Athira Pharma Inc (ATHA) 2021 Q4 法說會逐字稿

Welcome to Athira Pharma's conference call to discuss its full-year 2021 financial results and business update. At this time, all participants are in a listen-only mode. Following the conclusion of the prepared remarks, we will conduct a question-and-answer session and instructions will follow at that time. This conference call is being recorded today, March 24, 2022.

歡迎參加 Athira Pharma 的電話會議，討論其 2021 年全年財務表現和業務更新。目前，所有與會者均處於聆聽模式。在準備好的演講結束後，我們將進行問答環節，屆時將提供相關說明。本次電話會議將於今天（2022 年 3 月 24 日）錄製。

I would like to turn the conference call over to Julie Rathbun, Head of Investor and Public Relations at Athira Pharma.

我想將電話會議交給 Athira Pharma 投資者和公共關係主管 Julie Rathbun。

Thank you, operator. Following the close of the US financial market today, we issued full-year 2021 financial results and recent business updates. This press release can be found on the investors section of our website.

謝謝接線生。今天美國金融市場收盤後，我們發布了2021年全年財務表現及近期業務更新。此新聞稿可在我們網站的「投資者」板塊查看。

Before we begin, I'd like to remind you that during this call, management will make forward-looking statements, which may include statements about research and clinical development plans and timelines and results of operations, the timing of and results from clinical trials and preclinical development activities, the potential efficacy, safety profile, future development plans, addressable market, regulatory success and commercial potential of our product candidate, the anticipated timing of IND or IND-equivalent submissions, and the initiation of future clinical trials for our product candidates, the efficacy of our clinical trial designs, our ability to successfully develop our proprietary development program, the timing and results of our interactions with regulators, the timing and anticipated enrollment in our clinical trials, and the timing of potential publication or presentation of future clinical data.

在我們開始之前，我想提醒您，在本次電話會議中，管理層將做出前瞻性陳述，其中可能包括有關研究和臨床開發計劃以及時間表和經營成果的陳述、臨床試驗和臨床前開發活動的時間和結果、潛在功效、安全性、未來發展計劃、目標市場、我們候選產品的監管成功和商業潛力、預期的 IND 或 IND等效提交時間以及我們候選產品未來臨床試驗的啟動、我們臨床試驗設計的有效性、我們成功開發專有開發計劃的能力、我們與監管機構互動的時間和結果、我們臨床試驗的時間和預期註冊情況，以及未來臨床數據的潛在發布或展示時間。

Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings. Our results may differ materially from those projected on today's call. Athira is not under any obligation to update statements regarding the future or to conform these statements in relation to actual results unless required by law.

前瞻性陳述受諸多風險和不確定性因素影響，其中許多因素超出我們的控制範圍，包括我們向美國證券交易委員會 (SEC) 提交的文件中不時描述的風險和不確定性。我們的業績可能與今天電話會議的預測有重大差異。除非法律要求，否則 Athira 沒有義務更新有關未來的陳述或使這些陳述與實際結果相符。

On today's call, we are joined by Mark Litton, Ph.D., Athira's President and Chief Executive Officer; Hans Moebius MD, Ph.D., Athira's Chief Medical Officer; Rachel Lenington, Athira's Chief Operating Officer; Glenna Mileson, Athira's Chief Financial Officer; and Kevin Church Ph.D., Athira's Executive Vice President of Research. Following prepared remarks, we will open the call to your questions.

今天的電話會議邀請了 Athira 總裁兼首席執行官 Mark Litton 博士、Athira 首席醫療官 Hans Moebius 博士、Athira 首席營運官 Rachel Lenington、Athira 首席財務官 Glenna Mileson 以及 Athira 研究執行副總裁 Kevin Church 博士。在準備好發言稿後，我們將開始回答大家的提問。

I'll now turn the call over to Dr. Mark Litton.

現在我將電話轉給馬克·利頓博士。

Thanks, Julie. And thank you, all, for joining us this afternoon. 2022 has gotten off to an exciting start with progress across a number of our key clinical programs. Our achievements throughout 2021, including the completion of the Phase 2 ACT-AD enrollment laid the groundwork for us to pursue our clinical and corporate strategy, and we are looking forward to the results of these efforts.

謝謝，朱莉。也感謝大家今天下午加入我們。 2022年開局令人振奮，我們多個關鍵臨床計畫都取得了進展。我們在2021年所取得的成就，包括完成2期ACT-AD臨床試驗的入組，為我們推進臨床和企業策略奠定了基礎，我們期待這些努力的成果。

To date, the new year has been highlighted by the dosing of the first patient in our SHAPE Phase 2 study of fosgonimeton or fosgo in Parkinson's disease dementia and dementia with Lewy bodies; the peer-reviewed publication of our Phase 1 study results of fosgo; and the presentation of preclinical evidence supporting our novel innovative approach to restoring neuronal health and slowing neurodegeneration across our lead program with fosgo and our first oral candidate ATH-1020.

迄今為止，新年的亮點包括：我們在 SHAPE 第 2 階段研究中為第一位患者給藥，該研究旨在研究 fosgonimeton 或 fosgo 治療帕金森病癡呆和路易體癡呆；同行評審發表了 fosgo 第 1 階段研究結果；以及在我們採用 fosgo 和首個口服候選藥物 ATH-1020 的主導性證據中，展示了臨床健康和首個口服候選藥物 ATH-1020 的主導神經元。

In addition to our considerable clinical progress, we expanded our Board of Directors with the addition of two talented industry leaders: Dr. Michael Panzara, an industry veteran with more than 20 years of CNS drug development and commercialization experience; and Grant Pickering, a proven life sciences leader with considerable experience across all stages of corporate and clinical development. Our growing body of scientific and clinical evidence is compelling. It gives us further confidence in our clinical development programs.

除了臨床研究取得的顯著進展外，我們還擴充了董事會，新增了兩位才華橫溢的行業領袖：Michael Panzara 博士，一位擁有 20 多年中樞神經系統藥物開發和商業化經驗的行業資深人士；以及 Grant Pickering，一位在企業和臨床開發各個階段擁有豐富經驗的生命科學領域資深領導者。我們不斷增長的科學和臨床證據令人信服，這增強了我們對臨床開發項目的信心。

Importantly, we are on track to have topline data from our Phase 2 ACT-AD study in the second quarter and expect to complete enrollment in our potentially pivotal Phase 3 LIFT-AD study in the third quarter. These are exciting inflection points for Athira, and we are gearing up for an especially active year ahead.

重要的是，我們預計在第二季度獲得 ACT-AD II 期研究的頂線數據，並預計將在第三季度完成可能至關重要的 LIFT-AD III 期研究的入組工作。這些都是 Athira 令人興奮的轉捩點，我們正為未來格外活躍的一年做好準備。

With that, let me turn the call over to our Chief Medical Officer, Dr. Hans Moebius, for a review of our clinical development pipeline. For those of you who don't know Hans, Hans is an internationally recognized expert in neuropsychiatry drug development and regulatory strategy. He has led the development and approval of several drugs, including memantine and has been instrumental in shaping the development strategy for fosgo. Hans has taken the lessons learned in his decades of drug development to increase the probability of technical and regulatory success for our lead clinical program.

接下來，請容許我把電話轉給我們的首席醫療官漢斯·莫比斯博士，請他回顧我們的臨床開發管線。對於那些不認識漢斯的人來說，漢斯是一位國際公認的神經精神科藥物開發和監管策略專家。他領導了包括美金剛在內的多種藥物的開發和審批，並在製定福戈的開發策略方面發揮了重要作用。漢斯汲取了數十年藥物開發經驗，以提高我們主要臨床計畫在技術和監管方面取得成功的可能性。

With that, Hans, the floor is yours.

好了，漢斯，現在輪到你發言了。

Thank you, Mark, for that generous introduction. As many of you know, in the past 20 years of Alzheimer's disease, research and development were spent trying to replicate effects seen in transgenic animal models into humans, namely by monoclonal antibodies, in order to achieve disease modification. This approach requires to treat early pre-dementia-stage Alzheimer's disease. And there was far less attention to mild to moderate-stage Alzheimer's disease.

謝謝馬克的慷慨介紹。眾所周知，在過去20年裡，阿茲海默症的研發工作主要致力於將基因改造動物模型中觀察到的效果複製到人類身上，也就是透過單株抗體，以達到改善病情的目的。這種方法需要治療早期癡呆前期的阿茲海默症。而對輕度至中度阿茲海默症的關注則少得多。

At Athira, we have undertaken a novel mechanistic approach that does not follow this search for the holy grail of disease alteration, but rather focuses on the symptomatic stage as a first step. Our approach is to develop small molecule therapeutics for a broad range of neurodegenerative diseases including Alzheimer's disease by promoting the HGF/MET system, a naturally occurring mechanism to repair and restore neuronal health. HGF/MET is critical for healthy brain function. MET receptor expression is reduced in Alzheimer's disease and other neurological diseases.

在 Athira，我們採用了一種新穎的機制方法，這種方法並非追尋改變疾病的終極目標，而是將症狀階段作為第一步。我們的方法是透過促進 HGF/MET 系統（一種自然存在的修復和恢復神經元健康的機制）來開發針對多種神經退化性疾病（包括阿茲海默症）的小分子療法。 HGF/MET 對健康的大腦功能至關重要。在阿茲海默症和其他神經系統疾病中，MET 受體表現會降低。

Our late-stage product candidate is a small molecule product with an active metabolite that is brain penetrable and positively modulates the activity of the HGF/MET system with high specificity. We have demonstrated this extensively in preclinical models and have used electrophysiology, both quantitative EEG and the objective task-related measure of event-related potential P300 latency to determine an active dose range. The compelling pharmacodynamic results from a small cohort of Alzheimer's disease subjects in our Phase 1b study as well as supportive long-term toxicology results gave us confidence to initiate Phase 2 and 3 clinical development program.

我們的後期候選產品是一種小分子產品，其活性代謝物可穿透腦部，並以高特異性正向調節HGF/MET系統的活性。我們已在臨床前模型中充分證明了這一點，並利用電生理學方法（包括定量腦電圖和客觀任務相關測量事件相關電位P300潛伏期）確定了活性劑量範圍。在我們1b期研究中，小規模阿茲海默症受試者獲得了令人信服的藥效動力學結果，以及支持性的長期毒理學結果，這讓我們有信心啟動2期和3期臨床開發計畫。

The study design was discussed with the FDA in order to gain agreement that the Phase 3 LIFT-AD study could potentially serve as a pivotal trial if successful. The Phase 2 trial was branded ACT-AD, and the Phase 3 trial, LIFT study. Their design is largely mirroring. For example, diagnostics, severity range, doses, double-blind duration and most outcomes.

為了獲得FDA的認可，該研究的設計已與FDA進行了討論，以確保3期LIFT-AD研究如果成功，有可能成為一項關鍵性試驗。 2期試驗命名為ACT-AD，3期試驗則命名為LIFT研究。兩期試驗的設計在很大程度上是相同的，例如診斷方法、嚴重程度範圍、劑量、雙盲持續時間以及大多數結果。

Both trials started in parallel. So the smaller Phase 2 trial will readout first, allowing us to leverage insights from the ACT-AD results for the optimization of the LIFT-AD statistical analysis plan. Importantly, we are able to do this without a formal interim analysis in the Phase 3 trial, which carries statistical penalties and inevitably brings operational delays.

兩項試驗同時啟動。因此，規模較小的II期試驗將首先進行資料讀取，這使我們能夠利用ACT-AD結果的洞見來優化LIFT-AD統計分析計畫。重要的是，我們無需在III期試驗中進行正式的中期分析即可完成資料讀取，因為中期分析會帶來統計懲罰，並且不可避免地會導致營運延遲。

In short, both ACT-AD and LIFT-AD are randomized double-blind placebo-controlled trials evaluating 40-milligram and 70-milligram fosgo daily for the treatment of mild to moderate AD. Participants are randomized evenly to the two dose groups and the placebo group to receive a subcutaneous injection of fosgo or placebo once-daily over a double-blind period of 26 weeks.

簡而言之，ACT-AD 和 LIFT-AD 均為隨機雙盲安慰劑對照試驗，評估每日服用 40 毫克和 70 毫克 fosgo 治療輕度至中度 AD 的效果。受試者被隨機分配到兩個劑量組和安慰劑組，在 26 週的雙盲試驗期內，每日接受一次 fosgo 或安慰劑皮下注射。

The primary endpoint of ACT-AD is changed in event-related potential P300 latency, a functional objective measure of working memory processing speed. Secondary endpoints in ACT-AD include ADAS-Cog11, a measure of cognition; ADCS-CGIC, a measure of global clinical change; and ADCS-ADL23, a measure of functional abilities.

ACT-AD 的主要終點是事件相關電位 P300 潛伏期的變化，P300 潛伏期是衡量工作記憶處理速度的功能性客觀指標。 ACT-AD 的次要終點包括 ADAS-Cog11（認知指標）、ADCS-CGIC（整體臨床變化指標）和 ADCS-ADL23（功能能力指標）。

In addition, we are assessing the plasma pharmacokinetics of fosgo in this patient population. Enrollment of ACT-AD was completed last October with 77 participants enrolled. And as Mark noted earlier, we are on track to report topline data in the second quarter of 2022.

此外，我們正在評估福戈在該患者族群中的血漿藥物動力學。 ACT-AD 試驗的入組工作已於去年 10 月完成，共 77 名參與者入組。正如馬克之前提到的，我們預計在 2022 年第二季報告總數據。

The Phase 3 LIFT-AD study is currently enrolling up to 420 subjects in the US. In contrast to ACT-AD, LIFT-AD has a composite primary endpoint, the Global Statistical Test, which is an unweighted and unbiased mathematical algorithm that combines the scores from ADAS-Cog11 and either ADCS-CGIC or ADCS-ADL23, which are amongst the secondary endpoints.

目前，LIFT-AD 三期研究正在美國招募多達 420 名受試者。與 ACT-AD 不同，LIFT-AD 有一個綜合主要終點—整體統計檢定 (Global Statistical Test)。該測試是一種無加權、無偏差的數學演算法，結合了 ADAS-Cog11 評分以及 ADCS-CGIC 或 ADCS-ADL23 評分（次要終點之一）。

You may recall that earlier this year, we opportunistically expanded the target recruitment number for the study by approximately 120 patients in order to strengthen the statistical power of these secondary endpoints. We believe this will enhance the potential for filing a new drug application based on a single pivotal clinical study.

您可能還記得，今年早些時候，我們特意將研究的目標招募人數增加了約120名患者，以增強這些次要終點的統計效力。我們相信，這將提高基於一項關鍵臨床研究提交新藥申請的可能性。

The increased sample size and resulting power for ADAS-Cog11 is based on our unchanged original statistical modeling and is consistent with the design of previous Phase 3 trials in the treatment of mild to moderate Alzheimer's disease. As noted earlier, if we leverage insights from the ACT-AD trial analysis in the second quarter to optimize and refine the statistical analysis plan for LIFT-AD, moving forward, we anticipate completing enrollment in LIFT-AD in the third quarter of 2022, resulting in topline data in the first half of 2023.

ADAS-Cog11 的樣本量及其由此帶來的功效的增加，是基於我們未改變的原始統計模型，並與先前針對輕度至中度阿茲海默症治療的 3 期臨床試驗的設計一致。如前所述，如果我們利用第二季 ACT-AD 試驗分析的洞見來優化和完善 LIFT-AD 的統計分析計劃，我們預計將於 2022 年第三季完成 LIFT-AD 的受試者入組，並於 2023 年上半年獲得頂線數據。

There is a growing body of preclinical and clinical evidence in support of targeting the HGF/MET neurotrophic system. The encouraging results from the Phase 1a/b study of fosgo were recently published in the peer-reviewed Journal of Alzheimer's Disease.

越來越多的臨床前和臨床證據支持靶向HGF/MET神經營養系統。 fosgo 1a/b期臨床研究的令人鼓舞的結果最近發表在同行評審的《阿茲海默症雜誌》上。

To summarize, fosgo was well-tolerated across a wide dose range. Pharmacokinetics are dose linear, and pharmacodynamics suggest human blood brain barrier penetration. The statistically significant large reduction of ERP P300 latency seen in the Alzheimer's disease cohort on active drug versus placebo treatment may be suggestive of enhanced synaptic function and ultimately the potential pro-cognitive properties of fosgo. Second, the baseline demographics of ACT-AD presented last week at the AD/PD annual meeting demonstrate a well-balanced trial population appropriate to replicate these initial Phase 1b findings on ERP P300, which is the functional measure of working memory processing speed.

總而言之，fosgo 在較寬的劑量範圍內均具有良好的耐受性。藥物動力學與劑量呈線性關係，藥效學顯示其可穿透人類血腦障壁。與安慰劑組相比，接受活性藥物治療的阿茲海默症患者群體中 ERP P300 潛伏期顯著縮短，這在統計學上具有顯著意義，這可能提示 fosgo 的突觸功能增強，並最終可能具有促認知特性。其次，上週在 AD/PD 年會上公佈的 ACT-AD 基線人口統計數據表明，試驗人群均衡，足以複製 ERP P300（工作記憶處理速度的功能性指標）的 1b 期初步研究結果。

Finally, in this type of population, one would expect to see about 20% to 35% of discontinuations largely due to treatment-emergent adverse events. Our models assumed a 20% drop out rate. And we can now report that the discontinuation rate for ACT-AD was considerably below that rate, coming in at approximately 14%. This fact and the absence of target organ toxicity is a favorable result.

最後，在這類人群中，預計約有20%至35%的停藥率主要由於治療中出現的不良事件。我們的模型假設的停藥率為20%。現在我們可以報告，ACT-AD的停藥率遠低於該比例，約為14%。這一事實以及沒有目標器官毒性是一個有利的結果。

Consequently, the majority of subjects completing ACT-AD have opted to participate in the 26-week open label extension study. Remember, two-thirds of subjects have been on active drug during the double-blind portion of the study. We think this speaks to the tolerability of this novel intervention, in particular, in an elderly frail polypharmacy population with increased susceptibility to adverse events.

因此，完成 ACT-AD 的大多數受試者選擇參加為期 26 週的開放標籤擴展研究。需要注意的是，三分之二的受試者在研究的雙盲階段一直在服用活性藥物。我們認為這證明了這項新幹預措施的耐受性，尤其是在老年體弱、多重用藥且對不良事件易感性較高的人群中。

Because positive modulation of HGF/MET is not dependent or based on a specific pathology or hypothesis, we expanded in parallel into other neurodegenerative indications. Earlier this year, we initiated our SHAPE study, a randomized double-blind placebo-controlled parallel group Phase 2 trial evaluating fosgo in subjects with Parkinson's disease dementia or dementia with Lewy bodies. This proof-of-concept study will enroll approximately 75 individuals in the US, utilizing the same dose regiment as ACT-AD and LIFT-AD over the same double-blind treatment course of 26 weeks.

由於HGF/MET的正向調節並不依賴或基於特定的病理或假設，我們將研究範圍擴展到其他神經退化性疾病。今年早些時候，我們啟動了SHAPE研究，這是一項隨機雙盲安慰劑對照平行組II期臨床試驗，旨在評估fosgo對帕金森氏症癡呆或路易氏體癡呆患者的作用。這項概念驗證研究將在美國招募約75名受試者，採用與ACT-AD和LIFT-AD相同的劑量方案，進行26週的雙盲治療。

The primary endpoint for SHAPE is also the composite Global Statistical Test utilizing cognitive change and P300 latency, which has also been shown to be affected in Parkinson's disease dementia. Secondary endpoints include motor and non-motor skills. Since most Parkinson's disease patients develop dementia, this is an area of high medical need with only one approved drug on the market.

SHAPE 的主要終點也是綜合整體統計測試，該測試利用認知變化和 P300 潛伏期進行，而 P300 潛伏期已被證明會影響帕金森氏症癡呆症患者。次要終點包括運動技能和非運動技能。由於大多數帕金森氏症患者都會發展為癡呆症，因此該領域醫療需求旺盛，目前市場上僅有一種核准藥物。

In addition to expanding the indications for fosgo, we are advancing another compound from our discovery group ATH-1020. Compelling preclinical results were presented at the recent American Society for Experimental Neurotherapeutics annual meeting which showed that ATH-1020 demonstrated in vitro and in vivo efficacy including its ability to augment MET activation, promote activation of downstream signaling pathways, and in distinct animal models, address the person-like behaviors and normalize an established electroencephalography hallmark of schizophrenia.

除了擴大fosgo的適應症外，我們還在推動研發團隊的另一款化合物ATH-1020。在最近的美國實驗神經治療學會年會上，我們展示了令人信服的臨床前結果，結果表明ATH-1020在體外和體內均表現出療效，包括增強MET活化、促進下游信號通路的激活，並在不同的動物模型中改善類人行為，並使精神分裂症的既定腦電圖特徵正常化。

Following clearance of our investigational new drug application with the FDA in January, the study is now underway. And dosing for the first subject with ATH-1020 in the Phase 1 human pharmacology trial is now imminent.

我們的新藥臨床試驗申請已於今年一月獲得美國食品藥物管理局 (FDA) 批准，目前正在進行中。 ATH-1020 的 1 期人體藥理學試驗首例受試者即將開始給藥。

In summary, Athira is pursuing a diverse clinical development pipeline, both in terms of target indication and development stages. We believe that our work will provide a bolus of data for presentation and publication in the years ahead that will hopefully translate into new medicines for patients in need. And at the same time, will create shareholder value.

總而言之，Athira 正在尋求多元化的臨床開發管線，涵蓋目標適應症和開發階段。我們相信，我們的工作將為未來幾年的展示和出版提供大量數據，並有望轉化為有需要的患者所需的新藥。同時，也將創造股東價值。

With that overview, let me turn the call back to Mark.

概述完這些之後，讓我把電話轉回給馬克。

Thanks, Hans, for that detailed review of our clinical programs. Given how close we are to topline data from our Phase 2 study, we are still frequently asked, so what does success look like for ACT-AD?

感謝漢斯對我們臨床計畫的詳細回顧。鑑於我們距離二期研究的最終數據已經非常接近，我們仍然經常被問到：ACT-AD 的成功率幾何？

Obviously, achieving statistical significance on the primary P300 endpoint would be a success. In addition, should we see trends in some of the key secondary endpoints, we would also see that as a big win. We say trends, because this study was not powered to show statistical significance in these cognitive clinical and functional endpoints. That said, we are hopeful that we will see some trends towards clinical benefit as this would corroborate our thesis and further support our confidence in a favorable outcome in our Phase 3 LIFT-AD study.

顯然，在主要P300終點達到統計學顯著性就是一種成功。此外，如果我們看到一些關鍵次要終點的趨勢，我們也會認為這是一個巨大的勝利。我們說趨勢，是因為這項研究的效能不足以證明這些認知、臨床和功能終點的統計顯著性。即便如此，我們仍然希望看到一些臨床效益的趨勢，因為這將證實我們的論點，並進一步增強我們對3期LIFT-AD研究取得良好結果的信心。

Our goal with fosgo is to bring clinical benefit to patients suffering with neurodegenerative diseases and to provide tangible, rapid, and lasting cognitive improvement with our novel approach. We want to provide patients with what is most important to them, memory improvements and extended independents. This is most critical in the mild to moderate patients where the rate of cognitive and behavioral declines is seen most dramatically. It is also important as the mild to moderate AD segment accounts for nearly 80% of all Alzheimer's patients, and 78% of these patients are currently on marketed drugs.

我們研發fosgo的目標是為神經退化性疾病患者帶來臨床益處，並透過我們創新的方法提供切實、快速且持久的認知改善。我們希望為患者提供對他們來說最重要的東西：記憶力的提升和更長的獨立生活。這對於輕度至中度阿茲海默症患者尤其關鍵，因為這些患者的認知和行為衰退速度最為顯著。此外，由於輕度至中度阿茲海默症患者佔所有阿茲海默症患者的近80%，而其中78%的患者目前正在服用已上市藥物，因此這一點至關重要。

There is a real need for innovation in this space, and we believe our unique HGF/MET approach can help fill this void. As we move closer to a potentially pivotal Phase 3 data readout next year, we have spent considerable time evaluating the market opportunity and market access. Currently, there are 55 million people suffering with Alzheimer's disease worldwide. And that number is expected to grow to 100 million by 2050, given the aging population and other dynamics.

該領域亟需創新，我們相信我們獨特的HGF/MET方法能夠填補這一空白。隨著明年可能至關重要的3期臨床試驗數據即將公佈，我們投入了大量時間來評估市場機會和市場准入。目前，全球有5500萬人患有阿茲海默症。考慮到人口老化和其他因素，預計到2050年，這一數字將增長到1億。

Currently, there are only three to four drugs available to treat mild to moderate Alzheimer's disease. And as we've noted, there is considerable room for improvement. Contrast that with cancer drugs, which have a multitude of treatment options across a variety of targets, and it underscores how woefully underdeveloped Alzheimer's disease treatment options are today. Importantly, given this gap, we see there is room for a lot more success for any number of players in the sector.

目前，治療輕度至中度阿茲海默症的藥物僅有三到四種。正如我們所指出的，該領域還有相當大的改進空間。相較之下，癌症藥物擁有涵蓋多種標靶的多種治療方案，這凸顯了阿茲海默症治療方案目前的發展程度有多麼令人擔憂。重要的是，鑑於這一差距，我們認為該領域任何數量的參與者都還有更大的成功空間。

Now, let me turn to a brief review of our financials. We continued to invest in our clinical development programs with a focus on advancing fosgo towards approval, with an overarching goal to benefit patients worldwide. We are prudently building our team in order to deliver on the potential of our novel HGF/MET platform. We are keenly aware of the trust put in us by you, our shareholders, and we work diligently to be good stewards of those resources by balancing our investments with disciplined financial management.

現在，讓我簡單回顧一下我們的財務狀況。我們持續投資於臨床開發項目，重點是推動fosgo獲得批准，最終目標是造福全球患者。我們正在審慎地組建團隊，以充分發揮我們創新HGF/MET平台的潛力。我們深知各位股東對我們的信任，並將勤奮地做好這些資源的管理，透過平衡投資與嚴謹的財務管理來確保投資的有效性。

Now, let's look at the details of our financial results. Our research and development expenses were $42.8 million for the year ended December 31, 2021, as compared to $13.3 million for the full year ended December 31, 2020. The increase was driven primarily by costs related to an increased clinical trial activities, expanded personnel, and increased preclinical research and development expenses.

現在，讓我們來看看我們財務表現的具體細節。截至2021年12月31日止年度，我們的研發費用為4,280萬美元，而截至2020年12月31日止年度的研發費用為1,330萬美元。研發費用的成長主要源自於臨床試驗活動增加、人員擴充、臨床前研發費用增加的相關成本。

General and administrative expenses were $21.2 million for the year ended December 31, 2021, as compared to $6.7 million for the same quarter in 2020. These were primarily due to an increased personnel expense as we expanded headcount and infrastructure. And that includes insurance, legal, facilities, new product planning, and investor relation costs.

截至2021年12月31日止年度，一般及行政開支為2,120萬美元，而2020年同期為670萬美元。這主要歸因於我們擴大員工隊伍和基礎設施建設導致人員開支增加。這其中包括保險、法律、設施、新產品規劃和投資者關係成本。

We had a net loss of $54.9 million or $1.49 per share basic and diluted for the year ended December 31, 2021, compared to a net loss of $19.9 million or $1.67 per share basic and diluted for the year ended December 31, 2020. Importantly, we ended 2021 with cash, cash equivalents, and investments of $319.7 million compared to $268.2 million as of December 31, 2020. This puts us in a strong position to support our lead clinical programs through important potentially value-creating data readouts and beyond.

截至 2021 年 12 月 31 日止年度，我們的淨虧損為 5,490 萬美元，即基本虧損及攤薄虧損 1.49 美元，而截至 2020 年 12 月 31 日止年度的淨虧損為 1,990 萬美元，即基本虧損 1.67 美元。重要的是，截至 2021 年，我們的現金、現金等價物和投資為 3.197 億美元，而截至 2020 年 12 月 31 日為 2.682 億美元。這使我們能夠透過重要的潛在創造價值數據讀數及其他方式來支持我們的主要臨床項目。

Before we open the call to your questions, I'd like to remind you that we are joined by Rachel Lenington, our Chief Operating Officer; Kevin Church, our EVP of Research; and Glenna Mileson, our CFO. Collectively, our team has presided over the development, approvals, and successful launches of many meaningful drugs.

在開始問答環節之前，我想提醒大家，我們的嘉賓包括營運長Rachel Lenington、研發執行副總裁Kevin Church和財務長Glenna Mileson。我們的團隊共同主持了許多重要藥物的研發、批准和成功上市。

In closing, I want to take a moment to thank the talented and dedicated Athira team, who are all working tirelessly in pursuit of our goals. The energy and excitement at Athira is very high as we truly believe we have a unique opportunity to reshape the course of neurodegenerative diseases. We look forward to making our vision a reality for these patients.

最後，我想藉此機會感謝才華橫溢、敬業奉獻的 Athira 團隊，他們孜孜不倦地追求著我們的目標。 Athira 團隊充滿活力，充滿熱情，因為我們堅信，我們擁有重塑神經退化性疾病進程的獨特機會。我們期待為這些患者實現我們的願景。

With that, operator, let's open the call up for questions.

接線員，現在讓我們開始提問吧。

Certainly. (Operator Instructions) Andrew Tsai, Jefferies.

當然。 （操作員指示） Andrew Tsai，傑富瑞。

Thanks, and good afternoon. Thanks for all the updates. First question is just a high-level one on ACT-AD.

謝謝，下午好。感謝您提供的所有更新。第一個問題是關於ACT-AD的高階問題。

Can you remind us how you're thinking about sharing the topline release in Q2? There's a lot you could share in terms of the number of endpoints that you have. So how much are you planning to share? Will we see efficacy curves after six months? I guess, what should we be expecting? Thanks.

您能否介紹一下您計劃在第二季發布的關鍵數據？關於您擁有的終點數量，有很多資訊可以分享。那麼您計劃分享多少呢？六個月後我們能看到療效曲線嗎？我想，我們該期待什麼？謝謝。

Yes. Thank you, Andrew. So just to expect, the primary endpoint is P300, and we will show, hopefully, statistically significant data throughout six months for P300.

是的。謝謝你，安德魯。所以，我們預期的主要終點是 P300，我們希望能夠顯示 P300 在六個月內具有統計意義的數據。

And then the plan is to show ADAS-Cog11. And we're hopeful to see trends, because ADAS-Cog11, as you know, is not powered to be statistically significant. So, those will be the colors that we will show. We do plan to give more color in upcoming scientific conference. So to be clear in your things, we probably will not show the graphs over time.

然後計劃展示ADAS-Cog11。我們希望看到趨勢，因為如你所知，ADAS-Cog11的統計顯著性並不高。所以，這些就是我們將要展示的顏色。我們計劃在即將舉行的科學會議上提供更多顏色。所以，為了讓你看得更清楚，我們可能不會展示隨時間變化的圖表。

Got it. And just a reference point would be helpful on these harder endpoints on ADAS-Cog, CGIC, ADL. What do the approved drugs for mild-moderate Alzheimer's show at six months for these three efficacy endpoints?

明白了。對於ADAS-Cog、CGIC和ADL這些較難的終點，一個參考點會很有幫助。已核准的用於治療輕度至中度阿茲海默症的藥物在六個月內對這三個療效終點的療效如何？

Sure. So now we're talking historically. I think I'm going to hand that over to Hans to answer on that.

當然。我們現在來談談歷史。我想把這個問題交給漢斯來回答。

In the mild to moderate Alzheimer's disease population and in a 26-week or six months trial, you would historically expect to see two to three points benefit over placebo. That is, however, highly dependent on the individual setting and the placebo decline that has been adverse. There were a number of trials that were showing little placebo decline in the past.

在輕度至中度阿茲海默症患者中，在為期26週或6個月的試驗中，通常預期療效會比安慰劑組好2到3個百分點。然而，這在很大程度上取決於個體情況以及安慰劑組出現的不良反應。過去有許多試驗顯示，安慰劑組療效幾乎沒有下降。

Okay. And then my last question is, you shared some interesting AD/PD data update on ACT-AD. I think 50% to 60% of your patients in this study are on acetylcholinesterase inhibitor. So 40% are, I believe, treatment-naive. I believe that naturally the old studies in the past probably were done in naive patients. So here, if 50% to 60% of patients are on a combo therapy, how does that dynamic affect both the placebo and the drug arm on ADAS-Cog? Thanks.

好的。我的最後一個問題是，您分享了一些關於ACT-AD的有趣的AD/PD數據更新。我認為這項研究中有50%到60%的患者正在服用乙醯膽鹼酯酶抑制劑。所以我認為其中40%的患者是初治患者。我相信過去的研究很可能是針對初治患者進行的。那麼，如果50%到60%的患者正在接受聯合治療，這種動態會如何影響ADAS-Cog的安慰劑組和藥物組？謝謝。

Yeah. Okay. You go Hans.

好的。好的。你去吧，漢斯。

Okay. So you're correct. I reported on average quite precisely 60%, currently taking cholinergic medication. In these historical trials, indeed the number was smaller. I will remind that also in Phase 1b, we had drug-naive subjects, as always in Phase 1 trials.

好的。所以你說得對。我報告的平均數據相當準確，有60%的人目前正在服用膽鹼能藥物。在這些歷史試驗中，這個數字確實要小一些。我要提醒的是，在1b期臨床試驗中，我們也納入了未接受藥物治療的受試者，就像1期試驗一樣。

We believe that it can only be helpful to support the traffic situation of cholinergic neurons that are, of course, together with other transmitter-addressed neurons, key areas in the brain that are responsible for memory and language. So we do see that as rather an advantage than a potential disadvantage.

我們認為，支持膽鹼能神經元的交通狀況只會有益無害。膽鹼能神經元當然與其他傳導物質尋址神經元一起，是大腦中負責記憶和語言的關鍵區域。因此，我們認為這與其說是潛在的缺點，不如說是優勢。

Very good. Thanks for all the color.

非常好。謝謝你的色彩。

Thanks, Andrew.

謝謝，安德魯。

Paul Matteis, Stifel.

保羅·馬泰斯（Paul Matteis），Stifel。

Great. Thanks so much for the detail you're offering. I wanted to clarify a couple of things, if I might. So one is, I guess for LIFT, the hope here is that you hit on both cognition and function, is that right?

太好了。非常感謝你提供的細節。如果可以的話，我想澄清幾件事。首先，我想對 LIFT 來說，你希望能夠同時兼顧認知和功能，對嗎？

Is that still your assumption that ADAS-Cog alone would not be enough to get registered? And if that's right, how much flexibility do you see on which functional scale you need to succeed on? And how much time do you have, I guess, to pre-specify which you're using in the Global Statistical Test?

您是否仍認為僅靠 ADAS-Cog 不足以獲得註冊？如果是這樣，您認為在哪些功能量表上取得成功需要多大的彈性？我想，您有多少時間來預先確定在整體統計測試中使用的功能量表？

And then the one last thing I just wanted to ask out of curiosity. Not sure if you're willing to disclose, but just when you look at the baseline data in ACT, right? You did a number of different baseline data cuts which is appreciated. When you look at patients across disease severity at baseline, do you see any association with their baseline P300 latency? Thanks so much.

最後，出於好奇，我想問一下。不知道您是否願意透露，但只是當您查看ACT中的基線數據時，對嗎？您做了許多不同的基線數據截斷，值得讚賞。當您觀察不同疾病嚴重程度的患者基線數據時，您是否發現他們的基線P300潛伏期有任何關聯？非常感謝。

Yeah. Let me answer the last question first. We have not specifically looked in that difference of baseline. We have been looking into the baseline of the entire group. And what we found was that the mean baseline in ACT was 381 milliseconds plus-minus 4.1, which is very well in keeping with published data in the same target population.

是的。我先回答最後一個問題。我們並沒有專門研究基線差異。我們一直在研究整個群體的基線。我們發現，ACT 的平均基線為 381 毫秒，誤差為 4.1 毫秒，這與同一目標族群的已發表數據非常吻合。

I think your second question related to the selection and the time of the selection for the co-key secondaries in LIFT and the time we have. The answer is we have plenty of time, because in quarter two, within quarter two, we will have unblinded results from ACT, which allows us irrespective of an effect size that we may or may not see. We will see the sources of variance. And that is particularly valuable for us because it really allows us to optimize the statistical analysis plan for LIFT.

我認為您的第二個問題與 LIFT 中共同關鍵次要研究的選擇和時間以及我們擁有的時間有關。答案是，我們有充足的時間，因為在第二季度內，我們將獲得 ACT 的非盲結果，這使我們能夠不受可能或可能看不到的效應大小的影響。我們將看到變異的來源。這對我們來說尤其有價值，因為它確實使我們能夠優化 LIFT 的統計分析計劃。

And on that occasion, we will then also define which additional co-key secondary endpoint in addition to ADAS-Cog11 will be defined. And usually, the last moment to file the statistical analysis plan is before unblinding, but I think we have a plenty of time to do that way before.

屆時，我們還會確定除 ADAS-Cog11 之外，還有哪些額外的共同關鍵次要終點。通常，提交統計分析計劃的最後時刻是在揭盲之前，但我認為我們之前有充足的時間來完成這項工作。

And the first question, you were -- please quickly give me a reminder of what you were --

第一個問題，請快速提醒我你當時在問什麼——

Yeah. No. Thanks, Hans. I was just kind of making sure that you agree with the premise that you likely need to hit cleanly on both the cognitive and functional endpoint for registration. And there is one, I think it's Mark's prepared remarks surrounding sharing ADAS-Cog in the top line, but it doesn't sound like you're going to share any functional scales. I'm honestly a little bit sure why that is, but yeah, maybe you can just give any more color would be great.

是的。不，謝謝，漢斯。我只是想確認你是否同意這個前提，即你可能需要清晰地達到認知和功能兩個端點才能註冊。還有一點，我想是馬克準備好的關於在最上面分享ADAS-Cog的評論，但聽起來你不會分享任何功能量表。說實話，我有點明白為什麼會這樣，不過，是的，也許你能再多解釋一下就更好了。

Yeah. Look, I think in keeping with the philosophy of the FDA, it is really important to look at the totality of the data. And that requires a bit of time, and this will also require a good discussion.

是的。我認為，依照FDA的理念，審查所有數據非常重要。這需要一些時間，也需要充分的討論。

And so beyond the initial publication via press release, we are obviously aiming to discuss this totality of the ACT findings in the context of a scientific conference as quickly as possible. I think that is in any event the better place for such an in-depth analysis, which by the way, let me add that to what was said before, also has to include, of course, safety and tolerability data.

因此，除了透過新聞稿首次發布之外，我們顯然計劃盡快在科學會議上討論ACT研究的全部發現。我認為無論如何，這都是深入分析的最佳地點。順便說一句，除了之前提到的，分析還必須包括安全性和耐受性數據。

And just to remind you that this is only 77 patients, right? So it's just going to be exploratory on the co-secondary endpoints?

提醒一下，這只有77名患者，對吧？所以這只是對聯合次要終點的探索性研究？

Correct.

正確的。

That's not (inaudible). Thanks for that.

那不是（聽不清楚）。謝謝。

Yeah. Totally understood. Thanks very much.

是的。完全理解。非常感謝。

Thanks, Paul.

謝謝，保羅。

Corinne Jenkins, Goldman Sachs.

高盛的科琳‧詹金斯 (Corinne Jenkins)。

Hey. Good afternoon, everyone. I just had one quick follow up. In terms of the ACT-AD study, have you taken a blinded look at the data? And if so, is there any color that you can provide on that?

大家下午好。我只想快速跟進一下。關於ACT-AD研究，你們是否對數據進行了盲測？如果是的話，您能提供一些細節嗎？

We are very careful in this type of approach. And since the trial is still blinded, I cannot comment on any such behind its findings.

我們對這種方法非常謹慎。由於該試驗仍處於盲法狀態，我無法對其結果背後的任何因素發表評論。

And then, I think maybe just an enrollment update on LIFT. Since you announced the expansion, I'm just curious if there's -- I know part of it that was used are really good enrollment and then we had Omicron. So I'm curious if you could provide any color on the pace of enrollment in LIFT and actually the thoughts in the data timing there?

然後，我想也許只是 LIFT 的招生更新。自從您宣布擴展以來，我很好奇——我知道其中一部分招生情況非常好，然後我們又有了 Omicron。所以，我很好奇您能否提供一些關於 LIFT 招生速度的細節，以及數據時間安排方面的想法？

Yeah. Corinne, we're still shooting for getting complete enrollment by the end of Q3. So that's what we're pushing for.

是的。科琳，我們仍然在爭取在第三季末完成全部註冊。這就是我們正在努力的目標。

And will you announce that when you hit enrollment [positions], or is that some data you won't disclose?

當你們開始招生時，你們會宣布這個消息嗎？或者你們不會透露這些數據？

No, no. We will definitely -- we will announce that as we've completed enrollment.

不，不。我們一定會——我們會在招生完成後宣布。

Great. Thank you so much.

太好了。非常感謝。

Thanks, Corinne.

謝謝，科琳。

Jason Butler, JMP Securities.

JMP證券的Jason Butler。

Hey. Thanks for taking the questions. Just one on the cognition trends you look for in ACT. Mark, I think you said you're not going to show the graphs, but just how should we think about the potential time course of impact on cognition here versus the relatively rapid effects you see on P300, also on P300 in the Phase 1 trial. The correlation there between P300 and cognition timelines for other drugs, is that relevant here?

嘿。謝謝你回答這些問題。我只想問一個關於你在ACT研究中尋找的認知趨勢的問題。馬克，我記得你說過你不會展示圖表，但我們應該如何看待它對認知的潛在時間進程，以及你在P300上看到的相對快速的影響，以及在1期試驗中對P300的影響。其他藥物的P300和認知時間線之間的相關性，這裡適用嗎？

Yeah. So let me answer the first. Jason's question about timing. Right? So we're looking for what happens over six months. So we will, at the end of six months, we will announce that there was a difference of X, Y, and Z for P300, right, and ADAS-Cog 11, just to show a difference. Because truly, the ADAS-Cog 11 is really, really important. But Hans, do you want to invite many of that? Hans can you mention when the placebo effect goes away over time?

是的。那我來回答第一個問題。傑森關於時間的問題。對吧？我們關注的是六個月後的情況。所以，在六個月結束時，我們會公佈 P300 和 ADAS-Cog 11 在 X、Y 和 Z 方面的差異，只是為了展示差異。因為 ADAS-Cog 11 真的非常重要。但漢斯，你想邀請很多人嗎？漢斯，你能不能說安慰劑效應會隨著時間的推移而消失？

Yeah. Well, in this type of trial you would expect placebo response anywhere between six and 12 weeks, but this is then disappearing. And that's why we are running 26-week trials to really escape any potential placebo effect.

是的。在這種類型的試驗中，你通常會在6到12週之間出現安慰劑效應，但這種效應很快就會消失。這就是為什麼我們進行26週的試驗，以真正避免任何潛在的安慰劑效應。

I wanted to add that we are -- after entry of the baseline, we have the first assessment of both P300 and ADAS-Cog 11 after two weeks. And then we have multiple visits ending with visit eight after 26 weeks. So of course, we are at all these timepoints looking at the development of P300 and ADAS-Cog 11, hoping to show that their development goes hand-in-hand in replication of the data as you know from the literature.

我想補充一點，在基線開始後，我們會在兩週後對 P300 和 ADAS-Cog 11 進行首次評估。之後我們會進行多次隨訪，最後在 26 週後進行第八次隨訪。所以，當然，我們會在所有這些時間點觀察 P300 和 ADAS-Cog 11 的發展，希望能夠證明它們的進展與文獻中提到的資料複製過程相輔相成。

Got it. And then just a couple of quick questions on the SHAPE trial.

明白了。接下來我簡單問幾個關於SHAPE試驗的問題。

Could you just maybe remind us of the mechanistic rationale in PDD and DLB? Do you see the same kind of dysfunction in the HGF/MET system that you see in Alzheimer's patients? And then I think it's pretty clear what potential impacts of the ACT results on the LIFT trial, but are there any changes that you would consider making to the SHAPE trial based on the results you get from ACT? Thanks.

能否簡單介紹一下PDD和DLB的機制原理？您是否觀察到HGF/MET系統的功能障礙與阿茲海默症患者相同？我認為ACT研究結果對LIFT試驗的潛在影響已經非常明確，但您是否會根據ACT研究的結果考慮對SHAPE試驗做出一些調整？謝謝。

Yeah. Look, the answer is no. So this is really opening up a quite different type of dementia investigation. And we are indeed in a situation where P300 latency extension has been described also for Parkinson's disease dementia.

是的。答案是否定的。所以這其實開啟了一種截然不同的失智症研究。我們確實處於這樣的情況：帕金森氏症癡呆症也出現了P300潛伏期延長的描述。

And the underlying mode of action rationale is very much in keeping with what we have been presenting and end up deciding before. Mainly, it's the whole cascade of neurotrophic effect that do not stop at the nigrostriatal system. So the specific neuronal population that is affected in Parkinson's disease, at least in the beginning before it is spreading out, could theoretically benefit from positive modulation of the HGF/MET system. And that's what we are leveraging.

其根本作用機制與我們先前提出並最終確定的方案非常一致。主要在於，它涉及的是整個神經營養效應的級聯，而不僅限於黑質紋狀體系統。因此，理論上，帕金森氏症中受影響的特定神經元群體，至少在疾病擴散之前的初期，可以從 HGF/MET 系統的正向調節中受益。而這正是我們正在利用的。

Okay, great. That's helpful. Thanks for taking the questions.

好的，太好了。這很有幫助。感謝您回答這些問題。

Thanks, Jason.

謝謝，傑森。

Thank you. I'll now turn the call back over to Dr. Mark Litton for any closing remarks.

謝謝。現在我將把電話轉回給馬克·利頓博士，請他做最後發言。

Thank you everyone for taking the time today. And we're really looking forward to an exciting 2022. Thanks so much.

感謝大家今天抽出時間。我們非常期待令人興奮的2022年。非常感謝。

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.

女士們，先生們，今天的電話會議到此結束。感謝各位的參與，現在可以掛斷電話了。