Cerevel Therapeutics Holdings Inc (CERE) 2023 Q3 法說會逐字稿

Good morning, and welcome to the Cerevel Therapeutics Third Quarter Financial Results Conference Call. At this time, all participants are in listen-only mode. Later, you will have the opportunity to ask questions during the Q&A portion of the call. Please note that this call may be recorded.

早安，歡迎參加 Cerevel Therapeutics 第三季財務業績電話會議。此時，所有參與者都處於只聽模式。稍後，您將有機會在通話的問答環節提出問題。請注意，此次通話可能會被錄音。

I will now hand the call over to Matt Calistri, Vice President of Investor Relations.

現在我將電話轉給投資者關係副總裁 Matt Calistri。

Thank you. Good morning, everyone. We appreciate you joining us for our third quarter 2023 earnings call. On today's call, you'll be hearing from Ron Renaud, our President and Chief Executive Officer; Dr. Ray Sanchez, our Chief Medical Officer; Dr. John Renger, our Chief Scientific Officer; and Dr. Susan Altschuller, our Chief Financial Officer. During our call today, please refer to our press release from this morning, detailing our third quarter 2023 financial performance, as well as our updated corporate presentation, both of which are available on our website.

謝謝。大家早安。感謝您參加我們的 2023 年第三季財報電話會議。在今天的電話會議上，您將聽到我們的總裁兼執行長 Ron Renaud 的演講；我們的首席醫療官 Ray Sanchez 博士；我們的首席科學官 John Renger 博士；以及我們的財務長 Susan Altschuller 博士。在今天的電話會議中，請參閱我們今天早上的新聞稿，其中詳細介紹了我們 2023 年第三季度的財務業績以及我們更新的公司介紹，均可在我們的網站上查閱。

I would like to remind you that we will be making forward-looking statements that reflect our current views related to, among other things, the potential attributes and benefits of our product candidates and the format and timing of our product development activities and clinical trials. We strongly encourage you to review the information that we filed with the SEC regarding specific risks and uncertainties.

我想提醒您，我們將做出前瞻性的聲明，反映我們目前的觀點，其中包括我們候選產品的潛在屬性和優勢以及我們的產品開發活動和臨床試驗的形式和時間。我們強烈建議您查看我們向美國證券交易委員會提交的有關特定風險和不確定性的資訊。

I will now hand the call over to Ron Renaud, President and CEO of Cerevel, to provide an overview of our achievements and outlook.

現在，我將把電話交給 Cerevel 總裁兼執行長 Ron Renaud，讓他概述我們的成就和前景。

Thanks, Matt, and good morning, everyone. And thank you for joining us for our third quarter 2023 business results call. I'm pleased to be with all of you today to review our third quarter results and to discuss how we're preparing for what we expect will be an exciting 2024.

謝謝，馬特，大家早安。感謝您參加我們的 2023 年第三季業務業績電話會議。我很高興今天能與大家一起回顧我們第三季度的業績，並討論我們如何為預期的令人興奮的 2024 年做準備。

Let me start with some high-level thoughts on how the management team is thinking about and planning for the future of Cerevel. To begin, we believe this organization has one of the most robust neuroscience pipelines in the industry. And next year will be a pivotal one for Cerevel as we look forward to multiple mid- and late-stage readouts across 3 different assets in 3 different indications.

首先，我想從高階的角度談談管理團隊對 Cerevel 未來的思考與規劃。首先，我們相信該組織擁有業內最強大的神經科學管道之一。明年對 Cerevel 來說將是關鍵的一年，我們期待在 3 種不同適應症的 3 種不同資產上獲得多個中期和後期讀數。

Our recent capital raise significantly bolstered the balance sheet, extending our runway into 2026, well over 12 months beyond all of our expected data readouts next year. As an organization, we are laser focused on execution and maximizing the value creation opportunities for each of our lead assets.

我們最近的融資大大增強了資產負債表，將我們的業務跑道延長至 2026 年，遠遠超出了我們明年預期的所有數據讀數 12 個月以上。作為一個組織，我們專注於執行並最大化我們每個主要資產的價值創造機會。

Our ongoing clinical trials are progressing well, and we expect to deliver data for tavapadon, darigabat, and emraclidine on the time lines we laid out last quarter. We are planning for success in proactively preparing to potentially file 2 NDAs in 2025 in tavapadon and emraclidine if data are positive. Furthermore, we are diligently exploring life cycle opportunities for our lead programs and other indications.

我們正在進行的臨床試驗進展順利，我們預計將按照上個季度製定的時間表提供 tavapadon、darigabat 和 emraclidine 的數據。如果資料是正面的，我們正在積極準備在 2025 年成功提交 tavapadon 和 emraclidine 的 2 份 NDA。此外，我們正在努力探索我們的先導項目和其他適應症的生命週期機會。

Let me now provide an overview of our lead programs. Emraclidine, our M4 selective positive allosteric modulator, or PAM, is currently in development for schizophrenia and Alzheimer's disease psychosis as a once-daily medicine without the need for titration. Emraclidine is the potential next-generation antipsychotic with a novel mechanism of action that targets BM4 pathway. By selectively targeting M4, we believe emraclidine may reduce psychotic symptoms without challenging side effects of current antipsychotics.

現在讓我概述一下我們的主導項目。恩拉克利定是我們的 M4 選擇性正變構調節劑 (PAM)，目前正在開髮用於治療精神分裂症和阿茲海默症精神病，作為一種每日一次的藥物，無需滴定。恩拉克利定是一種潛在的下一代抗精神病藥，具有針對 BM4 路徑的新型作用機制。透過選擇性地針對 M4，我們相信恩拉克利定可以減輕精神病症狀，並且不會產生當前抗精神病藥物的副作用。

Our 2 potential registrational trials in EMPOWER-1 and EMPOWER-2 are enrolling well, and we expect data to read out in the second half of 2024. We are excited about the potential of emraclidine and the benefit it may bring to patients with schizophrenia who have not seen innovation in decades.

我們在 EMPOWER-1 和 EMPOWER-2 中的兩項潛在註冊試驗的招募情況良好，我們預計數據將在 2024 年下半年讀出。

Moving to tavapadon, the first D1/D5 partial agonist in development for the treatment of Parkinson's disease. We expect our TEMPO-3 adjunctive trial to be our first data readout in the first half of 2024, with the TEMPO-1 and TEMPO-2 monotherapy readouts coming in the second half of the year.

轉向 tavapadon，這是第一個用於治療帕金森氏症的 D1/D5 部分激動劑。我們預計，TEMPO-3 輔助試驗將在 2024 年上半年首次獲得數據讀數，而 TEMPO-1 和 TEMPO-2 單藥治療的讀數將在下半年公佈。

Building on our excitement for this program, we are pleased to announce that we will host a tavapadon investor webcast on December 11. During which, we will explore this novel mechanism and its potential to address patient needs in greater depth. We believe there is a significant opportunity in Parkinson's disease to deliver sustained motor control with a favorable side effect profile.

基於對該計劃的興奮，我們很高興地宣布，我們將於 12 月 11 日舉辦 tavapadon 投資者網路廣播。我們相信，在治療帕金森氏症方面存在著巨大潛力，能夠提供持續的運動控制，且副作用較小。

And finally, let me turn to Darigabat, our selective alpha-2/3/5 GABAA PAM currently in development for both focal epilepsy and panic disorder. As we recognized epilepsy awareness month in November and the 3.4 million people living with epilepsy in the United States, we are hopeful that we can bring forward a new treatment option for people living with this difficult disease.

最後，讓我來談談 Darigabat，這是我們目前正在開發的選擇性 alpha-2/3/5 GABAA PAM，用於治療局部癲癇和恐慌症。當我們意識到 11 月是癲癇宣傳月，而美國有 340 萬癲癇患者時，我們希望能夠為患有這種難治疾病的人提供新的治療選擇。

Our Phase II REALIZE trial in focal epilepsy to be our second readout of 2024 coming midyear. We've also initiated our ADAPT trial, a Phase II proof of concept trial in panic disorder.

我們的局部癲癇 II 期 REALIZE 試驗將是我們在 2024 年年中進行的第二次讀數。我們也啟動了 ADAPT 試驗，這是針對恐慌症的第二階段概念驗證試驗。

Behind our mid-to-late stage pipeline is an innovative discovery engine that is focused on bringing forward additional novel mechanisms to address neuroscience diseases. And we look forward to providing greater detail on those programs, including our capital opioid receptor antagonist, as we make further progress.

我們中後期研發管線背後是一個創新的發現引擎，專注於提出更多新機制來治療神經科學疾病。隨著我們取得進一步進展，我們期待提供有關這些計劃的更多細節，包括我們的資本阿片受體拮抗劑。

I'm quite excited about all that we're doing here at Cerevel and all that is to come for our pipeline and the potential benefits we hope to bring to patients. We are well positioned as we go into 2024 to truly transform what is possible in neuroscience.

我對 Cerevel 所做的一切、我們未來的產品線以及我們希望為患者帶來的潛在益處感到非常興奮。邁入 2024 年，我們已做好準備，真正實現神經科學領域的變革。

With that, I'll now turn the call over to Dr. Ray Sanchez, our Chief Medical Officer, to provide some added color about our lead programs. Ray?

說完這些，我現在將電話轉給我們的首席醫療官雷·桑切斯博士，讓他為我們的主要項目提供一些詳細資訊。射線？

Thank you, Ron, and good morning, everyone. I want to echo Ron's sentiments about the excitement around our pipeline. As a former clinician, I can tell you that I am energized by the potential we have here at Cerevel to make a meaningful difference in the lives of patients with neuroscience diseases.

謝謝你，羅恩，大家早安。我想呼應羅恩對我們的管道感到興奮的感受。作為一名前臨床醫生，我可以告訴你，我對 Cerevel 的潛力感到振奮，我們有能力為神經系統疾病患者的生活帶來有意義的改變。

Beginning with emraclidine, our EMPOWER program is advancing and data are expected in the second half of 2024. Preserving data quality while mitigating placebo response risk remains the utmost priority for these trials, and we are pleased with our recent efforts to reinvigorate enrollment.

從恩拉克利定開始，我們的 EMPOWER 計劃正在推進，預計在 2024 年下半年獲得數據。

As a reminder, EMPOWER-1 and EMPOWER-2 are 2 adequately powered 3-arm trials that include adults living with schizophrenia and experiencing an acute exacerbation of psychotic symptoms. We designed these trials to potentially meet the criteria necessary to service pivotal trials based on what we expect the FDA will evaluate in a registrational package.

提醒一下，EMPOWER-1 和 EMPOWER-2 是兩項具有足夠動力的三組試驗，其中包括患有精神分裂症並經歷精神病症狀急性惡化的成年人。根據我們預期 FDA 將在註冊文件包中評估的內容，我們設計這些試驗以潛在地滿足服務關鍵試驗所需的標準。

We're also enrolling our 52-week open-label safety extension trial, EMPOWER-3, and prioritizing the completion of non-clinical and clinical pharmacology studies to accelerate a potential registrational package for maracalgenos schizophrenia. We believe emraclidine has tremendous potential in other disease areas and plans for further development are underway. In Alzheimer's disease psychosis, or ADP, our Phase I healthy elderly volunteer trial is ongoing, and the results of this trial will guide our clinical development plan as we advance important indication with a substantial unmet need.

我們也正在進行為期 52 週的開放標籤安全擴展試驗 EMPOWER-3，並優先完成非臨床和臨床藥理學研究，以加速完成馬拉卡爾傑諾斯精神分裂症的潛在註冊方案。我們相信恩拉克利定在其他疾病領域具有巨大的潛力，並且進一步開發計劃正在進行中。在阿茲海默症精神病（ADP）中，我們正在進行 I 期健康老年志願者試驗，該試驗的結果將指導我們的臨床開發計劃，因為我們將推進具有大量未滿足需求的重要適應症。

Turning now to tavapadon, our D1/D5 partial agonist in Parkinson's disease. Our Phase III trials, known collectively as the TEMPO trials, are ongoing along with the corresponding open-label extension in which we are encouraged by a greater than 90% rollover rate. We expect data for TEMPO-3 in the first half of 2024, with data for TEMPO-1 and 2 coming in the second half of 2024. We look forward to walking you through the scientific rationale and prior data for tavapadon as well as its clinical potential during our investor event in December.

現在來談談 tavapadon，這是我們治療帕金森氏症的 D1/D5 部分激動劑。我們的 III 期試驗（統稱為 TEMPO 試驗）正在進行中，同時還有相應的開放標籤擴展試驗，其中超過 90% 的滾動率令我們感到鼓舞。我們預計 TEMPO-3 的數據將在 2024 年上半年獲得，TEMPO-1 和 2 的數據將在 2024 年下半年獲得。 我們期待在 12 月的投資者活動期間向您介紹 tavapadon 的科學原理和先前數據及其臨床潛力。

With darigabat, or selective GABAA PAM, we believe there is potential for both antiepileptic and angilotic activity comparable to benzazepine with an improved side effect profile. Unlike benzodiazepines, which are only used for acute episodes due to tolerability, abuse potential, and other debilitating side effects, darigabat's novel mechanism of action and anticipated favorable tolerability profile provides the potential for chronic dosing. We expect results from our Phase II REALIZE trial in focal epilepsy in midyear 2024, and we are encouraged by a continued high rollover rate into the realized open-label extension.

我們相信，darigabat 或選擇性 GABAA PAM 具有與苯並氮平相當的抗癲癇和血管緊張素轉換酶活性，且副作用有所改善。與苯二氮平類藥物不同，由於其耐受性、濫用可能性和其他使人衰弱的副作用，苯二氮平類藥物僅用於急性發作，而達加巴特的新穎作用機制和預期的良好耐受性特徵為慢性用藥提供了潛力。我們預計，針對局部癲癇的 II 期 REALIZE 試驗的結果將於 2024 年中期公佈，我們對已實現的開放標籤擴展的持續高滾動率感到鼓舞。

Beyond focal epilepsy, our ADAPT Phase II trial panic disorder is currently underway. A new drug has not been approved in panic disorder in nearly 20 years, and we are excited about the potential of providing darigabat as a daily chronic therapy to patients in need. Cerevel's mid to late-stage pipeline has the potential to bring forward numerous treatments to address some of the most devastating neuroscience diseases, and I am so proud of the team that is working diligently to make the potential -- this potential a reality.

除了局部癲癇之外，我們對恐慌症的 ADAPT 第二階段試驗目前正在進行中。近 20 年來，尚未有一種新藥獲準用於治療恐慌症，我們對為有需要的患者提供達裡加巴特作為日常慢性治療的潛力感到興奮。 Cerevel 的中後期研發管線有可能帶來多種治療方法，以治療一些最具破壞性的神經科學疾病，我為努力將這種潛力變為現實的團隊感到自豪。

With that, let me turn it over to Dr. John Renger, our Chief Scientific Officer, to provide an update on our early stage portfolio. John?

接下來，請容許我把主題轉到我們的首席科學官 John Renger 博士身上，來介紹一下我們早期投資組合的最新情況。約翰？

Thank you, Ray, and good morning, everyone. I'm very pleased with the progress we've made in discovery research and early clinical development here at Cerevel. Today, I'd like to focus on our kappa opioid receptor antagonist or KORA program, also known as CVL-354.

謝謝你，雷，大家早安。我對 Cerevel 在發現研究和早期臨床開發方面取得的進展感到非常高興。今天，我想重點介紹我們的 kappa 鴉片受體拮抗劑或 KORA 項目，也稱為 CVL-354。

We have completed both our single and multiple ascending dose trials in which CVL-354 has been generally well tolerated. Further, we currently believe we will be able to interrogate a range of receptor occupancies in both the kappa and mu opioid receptors. We believe and anticipate we'll be able to explore multiple indications of interest such as major depressive disorder and substance use disorder.

我們已經完成了單次和多次遞增劑量試驗，其中 CVL-354 整體耐受性良好。此外，我們目前相信我們將能夠探討 kappa 和 mu 鴉片受體中的一系列受體佔有率。我們相信並期待我們將能夠探索多種感興趣的症狀，例如重度憂鬱症和物質使用障礙。

Our ongoing Phase I receptor occupancy trial will clarify both kappa and mu receptor penetration displacement to further characterize selectivity across the compound exposures. We are encouraged by the potential impact of this asset, and we look forward to providing more updates on our plans in the near future.

我們正在進行的 I 期受體佔有率試驗將闡明 kappa 和 mu 受體的滲透位移，以進一步表徵化合物暴露的選擇性。這項資產的潛在影響令我們感到鼓舞，我們期待在不久的將來提供有關我們計劃的更多更新。

Beyond KORA, we have a growing number of programs, some in issue within our labs and exclusively developed here at Cerevel, which we continue to progress, including our M4-selective agonist, a PDE4D-sparing antagonist, and a selective TMM-175 potentiator program. We will provide further updates and plans for these specific programs as appropriate.

除了 KORA 之外，我們還有越來越多的項目，其中一些是在我們的實驗室內研究的，並且是由 Cerevel 獨家開發的，我們正在繼續推進這些項目，包括我們的 M4 選擇性激動劑、PDE4D 保留拮抗劑和選擇性 TMM-175 增效劑項目。我們將根據需要為這些具體項目提供進一步的更新和計劃。

With that, I'm going to turn it over to our Chief Financial Officer, Dr. Susan Altschuller, to review our financial performance for the third quarter. Susan?

接下來，我將把任務交給我們的財務長 Susan Altschuller 博士，來審查我們第三季的財務表現。蘇珊？

Thank you, John. Turning to our financials. In October, we opportunistically bolstered our balance sheet with a $499 million capital raise, providing strong validation of Cerevel's potential from both new and existing high-quality investors. This additional capital, along with the roughly $758 million in cash, cash equivalents, and marketable securities we ended the third quarter with will support our operations into 2026.

謝謝你，約翰。談到我們的財務狀況。 10 月份，我們抓住機會，籌集了 4.99 億美元的資金，增強了我們的資產負債表，為新舊優質投資者提供了對 Cerevel 潛力的強有力驗證。這筆額外資本加上我們在第三季末所持有的約 7.58 億美元現金、現金等價物和有價證券將支持我們到 2026 年的營運。

Turning to the third quarter of 2023. Operating expenses were approximately $111 million, comprised of $85 million of research and development expenses and $26 million of general and administrative expenses. Looking forward, our financial strength enables us to focus on execution and provides optionality to maximize the value of our pipeline. That said, we will take a disciplined approach to resource allocation as we further build our pipeline, advance our lead assets, and prepare for 2 potential NDA filings in parallel.

轉向 2023 年第三季。展望未來，我們的財務實力使我們能夠專注於執行，並提供可選性以最大化我們管道的價值。儘管如此，我們將採取嚴謹的方式來分配資源，進一步建立我們的產品線，推進我們的主要資產，並同時準備 2 份潛在的 NDA 申請。

With that, I will hand the call back over to Ron for his concluding remarks.

說完這些，我將把電話交還給羅恩，請他作最後發言。

Thank you, Susan. At Cerevel, we believe we have an unparalleled pipeline in neuroscience, with multiple mid- and late-stage readouts across 3 different assets expected next year and a balance sheet that provides us with past runway into 2026. We are focused and aligned on executing our trials, delivering high-quality data next year, and, as Susan mentioned, preparing for 2 potential NDA filings.

謝謝你，蘇珊。在 Cerevel，我們相信我們在神經科學領域擁有無與倫比的產品線，預計明年將有 3 種不同資產的多個中期和後期讀數，以及一份為我們提供到 2026 年跑道的資產負債表。我們專注於並致力於執行我們的試驗，在明年提供高質量的數據，並且正如 Susan 提到的那樣，準備提交 2 份潛在的 NDA 文件。

These are exciting times at Cerevel, and I'm so proud to be leading this organization. I want to offer my sincere appreciation to all of our employees who work tirelessly every day to deliver on Cerevel's mission. And I also want to thank our investigators and participants in our clinical trials, without whom, none of this would -- none of what we seek to achieve would be possible.

這是 Cerevel 激動人心的時刻，我很自豪能夠領導這個組織。我要向所有每天不知疲倦地致力於實現 Cerevel 使命的員工表達最誠摯的感謝。我還要感謝我們的臨床試驗的研究人員和參與者，沒有他們，我們所追求的一切都不可能實現。

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

現在，我們開始提問。

Thank you. (Operator Instructions). One moment for our first question. And our first question comes from Michael Yee of Jefferies.

謝謝。 （操作員指令）。請稍等片刻，回答我們第一個問題。我們的第一個問題來自 Jefferies 的 Michael Yee。

Thanks for the question, and thanks for the update, Ron. I know everyone's focused on execution. Two questions.

感謝您的提問，也感謝您的更新，羅恩。我知道每個人都專注於執行。兩個問題。

First, on emraclidine. Obviously, since last quarter, there was some concern about some of the timeline changes. Can you maybe just describe what initiatives give you the confidence that things are progressing on time and, specifically maybe for the team, what the right patients are, the right site selections are, that gives you the confidence on executing on that enrollment?

首先，關於恩拉克利定。顯然，自上個季度以來，人們對一些時間表的變化感到擔憂。您能否描述哪些舉措讓您有信心事情會按時進展，特別是對於團隊而言，哪些是正確的患者，哪些是正確的地點選擇，這些讓您有信心執行這項招募？

And the second question is on epilepsy. There's actually a bunch of competitor readouts happening. And maybe you could help us understand about the placebo arms and what things you're integrating into your study that might help us give us confidence there because that has historically been an issue. And I know that's a concern for others as well.

第二個問題是關於癲癇的。實際上有很多競爭對手的讀數正在發生。也許您可以幫助我們了解安慰劑組的情況，以及您在研究中融入了哪些可能有助於我們增強信心的東西，因為這在歷史上一直是一個問題。我知道其他人也同樣擔心這一點。

Yes, sure. So let me take the first part of your first question, and then I'll let Ray address the second part in terms of site selection from emraclidine and then the placebo work on our epilepsy study.

是的，當然。那麼，讓我來回答您第一個問題的第一部分，然後我會讓 Ray 回答第二部分，即從恩拉克利定的試驗地點選擇，到我們癲癇研究的安慰劑研究。

So look, as we mentioned last quarter, we are focused on trying to address the challenges that we saw with some of the enrollment issues that we had. And look, we're doing that with boots on the ground.

所以，正如我們在上個季度提到的那樣，我們正專注於嘗試解決我們所遇到的一些招生問題。你看，我們正在透過實地行動來做這些事情。

I've spent time at sites with Ray and the team and the leader of our clinops and clinical development groups and really working with the site to see what's going on. And I think we're quite pleased with the progress that we've seen so far. And that's why we can stand by the guidance that we've given here in the quarter.

我和 Ray、團隊以及臨床操作和臨床開發小組的負責人一起在現場度過了一段時間，並真正與現場合作，了解正在發生的事情。我認為我們對目前所取得的進展感到非常滿意。這就是我們堅持本季度給出的指導的原因。

That all said, our focus will always remain on ensuring the quality of the data, and I think that gets to the second part of the question. We're going to maintain -- continue to maintain rigorous site selection and focus on our placebo variability reduction strategies. But I'll let Ray address how we think about the sites and how we think about all of those things as we continue to make progress here and also talk about our placebo group in the epilepsy studies.

儘管如此，我們的重點始終是確保數據質量，我認為這涉及問題的第二部分。我們將繼續保持嚴格的場地選擇，並專注於減少安慰劑變異性的策略。但我會讓雷談談我們如何看待這些站點，以及我們如何看待所有這些事情，因為我們在這裡繼續取得進展，同時也談談我們在癲癇研究中的安慰劑組。

Thank you, Michael. So as you know, Michael, I've historically defined what does a good side look like. It's really the access to the right patients and having good solid raters. And that really determines, for the most part, the success of the trial. So that's where we have been achieving and are continuing to try to achieve.

謝謝你，麥可。所以如你所知，邁克爾，我從歷史上定義了好的一面是什麼樣的。這確實可以接觸到合適的患者並擁有良好可靠的評估者。這在很大程度上決定了試驗的成功。這就是我們一直以來所取得的成就，並且將繼續努力實現它。

But if you look at when we started the emraclidine trials, they started quite robustly for the first year, and then the momentum slowed down in the spring of this year. What we've learned is how to manage the competitive landscape a bit more effectively. And to that end, we're seeing increased momentum in our enrollment without, as Ron mentioned, diluting the data quality in any way. So again, having very close communication with the sites, ensuring that the radar recertifications occur frequently, and continuing that communication ensures us that we have the greatest likelihood of success moving forward.

但如果你回顧我們開始進行依姆拉克定試驗的時候，你會發現第一年的效果非常強勁，但今年春天勢頭就減弱了。我們學到的是如何更有效地管理競爭格局。為此，我們看到招生勢頭強勁，而正如羅恩所提到的那樣，數據品質卻沒有受到任何影響。因此，再次強調，與現場保持密切溝通，確保雷達重新認證頻繁進行，並持續溝通，確保我們在未來取得最大的成功。

In terms of epilepsy and the placebo responses, as you know, that we are seeing placebo response in indications like spinal cerebellar ataxia and epilepsy, and that surprises many. But we are also taking the same aggressive approach and dedicated approach to mitigating the placebo response in our focal humps and epilepsy trial by having placebo mitigation protocols at each site. But also, it's about patient selection, making sure that the right patient profile is included in these trials, and really monitoring the data -- the blinded data to ensure the quality is there.

就癲癇和安慰劑反應而言，如您所知，我們在脊髓性小腦共濟失調和癲癇等症狀中看到了安慰劑反應，這讓許多人感到驚訝。但是，我們也採取同樣積極和專注的方法，透過在每個地點制定安慰劑緩解方案，減輕局部駝峰和癲癇試驗中的安慰劑反應。但同時，這也與患者的選擇有關，確保這些試驗中納入了正確的患者資料，並真正監測數據——盲法數據以確保品質。

So all taken together, really, the approach we're taking to epilepsy to reduce placebo response is really the same approach we've taken to all our trials to reduce placebo response. And we're confident that we're positioning these trials for the greatest likelihood of success.

所以總的來說，我們針對癲癇採取的減少安慰劑反應的方法實際上與我們在所有試驗中採取的減少安慰劑反應的方法相同。我們有信心使這些試驗獲得最大的成功。

Thank you. One moment for our next question. And our next question comes from Paul Matteis of Stifel.

謝謝。請稍候，回答下一個問題。我們的下一個問題來自 Stifel 的 Paul Matteis。

I honestly wanted to ask a really similar question on emraclidine, and that is related to this recent TAR-1 setback and the implications of that. I guess when you look at that data and the huge placebo response they saw and anything else within those results, what sort of metrics are you tracking specifically on a blinded basis in the emraclidine studies beyond the obvious, like just changing PANSS, that I guess today give you confidence that you're getting the patient and site quality that you intended or hope to?

說實話，我想問一個關於恩拉克利定的非常類似的問題，這與最近 TAR-1 挫折及其影響有關。我想，當您查看這些數據和他們看到的巨大的安慰劑反應以及這些結果中的任何其他內容時，除了顯而易見的指標（例如僅僅改變 PANSS）之外，您在盲法基礎上具體跟踪了哪些指標，我想這些指標今天讓您有信心您獲得了您想要或希望的患者和站點質量？

And then on the kappa program, I wanted to ask a quick question for John. Just in the navacaprant and aticaprant both cite really high selectivity per kappa over mu. What's behind your thesis that mu might actually contribute to efficacy and some of the conditions that you plan on pursuing?

然後關於 Kappa 計劃，我想問約翰一個簡單的問題。僅在 navacaprant 和 aticaprant 中就提到了每 kappa 對 mu 的選擇性確實很高。您認為 mu 實際上可能對功效和您計劃追求的一些條件有貢獻，您的論點背後有什麼依據？

Yes. I'll let Ray take the first part.

是的。我會讓雷負責第一部分。

So Paul, good question. So we review the data on a monthly basis and sometimes more frequently, but it is blinded. So really, in terms of data quality, we want to ensure that all of the parameters that we're assessing are correct and that they're not conflicting. And so, if that occurs, we obviously intervene at the site level to make sure that the raters are doing what they need to do or they need to have a refresher. And that validation, of course, occurs frequently with the raters.

保羅，你問得好。因此，我們每月都會審查一次數據，有時甚至更頻繁，但這是盲目的。因此，就數據品質而言，我們希望確保我們評估的所有參數都是正確的，並且它們沒有衝突。因此，如果發生這種情況，我們顯然會在站點層面進行幹預，以確保評估員正在做他們需要做的事情，或者他們需要複習。當然，評估者經常會進行這種驗證。

In terms of having the confidence that we're mitigating that placebo response, it's really around other measures that I mentioned earlier in Michael's question in terms of looking at the right patients and how do we do that. We have an independent committee that really looks at the patient qualifications to ensure that they meet the criteria for the profile that needs to occur for them to be enrolled in the trials.

為了有信心減輕安慰劑反應，我們實際上需要採取其他措施，正如我在邁克爾的問題中提到的那樣，尋找合適的患者，以及我們如何做到這一點。我們有一個獨立委員會，負責嚴格審查患者的資格，以確保他們符合參加試驗所需的標準。

So -- and then we have a placebo protocol at each site that allows us to standardize the way we actually approach each patient at every site to increase the likelihood of success and mitigate that placebo response. So really, we've taken the learnings from so many years as well as the advice from key advisers who understand placebo response and have infused them into our programs.

所以 — — 我們在每個站點都有安慰劑方案，這使我們能夠標準化我們在每個站點實際對待每個患者的方式，以增加成功的可能性並減輕安慰劑反應。因此，我們實際上吸取了多年來的經驗教訓以及了解安慰劑反應的主要顧問的建議，並將其融入我們的計畫中。

So we're confident that we're taking all measures to ensure that that placebo response is mitigated. We're also limiting the number of countries, limiting the number of sites, all of which contribute to a placebo response. If you look at the trials that you've mentioned, the recent trial that -- over 6 countries, over 35 sites in those trials. And so all of that contributes to variability, everything that we're trying to minimize to ensure the greatest likelihood of success.

因此，我們有信心採取一切措施確保減輕安慰劑反應。我們也限制國家數量、限制地點數量，所有這些都會導致安慰劑反應。如果你看一下你提到的試驗，最近的試驗——超過 6 個國家，超過 35 個地點進行了試驗。所有這些都導致​​了可變性，我們試圖將一切都最小化以確保最大的成功可能性。

Good morning, Paul, and thanks for the question on kappa opioid receptor antagonist. So to your question about what does mu provide in terms of potential therapeutic benefit in indications. And so, as an example, what I would do is point to opioid withdrawal syndrome patients.

早上好，保羅，感謝您提出關於 kappa 鴉片受體拮抗劑的問題。那麼對於您關於 mu 在適應症方面具有什麼潛在治療益處的問題。因此，舉個例子，我要指出的是鴉片類藥物戒斷症候群患者。

And so if you think about what it is you want to achieve potentially with our compound with our profile, what we can do is we can go through a receptor occupancy range at kappa where we can have selectivity to kappa. But if we continue to go up the receptor occupancy curve and exposure curves, we can bring in mu.

因此，如果您考慮您想利用我們的化合物和我們的配置潛在地實現什麼目標，我們可以做的是，我們可以透過 kappa 的受體佔有範圍，從而對 kappa 進行選擇性。但如果我們繼續提高受體佔有曲線和暴露曲線，我們就可以引入 mu。

And so, why does that provide something that to us seems exciting? It's because what you can get is a therapeutic benefit from Kappa. And what we believe the potential there is to reduce things like the Q industry and statement data that you see in the preclinical models where you can remove some of the things that would cause relapse in patients that are undergoing withdrawal or undergoing abstains from use of opioids.

那麼，為什麼這會為我們帶來一些令人興奮的東西呢？這是因為您可以從 Kappa 獲得治療益處。我們相信，可以減少 Q 產業和臨床前模型中的聲明數據等因素，從而消除一些可能導致正在戒斷或停止使用鴉片類藥物的患者復發的因素。

But if you think about what you're actually trying to achieve in the long term, it's also reducing the potential for exposure to mu agonists. And so if you think about how you could approach that population, you can actually begin with a lower dose range, gain the benefit of the kappa without having any kind of mu antagonism that might induce withdrawal symptoms. And then as the patient progresses, you can actually increase the dose so you actually bring in the mu antagonism potential.

但如果你考慮一下你實際上想要實現的長期目標，它也降低了接觸 μ 激動劑的可能性。因此，如果您考慮如何接近該人群，您實際上可以從較低的劑量範圍開始，獲得 kappa 的好處，而不會產生任何可能引起戒斷症狀的 mu 拮抗作用。然後隨著患者病情的進展，您實際上可以增加劑量，這樣您實際上就帶來了拮抗作用的潛力。

What that does is it has the ability to block opioid activation if there is an exposure to an opioid in the future for that patient. So let's say they have a relapse, they take an opioid agonist at that point. Having an antagonist could benefit that patient population, both as a safety measure in terms of blocking activation with an opioid so you could prevent the potential for harm. But you can also potentially, depending on what exposure they get to what opioid, you can actually prevent the rewarding benefit.

其作用是，如果患者將來接觸阿片類藥物，它能夠阻斷阿片類藥物的活化。假設他們病情復發，他們就會服用鴉片類激動劑。使用拮抗劑可以使患者群體受益，既可以作為阻斷阿片類藥物活化的安全措施，也可以防止潛在的傷害。但你也有可能，根據他們接觸阿片類藥物的情況，你實際上可以阻止獲得獎勵利益。

And so you can imagine where you would start the patient going through the phase of withdrawal, starting with more of a kappa selectivity dose range. And what you could do is build up that dose range over time so that if there is an exposure, you have the protection of having a mu antagonism benefit on board in that same patient. So that's how we're thinking about it.

因此，您可以想像一下，患者從哪裡開始經歷戒斷階段，從更大的 kappa 選擇性劑量範圍開始。您可以做的是隨著時間的推移擴大劑量範圍，這樣如果發生暴露，您就可以在同一患者身上獲得 mu 拮抗劑的保護。這就是我們的想法。

Thanks a lot.

多謝。

Thank you. One moment for our next question. And our next question comes from Mohit Bansal of Wells Fargo.

謝謝。請稍候，回答下一個問題。下一個問題來自富國銀行的 Mohit Bansal。

And thank you for having an uneventful quarter. Really appreciate it. Congrats on the financing. I have 2 questions. One is on tavapadon.

感謝您度過了一個平靜的季度。真的很感激。恭喜獲得融資。我有兩個問題。一個是 tavapadon。

In our checks, doctors are suggesting that the dopamine agonists are a little bit out of fashion , they are not used as much. So could you talk a little bit about how you're thinking about the bar for success clinically, not just static benefit, what it should be? And then second one, can you remind me darigabat -- about darigabat? What was the reason for slow enrollment and how you are mitigating that?

在我們的檢查中，醫生認為多巴胺激動劑有點過時了，它們並不常用。那麼，您能否談談您如何看待臨床成功的標準，而不僅僅是靜態效益，它應該是什麼？然後第二個，你能提醒我關於 darigabat 的事情嗎？入學緩慢的原因是什麼？

So Mohit, thanks for that question on tavapadon. If you think about the novel mechanism of tavapadon being a D1/D5 partial agonist that selectively targets those receptors of the direct nigrostriatal pathway really gives us the confidence that it's going to be a transformative therapy in symptomatically treating Parkinson's disease.

所以 Mohit，感謝您關於 tavapadon 的提問。如果您考慮到 tavapadon 作為 D1/D5 部分激動劑的新機制，該機制選擇性地靶向直接黑質紋狀體通路的受體，這確實讓我們有信心，它將成為對症治療帕金森氏症的變革性療法。

Clinically, we've designed a program to show the benefit as both a monotherapy and as an adjunctive therapy. In the monotherapy, 27-week trials looking at the UPDRS; Part 2, which looks at the daily functioning; and Part 3 that looks at the motor symptoms. And that's the primary endpoint. And change from baseline is the primary endpoint on that. So to show really the benefits on not only motor symptoms, but the quality of life as impacted by motor symptoms.

臨床上，我們設計了一個方案來展示其作為單一療法和輔助療法的益處。在單一療法中，進行了 27 週的試驗以觀察 UPDRS；第二部分，著重日常運作；第 3 部分討論運動症狀。這是主要終點。與基線相比的變化是其主要終點。因此，真正展現出的益處不只是對運動症狀有益，而且對受運動症狀影響的生活品質也有益。

For the adjunctive trial, which is our first trial to readout in the first half of next year, we're looking at the benefit of tavapadon as the best adjunctive treatment with levodopa to decrease the off-time, but importantly, increase the on-time without troublesome dyskinesis, which is the primary end point and really what's clinically relevant. So that's how we are thinking about that program.

對於輔助試驗，這是我們將在明年上半年進行的第一次試驗，我們正在研究 tavapadon 作為左旋多巴的最佳輔助治療的益處，以減少關態時間，但重要的是，增加開態時間而不會出現麻煩的運動障礙，這是主要終點，也是真正具有臨床意義的。這就是我們對該計劃的看法。

And really, we're thinking of it as really backbone therapy. Meaning that when the patient is first diagnosed as being the best therapy to initiate patients on and then when levodopa needs to be introduced as the best adjunctive treatment. So we're hoping that if the results read out as we expect that they will next year that we will then proceed to file an NDA and give patients a transformative therapy for symptomatic treatment of Parkinson's.

事實上，我們認為它是一種真正的骨幹療法。這意味著當患者首次被診斷為最佳治療方法時，然後需要引入左旋多巴作為最佳輔助治療。因此我們希望，如果結果如我們預期的那樣，明年我們將繼續提交保密申請，並為患者提供帕金森氏症對症治療的變革性療法。

Mohit, can you repeat that question?

Mohit，你能重複一下這個問題嗎？

Yes. I mean, so the question was, can you remind what was the reason for slow enrollment in the beginning? And how are you trying to mitigate that? I think it was more to do with the fact that you were taking patients off the background medication, right? I mean what's the issue there?

是的。我的意思是，所以問題是，您能否提醒一下一開始招生緩慢的原因是什麼？那麼您打算如何緩解這種情況呢？我認為這與您讓患者停止服用背景藥物有關，對嗎？我的意思是那裡有什麼問題？

No. So there are a couple of reasons for the enrollment issues with the epilepsy program. Remember, these are patients who are drug resistant. There are at least 1 and no more than 3 antiepileptics. They continue on those therapies at a static dose. So those that's not changed.

不。請記住，這些都是有抗藥性的病人。抗癲癇藥物有至少 1 種且不超過 3 種。他們繼續以固定劑量進行這些治療。那些沒有改變。

One of the challenges that that program has had is the fact that the concomitant medications, concomitant antiepileptics, are 3A4-inducers. In fact, they are all 3A4-inducers. And we, as you know, cannot allow patients who are on drugs that are 3A8-inducers because it impacts the pharmacokinetic profile of the therapy and it will impact the outcome of the trial.

該計劃面臨的挑戰之一是同時使用的藥物，即抗癲癇藥物，是 3A4 誘導劑。事實上，它們都是 3A4 誘導劑。而且如您所知，我們不能允許正在服用 3A8 誘導劑的患者參加該試驗，因為這會影響治療的藥物動力學特徵，並會影響試驗結果。

So the challenge there has been to find the right patient profile, but there are not on concomitant medications like carbamazepine, oxcarbazepine, and other therapies that are 3A4 inducers. So we've been challenged by that. The good news is that John and his team are -- have conducted a drug-drug interaction trial that will allow us to then overcome that obstacle in Phase III.

因此，面臨的挑戰是找到正確的患者概況，但他們並沒有同時使用卡馬西平、奧卡西平等 3A4 誘導劑治療。所以我們面臨這個挑戰。好消息是，約翰和他的團隊已經進行了藥物交互作用試驗，這將使我們能夠在第三階段克服這一障礙。

But we've really had to know the actual dose data based on those individuals that are not on those concomitant medications that would impact the pharmacokinetic profile. So what we've done is we then heightened the number of sites, the number of countries that we know well, to increase the enrollment. We've seen great momentum. And so the good news is that we are planning to read out in midyear next year. And if the results are what they are, then we can proceed with a robust Phase III program.

但我們必須真正了解那些未服用會影響藥物動力學特徵的伴隨藥物的個體的實際劑量數據。因此，我們所做的就是增加站點數量和我們熟悉的國家數量，以增加入學人數。我們看到了強勁的勢頭。好消息是我們計劃在明年年中宣讀。如果結果確實如此，我們就可以繼續進行強而有力的第三階段計畫。

The other thing I might add here, I know there's going to be more questions on tavapadon, Mohit. And as I mentioned in my prepared comments, we're going to host an investor webcast focused on tavapadon on December 11 at 10:00 a.m. So tune in to that. And I think if you have additional questions, that will be a good forum to get some clarity.

我在這裡想補充的另一件事是，我知道關於 tavapadon 會有更多問題，Mohit。正如我在準備好的評論中提到的那樣，我們將於 12 月 11 日上午 10:00 舉辦一場以 tavapadon 為重點的投資者網絡廣播。我認為如果您還有其他問題，這將是一個很好的論壇來澄清一些問題。

One moment for our next question. And our next question comes from Joseph Thome of TD Cowen. One moment for our next question. And our next question comes from Jeff Hung of Morgan Stanley

請稍候，回答下一個問題。我們的下一個問題來自 TD Cowen 的 Joseph Thome。請稍候，回答下一個問題。下一個問題來自摩根士丹利的 Jeff Hung

For CVL-871, can you talk about the challenges clinical sites you're facing on patient identification for dementia-related apathy? And then for the darigabat study in focal epilepsy, what do you need to see next year to consider the proof of concept a success? Is there a particular bar for reduction in seizure frequency?

對於 CVL-871，您能談談臨床站點在失智症相關冷漠症患者識別方面面臨的挑戰嗎？那麼，對於局部癲癇的 darigabat 研究，您明年需要看到什麼才能認為概念驗證成功？是否有一個特定的標準來減少癲癇發作的頻率？

So the apathy program, as you know, the 871 program, is a Phase IIa trial that's really experimental in nature. As you know, it's the leading neuropsychiatric syndrome that you see in patients with dementia and we're conducting in all of the dementia experimentally as a first step. It's also a predictor of disease progression.

如你所知，冷漠計劃，871計劃，是一個 IIa 期試驗，本質上是實驗性的。如您所知，這是癡呆症患者中最常見的神經精神綜合症，我們正在對所有癡呆症患者進行實驗，作為第一步。它也是疾病進展的預測指標。

There's 3 components, and it's really decrease gold directed behavior, decreased emotional responsiveness, and lack of motivation. The challenge with that is that the landscape is really still trying to understand what that patient profile looks like.

它有三個組成部分，實際上是減少黃金導向行為、降低情緒反應能力以及缺乏動力。這樣做的挑戰在於，我們實際上仍在試圖了解患者的概況。

Remember, these are patients that are not agitated. They're not really a problem clinically. But it does impact their quality of life. It does impact the longevity of their disease. So one of the challenges is really identifying the right patient profile.

請記住，這些病人並沒有焦躁不安。從臨床上來說，它們並不是什麼問題。但它確實影響了他們的生活品質。它確實會影響疾病的持續時間。因此，其中一個挑戰實際上是確定正確的患者特徵。

So to that end, that's one of the challenges that we've encountered. But we believe that the therapy has a great potential of being a novel therapy that will work in that population. But again, I think the landscape is trying to catch up and really to clinically understand what that profile looks like.

因此，這是我們面臨的挑戰之一。但我們相信，該療法具有巨大的潛力，可以成為一種對該族群有效的新療法。但是，我認為情況正在努力趕上並真正從臨床上了解該概況是什麼樣的。

So that's been a limiting step for that program, but we're continuing to move it along. We're continuing to identify the sites that have access to the right patients. And that's really critical to get the signal detection that we need for success. So that's where we are with that program now.

所以這對該計劃來說是一個限制性步驟，但我們會繼續前進。我們正在繼續尋找能夠接觸到合適患者的站點。這對於獲取我們成功所需的訊號檢測至關重要。這就是我們現在的計劃。

And the other question was on darigabat for the REALIZE study. What are you looking for success? What are you --

另一個問題是關於 REALIZE 研究的 darigabat。您尋求的成功是什麼？你是做什麼的 -

So for epilepsy, for darigabat -- so remember, it's 80% powered to detect at least a 30% placebo-adjusted difference in reduction of seizure frequency. So if we achieve it, that's terrific.

因此對於癲癇，對於 darigabat — — 請記住，它有 80% 的功效檢測到至少 30% 安慰劑調整後癲癇發作頻率減少的差異。如果我們實現了這個目標，那就太棒了。

As you know, we've got the Xenon product. We've got cenobamate that have had very compelling, very compelling outcomes, which fall into the mid-30s. Keppra falls around 28%. So if we achieve our 30% threshold and above, that would be really a successful outcome for us.

如您所知，我們有 Xenon 產品。我們得到的 cenobamate 具有非常引人注目的結果，其效率達到了 30% 左右。 Keppra 下跌約 28%。 因此，如果我們達到 30% 以上的門檻，對我們來說才是一個真正成功的結果。

So we'll stay tuned for that. And based on that data, it will allow us to then tailor our Phase III program accordingly. But based on the mechanism of action selectivity of the GABAA PAM compound, we are very hopeful that this will introduce a novel therapy that will benefit patients with epilepsy.

我們會繼續關注。根據這些數據，我們可以相應地調整我們的第三階段計劃。但基於 GABAA PAM 化合物的作用機制選擇性，我們非常希望這將引入一種有益於癲癇患者的新療法。

Thank you. One moment for our next question. Our next question comes from Graig Suvannavejh of Mizuho.

謝謝。請稍候，回答下一個問題。下一個問題來自瑞穗的 Graig Suvannavejh。

This is Yihao Wang for Graig Suvannavejh. Congrats to the team for the recent capital raise and just 2 quick questions from us. For emraclidine, what is needed from non-clinical and clinical pharmacology studies in order to support a potential registrational package in schizophrenia? And what drove the decision to proactively raise equity capital ahead of your multiple clinical data events in 2024?

我是 Graig Suvannavejh 的王一豪。祝賀團隊最近獲得融資，我們只想問兩個快速問題。對於恩拉克利定，需要進行哪些非臨床和臨床藥理學研究才能支持其在精神分裂症領域的潛在註冊方案？那麼，是什麼促使您決定在 2024 年的多個臨床數據活動之前主動籌集股本呢？

Sure. Thanks for the question. Yes. So we have been looking forward to getting the package ready to submit to the NDA. So to summarize briefly, we've done almost all the work that we need to do actually to prepare the preclinical section of the NDA already. So we have a few things to finish up, but there's nothing that's going to be on the critical path from that area at all. So I hope that addresses your question.

當然。謝謝你的提問。是的。因此，我們一直期待著準備好提交給保密協議 (NDA) 的方案。簡單總結一下，我們實際上已經完成了準備 NDA 臨床前部分所需的幾乎所有工作。因此，我們還有一些事情需要完成，但是從該區域出發，關鍵路徑上根本沒有任何事可做。我希望這能解答你的問題。

Yes. And then I think on the capital raise, I'll let Susan add to this as well. But I think largely, this was one thing that we have been talking to a number of investors about over the last few months. And there was a significant amount of interest in doing the raise from outside investors.

是的。然後我想在籌集資金方面，我也會讓蘇珊對此做出補充。但我認為總體而言，這是我們過去幾個月一直在與許多投資者談論的事情之一。外部投資者對此次融資表現出了濃厚的興趣。

And so we thought it was a good time to do that so that we could really be focused on execution in 2024. As we mentioned, we're going to be working on 2 NDAs in parallel. And so to be able to have the balance sheet shored up and really have a line of sight and focus on execution on those lead programs was really the primary driver behind that. I'm not sure if there's anything to add that, Susan.

因此，我們認為現在是這樣做的好時機，這樣我們就可以真正專注於 2024 年的執行。 正如我們所提到的，我們將同時處理 2 個保密協議。因此，能夠支撐資產負債表並真正擁有視線並專注於那些主要項目的執行才是真正的主要驅動力。蘇珊，我不確定是否還有什麼可以補充的。

We'll continue to be judicious with our spending. I mean, ultimately, what the capital raise enabled us to do, as Ron said, was focused on execution. This runway gets us into 2026, so we can turn over the data cards next year and not have any overhang limiting our upside potential.

我們將繼續謹慎支配開支。我的意思是，正如羅恩所說，最終，籌集的資金使我們能夠專注於執行。這條跑道可以讓我們進入 2026 年，因此我們可以在明年交出數據卡，而不會受到任何限制我們上行潛力的懸而未決的問題的影響。

And our next question comes from Charles Duncan of Cantor Fitzgerald.

我們的下一個問題來自 Cantor Fitzgerald 的查爾斯鄧肯。

Congrats on the progress. Had a quick question on emraclidine and one follow-up on darigabat. In emraclidine, the ADP study, I'm wondering if you could give us a little more color on timing of data and really the kind of rate-limiting step for enrollment of that study. And what would -- what's the key parameter that you're looking for or looking at to decide whether or not to move forward in ADP?

祝賀你取得進展。我有一個關於 emraclidine 的快速問題以及一個關於 darigabat 的後續問題。在恩拉克利定的 ADP 研究中，我想知道您是否可以提供更多關於數據時間的信息，以及該研究入組的實際限速步驟。那麼，您正在尋找或查看的關鍵參數是什麼，以決定是否在 ADP 中前進？

Yes, Charles. So as we've talked about in the past, this is more or less a first-of-its-kind type of study. And right now, we're in healthy elderly volunteers. And so, we haven't -- to that end, we haven't given any guidance on when we expect to enroll that study.

是的，查爾斯。正如我們過去談到的，這或多或少是一種首創的研究類型。目前，我們正在尋找健康的老年志工。因此，為此，我們還沒有給出任何有關何時預計開展該研究的指導。

I'll let Ray address how we're thinking about the indication itself. But just stay tuned on that. That's something that we will continue to move ahead, and we're looking forward to. But we're not going to provide any guidance on enrollment on that program at this time.

我讓雷來談談我們如何看待這個跡象本身。但請繼續關注。我們會繼續推進這一目標，並且對此充滿期待。但我們目前不會提供有關該計劃的任何註冊指導。

So to follow up with that, Charles, for ADP, currently, we're doing, as Ron mentioned, multiple ascending dose trial in healthy volunteers. There's other work that needs to be done subsequent to that that will allow us to understand the dosing in that population, which is important because there's a very different manifestation, symptomatically but also population, in terms of the psychotic symptoms that they experience, mostly hallucinations and delusions. The good news is we got fast track from the FDA, which will allow us to work closely with them in terms of what that development program looks like. So stay tuned for that.

因此，為了跟進這一點，查爾斯，對於 ADP 來說，正如羅恩所提到的，目前我們正在對健康志願者進行多次遞增劑量試驗。隨後還需要進行其他工作，以便我們了解該族群的用藥劑量，這很重要，因為從症狀上看，以及從人群上看，他們所經歷的精神病症狀（主要是幻覺和妄想）的表現都非常不同。好消息是，我們獲得了 FDA 的快速審批，這將使我們能夠在開發計劃方面與他們密切合作。請繼續關注。

And then Charles, I think you got a follow-up on darigabat.

然後查爾斯，我想你對 darigabat 有一個後續行動。

Yes, quickly. Just I think Ray mentioned that he's encouraged with high rollover rate, probably not a surprise in focal onset epilepsy if there is perceived efficacy. So I'm just wondering what a high rollover rate means. And more importantly, what are you seeing in terms of persistence in that open-label part of that study?

是的，很快。我只是認為雷提到他對高翻滾率感到鼓舞，如果有明顯的療效，那麼局部癲癇的治療可能並不令人意外。所以我只是想知道高滾動率意味著什麼。更重要的是，您在該研究的開放標籤部分的持久性方面看到了什麼？

Yes. So Charles, obviously, we're always encouraged by patients rolling over into the open label extension, meaning that they are tolerating the therapy well. In terms of efficacy, it's really hard to really understand that because the data is blinded. And it's in the patient's purview to roll over if they feel that there's benefit or they want to continue with the therapy.

是的。因此，查爾斯，顯然，我們總是鼓勵患者轉入開放標籤擴展，這意味著他們能夠很好地耐受這種療法。就功效而言，由於數據是盲目的，所以很難真正理解。如果患者認為有益或想繼續治療，他們有權選擇放棄治療。

We can't comment on the open-label extension data. That will be disclosed when we lock that database and that data becomes available mid-year next year. So while we review the data for data quality, we don't review it in terms of patterns of anything other than that at this juncture. So we'll stay tuned for that data readout in mid-2024.

我們無法評論開放標籤擴展資料。當我們鎖定資料庫時，這一點就會被揭露，並且明年年中資料將可用。因此，雖然我們審查數據的質量，但目前我們不會以任何其他模式來審查數據。因此，我們將繼續關注 2024 年中期的數據讀數。

I look forward to the progress.

我期待取得進展。

Thank you. One moment for our next question -- and our next question comes from David Amsellem of Piper Sandler.

謝謝。請稍等片刻，回答我們的下一個問題——下一個問題來自 Piper Sandler 的 David Amsellem。

So just a couple of quick ones. Looking more broadly at emraclidine, how important is it to develop it and explore clinical work as an adjunct to D2 blockers? How do you think about that commercially? And then secondly, as you look at the kappa, can you talk about what you think makes sense in MDD, vis-a-vis monotherapy or adjunctive therapy and how you're thinking about it based on the body of data for your competitors and what you've seen to date?

簡單說幾個吧。更廣泛地看待恩拉克利定，開發它並探索作為 D2 阻斷劑的輔助藥物的臨床工作有多重要？從商業角度來說您如何看待這一點？其次，當您查看 kappa 時，您能否談談您認為在 MDD 中什麼是有意義的，相對於單一療法或輔助療法，以及您如何根據競爭對手的數據和您迄今為止所看到的情況對此進行思考？

Okay. So in terms of objective treatment, so we are very encouraged that we do believe that emraclidine will be a best-in-class muscarinic agent with once-a-day dosing, no need for titration, and a very benign tolerability profile. No doubt that adjunctive treatment plays a role in the clinical landscape and probably has utility.

好的。因此，從客觀治療的角度來看，我們非常高興地相信，恩拉克利定將成為一流的毒蕈鹼藥物，每日一次給藥，無需滴定，並且具有非常良好的耐受性。毫無疑問，輔助治療在臨床領域發揮作用並且可能具有實用性。

The first step is for us to really understand the dose range in the trials that will read out in the second half of next year. Following that then, we will pursue other programs in schizophrenia. Adjunctive treatment may potentially be one of them. So we're not going to comment on that just yet because we really want to understand the profile of emraclidine and schizophrenia first before we consider it as an adjunctive treatment.

第一步是我們真正了解明年下半年將要公佈的試驗中的劑量範圍。隨後，我們將開展有關精神分裂症的其他項目。輔助治療可能就是其中之一。因此我們暫時不會對此發表評論，因為我們確實想先了解恩拉克利定和精神分裂症的情況，然後才將其視為輔助治療。

In terms of KORA, MDD monotherapy versus adjunctive therapy, as you know, there are 2 companies that have done -- one has done a monotherapy. A second one has done adjunctive therapy. If you look at the outcomes of those trials that really are very similar, the monotherapy, to what standard of care has shown, and the adjunctive treatment is very similar to what the standard of care as adjunctive treatment, basically the neuroleptics, have shown.

就 KORA、MDD 單一療法與輔助療法而言，如您所知，有兩家公司已經開展了此項研究——其中一家公司開展了單一療法。第二位患者接受了輔助治療。如果您查看這些試驗的結果，您會發現它們確實非常相似，單一療法與標準治療的結果非常相似，而輔助治療與作為輔助治療的標準治療（基本上是抗精神病藥物）的結果非常相似。

So if you think about the value proposition of KORA as adjunctive treatment to displace the neuroleptics because of a better tolerability profile based on the neuroleptic tolerability profile, it seems like a very exciting approach and also has great commercial and also potential but also in the best interest of the patients. So we think that that's probably the best approach, but we're evaluating all that. We're continuing to understand our KORA compound internally, which we believe has the potential to be another best-in-class therapy. So we'll stay tuned for all that moving forward.

因此，如果您將 KORA 的價值主張視為一種輔助治療，以取代神經安定藥，因為基於神經安定藥的耐受性特徵，KORA 具有更好的耐受性，那麼這似乎是一種非常令人興奮的方法，並且具有巨大的商業和潛力，同時也符合患者的最佳利益。因此我們認為這可能是最好的方法，但我們正在評估所有這些。我們正在繼續內部了解我們的 KORA 化合物，我們相信它有可能成為另一種一流的治療方法。因此，我們將繼續專注於下一步進展。

One moment for our next question. And our next question comes from Joseph Thome of TD Cowen

請稍候，回答下一個問題。下一個問題來自 TD Cowen 的 Joseph Thome

Great. Just a quick question on the tavapadon filing strategy. I think it was mentioned earlier that it was going to be a 2025 submission. So would early and late Parkinson's be filed together? And is there anything else aside from the open label that is kind of gating to that submission?

偉大的。我只是想問一下關於 tavapadon 歸檔策略的問題。我認為之前曾提到這將是一份 2025 年的提交。那麼早期帕金森氏症和晚期帕金森氏症應該歸為一類嗎？除了開放標籤之外，還有什麼其他因素可以限制該提交嗎？

And then maybe a second on the panic disorder study for darigabat. I know there's a minimum number of panic attacks that patients need to have. But is there a maximum number that patients could have, given that the primary endpoint is panic attack freedom?

然後我們再花點時間討論一下 darigabat 的恐慌症研究。我知道患者需要經歷的恐慌發作次數是最低限度的。但是，考慮到主要終點是擺脫恐慌發作，患者可以擁有的最大數量是否有限制？

Joseph, thank you for the question. So for tavapadon, yes, we plan to file in 2025. As you know, those studies will read out next year. Nothing is gating. In fact, the open-label extension has progressed well, and those exposures have been met. So we're excited about that potential in the Parkinson's arena.

約瑟夫，謝謝你的提問。所以對於 tavapadon，是的，我們計劃在 2025 年提交申請。沒有什麼是門控的。事實上，開放標籤擴展進展順利，並且這些要求都已滿足。因此，我們對帕金森氏症領域的潛力感到非常興奮。

In terms of the panic program, you are correct that they have to have at least 8 panic attacks in the month prior to screening and then 4 panic attacks in the 2 weeks of screening in order to qualify for the trial. So we don't have a floor effect. We actually can show that there is potential to reduce panic attack symptoms, but there is no maximum. So it's really around meeting the -- that minimum threshold. And then from there, you can have as many panic attacks as the patient is experiencing.

關於恐慌症計劃，您說得對，他們必須在篩檢前一個月內至少發生 8 次恐慌症，然後在篩檢後的 2 週內發生 4 次恐慌症，才有資格參加試驗。因此，我們沒有地板效應。我們實際上可以證明，減少恐慌症症狀是有潛力的，但沒有最大值。因此，這實際上是為了滿足最低門檻。然後從那時起，你就會像病人所經歷的一樣多次出現恐慌發作。

We're really wanting to ensure, though, that we get the right patient profile that really drives success. And that's why that criteria is set that way, and there's precedent for that. So we are continuing to enroll in that program and excited about the potential derivative at really being an innovative therapy and a needed therapy in the anxiety disorder space. So we'll stay tuned for that data in the future.

然而，我們確實希望確保我們獲得真正推動成功的正確患者資料。這就是為什麼要這樣設定標準，而且是有先例可循的。因此，我們將繼續參與該計劃，並對該計劃的潛在衍生產品感到興奮，它真的是一種創新療法，也是焦慮症領域的必要療法。因此我們將繼續關注這些數據。

And part of Joseph's question about filing for tavapadon was is it early and/or late. Could you just give a little more detail on how you think about the filing for tavapadon?

約瑟夫關於申請 tavapadon 的問題之一是現在申請是早還是晚。您能否詳細介紹一下您對 tavapadon 申請的看法？

Right. So when we file the tavapadon NDA, we will file all 3 trials and the open-label extension. So we will get a label like others have received for the treatment of Parkinson's disease. So the NDA will consist of the TEMPO-3 trial, which will read out in the first half of next year, which is the adjunctive to levodopa trial, the 2 monotherapy trials that will read out in the second half of next year, as well as TEMPO-4, which is actually the open-label extension trial.

正確的。因此，當我們提交 tavapadon NDA 時，我們將提交所有 3 項試驗和開放標籤延期。因此，我們將獲得像其他人一樣用於治療帕金森氏症的標籤。因此，NDA 將包括 TEMPO-3 試驗（將於明年上半年完成，這是左旋多巴試驗的輔助試驗）、2 個單一療法試驗（將於明年下半年完成）以及 TEMPO-4（實際上是開放標籤擴展試驗）。

Thank you. I'm showing no further questions at this time. I would like to turn it back to Ron Renaud for closing remarks.

謝謝。我目前沒有其他問題。我想請羅恩雷諾作最後發言。

So I'd like to thank everybody for joining us this morning. And keep in mind, again, I'll just to remind folks about our tavapadon investor event on December 11. Thanks, and we'll talk soon.

因此，我要感謝大家今天早上的參加。請記住，我只是想提醒大家我們將於 12 月 11 日舉辦 tavapadon 投資者活動。

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

今天的電話會議到此結束。感謝您的參與，您現在可以斷開連接。