET, which would be a tau PET sub-study out, but we will also have plasma biomarkers on every on every body in the study, but the two, one seven and hopefully an microtubule binding region assay as well. So this will this will give us a that's the really the tau biomarkers are the ones that correlate most closely with clinical outcomes and really can be seen. I think is sort of a summing up the effect of the effects of these type of hypothetical effects of healthy benefits of healthy microglia on slowing the disease progression.

好吧，這又是阿茲海默症類型生理學的生物標記。最重要的是，我認為關於 tau 生物標記物，我們將進行 tau PET，這將是 tau PET 子研究，但我們還將在研究中的每個身體上進行血漿生物標記物，但是兩個，一個七，希望還有微管結合區域測定。因此，這將為我們提供一個事實：tau 生物標記是與臨床結果最密切相關且真正可見的生物標記。我認為這是對健康小膠質細胞的健康益處的這些假設效應對減緩疾病進展的影響的總結。

Great.

偉大的。

Thank you.

謝謝。

And congrats on the quarter for you.

恭喜您本季取得成功。

Thomas Shrader, BTIG.

托馬斯·施拉德 (Thomas Shrader)，BTIG。

Good afternoon.

午安.

This is Tom on for Tom or for the ongoing Phase two progress AD study, is there reason to perhaps stratify these patients based on a baseline program level for a possible topline out in the future? Thank you.

這是湯姆為湯姆或正在進行的第二階段進展 AD 研究，是否有理由根據基線計劃水平對這些患者進行分層，以獲得未來可能的頂線？謝謝。

Yes. Thanks for the question, Tom.

是的。謝謝你的提問，湯姆。

We did not do we're not doing that and that's because it's in part of the evidence in favor or in support of this mechanism is that even even modest that mutations that cause even very modest effects and progranulin levels increased the risk of Alzheimer's disease. And and so we didn't believe it was it would be necessary and our processes is that this would be effective in slowing disease progression regardless of your baseline progranulin levels. There's also animal data, whichever you want to may want to speak more to that shows that in various animal models of Alzheimer's disease that just elevating progranulin itself is protective against disease. It's disease progression.

我們沒有這樣做，我們沒有這樣做，那是因為支持或支持這種機制的部分證據是，即使是輕微的突變，即使引起非常輕微的影響和顆粒體蛋白前體水平，也會增加阿爾茨海默病的風險。因此，我們不認為這是必要的，我們的流程是，無論您的基線顆粒蛋白前體水平如何，這都將有效減緩疾病進展。還有動物數據，無論您想了解哪一個，都可以更多地了解這些數據，這些數據表明，在各種阿茲海默症動物模型中，僅提高顆粒體蛋白前體本身就可以預防疾病。這是疾病的進展。

Great thank you.

太好了謝謝。

Amanda Bush, HC. Wainwright.

阿曼達布什，HC。溫賴特。

Your line is open and say, Hey, congrats on the quarter given the biology of trend to and from your own or your data?

你的線路是開放的，然後說，嘿，考慮到你自己或你的數據的趨勢生物學，恭喜這個季度？

I think you know, there's little doubt that experts believe there is little doubt on the fact that the trend to might be involved in plaque removal.

我想你知道，毫無疑問，專家們相信這一趨勢可能與牙菌斑清除有關。

Have a one question which I have. And you know, that's based on the kind of go into an animal and also a lot of questions on tau tau biomarkers today here. Given the data from those two trials and the recent publication validating plasma, Pito two one seven, as you know, due to the MRI data that Talbot the Talbot EBITDA data, along with the plasma tau biomarkers, puts you into a position where you can negotiate an accelerated approval pathway, which strategically might be very similar to the Council, the Council, the approach.

有一個問題我有。你知道，這是基於對動物的研究，以及今天這裡關於 tau tau 生物標記物的許多問題。鑑於這兩項試驗的數據以及最近發表的驗證血漿的數據，Pito 二一七，如您所知，由於 MRI 數據，Talbot 的 Talbot EBITDA 數據以及血漿 tau 生物標記物使您處於這樣的位置：談判一個加速批准途徑，這在策略上可能與理事會、理事會的方法非常相似。

So that's the question.

這就是問題所在。

Thank you.

謝謝。

Yes, thank you.

是的，謝謝。

So if I understand your question, you're wondering whether based on on changes or just or treatment related changes until pad or until biomarkers. Could that could that be a basis of an accelerated approval approach?

因此，如果我理解您的問題，您想知道是基於變化還是僅基於治療相關的變化，直到墊或直到生物標記。這是否可以成為加速審批方法的基礎？

Right. I think if there is a clear clear sign that there is a remarkable change in the plasma tau biomarker based on the plaque removal up, is there a potential for accelerated approval pathway similar to cancel the approach?

正確的。我認為，如果有明顯跡象表明血漿 tau 生物標記因斑塊去除而發生顯著變化，是否有可能加速批准途徑，類似於取消該方法？

Yes, I would I would never say no, I would say that when we open this up and we see what we have based on the robustness of the findings, and we would certainly if we thought that it was robust enough. We would certainly consider that.

是的，我永遠不會說不，我想說的是，當我們打開這個問題時，我們會根據研究結果的穩健性看到我們所擁有的內容，如果我們認為它足夠穩健，我們當然會說不。我們當然會考慮這一點。

We've also had questions about well, if we see if we see very significant amyloid warning because that itself could that also be. And again, I think we're going to at this differently. That's not the original intention in this trial. And but of course, we opened it up and we see what we have. If we think that there are potential paths forward, we will certainly explore it.

我們也有疑問，如果我們看到是否看到非常重要的澱粉樣蛋白警告，因為這本身也可能是這樣。再說一次，我認為我們將以不同的方式處理這個問題。這並不是這次審判的初衷。當然，我們打開它，我們看到了我們擁有的東西。如果我們認為有潛在的前進道路，我們一定會探索它。

Sorry, thank you.

抱歉，謝謝。

I would now like to go ahead and call and turn the call back over to Marc Grasso for final remarks.

我現在想繼續打電話，然後將電話轉回馬克·格拉索（Marc Grasso）進行最後發言。

Thank you, operator, and thanks, everyone, for the thoughtful questions. Before we end the call, I'd like to share that we will be participating in a number of upcoming conferences, including TD Cowen's 44th Annual Healthcare Conference on March fifth in Boston clearance 2024 global Biopharma Conference on March 12th in Miami, Barclays Global Healthcare Conference on March 13th in Miami and Staples and S. days on March ninth 19th. Thank you again for your time and attention.

謝謝接線員，也謝謝大家提出的深思熟慮的問題。在結束通話之前，我想告訴大家，我們將參加一些即將舉行的會議，包括3 月5 日在波士頓舉行的TD Cowen 第44 屆年度醫療保健會議，以及3 月12 日在邁阿密舉行的2024 年全球生物製藥會議，巴克萊全球醫療保健會議於 3​​ 月 13 日在邁阿密舉行，斯台普斯和 3 月 9 日在 S.days 舉行。再次感謝您的時間和關注。

We'll now conclude today's call.

我們現在結束今天的電話會議。

This concludes today's conference call. You may all disconnect.

今天的電話會議到此結束。你們都可以斷開連線。