Karuna Therapeutics Inc (KRTX) 2023 Q3 法說會逐字稿

Welcome to the Karuna Therapeutics Third Quarter 2023 Financial Results Conference Call. (Operator Instructions) Please note, this call is being recorded. I will now turn the call over to Alexis Smith, Head of Corporate Affairs and Investor Relations.

歡迎參加 Karuna Therapeutics 2023 年第三季財務業績電話會議。 （操作員指示）請注意，此通話正在錄音。現在我將把電話轉給公司事務和投資者關係主管 Alexis Smith。

Good morning, everyone, and thank you for joining the third quarter 2023 Financial Results Conference Call. I'm joined today by Bill Meury, President and Chief Executive Officer; and Jason Brown, Chief Financial Officer, who will begin our call prepared remarks. Andrew Miller, Founder and Chief Operating Officer; and Will Kane, Chief Commercial Officer, will join Bill and Jason for the Q&A portion of our call.

大家早安，感謝您參加 2023 年第三季財務業績電話會議。今天與我一起出席的還有總裁兼執行長 Bill Meury；以及財務長 Jason Brown，他將在我們的電話會議上發表準備好的演講。安德魯‧米勒 (Andrew Miller)，創辦人兼營運長；首席商務官威爾凱恩 (Will Kane) 將與比爾 (Bill) 和傑森 (Jason) 一起參加電話會議的問答環節。

Before we begin, I encourage everyone to visit the Investors page of our website at investors.karunatx.com to find our press release and presentation related to today's call. Forward-looking statements related to our product development, regulatory and commercialization plans, our research activities and financial outlook may be presented during this call. Please refer to today's press release and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. And with that, I'll hand it over to Bill.

在我們開始之前，我鼓勵大家造訪我們網站 investors.karunatx.com 的投資者頁面，尋找與今天的電話會議相關的新聞稿和簡報。本次電話會議中可能會出現與我們的產品開發、監管和商業化計劃、我們的研究活動和財務前景相關的前瞻性陳述。請參閱今天的新聞稿和我們向美國證券交易委員會提交的文件，以了解可能導致我們的實際業績和結果與這些前瞻性陳述中表達或暗示的業績和結果存在重大差異的重要風險因素。說完這些，我就把麥克風交給比爾。

Thanks, Alexis. Good morning, everyone. I want to begin by thanking our R&D team and our external partners on a high-quality and timely NDA submission for KarXT for the treatment of schizophrenia. The team worked many long days and weekends over the past several months to write and submit our NDA. It was a major achievement for Karuna and represents the culmination of years of preclinical, clinical, CMC and regulatory work on KarXT detailed across several hundred thousand pages of information.

謝謝，亞歷克西斯。大家早安。首先，我要感謝我們的研發團隊和外部合作夥伴，他們及時且高品質地提交了用於治療精神分裂症的 KarXT 的 NDA 申請。在過去的幾個月裡，團隊花了許多白天和週末的時間來撰寫和提交我們的保密協議。這是 Karuna 的一項重大成就，代表了多年來對 KarXT 進行臨床前、臨床、CMC 和監管工作的成果，詳細資料達數十萬頁。

Now the submission of course is just the first step in the NDA review process. There are several other important milestones and activities ahead including top line data from the Phase Ib ABPM trial this month. We expect to hear back from the FDA on their filing decision later this month as well and we're already preparing information for our day 120 safety update and site inspections among other things.

當然，提交只是 NDA 審查流程的第一步。未來還有其他幾個重要的里程碑和活動，包括本月 Ib 期 ABPM 試驗的頂線資料。我們預計本月稍後也會收到 FDA 關於其申請決定的回复，並且我們已經在為第 120 天的安全更新和現場檢查等準備資訊。

As we've talked about, we expect the standard review and therefore, a potential approval and launch in the second half of next year. As you know, the treatment of schizophrenia has been served by 1 class of medication for over 30 years and the potential approval of KarXT would change that for patients and their physicians. And I continue to believe this could be one of the most important product launches in biopharma in 2024-25.

正如我們所討論的，我們預計標準審查將在明年下半年進行，並可能獲得批准和發布。眾所周知，30 多年來，精神分裂症一直由一類藥物治療，而 KarXT 的潛在批准將改變患者及其醫生的治療現狀。我始終相信這可能是 2024-25 年生物製藥領域最重要的產品之一。

In terms of the prelaunch activities, they remain on track. We have the capabilities and the funding needed to optimize this program. We've built out our managed care access and MSL teams, we're focused primarily on pre-approval scientific exchange meetings with payers, which started several weeks ago and on responding to medical information requests from psychiatrists and nurse practitioners. Interest and anticipation for KarXT is very high in the community right now and we'll continue to build over the next several quarters.

就預發布活動而言，一切仍在按計劃進行。我們擁有優化該計劃所需的能力和資金。我們已經建立了自己的管理式醫療訪問和 MSL 團隊，主要專注於與付款人進行幾週前開始的批准前科學交流會議，以及響應精神科醫生和執業護士的醫療信息請求。 目前社群對 KarXT 的興趣和期待非常高，我們將在接下來的幾季繼續推進。

Additionally, we have and will continue to present and publish new data from our emerging program this year and next year. Last month, we presented data from EMERGENT-3 at the European College of Neuropsychopharmacology meeting that highlighted KarXT's differentiated tolerability profile demonstrated in the trial and potential to provide clinically meaningful symptom relief. The data includes new analysis on PANSS responders, which was the final prespecified secondary endpoint in the trial, and EMERGENT-3, nearly 60% of patients receiving KarXT achieved a 20% reduction of pain symptoms by week 5 at the end of the trial.

此外，我們已經並將在今年和明年繼續展示和發布我們新興計劃的新數據。上個月，我們在歐洲神經精神藥理學會會議上展示了 EMERGENT-3 的數據，強調了 KarXT 在試驗中表現出的差異化耐受性特徵以及提供具有臨床意義的症狀緩解的潛力。數據包括對 PANSS 反應者的新分析（這是試驗中最終預先指定的次要終點）和 EMERGENT-3，在試驗結束時的第 5 週，近 60% 接受 KarXT 治療的患者疼痛症狀減少了 20%。

We also shared data on the PANSS motor symptom domain, including the PANSS Marder positive, disorganized thoughts, uncontrolled hostility, excitement and anxiety depression factors, where KarXT demonstrated statistically significant improvements from baseline to week 5 compared to placebo.

我們也分享了 PANSS 運動症狀領域的數據，包括 PANSS Marder 陽性、思維混亂、無法控制的敵意、興奮和焦慮憂鬱因素，其中與安慰劑相比，KarXT 從基線到第 5 週表現出統計學上的顯著改善。

On safety, we provided additional data to characterize the adverse events associated with KarXT and EMERGENT-3 were consistent with EMERGENT-1 and 2, the most common treatment-emergent adverse events were GI in nature, primarily occurred within the first 2 weeks of treatment, mild in severity and transient over time. Looking ahead, we'll be sharing pooled efficacy and safety analysis from the EMERGENT-1, 2 and 3 trials as well as additional analysis on negative symptoms and adverse events at NEI in Colorado Springs and CNS Summit in Boston this month.

在安全性方面，我們提供了額外的數據來描述與 KarXT 和 EMERGENT-3 相關的不良事件，這些不良事件與 EMERGENT-1 和 2 一致，最常見的治療中出現的不良事件是胃腸道性質的，主要發生在治療後的前 2 週內，嚴重程度較輕且隨時間推移是短暫的性質。展望未來，我們將於本月在科羅拉多斯普林斯的 NEI 和波士頓的 CNS 峰會上分享 EMERGENT-1、2 和 3 試驗的匯總療效和安全性分析以及對負面症狀和不良事件的額外分析。

On the commercial front, preparations for the anticipated launch are on track too, including market research, sales force sizing and deployment and our peer-to-peer and consumer outreach programs. We have a team of people with a great deal of new product launch experience in neuroscience. They know what works and what doesn't and are carefully evaluating all strategic and operational decisions to support the launch.

在商業方面，預期發布的準備工作也在按計劃進行，包括市場調查、銷售團隊規模和部署以及我們的點對點和消費者拓展計劃。我們擁有一支在神經科學領域擁有豐富新產品發表經驗的團隊。他們知道什麼可行，什麼不可行，並正在仔細評估所有支援此次發布的策略和營運決策。

Equally important to our regulatory achievements and pre-commercialization work for KarXT is the continued execution of our ongoing Phase III program, a rise and depth, which we believe reinforce the value proposition of KarXT as a potential treatment for psychosis-related conditions. For ARISE, site activation and improvement is ongoing with about 50 sites currently active across the United States and Europe. As we maintain our target of sharing top line data in the second half of 2024, we continue to monitor site activation and enrollment rates very closely and manage factors that may impact enrollment on a day-to-day basis.

對於我們在 KarXT 方面的監管成就和商業化前工作而言，同樣重要的是持續執行我們正在進行的第三階段計劃，這是一個上升和深入的過程，我們相信這將強化 KarXT 作為精神病相關疾病的潛在治療方法的價值主張。對於 ARISE，網站活化和改進正在進行中，目前在美國和歐洲大約有 50 個站點活躍。我們保持在 2024 年下半年共享營收資料的目標的同時，也將繼續密切監控站點啟動率和註冊率，並管理可能影響日常註冊的因素。

Although there is no approved therapy for the adjunctive treatment of schizophrenia, the use of antipsychotics as combination treatment is seen in around 30% of patients despite the lack of clear pharmacological rationale and clinical evidence to support adjunctive use. Through ARISE, we hope to reinforce the unique weakness of KarXT's differentiating clinical profile, and demonstrate that KarXT can be safely and effectively added on top of standard of care.

雖然目前尚無批准用於精神分裂症輔助治療的療法，但大約 30% 的患者使用抗精神病藥物作為聯合治療，儘管缺乏明確的藥理學原理和臨床證據支持輔助使用。透過 ARISE，我們希望強化 KarXT 差異化臨床特徵的獨特弱點，並證明 KarXT 可以在標準治療之上安全有效地添加。

I'm also pleased to share our ADEPT program evaluating KarXT for the treatment of psychosis and Alzheimer's is fully underway following the initiation of ADEPT-2 and 3 in the third quarter. We remain on track to share data from ADEPT-1 and 2, our relapse prevention and acute efficacy trials in 2025. As a reminder, the fundamental concept of KarXT originates from an Alzheimer's trial, where xanomeline demonstrated promising therapeutic benefit in treating psychosis and related behavioral symptoms as well as cognition.

我也很高興地告訴大家，我們的 ADEPT 計劃正在全面推進中，該計劃旨在評估 KarXT 對精神病和阿茲海默症的治療效果，而 ADEPT-2 和 3 則於第三季度啟動。我們仍計劃在 2025 年分享 ADEPT-1 和 2（我們的復發預防和急性療效試驗）的數據。

Our ADEPT program is designed based on the insights from that initial strategy and our Phase Ib trial in healthy volunteers. And while our primary objective with ADEPT is to evaluate the efficacy and safety of KarXT in treating hallucinations and delusions associated with Alzheimer's. We will also be collecting data, providing additional insights into the potential of KarXT in treating other prominent and clinically relevant symptoms of Alzheimer's, including agitation, aggression and cognition.

我們的 ADEPT 計劃是根據初步策略和在健康志願者中進行的 Ib 期試驗的見解而設計的。而我們對 ADEPT 的主要目標是評估 KarXT 在治療與阿茲海默症相關的幻覺和妄想方面的有效性和安全性。我們還將收集數據，進一步了解 KarXT 在治療阿茲海默症其他突出和臨床相關症狀（包括激動、攻擊性和認知）方面的潛力。

The data from ADEPT may not only reinforce KarXT's promise as the potential treatment for Alzheimer's psychosis, but also help inform future developments with KarXT. Outside of KarXT, we're also making headway in our early stage and discovery program, most notably with KAR-2618, a TRPC4/5 inhibitor that we have acquired from Goldfinch Bio at the start of this year. We plan to evaluate KAR-2618 for the treatment of major depressive disorder and anticipate initiating the Phase Ib clinical trial in 2024 with additional details such as trial design and refined timing to be shared early next year.

ADEPT 的數據不僅可以增強 KarXT 作為阿茲海默症潛在治療方法的前景，而且還有助於指導 KarXT 未來的發展。除了 KarXT，我們的早期階段和發現項目也取得了進展，最值得注意的是 KAR-2618，這是一種 TRPC4/5 抑制劑，是我們今年年初從 Goldfinch Bio 收購的。我們計劃評估 KAR-2618 治療重度憂鬱症的效果，並預計於 2024 年啟動 Ib 期臨床試驗，並將於明年初分享試驗設計和具體時間等更多細節。

Now on our earnings call earlier this year, I had highlighted 3 strategic and operational priorities that we set out to achieve in 2023. Those priorities were maximize the value of KarXT from a development perspective; two, expand our pipeline; and three, scale the operational capabilities of our company as we transition to a fully integrated R&D commercial organizations.

在今年稍早的財報電話會議上，我強調了我們計劃在 2023 年實現的 3 個策略和營運重點。二是擴大我們的產品線；第三，在我們轉型為完全整合的研發商業組織的過程中，擴大我們公司的營運能力。

We've made excellent progress on these 3 fronts, which reflects the hard work and scale of our organization. With just a couple of months left in 2023, we look forward to finishing the year strong. With that, I'll hand it over to Jason.

我們在這三個方面取得了卓越的進展，這反映了我們組織的辛勤工作和規模。 2023 年僅剩幾個月了，我們期待圓滿結束這一年。說完這些，我就把它交給傑森。

Thank you, Bill. I'm pleased to be with you all today to share our third quarter financial results and to discuss our full year 2023 guidance. Q3 was another strong quarter for the company driven by continued progress across our ongoing KarXT Phase III programs, the submission of our NDA for KarXT, pre-commercialization efforts as well as significant growth across the organization. Total operating expenses for the third quarter were $136.2 million compared to $81.1 million for the same period in 2022.

謝謝你，比爾。我很高興今天能與大家分享我們的第三季財務表現並討論我們的 2023 年全年指引。第三季度對公司來說又是一個強勁的季度，這得益於我們正在進行的 KarXT 第三階段計劃的持續進展、KarXT 保密協議的提交、商業化前的努力以及整個組織的顯著增長。第三季總營運費用為 1.362 億美元，而 2022 年同期為 8,110 萬美元。

Operating expenses were slightly offset by $17 million in interest income, resulting in a net loss of $119.1 million. Research and development expenses for the third quarter were $104 million compared to $62 million for the prior year period. The increase to $42 million was primarily driven by expenses related to our ongoing RXT clinical programs, increased employee head count and higher stock-based compensation.

營業支出略微被1700萬美元的利息收入所抵消，導致淨虧損1.191億美元。第三季的研發費用為 1.04 億美元，去年同期為 6,200 萬美元。增加 4,200 萬美元的主要原因是我們正在進行的 RXT 臨床項目相關的費用、員工人數的增加以及股票薪酬的提高。

General and administrative expenses for the third quarter were $32.3 million compared to $19.1 million for the prior year period. The increase of $13.1 million was primarily driven by expenses related to our pre-commercialization efforts, increased employee head count and higher stock-based compensation.

第三季的一般及行政開支為 3,230 萬美元，去年同期為 1,910 萬美元。 1,310 萬美元的增加主要由於與我們的商業化前努力、員工人數增加和股票薪酬增加相關的費用。

Cash, cash equivalents and investment securities totaled $1.3 billion as of September 30, 2023, compared to $1.1 billion at the end of 2022, providing us with a cash runway comfortably through 2026. The increase was due to our follow-on public offering in March of this year that resulted in a net proceeds of approximately $437 million.

截至 2023 年 9 月 30 日，現金、現金等價物和投資證券總額為 13 億美元，而 2022 年底為 11 億美元，為我們提供了充足的現金儲備，直至 2026 年。

Looking ahead at the rest of the year, we anticipate R&D to decrease in the fourth quarter relative to the third quarter and reiterate our guidance for the full year 2023, with total operating expense is expected to come in towards the top end of the range at around $470 million. Of that, we expect R&D and G&A expenses to be in the range of $355 million and $115 million, respectively. With the increase in R&D guidance being primarily driven by continued enrollment in our long-term safety trials by activation costs associated with the ADEPT program and costs related to our ambulatory blood pressure monitoring trial. I'll now hand it back over to Bill.

展望今年剩餘時間，我們預計第四季度的研發費用將相對第三季減少，並重申我們對 2023 年全年的指導，預計總營運費用將達到約 4.7 億美元的最高水準。其中，我們預計研發和一般行政費用分別在 3.55 億美元和 1.15 億美元之間。研發指導的增加主要得益於我們長期安全試驗的持續參與，以及與 ADEPT 計劃相關的啟動成本和與我們的動態血壓監測試驗相關的成本。我現在將其交還給比爾。

Thank you, Jason. With that, we can open the call to questions.

謝謝你，傑森。現在，我們就可以開始提問了。

(Operator Instructions) Your first question is from the line of Yatin Suneja with Guggenheim.

（操作員指示）您的第一個問題來自古根漢的 Yatin Suneja。

Congrats on all the progress. Just 2 quick ones for me, if I may. So the first one is with regard to the ARISE study. Could you maybe talk about your expectation? Would you expect the drug to behave similarly to the monotherapy in terms of the onset and depth of responses? And how should we think about the added tolerability impact.

恭喜你所取得的所有進步。如果可以的話，我只想簡單問兩個問題。第一個問題是關於 ARISE 研究。您能談談您的期望嗎？您是否認為該藥物在反應的開始和深度方面的表現與單一療法相似？我們該如何看待增加的耐受性影響？

And then maybe on the pipeline front on 2618, you are prioritizing MDD. Could you maybe talk about the rationale going into MDD first over, let's say, other anxiety disorder.

然後也許在 2618 的管道前端，您正在優先考慮 MDD。您能否先談談 MDD 相對於其他焦慮症的理由。

Thank you, Yatin. Thank you for both questions. I'm going to turn it over to Andrew.

謝謝你，亞汀。感謝您提出這兩個問題。我要把它交給安德魯。

So with respect to the ARISE study from an expectations perspective, first, maybe to speak to efficacy. A reminder that the primary end point in the ARISE study, the total PANSS score is the same as the primary endpoint across EMERGENT 1, 2 and 3. So those do significantly inform our expectations about what we expect to see in the ARISE program.

因此，從預期角度來看 ARISE 研究，首先，也許可以談談功效。提醒一下，ARISE 研究中的主要終點，即 PANSS 總分與 EMERGENT 1、2 和 3 中的主要終點相同。

It's a key difference with the ARISE program being we do expect the baseline severity of symptoms to be lower given that patients are being actively treated with existing antipsychotic medicines. Because of that, we expect a little less dynamic range and our expectation from a statistical powering perspective, is it more conservative, 4- to 5-point change on total PANSS in comparison to the 8 to 11-point change that we observed in EMERGENT program. That still would meaningfully clear what we would consider clinically meaningful benefit in patients. And again, it's all based on the same primary end point across the ARISE and EMERGENT programs.

這與 ARISE 計劃的一個主要區別是，考慮到患者正在接受現有的抗精神病藥物積極治療，我們確實預期症狀的基線嚴重程度會較低。因此，我們預期動態範圍會稍微小一些，從統計動力角度來看，我們的預期是更為保守的，整體 PANSS 會有 4 到 5 個點的變化，而我們在 EMERGENT 程式中觀察到的變化是 8 到 11 個點。這仍然可以清楚地表明我們認為對患者俱有臨床意義的益處。再次強調，這一切都基於 ARISE 和 EMERGENT 計劃中的相同主要終點。

With respect to safety and overall tolerability, obviously, one of the things we're most excited about with KarXT is the completely unique pharmacology, focused on the M1 and M4 muscarinic receptors. And when you look at the tolerability and safety profile, I think it's very distinct in comparison to the adverse effects that are observed on current background standard of the care. So we continue to expect to see things consistent with the muscarinic pharmacology of KarXT and don't expect meaningful overlap or for instance, worsening of background side effects associated with (inaudible).

就安全性和整體耐受性而言，顯然，KarXT 最令我們興奮的事情之一是其完全獨特的藥理學，專注於 M1 和 M4 毒蕈鹼受體。當您查看耐受性和安全性時，我認為它與當前護理背景標準中觀察到的不良影響相比非常明顯。因此，我們繼續期望看到與 KarXT 的毒蕈鹼藥理學一致的事情，並且不希望出現有意義的重疊，或者例如與（聽不清楚）相關的背景副作用的惡化。

And then you want to comment on 2618 at the preclinical evidence supporting utilization (inaudible)?

然後您想對支持利用的臨床前證據 2618 進行評論（聽不清楚）？

I mean I think with 2618 and in general, TRPC4/5 as a therapeutic target for psychiatric illness and mental illness. I think there are a lot of interesting possibilities. I think that's really the basis of your question, is that there's evidence broadly to support both antidepressant and antilytic properties. Specifically, 2618 a molecule, but more broadly, TRPC4/5 as a target. I think our focus on MDD initially represents or representative of both our scientific confidence in that preclinical data, our ability to execute a study that we think will provide meaningful information specifically towards safety in a Phase Ib context, but also doing a study of patients that could provide some insight into the potential therapeutic benefits.

我的意思是，我認為 2618 和一般而言，TRPC4/5 是精神疾病和心理疾病的治療目標。我認為有很多有趣的可能性。我認為這確實是你問題的基礎，有廣泛的證據支持抗憂鬱和抗溶解特性。具體來說，2618 是一種分子，但更廣泛地說，TRPC4/5 是目標。我認為，我們對 MDD 的關注最初代表或代表了我們對臨床前數據的科學信心、我們執行一項研究的能力，我們認為該研究將為 Ib 期安全性提供有意義的信息，同時也代表了對患者的研究，該研究可以為潛在的治療益處提供一些見解。

We certainly remain quite interested in a number of different anxiety disorders. Particularly, I would say generalizing anxiety disorder is something that we're interested in evaluating with 2618 as well and look forward to being able to speak more of the details of that Phase Ib study here early next year as well as our longer-range plans for this program.

我們確實對許多不同的焦慮症仍然很感興趣。特別是，我想說廣泛性焦慮症也是我們有興趣透過 2618 進行評估的項目，並且期待能夠在明年初在這裡談論更多有關該 Ib 期研究的細節以及我們對該項目的長期計劃。

And the only other thing I would add is that everything available today in MDD is effectively serotonergic and noradrenergic. And so we, of course, have some work to do to produce human efficacy data. But MDD is attractive because this would essentially be to the depression market, what in many respects, KarXT could be to the schizophrenia and the atypical market, which is a completely novel pharmacological approach, but we'll know more at the end of '24, early 2025.

我唯一想補充的是，如今 MDD 中可用的所有東西都有效地具有血清素和去甲腎上腺素的功能。因此，我們當然還需要做一些工作來獲得人類功效數據。但是 MDD 很有吸引力，因為它本質上是對憂鬱症市場而言的，而從很多方面來說，KarXT 可能對精神分裂症和非典型市場而言是這樣的，這是一種全新的藥理學方法，但我們會在 2024 年底、2025 年初了解更多資訊。

Your next question is from the line of Laura Chico with Wedbush Securities.

您的下一個問題來自 Wedbush Securities 的 Laura Chico。

This is Ingrid on for Laura Chico. Wonder if you could talk a little bit about your expectations around real-world duration of treatment for KarXT cycling among therapies and even completely discontinuing therapies represents a hallmark of the schizophrenia space. How would you describe your base case expectations now that you've had longer-term experience with KarXT in clinical trials?

這是勞拉·奇科 (Laura Chico) 的英格麗德 (Ingrid)。想知道您是否可以談談您對 KarXT 現實世界治療持續時間的期望，在各種療法之間循環甚至完全停止治療代表了精神分裂症領域的一個標誌。鑑於您在臨床試驗中對 KarXT 有了長期的經驗，您如何描述您的基本預期？

I'll make a few comments first, Ingrid and then turn it over to Will Kane, our Chief Commercial Officer. What I can tell you right now is that when you look at real-world experience with the second-generation atypicals, adherence rates are in the range of about only 50% to 60%, and the number of missed days of therapy each year is probably between 100 and 150 depending on which real-world observational study that you will look at. And so noncompliance is a real problem given the efficacy and safety experience some patients have that results in relapse, that results in ER visits and then, of course, hospitalizations and increased healthcare costs.

英格麗德，我首先發表一些評論，然後將其交給我們的首席商務官威爾凱恩。我現在可以告訴你的是，當你觀察第二代非典型藥物在現實世界中的作用時，你會發現依從率僅在 50% 到 60% 左右，每年錯過治療的天數大概在 100 到 150 天之間，具體取決於你所觀察的現實世界觀察性研究。因此，考慮到療效和安全性體驗，不遵守規定是一個真正的問題，一些患者會導致復發，從而導致急診就診，當然，還會導致住院和醫療費用增加。

We, of course, don't have real-world experience yet. But we would expect that adherence with KarXT in the real-world setting could be higher, persistency could be longer and missed days of therapy lower. And I'll just turn it over to Will to add a little bit.

當然，我們還沒有現實世界的經驗。但我們預計，在現實環境中，KarXT 的依從性會更高，持久性會更長，錯過治療的天數會更少。我將把它交給威爾來做一點補充。

Thanks, Bill. I'll just echo some of the comments, Bill made, which is in the marketplace when we talk to clinicians and also to payers they see the potential for increased adherence is a real value add for KarXT. As Bill mentioned, there was the incremental increase from the typical to atypical, and given the mechanism and the clinical profile we've seen so far in the emergent program, there's strong interest in seeing long-term data to realize the full potential of KarXT. And so when we don't have real-world data, the data is indicating and signaling that there could be an opportunity here for increased adherence.

謝謝，比爾。我只是重複比爾提出的一些評論，當我們在市場上與臨床醫生和付款人交談時，他們認為提高依從性的潛力對於 KarXT 來說是一個真正的附加價值。正如比爾所提到的，從典型到非典型逐漸增加趨勢，鑑於我們在新興計畫中迄今為止看到的機制和臨床特徵，人們強烈希望看到長期數據，以充分發揮 KarXT 的潛力。因此，當我們沒有真實世界的數據時，數據就會顯示並發出訊號，這裡可能存在增加依從性的機會。

And as we've talked about on M&A occasions, there's a really high rate of nonadherence. Patients typically about 2/4 of them or 75% will discontinue in the first 18 months, and that's driven by a lack of either adequate efficacy or intolerability and KarXT may have the opportunity to really address both of those needs in the market.

正如我們在併購場合談到的那樣，不遵守規定的情況確實很高。大約 2/4 或 75% 的患者會在前 18 個月內停藥，這是由於缺乏足夠的療效或無法耐受，而 KarXT 可能有機會真正滿足市場上的這兩種需求。

Your next question is from the line of Myles Minter with William Blair.

您的下一個問題來自威廉布萊爾的邁爾斯明特 (Myles Minter)。

Congrats on the quarter. First 1 is just clarifying. Are you going to announce the NDA filing acceptance if you do get that? And would you also use that as a forum to give us the ambulatory blood pressure monitoring data at that time. And then the second one is EMERGENT-5 has been fully enrolled since the second quarter. That's patients that are treatment naive to KarXT in an outpatient setting. Can you just give us an update on the dropout rate and how that compares to a EMERGENT-4 that's ongoing in patients that have been experienced.

恭喜本季取得佳績。第一個只是為了澄清一下。如果您確實獲得了該許可，您會宣布 NDA 申請被接受嗎？您是否也會利用這個論壇向我們提供當時的動態血壓監測數據？第二個是EMERGENT-5自第二季以來已經完全註冊。這些患者是在門診接受過 KarXT 治療的初次患者。您能否向我們介紹一下退出率的最新情況，以及與正在進行的 EMERGENT-4 試驗相比情況如何？

Great, Myles. I'll take the first part of the question and then turn it over to Andrew to answer your second question. As it relates to the acceptance, we will announce that we expected at the end of the month. And then as it relates to the ABPM results, we expect to have those announced in the middle of the fourth quarter, which is only a couple of weeks away. Andrew?

太好了，邁爾斯。我將回答問題的第一部分，然後交給安德魯回答你的第二個問題。至於驗收事宜，我們將在月底公佈預期。至於 ABPM 的結果，我們預計在第四季中期公佈，只剩下幾週的時間了。安德魯？

Yes, Myles, with respect to EMERGENT-4 and EMERGENT-5, obviously those studies continue to be ongoing, as you mentioned, it's sort of premature to comment too specifically on any conclusions from those studies. I think we do look for those as being overall consistent with what we spoke to earlier, the pharmacology of KarXT unique being at the both M1 and M4 receptors. And our expectation is we'll see in those long-term studies, something looks quite consistent with the data we've been able to release from the short-term studies.

是的，邁爾斯，關於 EMERGENT-4 和 EMERGENT-5，顯然這些研究仍在繼續進行中，正如您所說，現在對這些研究的任何結論發表過於具體的評論還為時過早。我認為我們確實在尋找那些與我們之前所說的總體一致的東西，即 KarXT 獨特的藥理學作用於 M1 和 M4 受體。我們的期望是，我們將在這些長期研究中看到與我們能夠從短期研究中發布的數據非常一致的東西。

EMERGENT-1, 2 and 3, where we see predominantly an efficacy profile characterized by a robust effect, a broad effect and a safety and tolerability profile generally characterized by mild-to-moderate transient GI side effects.

EMERGENT-1、2 和 3，我們主要看到的是其功效特徵，其特點是作用強勁、作用廣泛，安全性和耐受性特徵通常以輕度至中度的短暫性胃腸道副作用為特徵。

We'll, of course, look forward to releasing all of that data at the right time here in 2024 as the study is complete. But again, those studies are a great opportunity for us to further demonstrate the potentially differentiated profile of KarXT.

當然，我們期待在 2024 年研究完成時的正確時間發布所有數據。但同樣，這些研究為我們進一步展示 KarXT 潛在的差異化特徵提供了絕佳的機會。

Your next question is from the line of Paul Matteis with Stifel.

您的下一個問題來自 Stifel 的 Paul Matteis。

Ahead of the ABPM data, I was just curious, what's your level of confidence right now that, that data with the FDA will not serve as a major amendment. Any more color you can provide or any analogs? And then just more broadly, how are you thinking about business development and the possibility of doing another TRPC4/5 like deal in the next year or so before the launch?

在公佈 ABPM 數據之前，我很好奇，您現在對 FDA 的數據不會成為重大修正的信心程度如何。您能提供更多顏色或類似物嗎？那麼從更廣泛的角度來看，您如何考慮業務發展以及在推出之前的未來一年左右進行另一項類似 TRPC4/5 的交易的可能性？

Thanks, Paul, for the questions. I'll let Andrew tackle the first question, then I can answer the second question for you.

謝謝保羅提出的問題。我讓安德魯解決第一個問題，然後我可以回答你的第二個問題。

And I think with respect to the ABPM study, that was specifically a topic of discussion with the FDA at our pre-NDA meeting in second quarter earlier this year. And specifically, the idea that study, which again is a Phase Ib safety study, will be submitted at the day 120 safety update, which obviously, based on our submission in late September will happen in the late January time frame. And again, I think we're highly confident that would not result in a sort of a major amendment to the NDA and NDA review process.

我認為，就 ABPM 研究而言，這是我們在今年稍早第二季 NDA 前會議上與 FDA 討論的議題。具體來說，該研究（再次是 Ib 期安全性研究）將在第 120 天的安全更新時提交，顯然，根據我們在 9 月底提交的申請，該研究將在 1 月底的時間範圍內提交。我再次強調，我們非常有信心這不會導致對 NDA 和 NDA 審查流程做出重大修改。

Again, because of specifically that conversation with the agency at pre-NDA meeting, but also I think the general precedent that study, that's a Phase Ib safety study submitted prior to midpoint review were certainly prior to day 120. We would not expect to result an extension to the PDUFA date.

再次，由於在 NDA 前會議上與該機構的對話，而且我認為，該研究的一般先例是，在中期審查之前提交的 Ib 期安全性研究肯定是在第 120 天之前。

Great. Thanks, Andrew. And then Paul, as it relates to business development, it's a good question. It's a very important priority for us to build the pipeline. I would say it's second only to the approval and launch of KarXT, which is obviously our most important priority. You mentioned the Goldfinch transaction, the TRPC4/5 inhibitor. Look, we look at new opportunities on a weekly, monthly basis. We think about them strategically, scientifically, financially.

偉大的。謝謝，安德魯。然後保羅，因為它與業務發展有關，所以這是一個很好的問題。修建管道對我們來說是一個非常重要的優先事項。我想說這僅次於 KarXT 的批准和推出，這顯然是我們最重要的優先事項。您提到了 Goldfinch 交易，即 TRPC4/5 抑制劑。看，我們每週、每月都會尋找新的機會。我們從策略、科學和財務的角度來考慮這些問題。

And I think that the TRPC4/5 inhibitor checked all of those boxes. We think about neuroscience fairly broadly with a focus on schizophrenia, Alzheimer's, depression, anxiety, several other conditions. If we see something that we like, fits our balance sheet, make sense given our capabilities and our neuroscience focus, yes, we would do something.

我認為 TRPC4/5 抑制劑滿足了所有這些要求。我們對神經科學的思考相當廣泛，重點在於精神分裂症、阿茲海默症、憂鬱症、焦慮症和其他幾種疾病。如果我們看到某種我們喜歡的東西，它符合我們的資產負債表，並且考慮到我們的能力和神經科學重點，是的，我們會採取行動。

Obviously, our #1 priority right now is KarXT, but number #2 is building the pipeline and new product flows for any company, the lifeblood. And so we'll continue to look at things. And if we see something that we like, we'll, of course, we'll do it.

顯然，我們現在的首要任務是 KarXT，但其次是建立管道和任何公司的新產品流，這是命脈。因此我們將繼續關注此事。如果我們看到喜歡的東西，我們當然會去做。

Your next question is from the line of Ash Verma with UBS.

您的下一個問題來自瑞銀的 Ash Verma。

So on the ABPM study, I wanted to ask, so I know we haven't seen any impressive effect for KarXT in previous study and study of M4 molecule was pretty clean on the ABPM. But just mechanistically or theoretically for KarXT, like could the additional M1 agonism in any way impact on patients' blood pressure?

因此，關於 ABPM 研究，我想問一下，所以我知道我們在先前的研究中沒有看到 KarXT 有任何令人印象深刻的效果，並且 M4 分子在 ABPM 上的研究相當乾淨。但僅從機製或理論上來說，對於 KarXT 來說，額外的 M1 激動劑是否會以任何方式影響患者的血壓？

Thanks for the question. I'll turn it over to Andrew.

謝謝你的提問。我將把它交給安德魯。

Yes. Thanks, Ash. So specifically from a pharmacology perspective, is often challenging to separate the individual contributions. We have a molecule hitting multiple targets. That being said, I think when you look at the data that exists for some of the allosteric modulator programs, et cetera, I think you tend to see any potential pressure effect being tied to the M4 receptor. So our expectation is not that we will see any meaningful pressure effect with RXT certainly on the basis of an M1 and the M4 pharmacology.

是的。謝謝，Ash。因此，具體從藥理學角度來看，分離各個貢獻通常具有挑戰性。我們有一個可以擊中多個目標的分子。話雖如此，我認為當您查看某些變構調節劑程序等的現有數據時，我認為您傾向於看到任何潛在的壓力效應都與 M4 受體有關。因此，我們的期望是不會看到 RXT 產生任何有意義的壓力效應，當然是基於 M1 和 M4 藥理學。

And I think as you referenced, we don't seem to see a sustained chronic increase across the emergent program already. I think the ABPM study offers us the ability to further confirm that. And we certainly remain confident here with the final data coming quite soon, that we will be able to reject that statistical hypothesis of any sort of sustained 3-millimeter increase in systolic blood pressure.

而且我認為正如您所說，我們似乎還沒有看到整個新興項目的持續慢性成長。我認為 ABPM 研究可以讓我們進一步證實這一點。我們當然仍然有信心，隨著最終數據的即將公佈，我們將能夠拒絕任何形式的收縮壓持續升高 3 毫米的統計假設。

Your next question is from the line of Mohit Bansal with Wells Fargo.

您的下一個問題來自富國銀行的 Mohit Bansal。

Congrats on all the progress. Just wanted to ask regarding your competitor's data on TRPC4/5 and there was this small increase -- was increase in suicidal ideation. Again, the numbers are small. So just wanted to understand, is it just the law of small numbers? Or is there any theoretical reason why you will see high suicidal ideation with this mechanism.

恭喜你所取得的所有進步。只是想問一下您競爭對手的 TRPC4/5 數據，發現自殺意念略有增加。再次，數量很少。所以只是想了解一下，這只是小數定律嗎？或者是否有任何理論原因可以解釋為什麼在這種機制下你會看到很高的自殺意念。

Mohit, we had trouble hearing what you said. Would you mind just repeating the question?

Mohit，我們聽不清楚你說的話。您介意重複一下這個問題嗎？

Sure. So this is regarding the TRPC4/5 and the data we saw in early October from Boehringer Ingelheim. So the trial was terminated due to slow recruitment, but there was a 15% rate of suicidal ideation in the treatment arm versus 4% in placebo. I'm just trying to understand, is this anything is it -- has this anything to do with the mechanism? Or it is just a law of small numbers, these are really small numbers here. Thank you.

當然。這是關於 TRPC4/5 以及我們 10 月初從勃林格殷格翰看到的數據。因此，由於招募緩慢，試驗被終止，但治療組的自殺意念發生率為 15%，而安慰劑組為 4%。我只是想知道，這跟機制有關係嗎？或者這只是一個小數定律，這些數字確實很小。謝謝。

Andrew. Go ahead.

安德魯。前進。

Yes. Thanks. So you're referring to a study where the results were recently posted on clinicaltrials.gov that was actually, a remote mobile-based study that was done by (inaudible) result of the pandemic. That study was terminated early. I think the final enrollment was like low single-digit number of subjects.

是的。謝謝。所以您指的是一項研究，其結果最近發佈在 clinicaltrials.gov 上，這實際上是一項基於遠程移動的研究，是由於疫情的影響而進行的（聽不清楚）。該研究提前終止。我認為最終的入學人數大概是個位數。

I think given that in some of the considerations around MDD and more generally, studies in depression or things like schizophrenia, it's really premature to read too much into that study -- those study results. Particularly when you speak to adverse effects or things like suicidal ideation, which tend to be rare. It's often more challenging to make any conclusions about that until you get larger numbers.

我認為，考慮到對 MDD 的一些考慮以及更普遍的憂鬱症或精神分裂症等研究，對該研究結果進行過多的解讀還為時過早。特別是當你談到不良影響或自殺意念之類的事情時，這些事情往往很少見。在獲得更大的數字之前，做出任何結論往往更具挑戰性。

There's also, I think, more details with respect to things like to suicidal ideation, there are specific rating scales for that. We implement that across the emergent program as well. So simply looking at TAEs is not, I would say, a thorough assessment of the potential effects. And I would further say that from our perspective, we certainly don't see any preclinical evidence or a specific scientific rationale for why that could be an adverse effect associated with TRPC4/5. We'll certainly obviously be carefully assessing that as anyone would and being diligent in conducting studies in expression when we push forward into (inaudible) with the 2618 program.

我認為，關於自殺意念等方面還有更多細節，有專門的評分量表。我們也在緊急計劃中實施了這一點。因此，我認為，僅僅觀察 TAE 並不能全面評估其潛在影響。我還要說的是，從我們的角度來看，我們確實沒有看到任何臨床前證據或特定的科學原理來解釋為什麼這可能是與 TRPC4/5 相關的不利影響。當我們推進（聽不清楚） 2618 計畫時，我們顯然會像任何人一樣仔細評估這一點，並勤奮地進行表達研究。

Next question is from the line of David Amsellem with Piper Sandler.

下一個問題來自 Piper Sandler 的 David Amsellem。

So on ARISE, can you talk to pace of enrollment? And are you still onboarding sites? Just wanted to get a flavor for where things are on that trial? And then secondly, on ADEPT and AD psychosis more specifically, how are you thinking about it vis-a-vis AD agitation. Some companies that are looking at agitation, you guys are looking at psychosis. Do you think that agitation and psychosis is sort of a distinction without much of a difference? And I just wanted to pick your brain on that.

那麼在 ARISE 上，您能談談入學速度嗎？你們還在使用入職網站嗎？只是想了解這次試驗的進度？其次，更具體地說，關於 ADEPT 和 AD 精神病，您如何看待它與 AD 躁動的關係。有些公司關注的是躁動，而你們關注的是精神病。您是否認為躁動和精神病之間沒有太大差異？我只是想就此徵求一下你的看法。

Thanks for the questions. David, go ahead Andrew.

感謝您的提問。大衛，安德魯，繼續說。

Yes. Specifically for the first question around the ARISE program, we have continued to activate sites over the course of this year, really in the second and third quarter, we initiated 2 new countries as part of that programmable area, so we have to cross this. There's about 20 sites that are active at this point in time.

是的。具體來說，對於有關 ARISE 計劃的第一個問題，我們在今年內繼續激活站點，實際上在第二季度和第三季度，我們啟動了 2 個新的國家作為該可編程區域的一部分，因此我們必須跨越這一點。目前大約有 20 個站點處於活躍狀態。

I think as Bill maybe mentioned a little earlier, obviously, whenever we're managing studies, it's always a day-to-day and week-to-week basis. I do think you're likely to see some additional site activations across the ARISE program. Again, that's pretty typical studies like this, you also see sites that will drop off over time who aren't actively enrolling. But I think we feel good about where we are with the ARISE program, continue to see momentum as part of that program. But obviously, we'll provide any additional updates going forward to the extent they are already.

我想正如比爾之前可能提到的那樣，顯然，無論何時我們管理研究，總是以日常和周為單位的。我確實認為您可能會在 ARISE 計劃中看到一些額外的網站啟動。再次，這是非常典型的研究，您還會看到隨著時間的推移，沒有積極註冊的網站會逐漸減少。但我認為，我們對 ARISE 計劃的進展感到滿意，並繼續看到該計劃的發展勢頭。但顯然，我們會在現有範圍內提供任何額外的更新。

And then with respect to the ADEPT program and our focus on psychosis, I think if you rewind the clock 10 to 15 years, there perhaps wasn't as much distinction among psychosis and agitation. We really look at that as a separating out of an agitation-related indication over the last 5 to 10 years, given, frankly, the lack of approval for anything more broadly for psychosis.

然後關於 ADEPT 計劃和我們對精神病的關注，我想如果將時鐘倒回 10 到 15 年前，精神病和躁動症之間可能就沒有那麼大的區別了。坦白說，鑑於對精神病的任何更廣泛治療手段均未獲得批准，我們確實將其視為過去 5 到 10 年間與躁動相關指徵的分離。

Specifically agitation and aggression, I think, are potentially more, I think, affected by drugs that have somnolence or sedative based effects, fundamentally, that's sort of a hetroparadigm. Whereas when you look at hallucinations and delusions in that sort of core psychosis, that's really where we look at taking advantage of the non-antipsychotic effects of xanomeline and as part of KarXT.

具體來說，我認為，激動和攻擊行為可能更容易受到具有嗜睡或鎮靜作用的藥物的影響，從根本上說，這是一種異質範式。而當您觀察這種核心精神病中的幻覺和妄想時，我們實際上就是在考慮利用 xanomeline 的非抗精神病作用以及將其作為 KarXT 的一部分。

Bill referred to this in the original or the opening of the call, that is the population, Alzheimer's patients where the antipsychotic effect of xanomeline was first discovered. And when you look at that data, which is all published, you see benefits specifically on hallucinations, delusions, agitation and aggression across that program. So we really look at the opportunity with KarXT as something to capture that broad effect. But specifically starting with hallucinations and delusions as the basis for the primary endpoints in the ADEPT program.

比爾在最初或電話會議開始時就提到了這一點，即首次發現 xanomeline 的抗精神病作用的人群，即阿茲海默症患者。當您查看已發表的數據時，您會看到該計劃對幻覺、妄想、激動和攻擊行為有特別的好處。因此，我們確實將 KarXT 視為實現廣泛影響的機會。但具體來說，ADEPT 計劃是以幻覺和妄想作為主要終點的基礎的。

And the only other thing I'd add to, David, we know that the product has a procognitive effect, which was observed in the very same trial that Andrew just talked about. And so when we think about that Alzheimer's population, of course, the first step would be an official indication or FDA approved indication for psychosis, but we know that there's data on other aspects of Alzheimer's disease, both agitation, aggression and cognition, which I think creates a compelling opportunity for us as we go into in this area. Thanks for the question.

大衛，我還要補充的是，我們知道該產品具有促進認知的作用，這一點是在安德魯剛才談到的同一項試驗中觀察到的。因此，當我們考慮阿茲海默症患者時，當然，第一步是獲得官方指徵或 FDA 批准的精神病指徵，但我們知道還有關於阿茲海默症其他方面的數據，包括激動、攻擊性和認知，我認為這為我們進入該領域創造了一個極具吸引力的機會。謝謝你的提問。

Your next question is from the line of Jay Olson with Oppenheimer.

您的下一個問題來自奧本海默公司的傑伊·奧爾森 (Jay Olson)。

Congrats on all the progress. Since there seems to be a lot of interest in the ABPM study, can you just remind us what blood pressure signals have you seen in the past? What's the rationale behind running this study? And ultimately, is there a legitimate blood pressure concern for KarXT that investors should be concerned about? Or is that just a false narrative contrived by competitors?

恭喜你所取得的所有進步。由於人們似乎對 ABPM 研究很感興趣，您能否提醒我們過去曾經看過哪些血壓訊號？進行這項研究的背後理由是什麼？最後，KarXT 是否存在值得投資人擔心的血壓問題？或者這只是競爭對手捏造的虛假說法？

Thanks for the question, Jay. Go ahead, Andrew.

謝謝你的提問，傑伊。繼續吧，安德魯。

Yes, sure. Happy to speak to sort of what we've seen, how that projects and ABPM and I think maybe I'll just start with, I think with respect to ABPM, it's not something that we have a lot of concern about internally. Obviously, we're running the study to provide a more definitive data point about what any blood pressure effect of KarXT could be. But when we look at the EMERGENT program, which has the same dosing also in patients living with schizophrenia (inaudible) paradigm as the ABPM study, even in that setting where we're measuring vital signs at Cmax of the drug 2 hours of the first dose.

是的，當然。很高興能談談我們所看到的情況，以及 ABPM 的專案情況，我想也許我先從 ABPM 開始，我認為就 ABPM 而言，我們內部並不太擔心這個問題。顯然，我們進行這項研究是為了提供更明確的數據點，說明 KarXT 對血壓的影響。但當我們觀察 EMERGENT 計畫時，會發現其對患有精神分裂症 (聽不清楚) 的患者所採用的劑量與 ABPM 研究相同，甚至在這種環境下，我們也是在首次服藥後 2 小時的 Cmax 藥物濃度下測量生命徵象。

We don't see a 3-millimeter increase even in that set, which you would describe more as kind of a fundamentally a worst-case scenario. So we translate that data into the ABPM paradigm. That's why we have such a high level of confidence in having a successful outcome from that study.

即使在那組中我們也沒有看到 3 毫米的增加，您可能會將其描述為基本上最壞的情況。因此我們將這些資料轉換成 ABPM 範式。這就是為什麼我們對該研究的成功結果如此有信心。

Consistently, across the program with KarXT, we generally have not observed any meaningful pressure effect and not something that was historical consideration with this mechanism really until you've seen some of the M4 or selective compounds come into early-stage clinical development over the last couple of years.

在整個 KarXT 計畫中，我們從未觀察到任何有意義的壓力效應，而且這並不是這種機制的歷史考慮，直到過去幾年看到一些 M4 或選擇性化合物進入早期臨床開發階段。

So from our perspective, we're obviously greatly looking forward to be able to see the final ABPM data and get that out into the public domain, which I think will provide in our minds, the most definitive data point around any potential pressure effects. But we expect that to be consistent with what we've already seen in our clinical assessment in the emergent program.

因此從我們的角度來看，我們顯然非常期待能夠看到最終的 ABPM 數據並將其發佈到公共領域，我認為這將為我們提供有關任何潛在壓力影響的最明確的數據點。但我們預計這與我們在新興計劃的臨床評估中已經看到的情況一致。

Your next question is from the line of Jeff Hung with Morgan Stanley.

您的下一個問題來自摩根士丹利的 Jeff Hung。

What is the latest feedback you're hearing from payers on KarXT? And how is the benefit on cognition resonating with payers and clinicians.

您從付款人那裡聽到的有關 KarXT 的最新反饋是什麼？認知方面的益處如何與付款人和臨床醫生產生共鳴？

Yes. Great question, and I'll just make a couple of comments, and then I'll turn it over to Will Kane. We've already started scientific exchange meetings with Medicaid programs all across the United States. So we're now more than 12 months away from launch. We're going to have plenty of opportunity to sort of lay the proper groundwork so that we achieve relatively high level of formulary coverage during the first year on the market.

是的。這個問題問得很好，我只想發表幾點評論，然後我會把時間交給威爾凱恩 (Will Kane)。我們已經開始與美國各地的醫療補助計畫進行科學交流會議。因此，現在距離發布還有 12 個多月的時間。我們將有充足的機會打下適當的基礎，以便在上市第一年就達到相對較高的處方覆蓋率。

I think we've already been to about 14 Medicaid programs, maybe more over the past several months. And I think the opportunity here for us to carve out a position on the formularies for KarXT is pretty significant. They haven't had a novel pharmacological class in 3 decades. I think if I was -- if we were getting ready to introduce another D2 antagonist, I think conversations with payers may be a little bit different, but this isn't that. With that, I'll turn it over to Will.

我認為，過去幾個月我們已經參與了大約 14 個醫療補助計劃，甚至可能更多。我認為，這對我們來說，在 KarXT 的處方集上佔有一席之地的機會相當重大。三十年來，他們還沒有推出過新穎的藥理學課程。我想如果我——如果我們準備好引入另一種 D2 拮抗劑，我認為與付款人的對話可能會有些不同，但事實並非如此。說完這些，我會把話題交給威爾。

Sure. Thanks, Bill. So I'm particularly pleased with the interactions we've had to date with the payer community. Since we initiated scientific exchange in September, we've had over 2 dozen interactions across channels, Medicaid, Medicare Part D and also commercial. And we have more than a dozen just on meeting scheduled between now and the end of the year, and that number continues to go up. I think it reflects a couple of things. One is there is interest, and we -- I've heard this directly in new treatment options for patients with serious mental illness in this case, particularly schizophrenia.

當然。謝謝，比爾。因此，我對我們迄今為止與付款人社群的互動感到特別高興。自從九月我們啟動科學交流以來，我們已經透過跨通路、醫療補助、醫療保險 D 部分以及商業管道進行了 20 多次互動。從現在到年底，我們已經安排了十幾次會議，而且這個數字還在增加。我認為這反映了一些事情。一是人們感興趣，我直接聽說了針對患有嚴重精神疾病，特別是精神分裂症的患者的新治療選擇。

There is -- one of the things the preapproval information exchange allows us the opportunity to learn, if you will, almost in real time as data is presented into medical meetings, et cetera. And so they look forward to that interaction, which is something we can really capitalize on over the next 12 months.

有一件事是，預先批准的資訊交換讓我們有機會學習，如果你願意的話，幾乎是即時的，因為數據會在醫學會議等會議上展示。因此他們期待這種互動，而這正是我們在未來 12 個月內真正可以利用的。

The data is well received. I think they certainly appreciate the unique mechanism of KarXT relative to the products that they're currently offering on their formularies. They really dive into some of the data we present, particularly the total PANSS, but questions about the subscales, which we find to be encouraging and of course, the fundamentally different safety and tolerability profile that's reflected in the data to date.

數據受到熱烈歡迎。我認為他們肯定很欣賞 KarXT 相對於他們目前在處方表中提供的產品的獨特機制。他們確實深入研究了我們提供的一些數據，特別是總體 PANSS，但關於子量表的問題，我們發現這是令人鼓舞的，當然，迄今為止的數據反映了根本不同的安全性和耐受性概況。

They do, to your question, have a real appreciation for the 3 symptom domains of schizophrenia, the positive, the negative anticognitive they know, just as the clinical community knows where the deficits are and they have relatively good drugs on the positive symptoms, but where the needs are negative and cognitive.

對於您的問題，他們確實真正了解精神分裂症的三個症狀領域，即他們所知道的積極和消極的抗認知，就像臨床界知道缺陷在哪裡並且他們針對積極症狀有相對較好的藥物，但需求是消極的和認知的。

So they're very interested to learn more about KarXT's evolving clinical program and where the drug may actually be able to offer potential benefits there. So far, I think, really engaging and positive and every one of them has welcomed the opportunity to come back in the future as we present more clinical data to continue to learn more over the next 10 to 12 months.

因此，他們非常有興趣了解更多有關 KarXT 不斷發展的臨床計劃以及該藥物實際上可能提供的潛在益處的資訊。到目前為止，我認為，會議確實非常有吸引力，而且非常積極。

And the only thing I would add is just in general, in the area of mental health I would say every corner of the healthcare system right now is moving in the right direction. In other words, we just talked about payers and even state governments are rethinking policies as it relates to formularies and reducing the use of certain drug utilization management sort of techniques to control prescribing and we see fewer and fewer states using prior authorizations.

我唯一想補充的是，總體而言，在心理健康領域，我認為目前醫療保健系統的每個角落都在朝著正確的方向發展。換句話說，我們剛才談到付款人，甚至州政府也在重新考慮與處方集有關的政策，減少使用某些藥物使用管理技術來控制處方，我們發現使用事先授權的州越來越少。

In fact, I think in 14 states, there's no PA allowed. You also see the elimination or the reduction in the use of step edits, and I think these are very, very good trends. If you take a look at patient advocacy groups that are doing more work than ever before to reduce stigma in isolation. And then if you look at the providers, there are more community mental health centers being set up in communities all across the United States.

事實上，我認為 14 個州都不允許 PA。您還會看到步驟編輯的使用被消除或減少，我認為這是非常非常好的趨勢。如果你看看病人權益團體，你會發現他們比以前做了更多的工作來減少因孤立而產生的恥辱感。如果你看看提供者，你會發現美國各地的社區正在建立更多的社區心理健康中心。

And I think all of these trends are more tailwinds than they are headwinds and will enable coverage and access to KarXT and frankly, and the other new compound that's introduced in the United States for serious mental illness? And I think it's a very different dynamic in mental health as compared to other therapeutic areas across those aspects of the market, and there's more momentum than there has been in years. And so that puts us in a very good position when we start to introduce KarXT in the United States next year. Thanks for the question.

我認為所有這些趨勢都是利大於弊，並將使 KarXT 的覆蓋和使用成為可能，坦白說，還有美國為治療嚴重精神疾病而推出的另一種新藥？我認為，與市場上的其他治療領域相比，心理健康領域的動態非常不同，而且發展勢頭比過去幾年更加強勁。因此，當我們明年開始在美國推出 KarXT 時，這將使我們處於非常有利的地位。謝謝你的提問。

Next question is from the line of Salveen Richter with Goldman Sachs.

下一個問題來自高盛的 Salveen Richter。

This is Anamed on for Salveen. Just on the KarXT launch next year. Could you provide some color on what the early days of launch could look like? Are there specific physicians or geographies that you're most interested in? And then on KAR-2618, I guess, is there a certain population with an MDD that would be most suitable for this asset?

這是 Anamed 為 Salveen 拍攝的。就在明年 KarXT 推出之際。能否詳細介紹一下發布初期的情況？您最感興趣的是特定的醫生或地區嗎？然後關於 KAR-2618，我猜，是否有特定患有 MDD 的人群最適合該資產？

Yes. Thank you for the question. I'll turn it over to Will. I would just say, as we think about the introduction of KarXT in the United States. This is going to be a broad-based program. There is great anticipation in the psychiatric community in the nurse practitioner community, for KarXT. And we're going to cover as many physicians as many as nurse practitioners as many community mental health centers as can be covered.

是的。感謝您的提問。我將把它交給威爾。我只想說，我們考慮在美國推出 KarXT。這將是一個基礎廣泛的計劃。護理師執業族群中的精神科界對 KarXT 抱持極大期待。我們將涵蓋盡可能多的醫生、執業護理師以及盡可能多的社區心理健康中心。

And of course, we have a lot of data that will instruct exactly where we deploy our sales organization, our managed care access teams, but there'll be a full comprehensive well-funded program here. And I don't think that there's a psychiatrist or a nurse practitioner in the United States that's not interested and at least evaluating KarXT.

當然，我們有大量的數據可以準確地指導我們在哪裡部署我們的銷售組織、我們的管理式醫療訪問團隊，但這裡將有一個全面且資金充足的計劃。我認為，美國沒有一位精神科醫生或執業護士對 KarXT 不感興趣，至少沒有對其評估過。

The data from the EMERGENT 1, 2 and 3 program, of course, still under review at the FDA, but it's very, very compelling. It's a completely novel approach. It may be complementary to the D2 antagonist. And so our job is to make sure everyone is aware of those data that they get a complete, accurate balance presentation of all the information that we have, which would be consistent with our label, and then they'll try it in patients that are either new patients, switched patients or patients perhaps that they see a utility and add on although we wouldn't have that indication at launch. And so there'll be no aspect of this market that we leave out and preparing it for launch.

當然，EMERGENT 1、2 和 3 計畫的數據仍在 FDA 的審查中，但它非常非常引人注目。這是一種全新的方法。它可能與 D2 拮抗劑起到補充作用。因此，我們的工作是確保每個人都了解這些數據，以便他們獲得我們擁有的所有資訊的完整、準確的平衡呈現，這與我們的標籤一致，然後他們會在新的患者、轉換的患者或可能看到效用和附加效果的患者身上嘗試它，儘管我們在推出時不會有這樣的跡象。因此，我們不會忽略這個市場的任何方面，也不會為推出它而做準備。

Thanks, Bill. I would just add on to that, that to build on those earlier comments about what we refer to as this mental health moment where we see opportunity, particularly in states since the Medicaid population is so important to KarXT, particularly out of the gate, where we see states that don't require prior authorizations (inaudible) 1 step. Those would be high priority states. And they tend to be a mix, but some large states are in that mix. So we'll be fully prepared to capitalize on that opportunity. We will be fully loaded. We'll have a very robust sampling program, our sales force analysis and structure is nearly complete. So we will go to market, there will be a launch that will support the potential of KarXT across clinicians and payers.

謝謝，比爾。我只想補充一點，基於之前關於我們所說的心理健康時刻的評論，我們看到了機會，特別是在一些州，因為醫療補助人群對 KarXT 非常重要，特別是在一些州，我們看到一些州不需要事先授權（聽不清）1 步驟。這些將是高優先級的州。 它們往往是混合的，但有些大州就屬於這種混合。因此我們將做好充分準備來利用這個機會。我們將全力以赴。我們將有一個非常強大的採樣計劃，我們的銷售隊伍分析和結構已接近完成。因此我們將進入市場，推出一款產品來支持 KarXT 在臨床醫生和付款人中的潛力。

And to this point, and again, that was something Bill said, any engagement we have with the psychiatry community, whether it's psychiatrist or nurse practitioners, et cetera. There's a high level of interest and excitement about KarXT and that they're looking to see our progress and potentially when that drug will be available to them.

就這一點而言，比爾再次強調，我們與精神病學界的任何接觸，無論是精神科醫生還是執業護士等等。人們對 KarXT 表現出了很高的興趣和熱情，他們期待著看到我們的進展並了解這種藥物何時能夠為他們提供。

Great. Andrew, do you want to take the second question?

偉大的。安德魯，你想回答第二個問題嗎？

Yes, specifically with respect to the TRPC4/5 program, 2618, at this point, we speak to our focus in MDD or major depressive disorder. We think about that broadly or being broadly applicable to that patient population, we're not at this point focused on a particular subset of MDD patients. I think we believe that there's potential benefit from a depression perspective but also from an anxiety perspective.

是的，具體關於 TRPC4/5 計劃 2618，目前我們討論的重點是 MDD 或重度憂鬱症。我們對這個問題進行了廣泛的思考，或廣泛適用於該患者群體，目前我們還沒有將重點放在特定的一組 MDD 患者上。我認為我們相信從憂鬱症的角度和焦慮症的角度來看這都有潛在的益處。

There's a substantial comorbidity between MDD and anxiety disorders. So that will be a natural place for us to look at the right time for specific benefits given the preclinical and scientific rationale for antilytic and antidepressant effects. But I think at this point, our focus remains on a role applicable sort of potential treatment for MDD.

重度憂鬱症 (MDD) 與焦慮症之間存在顯著的共病性。因此，考慮到抗溶解和抗憂鬱作用的臨床前和科學原理，我們自然而然地在適當的時間尋找具體的益處。但我認為在這一點上，我們的重點仍然是 MDD 的潛在治療效果的適用性。

Your next question is from the Jason Gerberry from Bank of America.

您的下一個問題來自美國銀行的 Jason Gerberry。

This is Diana Ann for Jason. Congrats on the progress with the NDA submission this quarter. Just a quick 1 on KAR-2618. I'm curious as how you're leveraging all the prior data with this molecule in specifically referring to the molecule failure and the FSGS trial? Was this because it was the wrong target and sort of just what underpins your confidence that it has the right profile for MDD and other CNS disorders.

我是傑森的戴安娜安。恭喜 NDA 本季度提交取得進展。對 KAR-2618 進行快速評估。我很好奇您如何利用該分子的所有先前數據來具體指涉分子失敗和 FSGS 試驗？這是因為它是錯誤的目標嗎？

Sure. Happy to speak to that. And with respect to 2618, you're referring to the previous development program that was running in renal disease. Obviously, medications are unrelated to depression or anxiety, but TRPC4/5 being a target that we've been following, given the biological rationale and preclinical data, which suggests both antidepressant as well as antilytic effects. We've replicated that data specifically with 2618, the molecules are not relying on other target compounds or tool compounds, but specifically with 2618 looking at those preclinical models. So that's really the basis of our confidence with respect to this molecule.

當然。很高興談論這個。關於 2618，您指的是先前在腎臟疾病領域進行的開發計畫。顯然，藥物與憂鬱或焦慮無關，但鑑於生物學原理和臨床前數據，TRPC4/5 是我們一直關注的目標，這表明它既有抗憂鬱作用，也有抗溶解作用。我們已經使用 2618 複製了該數據，這些分子並不依賴其他目標化合物或工具化合物，而是專門使用 2618 來觀察那些臨床前模型。這確實是我們對這種分子充滿信心的基礎。

I think it does offer us a great opportunity to leverage the previous human experience with 2618. Specifically, the program was administered to over 100 humans, 100 patients and up to a duration of 48 weeks. So that provides us a substantial amount of safety and tolerability data that we think is informative and we believe quite positive with respect to the profile of 2618.

我認為它確實為我們提供了一個很好的機會來利用 2618 之前的人類經驗。因此，這為我們提供了大量安全性和耐受性數據，我們認為這些數據很有參考價值，並且我們對 2618 的概況持非常積極的態度。

So given that a molecule substantial previous human experience, given the biological preclinical rationale for potential efficacy in treating MDD as well as anxiety disorders, that's kind of the basis of our confidence going forward and how we think about designing the right clinical trial to highlight those potential benefits.

因此，考慮到該分子先前在人類中的重要經驗，考慮到其在治療 MDD 和焦慮症方面具有潛在療效的生物學臨床前原理，這是我們未來信心的基礎，也是我們如何考慮設計正確的臨床試驗來突出這些潛在益處的基礎。

Thanks for the question.

謝謝你的提問。

Just one quick follow-up, sorry. So then would you anticipate being able to go straight into Phase III trials from Phase Ib given you do have all this prior safety data? Or is it still to be determined?

只需快速跟進一次，抱歉。那麼，鑑於您擁有所有這些先前的安全數據，您是否預計能夠從 Ib 期直接進入 III 期試驗？還是還有待確定？

Yes. I mean, I think we don't want to speculate too far in the future about our development in 2618. But I think what you're hearing us say is we do think we're ready to go into a Phase 1b study in patients with major stress disorder. I would say if you look at the program that we've run with KarXT in schizophrenia, there's not a substantial distinction between Phase II and Phase III, our EMERGENT-1 study, in our Phase II EMERGENT-2 and 3 being the Phase III studies are identical from a protocol perspective.

是的。我的意思是，我認為我們不想對 2618 的未來發展進行太多猜測。我想說的是，如果您看一下我們在精神分裂症中使用 KarXT 開展的項目，您會發現 II 期和 III 期之間沒有實質性區別，我們的 EMERGENT-1 研究、II 期 EMERGENT-2 和 3 以及 III 期研究從協議角度來看是相同的。

So again, I think we'll wait future results from that Phase Ib study prior to commenting to you specifically in our plans going forward from there. But we do think, given the substantial safety and tolerability data that already exists, it does offer us the opportunity to run an accelerated development program for 2618.

因此，我認為我們將等待 Ib 期研究的未來結果，然後再就我們的未來計劃向您具體發表評論。但我們確實認為，鑑於已經存在的大量安全性和耐受性數據，它確實為我們提供了運行 2618 加速開發計劃的機會。

Your next question is from the line of (inaudible) with JPMorgan.

您的下一個問題來自摩根大通（聽不清楚）。

This is Nick on for Jeff. You previously talked about your commercial preparedness in the U.S. and kind of your thoughts on an initial ramp there. But can you also recap your commercial strategy outside the U.S. and which countries could be logical first choice?

這是尼克 (Nick) 代替傑夫。您之前談到了您在美國的商業準備情況以及對美國初步發展的想法。但您能否也概括一下您在美國以外的商業策略以及哪些國家可能是合理的首選？

Yes. It's a good question, Nick. Thanks. Outside the United States, we, of course, have a partnership in China with Zai. And then the other 2 important geographies would be the EU and Japan. And as we said before, we'll clearly need a partner with regulatory development and commercial capabilities. KarXT has value outside the United States in both of those geographies. And we hope that, that is a strategy that will come into focus in the 2024 period, mid-'24, late 2024 and more to come.

是的。這是個好問題，尼克。謝謝。在美國以外，我們當然在中國與 Zai 建立了合作關係。另外兩個重要地區是歐盟和日本。正如我們之前所說，我們顯然需要一個具有監管開發和商業能力的合作夥伴。 KarXT 在美國以外的兩個地區都具有價值。我們希望，這項策略將在 2024 年、2024 年中、2024 年末及以後逐漸顯現。

Your next question is from the line of Marc Goldman with Leerink Partners.

您的下一個問題來自 Leerink Partners 的 Marc Goldman。

This is Rudy on the line for Marc. So can you talk about your current strategy for cognitive impairment in schizophrenia? Are you starting pivotal trials to pursue this as a separate indication. And secondly, can you also provide more color on your pre-commercialization work? How should we think about spending moving into 2024?

我是魯迪，找馬克。那麼您能談談您目前針對精神分裂症認知障礙的策略嗎？您是否已經開始進行關鍵性試驗，以將此作為單獨的適應症進行研究。其次，您能否詳細介紹一下您的商業化前的工作？我們應該如何考慮 2024 年的支出？

Great. Thanks for the question. Andrew will take the first part, and then we'll take the second part.

偉大的。謝謝你的提問。安德魯將負責第一部分，然後我們將負責第二部分。

Yes. Specifically with respect to cognitive impairment associated with schizophrenia. Obviously, we were able to collect cognitive performance data as an exploratory endpoint as part of the emergent program. That will also be included as we think about future data with respect to EMERGENT-4 and 5 as well as the ARISE program are all opportunities to just further collect cognitive data there, of course, with cognitive data collection and demonstrated benefit in the original studies (inaudible) as well in patients with Alzheimer's and patients with schizophrenia.

是的。特別是與精神分裂症相關的認知障礙。顯然，我們能夠收集認知表現數據作為新興計劃的一部分作為探索性終點。當我們考慮有關 EMERGENT-4 和 5 以及 ARISE 計劃的未來數據時，這也將包括在內，這些都是進一步收集認知數據的機會，當然，透過認知數據收集和原始研究（聽不清）中顯示的益處，以及對阿茲海默症患者和精神分裂症患者的益處。

Going forward, do you think we're contemplating additional work specifically dedicated towards cognition? And really what that means is studies that are specifically designed, recruited and have primary endpoint that reflects cognition rather than other symptoms of schizophrenia. So that's something that's certainly under consideration for us, we believe there is a broadly applicable potential benefit of KarXT across psychosis and cognition in a number of potential different indications. And I think you'll expect to hear more from us in 2024, specifically about dedicated development towards cognition of schizophrenia.

展望未來，您認為我們正在考慮專門針對認知進行更多工作嗎？這實際上意味著專門設計和招募的研究具有反映認知而不是精神分裂症其他症狀的主要終點。所以這是我們肯定正在考慮的事情，我們相信 KarXT 在多種潛在不同適應症的精神病和認知領域具有廣泛適用的潛在益處。我認為您將會在 2024 年聽到我們更多的消息，特別是關於精神分裂症認知的專門研發成果。

Thanks, Andrew. Will, you want to take the second question?

謝謝，安德魯。威爾，你想回答第二個問題嗎？

Sure. Then on the precommercialization word, so first, as we've indicated, our leadership is in place from a commercial perspective and the team is really focused on developing the right go-to-market strategies. As we mentioned before, we expect this to be a fully loaded campaign out of the gate. We see great opportunity for KarXT in a marketplace that is eagerly awaiting new treatment options.

當然。然後是關於商業化前的問題，首先，正如我們所指出的，從商業角度來看，我們的領導層已經到位，而且團隊真正專注於制定正確的市場進入策略。正如我們之前提到的，我們預計這將是一場充滿熱情的活動。我們看到，在熱切期待新治療方案的市場中，KarXT 有著巨大的機會。

Our scientific exchange, as we've mentioned, has begun. And I think we've gone in great form that the collaboration between our account director team and our medical science (inaudible) team. So they're able to continue that dialogue with clinicians and particularly with payers and clinicians on the (inaudible) to the extent they have questions that we can react to and provide information to our sales force planning and design work is nearing completion, as I said, that will give us the opportunity to go to market and really address healthcare prescribers, both psychiatry nurse practitioners in psychiatry and a primary care physicians that are obviously very active in this area.

正如我們所提到的，我們的科學交流已經開始。我認為我們的客戶總監團隊和醫學科學（聽不清楚）團隊之間的合作非常順利。因此，他們能夠繼續與臨床醫生，特別是付款人和臨床醫生就（聽不清）問題進行對話，我們可以對他們提出的問題作出反應，並向我們的銷售團隊提供信息。

But it also allow us to cover a broader landscape, if you will, to ensure we cover the certified community behavior health centers that we provide adequate reimbursement is important to help the offices get through any prior authorization or step processes that need to be in play. We have full sampling program that's all designed and ready to roll.

但它也使我們能夠涵蓋更廣泛的領域，如果你願意的話，以確保我們涵蓋經過認證的社區行為健康中心，我們提供足夠的報銷，這對於幫助辦公室完成任何需要進行的事先授權或步驟流程非常重要。我們擁有完整的採樣程序，並且已經設計完畢，可以投入使用。

So we're in a very good position. We still have more work to do. Obviously, we're ways away from a potential approval and we'll want to obviously find a labeling human form our messaging, et cetera. But I think to this point, I'm very pleased, and we're in good shape.

因此我們處於非常有利的地位。我們還有更多的工作要做。顯然，我們距離獲得潛在的批准還有很長的路要走，我們顯然希望找到一種能夠貼上人性化的標籤，形成我們的訊息傳遞方式，等等。但我認為到目前為止，我非常高興，而且我們狀況良好。

Yes, I would just second what Will said. We are on track. I would say we're ahead of schedule as it relates to getting ready. And the beauty here is that the psychiatric community is anticipating KarXT. There's a great deal of interest here. Of course, we can't promote it until we get approval, but all systems gone. Thanks for the question.

是的，我同意威爾的說法。我們正步入正軌。我想說，我們已經提前做好準備了。這裡的美妙之處在於精神病學界正在期待 KarXT。這裡有很多有趣的東西。當然，在獲得批准之前我們不能推廣它，但是所有系統都失效了。謝謝你的提問。

Your next question is from the line of Jason Butler with JMP Securities.

您的下一個問題來自 JMP Securities 的 Jason Butler。

And I'll have my congrats on the progress. Just another follow-up on commercial prep. Can you maybe speak to what you're hearing from physicians about how they're thinking about using the drug early in the launch? And specifically, with regards to dose flexibility, how willing they will be to push the dose to optimize efficacy early in their experience versus taking a slower and gaming experience with tolerability.

我對所取得的進展表示祝賀。這只是對商業準備的另一個後續行動。您能否談談您從醫生那裡聽到的關於他們在上市初期如何使用該藥物的想法？具體來說，關於劑量靈活性，他們願意在體驗早期加大劑量以優化療效，還是願意接受較慢且具有耐受性的體驗。

Great. Thanks for the question. I'll just make an opening comment and then turn it over to Will. I've been involved with probably 7 or 8 neuropsychiatry launches over the course of 25 years. And in my experience, psychiatrists are the most depth at dosing and generally follow-up principle of start low and go slow. I think that's true whether you're dealing with antidepressants or atypical for schizophrenia or a novel compound like KarXT for schizophrenia.

偉大的。謝謝你的提問。我只是做一個開場白，然後把麥克風交給威爾。在過去的 25 年裡，我參與過大概 7 到 8 次神經精神醫學的啟動。根據我的經驗，精神科醫師在劑量控制方面最為深入，並且通常遵循從低劑量開始、慢慢增加的原則。我認為，無論您使用的是抗憂鬱藥物、治療精神分裂症的非典型藥物，還是治療精神分裂症的新型藥物（如 KarXT），都是如此。

And I would expect that they'll follow the same practice with KarXT using the label, of course, as guidance as they do with other atypicals. I'll turn it over to Will let him sort of add his comments.

我希望他們對 KarXT 採取同樣的做法，當然，使用標籤作為指導，就像他們對其他非典型藥物所做的那樣。我將把它交給威爾，讓他補充他的評論。

Sure, I'll just add on to that, that we will go to market to enable that flexibility for the prescribing community to tailor the use of the drug per the label, but also for their clinical experience so that they can maximize the patient experience with the product right out of the gate. In terms of the approach of the patient segments, et cetera, it's a broad-based one, right? There are many patients with schizophrenia, looking for new treatment options.

當然，我只想補充一點，我們將進入市場，為處方社群提供靈活性，使他們能夠根據標籤定製藥物的使用，同時也為他們提供臨床經驗，以便他們能夠最大限度地提高患者對產品的體驗。就患者細分等方面的方法而言，它是一種廣泛的方法，對嗎？許多精神分裂症患者正在尋找新的治療選擇。

We've reiterated that many times in terms of the high rate of non-adherence and discontinuation, whether it's patients in that have lapsed and therefore, not on any therapy for which KarXT could be a new patient start, if you will, or those that are experiencing adequate efficacy or tolerability effects that are looking for a switch or in the case of this market with the increased use of polypharmacy of 2D2s, there will be some physicians who, even though we will not promote for that until we have an indication they will see the opportunity to potentially add KarXT on to be help on patient who are not adequately addressed from an efficacy perspective.

我們已多次重申，就高不依從性和停藥率而言，無論是已經失效而無法接受任何療法的患者，對於這些患者來說，KarXT 都可能是一個新起點，或者那些已經獲得了足夠的療效或耐受性而希望轉換療法的患者，或者在這個市場上，隨著 2D2 多種藥物使用量的增加，有些醫生會認為，在他們有機會為此有機會的結果

And so it is a broad-based population. Again, there's been very little novelty in this area, diagnostically for a long time for decades. And so you know that it really has, I think, captured their interest and they're already thinking about the breadth of patients that may benefit from the KarXT.

因此，這是一個基礎廣泛的人群。再者，幾十年來，從診斷上來說，這領域很少有新奇之處。所以，我認為，它確實引起了他們的興趣，而且他們已經在考慮哪些患者可能會從 KarXT 中受益。

I think Will is right. If you had another D2 antagonist, you might be thinking about the market more narrowly, a second or a third line type of treatment, but that's not what we're talking about here. And I think with you go on the far left of the continuum first episode psychosis, all the way to patients who are not on therapy and who have relapsed, I think the opportunity for KarXT is that broad and it should be that broad given what we've seen in the emerging program. Thanks for the question.

我認為威爾是對的。如果您有另一種 D2 拮抗劑，您可能會更狹隘地考慮市場，即二線或三線治療類型，但這不是我們在這裡討論的內容。我認為，從連續體首次發病的精神病患者最左邊開始，一直到未接受治療但復發的患者，我認為 KarXT 的機會非常廣泛，而且根據我們在新興項目中看到的情況，它的機會應該是非常廣泛的。謝謝你的提問。

Your next question is from the line of Charles Duncan with Cantor Fitzgerald.

您的下一個問題來自 Cantor Fitzgerald 的 Charles Duncan。

This is (inaudible) from Cantor. Great to hear all the progress made in 3Q, 2 questions for us. Can you talk about the progress of KarXT study in psychosis and Alzheimer's. And what are, if any, the rate limiting factors for patient enrollment? And the second question is for KarXT for schizophrenia. What are your expectations for an ADCOM? And what are possible key topics for that discussion?

這是（聽不清楚）來自 Cantor 的。很高興聽到第三季的所有進展，我們有兩個問題。您能談談KarXT在精神病和阿茲海默症方面的研究進展嗎？如果有的話，患者入組的速率限制因素是什麼？第二個問題是關於 KarXT 治療精神分裂症的。您對 ADCOM 有何期望？這次討論的可能關鍵議題是什麼？

Great. Thank you. Good questions, Andrew.

偉大的。謝謝。好問題，安德魯。

With respect to the ADEPT program, obviously, the ADEPT-1 study has been ongoing since the second half of 2022. ADEPT-2 just started more recently here in the third quarter. So those studies add slightly different points from an operational perspective, certainly in ADEPT 1, but also in ADEPT-2 focus on finding recruiting the right patients into that study. I think in any study in psychiatry, finding patients who sort of really fit the key inclusion criteria with respect to diagnosis and severity as well as general health tend to be the sort of limiting factors. That's all built into our assumptions around a number of sites and duration of time needed to successfully for those studies.

關於 ADEPT 計劃，顯然，ADEPT-1 研究自 2022 年下半年開始就一直在進行。因此，從操作角度來看，這些研究增加了略有不同的觀點，當然在 ADEPT 1 中，但在 ADEPT-2 中也專注於尋找招募合適的患者參與研究。我認為在任何精神病學研究中，找到在診斷、嚴重程度以及整體健康狀況方面真正符合關鍵納入標準的患者往往成為限制因素。這一切都建立在我們對於成功進行這些研究所需的站點數量和時間長度的假設之上。

So nothing specifically that I would point to you for the ADEPT program outside of sort of more general considerations.

因此，除了一些更一般的考慮之外，我對 ADEPT 計劃沒有什麼特別想指出的。

With respect to an ADCOM, we certainly have already begun our preparation process for a potential ADCOM. I think our views were less likely than 50% to receive an ADCOM. That's really on the basis of having a clinical program for an indication treatment of schizophrenia adults that's well precedented from a clinical trial design and endpoint and general methodology perspective. Our development program follows those presidents over the last several decades.

關於 ADCOM，我們當然已經開始了為潛在的 ADCOM 進行的準備工作。我認為我們的觀點獲得 ADCOM 認可的可能性不到 50%。這實際上是基於針對成人精神分裂症指徵治療的臨床計劃，該計劃從臨床試驗設計、終點和一般方法學角度來看已有先例。我們的發展計畫延續了過去幾十年來歷任總統的風格。

But of course, that's up to the FDA discretion whether they'd like to add an ADCOM and what the topic of that would be. But it's certainly something that we're already getting ready for and we'll certainly be ready for if an ADCOM does happen.

但當然，這取決於 FDA 的判斷，他們是否願意添加 ADCOM 以及主題是什麼。但我們確實已經為此做好了準備，而且如果 ADCOM 確實召開，我們肯定會做好準備。

Our final question comes from the line of Graig Suvannavejh with Mizuho.

我們的最後一個問題來自瑞穗的 Graig Suvannavejh。

This is (inaudible) Graig Suvannavejh. So just 2 questions from us. In terms of the Day 120 update, can you elaborate a little bit more specifically regarding who will be part of the update besides the ABPM data. And additionally, with the potential KarXT launch next year, how are preparations for FDA manufacturing inspections going.

這是（聽不清楚） Graig Suvannavejh。我們只想問兩個問題。就第 120 天的更新而言，您能否更具體地詳細說明除了 ABPM 資料之外，誰將參與更新。此外，由於 KarXT 可能在明年推出，FDA 生產檢查的準備工作進展如何？

Yes. So with respect to the day 120 safety update, really, the bulk of that information is simply a 120-day roll forward in all the patients that are currently ongoing in the immersion program. So typically, for the NDA and day 120 safety update, there's simply a date on the calendar by which all data that's been collected prior to that date is included in the submission. So we'll have a 4-month roll forward of that safety data set as part of the program. This is less about completing studies or specific data, but more a general roll forward of that database.

是的。因此，關於第 120 天的安全更新，實際上，大部分資訊只是對目前正在進行沉浸式治療計劃的所有患者的 120 天推進。因此通常，對於 NDA 和第 120 天安全更新，日曆上只會有一個日期，在此日期之前收集的所有資料都會包含在提交中。因此，作為該計劃的一部分，我們將把該安全資料集向前推進 4 個月。這不是要完成研究或特定的數據，而是要對該資料庫進行整體推進。

With respect to manufacturing, inspection readiness, et cetera, I think in general, from a CMC perspective, we feel, I think, in a very good place from a submission perspective, from a potential inspection as well as supporting the launch, we've been manufacturing KarXT at multi-hundred kilogram scale commercial sale for quite some period of time. We already have millions of capsules that are currently dispositioned and ready for a potential sale, assuming that we get approval.

關於製造、檢查準備等，我認為總體而言，從 CMC 的角度來看，我們認為從提交的角度來看，從潛在的檢查以及支援發布的角度來看，我們處於非常好的位置，我們已經在數百公斤規模的商業銷售中生產 KarXT 很長一段時間了。如果我們獲得批准，我們已經有數百萬個膠囊，目前正在處理並準備出售。

We use manufacturing sites that are known to the agency have been expected previously by the agency. And so we felt quite confident going forward that we have a CMC manufacturing strategy to support the potential approval as well as the launch.

我們使用的製造基地是該機構已知的並且是該機構先前預期的。因此，我們對未來充滿信心，我們擁有 CMC 製造策略來支援潛在的批准和發布。

Thanks, Andrew. Thank you for the question.

謝謝，安德魯。感謝您的提問。

Thank you. This does conclude today's call. Thank you for joining. You may now disconnect your lines.

謝謝。今天的電話會議到此結束。感謝您的加入。現在您可以斷開線路了。