Cassava Sciences Inc (SAVA) 2024 Q3 法說會逐字稿

Ladies and gentlemen, welcome to Cassava Sciences' report for the third-quarter 2024. (Operator Instructions) As a reminder, this audio webcast is being recorded.

女士們，先生們，歡迎閱讀 Cassava Sciences 2024 年第三季報告。 （操作員指示）提醒一下，此音訊網路廣播正在錄製中。

During this call, and the question-and-answer session afterwards, representatives of Cassava Sciences may make what are known as forward-looking statements. A forward-looking statement is one that is not historical fact. Forward-looking statements are not guarantees, and they involve risks, uncertainties, and assumptions. Such statements represent current expectations or beliefs concerning future events or future performance. Forward-looking statements are predictions only based upon information currently available to the company.

在本次電話會議以及隨後的問答環節中，Cassava Sciences 的代表可能會做出所謂的前瞻性陳述。前瞻性陳述並非歷史事實。前瞻性陳述不是保證，並且涉及風險、不確定性和假設。這些陳述代表了對未來事件或未來表現的當前期望或信念。前瞻性陳述僅基於公司目前可用的資訊所做的預測。

Actual events or results could differ materially from those made in any forward-looking statements due to a number of factors, risks, and uncertainties. Please refer to Cassava Sciences' recent filings with the SEC, including Forms 10-K and 10-Q, for a description of the factors that could cause the events or results to differ materially from those made in forward-looking statements.

由於多種因素、風險和不確定性，實際事件或結果可能與任何前瞻性陳述中所述的存在重大差異。請參閱 Cassava Sciences 最近向美國證券交易委員會提交的文件，包括 10-K 表和 10-Q 表，以了解可能導致事件或結果與前瞻性陳述大不相同的因素。

Importantly, this conference call contains time-sensitive information that is accurate only as of the date of the live webcast, November 7, 2024. Except as required by law, the company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this webcast.

重要的是，本次電話會議所包含的時間敏感資訊僅在現場網路直播日期（2024 年 11 月 7 日）時準確。除法律要求外，本公司不承擔修改或更新任何前瞻性陳述以反映本次網路直播日期之後的事件或情況的義務。

It's now my pleasure to turn today's meeting over to Rick Barry, President and Chief Executive Officer. The floor is yours.

現在我很高興將今天的會議交給總裁兼執行長 Rick Barry。現在請您發言。

Well, thank you, Noel, for the introduction. Good morning, everyone, and thank you for joining us. With me today is Chris Cook, our Swiss Army Knife and also our General Counsel. As well as Eric Schoen, who I think of as the Chancellor to the Exchequer, also known as our Chief Financial Officer. Dr. Jim Kupiec, our Chief Medical Officer and the star of the August investor call, will not be able to join us today.

好吧，謝謝諾埃爾的介紹。大家早安，感謝大家的收看。今天和我在一起的是克里斯庫克 (Chris Cook)，他是我們的瑞士軍刀，也是我們的總法律顧問。還有艾瑞克舒恩 (Eric Sc​​hool)，我認為他是財政大臣，也被稱為我們的財務長。我們的首席醫療官、八月份投資者電話會議的明星 Jim Kupiec 博士今天將無法參加我們的會議。

As you know, we announced the last patient, last visit of our first Phase III trial, ReThink-ALZ, several weeks ago. Database cleanup is ongoing. This is a routine process that takes place at the end of every clinical trial. The purpose is to ensure the accuracy of all information in the database before it is locked and the statistical analysis begins.

如您所知，我們幾週前宣布了第一階段 III 期試驗 ReThink-ALZ 的最後一位患者和最後一次就診。資料庫清理工作正在進行中。這是每次臨床試驗結束時進行的常規過程。目的是在鎖定資料庫並開始統計分析之前確保資料庫中所有資訊的準確性。

We expect to announce the top-line results of the trial before the end of this year. This is an exciting time for us. We remain optimistic that we will see promising data that could ultimately lead to a best-in-class treatment for Alzheimer's, but we will all see whether our optimism is warranted or misplaced before too long.

我們預計將在今年年底前公佈該試驗的最終結果。對我們來說這是一個令人興奮的時刻。我們仍然樂觀地認為，我們將看到有希望的數據，最終可能帶來治療阿茲海默症的最佳方法，但不久之後，我們就會看到我們的樂觀是否有道理或是否有誤。

There really isn't much more we can say about the trial until our data are unblinded and revealed to us by our biostatisticians at Panthera Corporation. We look forward to sharing our data with you. As a reminder, we expect to report our biomarker data from a subset of patients from the ReThink study at the same time as our cognition data. This will involve approximately 100 patients and provide plasma biomarker results for P-tau217; neurofilament light chain, otherwise known as NfL; Glial fibrillary acidic protein known as GFAP; and total tau.

在 Panthera Corporation 的生物統計學家揭開我們的數據之前，我們真的不能透露太多有關該試驗的資訊。我們期待與您分享我們的數據。提醒一下，我們希望同時報告來自 ReThink 研究中的一部分患者的生物標記數據和認知數據。這將涉及大約 100 名患者並提供 P-tau217 的血漿生物標記結果；神經絲輕鏈，也稱為 NfL；膠質纖維酸性蛋白，稱為 GFAP；和總 tau。

I want you to be reassured about a couple of things. Given the scrutiny this company has been under, you can expect that we will measure twice and cut once before we report our results. We will be especially careful to be sure that what we report is accurate to the best of our ability. Also, we will report our data to you, whether it is good, bad, or ambiguous.

我希望你能放心幾件事。鑑於該公司一直受到的嚴格審查，你可以預料到，在報告結果之前，我們會三思而後行。我們將特別小心，盡可能確保我們所報告的內容準確無誤。此外，我們會向您報告我們的數據，無論它是好的、壞的還是模糊的。

Last week, a team of us from Cassava attended the Clinical Trials for Alzheimer's Disease, or CTAD, conference in Madrid. First, I have to tell you how impressed I am by our clinical team, which is headed by Dr. Kupiec. If you aren't aware, Jim is a highly respected member of the Alzheimer's research community, having led Pfizer's Neuroscience group for many years, and he has surrounded himself with a team of professionals who are cut from the same dedicated cloth. Jim and his team have assembled a virtual all-star team of private investigators for our Phase III program.

上週，我們來自 Cassava 的團隊參加了在馬德里舉行的阿茲海默症臨床試驗 (CTAD) 會議。首先，我必須告訴你們，我們的臨床團隊給我留下了深刻的印象，該團隊由庫皮克博士領導。如果你不知道，吉姆是阿茲海默症研究界備受尊敬的成員，多年來一直領導輝瑞的神經科學團隊，他身邊還有一支同樣敬業的專業團隊。吉姆和他的團隊為我們的第三階段計劃組建了一支虛擬全明星私人調查員團隊。

I had the privilege to meet many of the principal investigators from our Phase III program as well as the people who ran the operation of their sites. Many of the investigators are considered the best in their business. These are the same investigators who were also involved, for example, in the successful trials for Eli Lilly's donanemab and Eisai's lecanemab. The many doctors I met decided to participate in our trials because they made their own assessment of simufilam, and they believe that based on a hypothesized mechanism of action, the drug had a reasonable chance of working.

我有幸見到了我們第三階段計劃的許多首席研究員以及負責他們站點運營的人員。許多調查員被認為是其行業內的佼佼者。這些研究人員也參與了禮來公司的 donanemab 和衛材公司的 lecanemab 的成功試驗。我遇到的許多醫生決定參加我們的試驗，因為他們對西姆非侖做出了自己的評估，並且他們相信，基於假設的作用機制，該藥物有合理的發揮作用的機會。

If the trials are successful, they know it would make a difference in the lives of their patients. These doctors live for innovation in Alzheimer's drug discovery and they want to be involved with something that could make a real difference. They know better than anyone that there is no sure thing in Alzheimer's, but they believe the drug needed to be studied.

他們知道，如果試驗成功，這將會改變患者的生活。這些醫生致力於阿茲海默症藥物研發的創新，他們希望參與一些能真正帶來改變的事情。他們比任何人都清楚，對於治療阿茲海默症，沒有萬無一失的方法，但他們認為這種藥物需要研究。

Additionally, I believe they chose to be involved because of the trust they have in Jim and his remarkable team. I am really proud to be associated with this team and I'm truly grateful to these courageous doctors, who have given simufilam the opportunity to demonstrate its potential by participating in our trials, when it would have been so much easier to have just said no.

此外，我相信他們選擇參與是因為他們對吉姆和他出色的團隊的信任。我真的很自豪能加入這個團隊，我由衷感謝這些勇敢的醫生，他們給了 Simufilam 機會，透過參與我們的試驗來展示其潛力，而如果我直接拒絕的話，那就容易多了。

We witnessed a lot of very interesting presentations at CTAD last week, but there are a few that I want to focus on. You may recall that in our last call, Jim Kupiec spoke of what he calls the biomarker revolution in Alzheimer's disease.

上週我們在 CTAD 上見證了很多非常有趣的演講，但我想重點談談其中的幾個。您可能還記得，在我們上次通話中，吉姆·庫皮克 (Jim Kupiec) 談到了他所謂的阿茲海默症的生物標記革命。

There's been an explosion of innovation in plasma and cerebral spinal fluid biomarkers over the last several years. We now find ourselves at a point where commercially available plasma biomarker tests are demonstrating an extremely high correlation with amyloid beta positivity in the brain as measured by CSF or PET scans. Neuroscientists believe that the presence of amyloid beta is one of the key hallmarks of Alzheimer's. Research indicates that a patient with amyloid beta in clinical symptoms has Alzheimer's or if asymptomatic is clearly at a high risk of developing the disease.

近幾年來，血漿和腦脊髓液生物標記的創新呈現爆炸性成長。我們現在已經發現，市售的血漿生物標記測試與腦脊髓液或 PET 掃描測量的大腦中的澱粉樣蛋白 β 陽性具有極高的相關性。神經科學家認為，澱粉樣β蛋白的存在是阿茲海默症的主要標誌之一。研究表明，臨床症狀中存在β澱粉樣蛋白的患者患有阿茲海默症，或無症狀的患者顯然患上該疾病的風險很高。

One CTAD presentation reported data from biomarker assays developed by companies such as Eli Lilly, Fujirebio, and C2N Diagnostics. All three showed positive predictive values, that is the probability that a person has the disease given a positive test result of over 90%. I think you'll agree that sure beats the postmortem analysis.

CTAD 的一份報告報告了由 Eli Lilly、Fujirebio 和 C2N Diagnostics 等公司開發的生物標記檢測數據。這三項檢測均顯示出陽性預測值，即如果檢測結果呈陽性，則該人患有該疾病的機率超過 90%。我想你會同意這肯定比事後分析更有效果。

Why am I bringing this up? Because these types of tools have the power to change the way medicine is practiced specifically with respect to the Alzheimer's patient journey. You may recall last quarter that I mentioned Cassava's planning for success. I specifically told you we were significantly expanding our manufacturing capabilities, including ramping up our active pharmaceutical ingredient production. Those activities are being informed by a commercial plan that we've been developing with the help of an experienced industry consultant.

我為什麼要提起這件事？因為這些類型的工具有能力改變醫療實踐方式，特別是針對阿茲海默症患者的治療歷程。您可能還記得上個季度我曾提到 Cassava 的成功規劃。我特別告訴你們，我們正在大幅擴大我們的製造能力，包括提高我們的活性藥物成分的產量。我們在一位經驗豐富的行業顧問的幫助下制定了一項商業計劃，以指導這些活動。

I'd like to share with you some of the things that we're thinking about and just beginning to map out. Before I do that, however, you need to understand that I'm not about to give you forecasts. We do not know how the trials will read out, and I'm not trying to hint that we know we're going to be successful. We do not. I'm just describing our vision of the potential opportunity, how we could focus on commercial efforts on that opportunity, and what the market could look like.

我想與大家分享一些我們正在思考和開始規劃的事情。然而，在我這樣做之前，你需要明白，我不會給你預測。我們不知道試驗結果會如何，我並不是暗示我們知道自己一定會成功。我們沒有。我只是在描述我們對潛在機會的願景，我們如何專注於該機會的商業努力，以及市場可能會是什麼樣子。

We all know that up until recently, physicians have had very few tools to diagnose and treat people with Alzheimer's. Cholinesterase inhibitors are still widely prescribed, even though they are not disease-modifying. Some doctors are prescribing the recently approved monoclonal antibody-based drugs from Lilly and Eisai. Although these new drugs have demonstrated disease-modifying capabilities, they have their own well-known limitations.

我們都知道，直到最近，醫生仍然擁有很少的工具來診斷和治療阿茲海默症患者。儘管膽鹼酯酶抑制劑不能改善病情，但仍被廣泛使用。一些醫生正在開禮來和衛材最近批准的單株抗體藥物。儘管這些新藥已顯示出改善疾病的能力，但它們也有其自身眾所周知的限制。

The primary care physician is typically the first to diagnose or suspect Alzheimer's. To date, these doctors have had few options at hand to help their patients. In fact, research tells us that 85% of patients get their initial diagnosis from the PCP, but quite often, diagnosis is delayed until a patient is in a moderate and advanced stages of the disease due to many factors, including diagnostic uncertainty.

初級保健醫生通常是第一個診斷或懷疑患有阿茲海默症的人。到目前為止，這些醫生幾乎沒有辦法幫助他們的病人。事實上，研究表明，85% 的患者是從 PCP 獲得初步診斷的，但由於診斷不確定性等多種因素，診斷常常被推遲到患者疾病處於中期和晚期。

Some PCPs don't feel adequately trained to determine a definitive diagnosis. Doctors also struggle with time constraints, stigma, and fear of causing the patient emotional distress, especially when treatment options are so limited. We envision a world where that PCP does have a treatment option that is superior to cholinesterase inhibitors and doesn't come with the challenges posed by the new monoclonal antibody-based drugs. If that option is twice a day more oral medication with an excellent safety profile, the PCP would be in a much better position to treat his or her patient.

有些 PCP 感覺自己沒有接受過足夠的培訓，無法做出明確的診斷。醫生還要面對時間限制、恥辱感以及害怕給患者造成情緒困擾等問題，尤其是在治療選擇非常有限的情況下。我們所設想的世界是，PCP 確實有一種優於膽鹼酯酶抑制劑的治療選擇，而且不會帶來新型單株抗體藥物的挑戰。如果該選擇是每天兩次口服具有良好安全性的藥物，那麼 PCP 將能夠更好地治療其患者。

Now couple that treatment with a readily available, cost-effective, and accurate plasma biomarker diagnostic assay and PCPs can actually diagnose and treat their patients. Reimagine the number of moments we can convert if we can accelerate the point at which treatment is initiated by preparing PCPs for this revolutionary opportunity. If we can realize our vision, the doctor could have high confidence in making a diagnosis and then prescribe a drug that is convenient, safe, and effective.

現在，將這種治療方法與隨時可用、經濟高效且準確的血漿生物標記診斷檢測結合起來，PCP 可以真正診斷和治療他們的患者。想像一下，如果我們能夠透過讓 PCP 為這項革命性機會做好準備，來加速治療的開始，那麼我們可以轉化多少個瞬間。如果我們能夠實現我們的願景，醫生就可以高度自信地做出診斷，然後開出方便、安全、有效的藥物。

What does the market look like? We know there is approximately 7 million patients currently diagnosed with Alzheimer's disease in the United States. But we also know that the disease is underdiagnosed. We know that half of these diagnosed Alzheimer's patients are considered to be mild. Our research tells us that 1.2 million Alzheimer's patients are diagnosed in the US each year, but only about 55% of Alzheimer's patients are treated with a prescription drug approved for the disease.

市場情況怎麼樣？我們知道，目前美國有大約 700 萬患者被診斷出患有阿茲海默症。但我們也知道這種疾病還未被充分診斷​​。我們知道，這些確診的阿茲海默症患者中有一半屬於輕度。我們的研究表明，美國每年有 120 萬名阿茲海默症患者被診斷出來，但只有大約 55% 的阿茲海默症患者能夠使用獲準治療該疾病的處方藥進行治療。

I want you to reimagine Alzheimer's disease treatment possibilities should simufilam's approval become a reality. Simufilam is potentially a first-of-a-kind, disease-modifying, specialty-like treatment that could be prescribed by a PCP. This is the scenario for which we are planning if our Phase III trials are successful. Even if simufilam is successful, it may still take more time than we would prefer before physicians become comfortable using biomarkers like P-tau217 to diagnose their patients. We understand that it will take brilliant execution on our part, even if simufilam shows the kind of results we would all like to see.

我希望你們重新設想一下，一旦 Simufilam 的批准成為現實，阿茲海默症的治療可能性。 Simufilam 可能是一種首創的、可改變病情的、類似專科的治療方法，可以由 PCP 開立。如果我們的第三階段試驗成功，這就是我們所規劃的情景。即使 simufilam 成功了，醫生可能仍然需要花費比我們所希望的更多的時間來習慣使用 P-tau217 等生物標記來診斷患者。我們明白，即使 simufilam 顯示了我們都希望看到的結果，我們也需要出色的執行。

We are up for the challenge. And if the past few months have proven anything about this, is that this team doesn't shy away from challenging situations. We lean in and we work our way through them. Our northstar is to be on the front lines of transforming the way this disease is diagnosed and treated so that the patients can experience the moments they deserve with their loved ones. Well, thank you for indulging the vision that motivates all of us at Cassava.

我們已準備好接受挑戰。如果說過去幾個月的情況證明了這一點，那就是這支球隊不迴避挑戰。我們傾力前行，並努力解決這些問題。我們的目標就是站在改變這種疾病的診斷和治療方法的前沿，以便患者能夠與親人一起享受他們應得的時光。好吧，感謝您對激勵 Cassava 所有人的願景的認可。

I'd now like to turn the call over to Eric Schoen who will provide you with a financial update. Eric?

現在我想將電話轉給 Eric Sc​​hool，他將向您提供財務最新情況。埃里克？

Thanks, Rick. Let's start with our cash and cash equivalents. We ended the September quarter with $149 million in cash. That balance is expected to be sufficient for operations through the conclusion of both ongoing Phase III trials and into calendar 2026.

謝謝，里克。讓我們從現金和現金等價物開始。截至九月當季，我們的現金餘額為 1.49 億美元。預計這一餘額將足以維持正在進行的第三階段試驗以及到 2026 年的運作。

Separate from the $149 million of cash is $40 million of restricted cash. That is a new and temporary line on our balance sheet. That bucket is being held in an escrow account for the sole purpose of satisfying the monetary penalty as part of our settlement with the Securities and Exchange Commission that we announced in September. That settlement is still subject to approval by the U.S. District Court, after which the escrow account will be released to the SEC. We don't anticipate any issues with court approval.

除了 1.49 億美元現金外，還有 4,000 萬美元的受限現金。這是我們資產負債表上的一條新的、暫時的線。該資金被存放在託管帳戶中，其唯一目的是用於支付我們 9 月宣布的與美國證券交易委員會達成的和解協議中所規定的罰款。和解協議仍需獲得美國地方法院的批准，之後託管帳戶將移交給美國證券交易委員會。我們預計法院批准不會有任何問題。

On the spending side of the equation, net cash used in operations during the nine months ended September 30 was $55.7 million, or roughly $18.5 million each quarter. Net cash used in operations for the second half of 2024 is expected to be between $80 million and $90 million. This is consistent with our previous guidance. That estimate includes the $40 million settlement I just referenced.

在支出方面，截至 9 月 30 日的九個月內，營運中使用的淨現金為 5,570 萬美元，或每季約 1,850 萬美元。預計 2024 年下半年營運所用淨現金將在 8,000 萬美元至 9,000 萬美元之間。這與我們先前的指導一致。這個估計包括我剛才提到的4000萬美元的和解金。

Considering this spending level, we believe we will end the year with between $117 million to $127 million in cash. That is the same amount as guided to in our last quarterly call. No change.

考慮到這一支出水平，我們認為今年年底我們的現金餘額將達到 1.17 億美元至 1.27 億美元之間。這與我們上次季度電話會議中預測的金額相同。沒有變化。

Now on to our profit and loss for the quarter. Our net loss was $27.9 million or $0.58 per share in Q3 compared to a net loss of $25.7 million or $0.61 per share for the same period in 2023. Research and development expenses for Q3 were $17.7 million. This compared to $23.6 million for the same period last year. R&D expenses are naturally decreasing as more and more patients complete the Phase III studies and roll over into the lower-cost open-label study.

現在來看看本季的損益情況。我們第三季的淨虧損為 2,790 萬美元或每股 0.58 美元，而 2023 年同期的淨虧損為 2,570 萬美元或每股 0.61 美元。第三季的研發費用為 1,770 萬美元。相比之下，去年同期的營收為 2,360 萬美元。隨著越來越多的患者完成第三階段研究並轉入成本較低的開放標籤研究，研發費用自然會減少。

General and administrative expenses for Q3 were $12.9 million compared to $4.3 million for the same quarter last year. The significant increase was due primarily to higher legal-related expenses, which were partially offset by insurance recoveries, increased compensation costs, including severance costs, as well as an increase in stock-based compensation expense due to new awards granted in late 2023 and 2024.

第三季的一般及行政開支為 1,290 萬美元，而去年同期為 430 萬美元。大幅成長主要歸因於法律相關費用增加，但部分被保險追償費用、包括遣散費在內的補償成本增加以及由於 2023 年末和 2024 年授予的新獎勵導致的股票薪酬費用增加所抵消。

Now I'll turn it back to Rick.

現在我將話題轉回給 Rick。

Thank you, Eric. Okay. Operator, could you please open the line for questions?

謝謝你，埃里克。好的。接線員，您可以開通熱線來回答問題嗎？

(Operator Instructions) Vernon Bernardino, HC Wainwright.

（操作員指示） Vernon Bernardino，HC Wainwright。

Congratulations on the progress. Looking forward to those top-line results. The only question I really had is something that has been developed and I was just wondering if I could get an update on status. And that is the status of SavaDx. One of thing that would be important for simufilam's success would be the biomarker diagnostic results as you mentioned. Obviously, p-tau was something that can be used for a biomarker. But I was wondering if you could give us an update on SavaDx.

祝賀你取得進展。期待這些最重要的結果。我真正唯一的疑問是一些已經開發的事情，我只是想知道是否可以獲得狀態更新。這就是 SavaDx 的現況。正如您所說，對 simufilam 的成功至關重要的因素之一是生物標記診斷結果。顯然，p-tau 可以用作生物標記。但我想知道您是否能向我們提供有關 SavaDx 的最新消息。

Sure. Thanks, Vernon. In a world where the diagnostic tools are becoming so good, particularly P-tau217, we wonder where Cassava DX is going to fit into that. And that doesn't mean we're not going to pursue it, we will. But we're a small company with limited resources, and there are other ways that we could spend our money such as looking at additional indications for simufilam.

當然。謝謝，弗農。在這個診斷工具越來越好，特別是 P-tau217 的世界裡，我們想知道 Cassava DX 將如何適應。但這並不意味著我們不會去追求它，我們會去追求。但我們是一家資源有限的小公司，我們也可以透過其他方式來花錢，例如研究 simufilam 的其他適應症。

And so there's a lot to think about once we have results, how do we want to allocate our capital. Do we want to put it into a diagnostic that may be an improvement over some of the diagnostics that are out there? Or do we want to pursue other indications? That's the best answer I can give you.

一旦我們有了結果，我們就有很多事情要考慮，例如我們要如何分配我們的資本。我們是否想將其放入可能比現有的某些診斷方法有所改進的診斷方法中？或者我們想尋求其他跡象？這是我能給你的最好答案。

Terrific. And as a follow-up, I was just wondering again. What kind of detail will you be providing in the top-line results before year-end as far as biomarkers are concerned?

了不起。作為後續問題，我只是再次感到疑惑。就生物標記而言，您將在年底之前在頂線結果中提供什麼樣的細節？

So on the biomarkers, we will be measuring P-tau217, NFL, GFAP, total tau, and I think that's it. And remember, we talked about this. In the second trial, we have a lot more. There's more patients, there's some CSF analysis, and there's also imaging analysis.

因此在生物標記方面，我們將測量 P-tau217、NFL、GFAP、總 tau，我認為就這些了。記住，我們討論過這個問題。在第二次試驗中，我們還有很多事情要做。有更多的病人，有一些腦脊髓液分析，還有影像分析。

And can you remind us the time point at which these in the Phase III are being measured?

您能提醒我們第三階段測量這些的時間點嗎？

From baseline to last visit.

從基線到最後一次訪問。

Baseline and last visit only?

僅基線和最後一次訪問？

I believe, so. I mean, I could get back to you. There might have been an interim draw, but I have it in my head that it was the baseline and finish.

我相信，如此。我的意思是，我可以回覆你。中間可能出現了平局，但我心裡明白，這就是底線和終點。

Looking forward to the results that you just mentioned.

期待您剛才提到的結果。

We are too. Thanks.

我們也是。謝謝。

Elemer Piros, Rodman.

埃萊默·皮羅斯，羅德曼。

Yes. What I'd like to verify Rick is that a statistical analysis plan has been locked down with the FDA, and maybe a part of that question is, you're talking about the ADAS-Cog and the ADL as co-primary end points. Would both of those or either of those would have to hit for success? And obviously, there is a different statistical treatment of either of those or both of those scenarios. If you could elaborate, please?

是的。我想向 Rick 核實的是，統計分析計劃已經與 FDA 敲定，也許這個問題的一部分是，您正在談論 ADAS-Cog 和 ADL 作為共同主要終點。是否需要兩者或其中一個才能成功？顯然，對於其中一種或兩種情況都有不同的統計處理。請詳細說明一下好嗎？

Sure. Thanks, Elemer, and thanks for the questions. There's been this, I don't know, misunderstanding about the SAP. And just to make it clear, so we submitted a statistical analysis plan to the FDA and you submit this to get their comments. And they gave us some comments, which are relatively minor.

當然。謝謝，Elemer，也謝謝您的提問。我不知道，有對 SAP 的誤解。為了說清楚，我們向 FDA 提交了一份統計分析計劃，您提交該計劃是為了獲得他們的意見。他們也給了我們一些評論，但這些評論相對較小。

Now we would be not very clever if we didn't take their comments into account and incorporate them in our plan. But we took their comments, we went back to Panthera and put their comments in, had Panthera make some changes. And then the important thing is that you have to sign the SAP before you lock your database, and we've done that.

如果我們不考慮他們的意見並將其納入我們的計劃，那我們就不是很聰明了。但我們採納了他們的意見，並回饋給了 Panthera，並把他們的意見納入其中，讓 Panthera 做出了一些修改。然後重要的是您必須在鎖定資料庫之前簽署 SAP，我們已經這樣做了。

As far as the endpoints of the trial, we have two primary endpoints, as you know: it's ADAS-Cog12 and its activities of daily living. And our SPA with FDA says we have to hit on both in order to call the trial a successful one. And there are secondary end points, et cetera, but they matter a lot less than hitting the primaries.

就試驗的終點而言，如您所知，我們有兩個主要終點：ADAS-Cog12 及其日常生活活動。我們與 FDA 簽訂的 SPA 表明，我們必須同時滿足這兩個要求，試驗才算成功。還有次要終點等等，但它們的重要性遠不及達到主要終點。

And Rick, the integrated endpoint of iADRS, is that out of the picture? Or is that relegated to as a secondary end point?

那麼 Rick，iADRS 的整合端點是否已經不存在了？還是這被降級為次要終點？

Yes, good question. It's a secondary endpoint.

是的，好問題。這是次要終點。

Okay. Now is there a preset analysis of mild AD patients only? And if you have to go to that sort of analysis, how does the statistics work there?

好的。現在有沒有隻針對輕度AD患者的預設分析？如果您必須進行這種分析，那麼統計數據是如何運作的？

There is. We are expecting to have an analysis of mild patients as well as moderate and then the combined. So I think, as you know, roughly 70% of the patients were mild in this trial. The rest are moderates.

有。我們希望對輕度患者、中度患者以及合併患者進行分析。所以我認為，如你所知，這次試驗中大約 70% 的患者病情較輕。其餘人都是溫和派。

Okay. And just one clarification of the Phospho-Tau measurement. I think the enrollment criteria was using Phospho-Tau 181 and you mentioned that you will provide analysis of Phospho-Tau 217 as how it may change due to treatment. If you could help us understand -- but I'm correct in assuming that and what's the significance of one versus the other? Has the field evolved into looking at Phospho-Tau 217 as a more prominent biomarker?

好的。只需對 Phospho-Tau 測量進行一點澄清。我認為入選標準是使用 Phospho-Tau 181，而您提到您將提供 Phospho-Tau 217 的分析，說明它可能如何因治療而改變。如果您能幫助我們理解——但我的假設是正確的，那麼一個與另一個相比的意義又是什麼？該領域是否已發展到將 Phospho-Tau 217 視為更突出的生物標記？

Yes, you got it, Elemer. When we started the trial, I think the scientific community with respect to Alzheimer's lean towards the pTau 181 as a better biomarker. But here we are three-plus years later. And I can tell you being at the conference last week, yes, people still talk a bit about 181. It's a pretty good tool. But 217 is what everybody in Alzheimer's is focused on right now. So I don't know, I think we're measuring 181 at the end of the trial as well. I don't think it's going to be that important of a biomarker.

是的，你明白了，埃萊默爾。當我們開始試驗時，我認為科學界對阿茲海默症的看法傾向於將 pTau 181 作為更好的生物標記。但三年多過去了。我可以告訴你，在上週的會議上，人們仍然在談論 181。這是一個非常好的工具。但 217 是目前所有阿茲海默症患者關注的焦點。所以我不知道，我認為我們在試驗結束時測量的結果也是 181。我不認為它會成為那麼重要的生物標記。

And maybe one last question. As you look through or work through the data cleanup, roughly what proportion of the total data you have been able to clean and set up for the analysis plan at this stage?

也許還有最後一個問題。當您查看或完成資料清理工作時，目前大致能夠清理並為分析計劃設定總資料的比例是多少？

And I can't blame you for asking the question. It's a great one. We don't want to go there.

我不會怪你問這個問題。這是一個很棒的經驗。我們不想去那裡。

So it's still by year-end.

所以還得等到年底。

By year-end, definitely.

到年底肯定會如此。

[Matthew Nachtrab]

[馬修·納赫特拉布]

Thanks for bringing me on the call. So the vision that you're laying out around the primary care physician is very exciting. I think all investors and humans are excited about that vision. What I wanted to talk about is, as I've studied the Phase II and placebo results of hundreds of AD studies, I believe that, hopefully, we'll repeat that in Phase III and show significant improvement for ADAS-Cog12. But I'm also considering a scenario of Phase III results showing that mild significantly improved, but an underperformance of moderate and potentially resulting in the population missing statistical significance.

感謝您讓我接聽電話。所以，您圍繞著初級保健醫生所描繪的願景非常令人興奮。我認為所有投資者和人類都對這個願景感到興奮。我想談的是，由於我研究了數百項 AD 研究的 II 期和安慰劑結果，我相信，希望我們能在 III 期重複這一點，並顯示 ADAS-Cog12 的顯著改善。但我也正在考慮這樣一種情況，即第三階段的結果顯示，輕度患者明顯改善，但中度患者表現不佳，可能導致人群缺乏統計意義。

I have two questions kind of related to that. First is, how are you thinking the company would navigate subset of patients performing great with the FDA and taking the drug to market? If it's the milds only that are significant. And then the second question I have is many families are reaching out to me asking, when they'll get access to the drug in the US and around the world. And if the drug does perform, what's your upper-level thoughts on when you think the drug could hit the market in the US and around the world?

我有兩個與此相關的問題。首先，您認為公司將如何引導一部分錶現良好的患者獲得 FDA 批准並將藥物推向市場？如果只有溫和的才是重要的。我的第二個問題是，許多家庭向我詢問，他們什麼時候能在美國和世界各地獲得這種藥物。如果該藥物確實有效，您認為該藥物何時會在美國和世界各地上市？

Very good question. So with respect to the potential results, and we're all speculating. Well, I guess the overarching thing is we don't want to rely on subgroup analysis. However, if we showed statistical significance in mild patients, and for some reason we miss our primary end points because of the moderates, we would have an interesting choice to make with respect to our ReFocus trial because we'd have the capability to revise our statistical analysis plan and resubmit to FDA to make the second trial -- put more of the alpha on the milds. That would be a really big decision to do it.

非常好的問題。因此，對於可能的結果，我們都在猜測。嗯，我想最重要的是我們不想依賴亞群分析。然而，如果我們在輕度患者中顯示出統計學意義，並且由於某種原因我們因為中度患者而錯過了主要終點，那麼我們將對我們的 ReFocus 試驗做出一個有趣的選擇，因為我們有能力修改我們的統計分析計劃並重新提交給 FDA 進行第二次試驗——將更多的 alpha 放在輕度患者身上。做出這個決定確實非常重大。

So with respect to subgroups, and I've spoken to a few investors about this, what we won't do is we're not going to pick out some niche group that seem to perform really well based on the drug and then try to convince investors that we're going to take that one over the goal line. That's just not a winning argument. But if you do have 70% of your trial with statistical significance and showing great results in milds, but it's the moderates that have killed your primary end point, that's a different story, and we would have to go and talk to the agency about that. So I wouldn't think that that situation is hopeless, but it's all going to depend on the data and how the agency responds to it.

因此，關於子群體，我已經與一些投資者談過這個問題，我們不會做的是，我們不會挑選出一些基於藥物表現似乎非常好的小眾群體，然後試圖說服投資者我們會將這個群體帶過目標線。這根本就不是一個有說服力的論點。但是，如果你的試驗中有 70% 具有統計意義，並且在輕度病例中顯示出很好的結果，但中度病例卻破壞了你的主要終點，那就另當別論了，我們必須去和該機構討論這個問題。所以我並不認為這種情況毫無希望，但這一切都取決於數據以及機構如何應對。

The second question about when will it be available, really a good one. We're kind of thinking, in all likelihood, it would be late summer, early fall would be an optimistic -- I'm sorry, late summer, early fall of 2026, not next year. Eric, the heart attack that he was just about to have because of it.

第二個問題關於什麼時候可以上市，這確實是一個好問題。我們覺得，最有可能的是，那會是夏末秋初，比較樂觀的估計是——抱歉，是 2026 年夏末秋初，而不是明年。艾瑞克，他差點因此心臟病發作。

Let's do it.

我們開始做吧。

There's a lot that depends on that. But I think that's a realistic target to get to market. You could make some really aggressive assumptions that I don't think I would necessarily make to get maybe a few months off that, but that's probably the right ballpark.

很多事情都取決於此。但我認為，這是進入市場的現實目標。您可以做出一些非常激進的假設，我不認為我一定會做出這樣的假設，也許幾個月後就會實現，但這可能是正確的估計。

I'd like another question, if you don't mind. Can you elaborate a little bit on what other indications you guys think there is the most potential impact from simufilam and how you might prioritize which indications you would pursue after you get past the Phase III for Alzheimer's?

如果您不介意的話，我還想問另一個問題。您能否詳細說明一下，您認為 Simufilam 最有可能對哪些其他適應症產生影響，以及在完成阿茲海默症的 III 期臨床試驗後，您將如何優先考慮哪些適應症？

Well, I don't want to go in too much of detail. There's a lot of theoreticals, where we have some scientific work that was done in the past, but we got to think about how we're going to allocate the resources and the probability of success. There is one indication that I think most people who know the company pretty well are aware of, and that is there was a study done by a professor at Yale, which was really a pretty fascinating study, where she took our drug and built an animal model based upon tuberous sclerosis, the childhood epilepsy part of it.

好吧，我不想說得太詳細。有很多理論，我們過去做過一些科學工作，但我們必須考慮如何分配資源和成功的可能性。我認為，大多數了解該公司的人都知道一個跡象，那就是耶魯大學的一位教授所做的研究，這確實是一個非常有趣的研究，她服用我們的藥物並建立了基於結節性硬化症（兒童癲癇部分）的動物模型。

And she's absolutely convinced that the drug will work in that indication. That would be an indication that would not require enormous trials, huge resources. You get an answer pretty quickly. I don't want to say that we're doing that, but that would be kind of a logical place for us to go next. We have some things that we got to work out, but we're working on them.

她完全相信該藥物能夠達到這項療效。這表明不需要進行大量試驗和耗費大量資源。您很快就會得到答案。我不想說我們正在這樣做，但這對我們來說是一個合乎邏輯的下一步。我們有一些事情需要解決，但我們正在努力。

I know the resources are strapped, but is this something that you guys are able to do some initial groundwork on now or in the recent past on these different indications? Just kind of get the process started.

我知道資源緊張，但你們現在或最近能針對這些不同的跡像做一些初步的基礎工作嗎？只需讓這個過程開始即可。

Well, we can with the one I was just talking about. The other is no. It's more theoretical.

好吧，我們可以討論我剛才談到的那個。另一個答案是否定的。它更加理論化。

This was the last question. I will now turn back to Rick Barry for closing remarks.

這是最後一個問題。現在我請瑞克·巴里作最後發言。

Thanks. Well, we really appreciate you joining the call today. We do, to repeat, expect to announce our top-line Phase III results before the end of 2024, and we really look forward to sharing them when they're available. Thanks so much for listening.

謝謝。好吧，我們非常感謝您今天參加電話會議。再次重申，我們預計將在 2024 年底前公佈我們的 III 期頂線研究結果，並且我們非常期待在這些結果公佈後與大家分享。非常感謝您的聆聽。

This does now conclude today's conference. You may now disconnect your lines at this time. Thank you for your participation. Goodbye.

今天的會議到此結束。現在您可以斷開您的線路了。感謝您的參與。再見。