Xenon Pharmaceuticals Inc (XENE) 2024 Q1 法說會逐字稿

Thank you for standing by, and my name is Liz, and I'll be your conference operator today. At this time, I would like to welcome everyone to the first quarter 2024 Xenon Pharmaceuticals Incorporated earnings conference call. (Operator Instructions) I'd now like to turn the call over to Chad Fugere, VP, Investor Relations. Please go ahead.

感謝您的耐心等待，我叫莉茲，今天我將擔任您的會議操作員。現在，我歡迎大家參加 Xenon Pharmaceuticals Incorporated 2024 年第一季財報電話會議。（操作員說明）我現在想將電話轉給投資者關係副總裁 Chad Fugere。請繼續。

Thank you, operator, and good afternoon. Thank you for joining us on our call and webcast to discuss Xenon's first quarter 2024 financial and operating results. Joining me today are Ian Mortimer, Xenon's President and Chief Executive Officer; Dr. Chris Kenney, Xenon's Chief Medical Officer; Dr. Chris Von Seggern, Xenon's Chief Commercial Officer; and Sherry Aulin, Xenon's, Chief Financial Officer.

謝謝您，接線員，下午好。感謝您加入我們的電話會議和網路廣播，討論 Xenon 2024 年第一季的財務和營運表現。今天與我一起出席的還有 Xenon 總裁兼執行長 Ian Mortimer； Xenon 首席醫療官 Chris Kenney 博士； Xenon 商務長 Chris Von Seggern 博士；以及 Xenon's 財務長 Sherry Aulin。

Ian will begin with a summary of our recent progress. Chris Kenney will provide an overview of our ongoing clinical stage programs, including our plans and major depressive disorder or MDD. Chris Von Seggern will summarize the key findings from recently completed market research. And Sherry Aulin will close with a summary of our financial results and anticipated milestone events before opening the call up to your questions.

伊恩將首先總結我們最近的進展。Chris Kenney 將概述我們正在進行的臨床階段計劃，包括我們的計劃和重度憂鬱症或 MDD。Chris Von Seggern 將總結最近完成的市場研究的主要發現。雪莉·奧林 (Sherry Aulin) 將在電話會議結束前總結我們的財務業績和預期的里程碑事件，然後回答大家的問題。

Please be advised that during this call, we will make a number of statements that are forward-looking, including statements regarding the timing of and potential results from clinical trials, the potential efficacy, safety profile, future development plans and current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners, product candidates, the efficacy of our clinical trial designs, our ability to successfully develop and achieve milestones in our clinical development programs, the timing and results of our interactions with regulators, our ability to successfully develop and obtain regulatory approvals, anticipated enrollment in our clinical trials and the timing thereof, and our expectation that we'll have sufficient cash to fund operations into 2027.

請注意，在這次電話會議中，我們將做出一些前瞻性聲明，包括有關臨床試驗的時間和潛在結果、潛在功效、安全性、未來開發計劃以及當前和預期適應症的聲明，我們和我們的合作夥伴的潛在市場、監管成功和商業潛力、候選產品、我們臨床試驗設計的有效性、我們成功開發和實現臨床開發計劃里程碑的能力、我們與監管機構互動的時間和結果、成功開發並獲得監管批准的能力、臨床試驗的預期註冊及其時間安排，以及我們對2027 年擁有足夠現金營運資金的期望。

Today's press release summarizing Xenon's first quarter 2024 financial results and the accompanying quarterly report on Form 10-Q will be made available under the Investors section of our website at xenon-pharma.com and filed with the SEC and on SEDAR+.

今天總結 Xenon 2024 年第一季財務業績的新聞稿以及隨附的 10-Q 表格季度報告將在我們網站 xenon-pharma.com 的投資者部分提供，並向 SEC 和 SEDAR+ 提交。

Now I would like to turn the call over to Ian. Ian?

現在我想把電話轉給伊恩。伊恩？

Thank you, Chad, and good afternoon, everyone, and thanks for joining us on our call today. Before I provide an update on our pipeline. I'm excited to announce that we have received approvals from the United States Adopted Names or USAN Council and the World Health Organization, International Nonproprietary Names or INN expert committee, for the use of azetukalner as the nonproprietary or generic name for XEN1101.

謝謝查德，大家下午好，謝謝您今天參加我們的電話會議。在我提供有關我們的管道的更新之前。我很高興地宣布，我們已獲得美國採用名稱或 USAN 委員會以及世界衛生組織、國際非專有名稱或 INN 專家委員會的批准，可以使用 azetukalner 作為 XEN1101 的非專有名稱或通用名稱。

Notably the kalner suffix refers to the molecule's novel Kv7 mechanism of action. If ultimately approved for use in patients, azetukalner would become the first medicine with a akalner suffix to be launched commercially. This is an important milestone for Xenon and represents another step forward as we advance azetukalner towards commercialization.

值得注意的是，kalner 後綴指的是該分子新穎的 Kv7 作用機制。如果最終批准用於患者，azetukalner 將成為第一個商業化推出的帶有 akalner 後綴的藥物。這是 Xenon 的一個重要里程碑，代表我們在推動 azetukalner 走向商業化方面又向前邁出了一步。

Moving now to our pipeline. This past quarter, we continued to make strong progress. Our team remains focused on three key areas. Number one, the continued execution of our azetukalner Phase 3 epilepsy program; number two, the expansion of azetukalner beyond epilepsy with our MDD program; and three, the continued advancement of our discovery portfolio.

現在轉向我們的管道。上個季度，我們持續取得強勁進展。我們的團隊仍然專注於三個關鍵領域。第一，繼續執行我們的 azetukalner 第三階段癲癇計畫；第二，透過我們的 MDD 計劃將 azetukalner 擴展到癲癇之外；第三，我們的發現組合的持續進展。

First, in our epilepsy program, patient enrollment continues to progress in our X-TOLE2 and X-TOLE3 clinical trials in focal onset seizures or FOS; and our X-ACKT clinical trial in primary generalized tonic-clonic seizures or PGTCS. We continue to anticipate the patient enrollment for the first of these trials X-TOLE2 will complete in late 2024 to early 2025.

首先，在我們的癲癇計畫中，在局部癲癇發作或 FOS 的 X-TOLE2 和 X-TOLE3 臨床試驗中，患者入組繼續取得進展；以及我們針對原發性全身強直陣攣發作或 PGTCS 的 X-ACKT 臨床試驗。我們繼續預期 X-TOLE2 首次試驗的患者入組將於 2024 年底至 2025 年初完成。

Second, we made important advancements in our azetukalner MDD program over this past quarter, including reaching alignment with the FDA through end of Phase 2 interactions on key components of our Phase 3 program, which we look forward to initiating in the second half of this year. We are also continuing to evaluate additional opportunities for azetukalner focusing specifically on other potential neuropsychiatric indications where a scientific rationale exists as well as a commercial fit with epilepsy and MDD. Later in the call, Chris Kenney will provide additional details on next steps in our MDD program.

其次，我們在上個季度的 azetukalner MDD 專案中取得了重要進展，包括透過結束對我們的 3 期專案關鍵組成部分的 2 期互動，與 FDA 達成一致，我們期待在今年下半年啟動該專案。我們也持續評估 azetukalner 的其他機會，特別關注其他潛在的神經精神適應症，這些適應症存在科學原理以及與癲癇和重度憂鬱症的商業契合。在稍後的電話會議中，Chris Kenney 將提供有關 MDD 計劃後續步驟的更多詳細資訊。

And third, we are continuing to progress our early-stage discovery efforts. As a reminder azetukalner is the most clinically validated and advanced Kv7 therapeutic in development across multiple indications. And we see the mechanism is having broad potential applicability. The breadth and depth of potential therapeutic indications for the mechanism provides a compelling strategic rationale for the development of additional Kv7 product candidates that are chemically diverse from azetukalner and could provide additional development opportunities.

第三，我們正在繼續推進我們的早期發現工作。提醒一下，azetukalner 是跨多種適應症正在開發的經過臨床驗證最先進、最先進的 Kv7 治療藥物。我們看到該機制具有廣泛的潛在適用性。該機制潛在治療適應症的廣度和深度為開發其他 Kv7 候選產品提供了客戶信服的策略理由，這些候選產品在化學上與 azetukalner 不同，並且可以提供額外的開發機會。

For that reason, we are excited to continue to leverage our ion channel expertise with the goal of progressing multiple Kv7 molecules forward into clinical development in order to extend the reach of this promising and differentiated mechanism to more patients in need. Beyond our robust potassium channel development efforts, we continue to evaluate and advance development candidates targeting sodium channels, including Nav1.1 and Nav1.7, which may have utility in treating seizure disorders and pain, respectively. We expect multiple candidates to move through GLP toxicology studies and into clinical development over the next few years.

因此，我們很高興繼續利用我們的離子通道專業知識，將多個 Kv7 分子推進臨床開發，從而將這種有前景的差異化機制的影響範圍擴大到更多有需要的患者。除了我們強而有力的鉀通道開發工作之外，我們還繼續評估和推進針對鈉通道的開發候選藥物，包括 Nav1.1 和 Nav1.7，它們可能分別可用於治療癲癇和疼痛。我們預計未來幾年將有多個候選藥物透過 GLP 毒理學研究並進入臨床開發。

During the first quarter, we also continued our outreach efforts to key opinion leaders and leading physicians. At the recent annual meeting of the American Academy of Neurology or AAN, we hosted two oral presentations related to our X-TOLE epilepsy program, and we engage with neurologists and epileptologists who continue to express significant excitement about that azetukalner's unique and compelling profile in both epilepsy and MDD.

在第一季度，我們也繼續對關鍵意見領袖和領先醫生進行外展工作。在最近舉行的美國神經病學會(AAN) 年會上，我們主辦了兩場與我們的X-TOLE 癲癇計畫相關的口頭演講，我們與神經科醫生和癲癇學家進行了交流，他們繼續對azetukalner 在這兩個領域的獨特而引人注目的形象表示極大的興奮。

We look forward to continuing to showcase azetukalner at upcoming medical conferences throughout the remainder of this year. And Chris will note some of the near term conferences where Xenon will have a presence. So we're off to a great start to the year, and I'm proud of the continued progress across Xenon's pipeline, including both clinical and preclinical efforts.

我們期待在今年剩餘時間繼續在即將舉行的醫學會議上展示 azetukalner。克里斯將指出 Xenon 將出席的一些近期會議。因此，我們今年有了一個良好的開端，我對 Xenon 管道（包括臨床和臨床前工作）的持續進展感到自豪。

So now I'll turn the call over to Chris Kenney, who will provide some additional details on the progress within our azetukalner clinical programs. Chris, over to you.

現在我將把電話轉給 Chris Kenney，他將提供有關我們 azetukalner 臨床項目進展的一些其他詳細資訊。克里斯，交給你了。

Okay. Thanks a lot, Ian. Before summarizing our clinical development programs, I'd like to touch on our recent presence at AAN, in March. Importantly, our abstracts focused on azetukalner in epilepsy, we're selected for two oral presentations, and we're grateful to our epilepsy opinion leaders, both doctors, Jackie French, and Dr. Roger Porter, for presenting data on our behalf.

好的。非常感謝，伊恩。在總結我們的臨床開發計劃之前，我想談談我們最近在 3 月參加的 AAN。重要的是，我們的摘要重點關注癲癇中的 azetukalner，我們被選為兩次口頭報告，我們感謝我們的癲癇意見領袖，兩位醫生 Jackie French 和 Roger Porter 醫生代表我們提供數據。

In particular, we highlighted results from our ongoing X-TOLE open-label extension study, which demonstrated impressive seizure freedom rates, including one in four patients who were on treatment for two years or more, achieving at least 12 months of consecutive seizure freedom. In addition, we have now generated more than 600 patient years of safety data with some patients having been on azetukalner for more than four years supportive of a well-tolerated drug profile.

我們特別強調了正在進行的X-TOLE 開放標籤擴展研究的結果，該研究顯示了令人印象深刻的無癲癇發作率，其中四分之一的患者接受治療兩年或更長時間，實現了至少12 個月的連續無癲癇發作。此外，我們現在已經產生了 600 多個患者年的安全性數據，其中一些患者已經服用 azetukalner 超過四年，這支持了藥物耐受性良好的情況。

Turning to an update on our clinical development efforts within our Phase 3 epilepsy program, our three clinical trials X-TOLE2 and X-TOLE3 in focal onset seizures, and X-ACKT in primary generalized tonic-clonic seizures, continue to progress. As Ian mentioned, we continue to anticipate completion of X-TOLE2 patient enrollment later this year or early 2025.

關於我們3 期癲癇計畫中的臨床開發工作的最新情況，我們針對局部癲癇發作的三項臨床試驗X-TOLE2 和X-TOLE3，以及針對原發性全身強直陣攣癲癇發作的X-ACKT仍在繼續取得進展。正如 Ian 所提到的，我們繼續預期 X-TOLE2 患者入組將在今年稍後或 2025 年初完成。

As a reminder, we intend to submit an NDA upon the successful completion of X-TOLE2, our first Phase 3 clinical trial, along with the existing data package from our Phase 2B X-TOLE clinical trial and additional safety data from other clinical trials to meet regulatory requirements. Within our MDD program, we've made significant progress towards advancing our Phase 3 development plans based on the encouraging top-line data generated from our Phase 2 proof of concept, X-NOVA study.

提醒一下，我們打算在成功完成我們的第一個3 期臨床試驗X-TOLE2 後提交NDA，連同我們2B 期X-TOLE 臨床試驗的現有數據包以及其他臨床試驗的額外安全數據，以供參考。在我們的 MDD 計劃中，基於第二階段概念驗證 X-NOVA 研究產生的令人鼓舞的頂線數據，我們在推進第三階段開發計劃方面取得了重大進展。

Earlier this year, we submitted to the FDA our end of Phase 2 briefing package, which included our draft Phase 3 protocol synopsis in preparation for an April in-person meeting. Prior to the meeting, we received preliminary written feedback from the FDA in response to our briefing package. The feedback was comprehensive and fully addressed our questions to FDA.

今年早些時候，我們向 FDA 提交了第二階段結束簡報包，其中包括我們的第三階段協議摘要草案，為四月份的面對面會議做準備。在會議之前，我們收到了 FDA 對我們的簡報包的初步書面回饋。回饋很全面，充分解決了我們向 FDA 提出的問題。

As a result, the in-person portion was determined not to be necessary. We're pleased to have been able to efficiently achieve alignment with FDA, enabling us to continue progressing our MDD program into late-stage development. Broadly, our development plans include three Phase 3 clinical trials in MDD, each with one active drug arm or 20 milligrams versus placebo.

因此，現場部分被確定為沒有必要。我們很高興能夠有效地與 FDA 達成一致，使我們能夠繼續將 MDD 專案推進到後期開發。總的來說，我們的開發計劃包括三個 MDD 3 期臨床試驗，每個試驗都有一個活性藥物組或 20 毫克與安慰劑相比。

Using the Hamilton Depression Rating Scale or HAM-D17 as the primary endpoint for assessing efficacy in depression and continuing to assess the efficacy of azetukalner on improvements in anhedonia as well as HAM-D17 at week one, with hopes to confirm the compelling data we generated around the rapidity of onset in the X-NOVA study.

使用漢密爾頓憂鬱評估量表或 HAM-D17 作為評估憂鬱症療效的主要終點，並在第一週繼續評估 azetukalner 對改善快感缺乏的功效以及 HAM-D17，希望證實我們產生的令人信服的數據圍繞X -NOVA 研究中的發病速度。

Having now reached alignment with FDA on key design elements of the Phase 3 program, we've also selected our CRO and are working to finalize our protocols. Once the final protocols are filed, we intend to provide additional details around the design of our MDD studies and look forward to initiating the first of these Phase 3 clinical trials in the second half of this year.

現在，我們已與 FDA 在第 3 階段專案的關鍵設計要素上達成一致，我們也選擇了 CRO，並正在努力敲定我們的方案。一旦最終方案提交，我們打算提供有關 MDD 研究設計的更多細節，並期待在今年下半年啟動第一個 3 期臨床試驗。

As Ian noted, we recognize the importance of continuing to educate the healthcare community about the potential benefits of azetukalner. This week, the Xenon team attended the Annual Meeting of the American Psychiatric Association or APA in New York. We're also pleased to announce that we will present the X-NOVA top-line data at the annual meeting of the American Society of Clinical Psychopharmacology or ASCP taking place in Miami from May 28 to 31. This will be the first time these promising results are presented at a major medical meeting and will represent yet another opportunity to raise awareness of azetukalner's differentiated profile and potential impact within the MDD population.

正如 Ian 指出的那樣，我們認識到繼續向醫療保健界宣傳 azetukalner 的潛在益處的重要性。本週，Xenon 團隊參加了在紐約舉行的美國精神醫學會 (APA) 年會。我們也很高興地宣布，我們將在 5 月 28 日至 31 日在邁阿密舉行的美國臨床精神藥理學會 (ASCP) 年會上展示 X-NOVA 的主要數據。這將是這些有希望的結果首次在重要的醫學會議上提出，並將提供另一個機會來提高對 azetukalner 的差異化特徵和 MDD 人群中潛在影響的認識。

I'll now turn the call over to Chris Von Seggern, who will summarize findings from recent market research outlining the azetukalner value proposition. Chris?

我現在會把電話轉給 Chris Von Seggern，他將總結最近的市場研究結果，概述 azetukalner 的價值主張。克里斯？

Thanks, Chris. On last quarter's call, we discussed our market research findings that have informed our clinical development and commercial plans in depression. To recap, we conducted primary research with 150 high volume prescribing physicians who expressed interest in azetukalner's potential profile with ease-of-use properties, such as once-daily dosing without the need for titration, rapid onset of effect, novel mechanism of action, differentiated safety profile compared to standard repair agents like SSRIs and SNRIs, and ability to address anhedonia, a common comorbidity of depression.

謝謝，克里斯。在上個季度的電話會議上，我們討論了我們的市場研究結果，這些結果為我們憂鬱症的臨床開發和商業計劃提供了資訊。回顧一下，我們對150 名大量開處方的醫生進行了初步研究，他們對azetukalner 的潛在特徵及其易於使用的特性感興趣，例如每日一次給藥，無需滴定，快速起效，新穎的作用機制，與 SSRI 和 SNRI 等標準修復藥物相比，具有差異化的安全性，並且能夠解決快感缺乏（憂鬱症的常見合併症）。

These findings suggest there could be a compelling product fit for azetukalner in the MDD treatment landscape, particularly for patients with remaining unmet medical need resulting from inadequate response to initial therapies or those that experienced common adverse events such as significant weight gain or sexual dysfunction.

這些發現表明，在MDD 治療領域，可能存在適合azetukalner 的引人注目的產品，特別是對於因對初始治療反應不足而導致醫療需求未得到滿足的患者，或經歷了體重顯著增加或性功能障礙等常見不良事件的患者。

This past quarter, we conducted further market research with practicing epileptologists and neurologists in the US to better understand the unmet medical need associated with depression in epilepsy patients. As we have mentioned previously, we believe the data generated in major depressive disorder to date add to our already clearly differentiated profile in epilepsy. Our past research has indicated that depression is a common co-morbidity in epilepsy and that the condition is often underappreciated and potentially undiagnosed, particularly in more difficult to treat patient populations.

上個季度，我們與美國執業癲癇學家和神經病學家進行了進一步的市場研究，以更好地了解與癲癇患者抑鬱症相關的未滿足的醫療需求。正如我們之前提到的，我們相信迄今為止在重度憂鬱症中產生的數據增加了我們在癲癇方面已經明確區分的概況。我們過去的研究表明，憂鬱症是癲癇症的常見併發症，而且這種情況經常被低估並且可能未被診斷，特別是在更難以治療的患者群體中。

We also know that co-morbid depression is associated with worse compliance and poor outcomes for patients suffering from epilepsy. Our recent research supports a clear need for a novel medicine and offers potent seizure reduction while potentially addressing mood related conditions.

我們也知道，共病憂鬱症與癲癇患者的依從性較差和預後不良有關。我們最近的研究支持了對一種新型藥物的明確需求，可以有效減少癲癇發作，同時可能解決與情緒相關的疾病。

Past researches reinforce the value proposition of azetukalner and FOS with physicians indicating significant interest in the novel Kv7 mechanism (technical difficulty) will require titration and demonstration of rapid efficacy at one week. A potential benefit in depression further enhances the profile of azetukalner in epilepsy and physicians cited lamotrigine is an analogue that offers mood benefit in this patient population.

過去的研究強化了 azetukalner 和 FOS 的價值主張，醫生表示對新穎的 Kv7 機制（技術難度）有濃厚興趣，需要在一周內進行滴定並證明快速療效。azetukalner 對憂鬱症的潛在益處進一步增強了 azetukalner 在癲癇中的作用，醫生稱拉莫三嗪是一種類似物，可為該患者群體提供情緒益處。

Our recent research serves to strengthen our conviction around the highly differentiated profile that is emerging for azetukalner and FOS. And we believe that if approved, azetukalner will be a mainstay of treatment for patients with focal onset seizures.

我們最近的研究增強了我們對 azetukalner 和 FOS 正在出現的高度差異化形象的信念。我們相信，如果獲得批准，azetukalner 將成為局部癲癇發作患者的主要治療方法。

I will now turn the call over to Sherry to summarize our financial results and upcoming milestones. Sherry?

我現在將把電話轉給雪莉，總結我們的財務表現和即將到來的里程碑。雪莉酒？

Thanks, Chris. Beginning briefly with our financial results, Xenon is well positioned with a strong balance sheet to support our plans for azetukalner and other earlier stage programs in our pipeline. As of March 31, 2024, cash and cash equivalents and marketable securities were $885.4 million compared to $930.9 million as of December 31, 2023. Based on current operating plans, including the completion of the azetukalner Phase 3 epilepsy studies and fully supporting late-stage clinical development of azetukalner and MDD, we anticipate having sufficient cash to fund operations into 2027.

謝謝，克里斯。從我們的財務表現開始，Xenon 處於有利地位，擁有強大的資產負債表，可以支持我們的 azetukalner 計劃和其他早期項目。截至 2024 年 3 月 31 日，現金及現金等價物以及有價證券為 8.854 億美元，而截至 2023 年 12 月 31 日為 9.309 億美元。根據目前的營運計劃，包括完成 azetukalner 3 期癲癇研究以及全力支持 azetukalner 和 MDD 的後期臨床開發，我們預計有足夠的現金為 2027 年的營運提供資金。

I would refer you to our news release and 10-Q report for further details around our financial results. We remain focused on our goal to improve outcomes for patients in areas of high unmet medical need. Looking ahead, we anticipate a number of important milestones and events and goals.

我建議您參閱我們的新聞稿和 10 季度報告，以了解有關我們財務業績的更多詳細資訊。我們仍然專注於改善醫療需求未被滿足的地區患者的治療結果的目標。展望未來，我們預計將出現一些重要的里程碑、事件和目標。

We will continue to advance our azetukalner Phase 3 epilepsy program, including our X-TOLE2 and X-TOLE3 clinical trials in FOS and our exact clinical trial in PGTCS with patient enrollment in X-TOLE2 expected to complete in late 2024 to early 2025. We expect to initiate the first of three Phase 3 clinical trials in MDD in the second half of 2024.

我們將繼續推進 azetukalner 3 期癲癇項目，包括 FOS 中的 X-TOLE2 和 X-TOLE3 臨床試驗以及 PGTCS 中的精確臨床試驗，X-TOLE2 的患者入組預計將於 2024 年底至 2025 年初完成。我們預計將於 2024 年下半年啟動 MDD 的三項 3 期臨床試驗中的第一項。

We will continue to explore other development opportunities for azetukalner, and we will continue to advance our early-stage preclinical ion-channel programs with the goal of advancing multiple candidates into IND-enabling studies in 2024 and 2025. Our strong belief in azetukalner's potential to play a role in epilepsy, major depressive disorder, and potentially other indications is centered around its unique mechanism of action and attractive product profiles supported by the clinical data generated to date.

我們將繼續探索 azetukalner 的其他發展機會，並將繼續推進我們的早期臨床前離子通道項目，目標是在 2024 年和 2025 年將多個候選藥物推進 IND 支持研究。我們堅信 azetukalner 在治療癲癇、重度憂鬱症和其他潛在適應症方面的潛力，其核心是其獨特的作用機制和迄今為止生成的臨床數據所支持的有吸引力的產品概況。

We look forward to keeping you updated on our progress. I'll now ask the operator to open the line for any questions. Operator?

我們期待向您通報我們的最新進展。如果有任何問題，我現在請接線員接通線路。操作員？

(Operator Instructions) Paul Matteis, Stifel.

（操作員說明）Paul Matteis，Stifel。

I have an X-TOLE question and just one quick Nav1.7 questions. On X-TOLE2, Ian, I was wondering, could you just give a little bit more granularity on where you are with enrollment? How things are tracking relative to the last quarter and sort of your comfort that the guidance is intact. I know you reiterated it today.

我有一個 X-TOLE 問題和一個 Nav1.7 快速問題。關於 X-TOLE2，Ian，我想知道，您能否更詳細地說明您的註冊情況？與上個季度相比，情況如何，以及您對指導完好無損的安慰程度。我知道你今天重申了這一點。

And then on 1.7 and doing a little bit more digging around the target, we came across an example of another compound in this space running into issues with syncope and hypotension. And there have been some questions on the expression of this target in the autonomic nervous system. And so I was just kind of curious, people always talk about selectivity with 1.7, but how do you think about beyond target margin and sort of where are you with the compounds that you're working on right now?

然後在 1.7 上，圍繞目標進行了更多挖掘，我們發現了該領域的另一種化合物的例子，遇到了暈厥和低血壓的問題。關於該標靶在自主神經系統中的表現存在一些疑問。所以我只是有點好奇，人們總是談論 1.7 的選擇性，但你如何看待超越目標裕度以及你現在正在研究的化合物的進展？

Great. Thanks, Paul. Yeah, so all I can answer your question on X-TOLE2, and I can give some comments on 1.7 and then if anyone else wants to jump in as well on our side. So yeah, as you mentioned on X-TOLE2, we reiterated guidance today. I think I'll use some comments that we've used with investors and on previous calls as well, we're targeting 360 subjects randomized in these Phase 3 studies, a little bit larger than the Phase 2 program.

偉大的。謝謝，保羅。是的，所以我只能回答你關於 X-TOLE2 的問題，我可以對 1.7 發表一些評論，然後如果其他人也想加入我們這邊。所以，是的，正如您在 X-TOLE2 上提到的，我們今天重申了指導。我想我將使用我們在投資者和之前的電話會議中使用過的一些評論，我們的目標是在這些第 3 階段研究中隨機分配 360 名受試者，比第 2 階段計劃稍大一些。

We need to go to about 80 to 100 medical centers to get the studies complete. And so you can just kind of do the math, there's a handful of patients on average, you get per center. And so we do naturally see some ups and downs and ebbs and flows of screening and enrollment. We reiterated guidance today. And so the best information we have on based on where we are. So we've made good progress since our last update. And guidance remains the same that we expect to complete patient enrollment later this year, early next year.

我們需要去大約 80 到 100 個醫療中心才能完成研究。所以你可以算一下，每個中心平均有幾個病人。因此，我們自然會看到篩選和註冊的一些起伏和潮起潮落。我們今天重申了指導意見。因此，我們所掌握的最佳資訊取決於我們所處的位置。因此，自上次更新以來我們已經取得了良好的進展。我們的指導方針保持不變，預計今年稍後、明年初完成患者入組。

On 1.7, obviously, in any target that we work on whether it be potassium channels, our sodium channels, whether it be 1.1 or 1.7, we're always looking at potential on-target or off-target effects. We're doing a lot of screening in panels. And then obviously, we're looking at safety margins in non-GLP. And then we will be as these move into GLP toxicology studies. So, often when we think about some of the potential risks of these targets, they can be hitting other targets or as you say, potentially even on target.

顯然，在 1.7 上，在我們研究的任何目標中，無論是鉀通道、鈉通道，無論是 1.1 還是 1.7，我們總是在關注潛在的目標或脫靶效應。我們正在小組中進行大量篩選。顯然，我們正在研究非 GLP 的安全裕度。然後我們將進入 GLP 毒理學研究。因此，通常當我們考慮這些目標的一些潛在風險時，它們可能會擊中其他目標，或者正如你所說，甚至可能擊中目標。

I mean, we do know that the genetic population that are the homozygous loss of function. So you kind of think about that as very difficult to recapitulate in a human but 100% receptor occupancy. These people other than not feeling pain regardless of noxious stimuli, other than that, are normal. Sometimes there is a sense of smell based on some 1.7 expression in the olfactory. But for the most -- other than that, we don't see other concerns when they have -- when -- in that genetic population that has a complete loss of function.

我的意思是，我們確實知道純合子喪失功能的遺傳群。所以你會認為在人類很難重現這一點，但受體佔有率為 100%。這些人除了無論受到有害刺激都不會感到疼痛之外，都是正常的。有時有基於嗅覺中的一些1.7表達的嗅覺。但對大多數人來說，除此之外，當他們的基因群體完全喪失功能時，我們沒有看到其他擔憂。

So I do think overall, when we compare 1.7 to some of the sodium and potassium channels that we look at in the CNS that we do have, we believe we're going to have larger margins and we see that preclinically. But whether as you mentioned, things like syncope, we would continue to look at those in all of our preclinical work as well as in healthy volunteers. But right now, we believe that these molecules should have really good therapeutic indices. Chris, do you have anything to add on either of those points?

所以我確實認為，總的來說，當我們將1.7 與我們在中樞神經系統中觀察到的一些鈉和鉀通道進行比較時，我們相信我們將擁有更大的利潤，並且我們在臨床前看到了這一點。但無論你提到什麼，例如暈厥，我們都會繼續在所有臨床前工作以及健康志願者中觀察這些情況。但現在，我們相信這些分子應該要有非常好的治療指數。克里斯，您對這兩點還有什麼要補充的嗎？

I mean, there are there are literature mentions of hypertension in that -- the Nav1.7 loss of function. So I mean, fortunately, that's pretty easy to keep track of in the clinic in terms of following vital signs, following blood pressure and see if it's dropping as patients change position from lying to standing. So it's something we'll keep a close eye on, but it's easy to follow.

我的意思是，有文獻提到高血壓——Nav1.7 功能喪失。所以我的意思是，幸運的是，在臨床上很容易追蹤生命徵象、血壓，並觀察患者從躺著到站著的姿勢變化時血壓是否下降。所以這是我們會密切關注的事情，但它很容易遵循。

All right. Thank you, guys.

好的。感謝你們。

(Operator Instructions) Brian Abrahams, RBC Capital Markets.

（操作員指示）Brian Abrahams，RBC 資本市場。

Hi, guys. This is Leo on for Brian, and thanks for taking our question. I wanted to ask one maybe just on the nature of the discussions with the FDA you had. I mean, it sounded like those were very positive. But I'm curious if you can maybe talk about some of the key questions you had and the answers you received. In particular, curious if you've got any more clarity on whether you can leverage the safety database across the indications and maybe how you're thinking about that enrollment split across the US versus ex-US geographies? Thanks.

嗨，大家好。我是 Leo 為 Brian 發言，謝謝您提出我們的問題。我想問一個問題，也許只是關於你們與 FDA 討論的性質。我的意思是，聽起來這些都是非常正面的。但我很好奇您是否可以談談您遇到的一些關鍵問題以及您收到的答案。特別是，您是否更清楚地了解是否可以跨適應症利用安全資料庫，以及您如何看待美國與美國以外地區的註冊情況？謝謝。

Thanks, Leo. Yeah, I can start and Chris can jump in. Yeah, I think some really good progress for the team. So I do want to -- when you go from top-line Phase 2 data late in Q4 and then have an end-of-Phase 2 meeting book in April and not have to go ahead with the meeting, I mean, that's actually incredible progress in that period of time. So that's kudos to the internal team at Xenon moving that very quickly.

謝謝，利奧。是的，我可以開始，克里斯也可以加入。是的，我認為團隊取得了一些非常好的進步。所以我確實想——當你在第四季末獲得第二階段的頂線數據，然後在四月份得到第二階段結束的會議記錄，而不必繼續舉行會議時，我的意思是，這實際上是令人難以置信的那段時間的進步。因此，Xenon 內部團隊的快速行動值得稱讚。

So we had mentioned before, we had a number of questions in front of the agencies, in front of FDA in terms of the overall clinical program. As Chris mentioned, we share our Phase 3 protocol synopsis with FDA and also, as you say, kind of leveraging the safety database. So I think the nice thing is we can leverage a huge amount of the work that we've done in epilepsy. So that's clinical pharmacology, CMC toxicology that we can leverage into the MDD program.

所以我們之前提到過，就整體臨床計畫而言，我們向各機構、FDA 提出了許多問題。正如 Chris 所提到的，我們與 FDA 分享了我們的第 3 階段協議概要，並且正如您所說，我們也利用了安全資料庫。所以我認為好處是我們可以利用我們在癲癇方面所做的大量工作。這就是我們可以在 MDD 計劃中利用的臨床藥理學、CMC 毒理學。

In MDD, we are going to run, as we mentioned, three Phase 3 clinical trials. Your question did ask about jurisdiction. We haven't nailed all of that down in terms of and all of the clinical trial sites. So as we said, there's kind of more details to come on the Phase 3 program. We'll have more details there. And obviously, we're going to have a lot of safety data from epilepsy that we can leverage. And then specifically, we're going to have a lot of data in MDD, given that we're going to be running the three Phase 3 clinical trials, then there's the X-NOVA data, and as you know, there's an IST ongoing as well.

正如我們所提到的，在 MDD 中，我們將進行三個 3 期臨床試驗。你的問題確實問到了管轄權。我們還沒有確定所有臨床試驗地點的所有內容。正如我們所說，第三階段計劃還有更多細節。我們將在那裡提供更多詳細資訊。顯然，我們將獲得大量可利用的癲癇安全數據。然後具體來說，我們將在 MDD 中獲得大量數據，因為我們將運行三個 3 期臨床試驗，然後是 X-NOVA 數據，正如你所知，還有一個正在進行的 IST以及。

So I think we're going to have lots of information that's available for FDA. So I think we feel really comfortable there. As we mentioned, we got everything we needed in the written response. And so the meeting wasn't required. Chris, any other details you want to add?

所以我認為我們將為 FDA 提供大量資訊。所以我認為我們在那裡感覺很舒服。正如我們所提到的，我們在書面答覆中得到了所需的一切。所以這次會議是沒有必要的。克里斯，您還想添加其他詳細資訊嗎？

Sure. Thanks, Ian. Yeah, I mean, in terms of the clarity that we were seeking with FDA, wanted to make sure that the development program on a high level was acceptable, so particularly the number of studies that needed to be done. We've already done an amazing amount or a large amount of work preclinically in terms of clinical pharmacology. And so we just wanted to make sure -- from the time of the last end of Phase 2 meeting a couple of years ago for epilepsy, make sure that all of that was still addressing everything that they wanted us to. And so we confirm that.

當然。謝謝，伊恩。是的，我的意思是，就我們向 FDA 尋求的明確性而言，希望確保高水準的開發計劃是可以接受的，特別是需要完成的研究數量。我們在臨床藥理學方面已經做了大量的臨床前工作。因此，我們只是想確保 - 從幾年前癲癇症第二階段會議最後一次結束時起，確保所有這些仍然能夠解決他們希望我們解決的所有問題。所以我們確認了這一點。

And then getting into more detail, Ian's already alluded to this, but you kind of get into the design elements, making sure that there is agreement on the primary endpoint and the statistical hierarchy. We've been very clear with what we think will be differentiating features for azetukalner and MDD. And we want to make sure that that's included in the statistical hierarchy. So we have a chance to actually promote on it if this drug is approved, make sure the size of the study is appropriate, those sorts of things.

然後進入更多細節，伊恩已經提到過這一點，但你要進入設計元素，確保在主要終點和統計層次上達成一致。我們非常清楚我們認為 azetukalner 和 MDD 的區別特徵是什麼。我們希望確保將其包含在統計層次結構中。因此，如果這種藥物獲得批准，我們就有機會實際推廣它，確保研究規模合適，諸如此類。

As far as leveraging the safety database question? Absolutely. Yes, we have --. If you look at ICH guidelines in terms of the exposures that you need we're going to be well over that with this compound. And so we're going to definitely leverage the work done in epilepsy and then continue to address all the safety data that the FDA has asked for us in the specifically in the major depressive disorder population.

至於利用安全資料庫問題？絕對地。是的我們有--.如果您根據您需要的暴露量來查看 ICH 指南，我們將遠遠超過該化合物的暴露量。因此，我們肯定會利用在癲癇方面所做的工作，然後繼續處理 FDA 要求我們提供的所有安全數據，特別是在重度憂鬱症族群中。

And then as far as -- the only thing I'll say about geography is that we don't think that we can pull off three large studies in MDD solely in the US. And so we're looking into all those options. But to Ian's point, we haven't drilled it down completely just yet.

關於地理，我唯一要說的是，我們認為我們無法只在美國完成三項關於 MDD 的大型研究。所以我們正在研究所有這些選擇。但就伊恩而言，我們還沒有完全深入研究它。

Jason Gerberry, Bank of America.

傑森‧格伯里，美國銀行。

Hey, good evening. Thanks for taking my question. I'm just curious in your FDA meeting on MDD. To the extent that you're willing to talk about this, any feedback that gives you confidence that perhaps you could interrogate the impact on anhedonia in a unique way versus how studies have been done in the past or to potentially generate a unique and differentiated label claim around anhedonia. So that's my question.

嘿，晚上好。感謝您提出我的問題。我只是對你們關於 MDD 的 FDA 會議感到好奇。如果您願意談論這個問題，任何讓您有信心的反饋，也許您可以以一種獨特的方式質疑對快感缺失的影響，而不是過去的研究方式，或者可能產生一個獨特和差異化的標籤圍繞著快感缺乏的主張。這就是我的問題。

Thanks, Jason and Chris, do you want to address? Maybe we should go through a little bit of the rationale and the mechanism what we saw in X-NOVA and obviously, we'll be looking at that in Phase 3 as well.

謝謝，傑森和克里斯，你們想發表演說嗎？也許我們應該回顧一下我們在 X-NOVA 中看到的基本原理和機制，顯然，我們也會在第三階段中研究這一點。

Yes. I mean, the anhedonia story is such an interesting one, and such an unmet need because not only is it an issue in terms of on the surface, people are unable to enjoy things in life that they normally would have. Anhedonia is closely linked with suicidality as well and so this is a meaningful thing to go after.

是的。我的意思是，快感缺失的故事是如此有趣，而且是一種未被滿足的需求，因為這不僅是表面上的問題，而且人們無法享受生活中他們通常會擁有的東西。快感缺乏也與自殺密切相關，因此這是一件有意義的事。

To answer your question, more specifically about leveraging anhedonia in a unique way in the label, I sort of already alluded to that. I guess I was a bit cryptic in the last answer, but just to be clear, we're really interested in anhedonia. There was the earlier study with the Kv7 compound that showed improvements in anhedonia. Azetukalner has done the same. We believe that this may be a real signal that needs to be confirmed in Phase 3.

為了回答你的問題，更具體地說，關於在標籤中以獨特的方式利用快感缺失，我已經提到過這一點。我想我在最後一個答案中有點神秘，但需要澄清的是，我們真的對快感缺乏感興趣。早期的 Kv7 化合物研究顯示快感缺失有所改善。阿澤圖卡爾納也做了同樣的事情。我們認為這可能是一個真正的訊號，需要在第三階段得到確認。

And so the manner in which we're assessing anhedonia will be included within the statistical hierarchy. And if it works at the end of the day, and we check a couple of other boxes, we're hoping to be able to have that in the label and to have the sales reps speaking with physicians about that, assuming the drugs approved.

因此，我們評估快感缺失的方式將包含在統計層次中。如果它最終有效，並且我們檢查了其他幾個方框，我們希望能夠將其包含在標籤中，並讓銷售代表與醫生討論這一點（假設藥物獲得批准）。

Thanks, Chris. Yeah, and maybe, Jason, we can even expand this a little bit. Chris Von Seggern can talk about when we've done. I know the market research that Chris was referring to in the prepared remarks was actually looking at the opportunity of addressing co-morbid depression and epilepsy. But we had done previously a lot of work with psychiatrists as well, I think the opportunity as a differentiating feature, as you mention of azetukalner with anhedonia is important. Chris, maybe you want to provide your perspective there?

謝謝，克里斯。是的，也許，傑森，我們甚至可以稍微擴展一下。當我們完成後，克里斯馮塞根 (Chris Von Seggern) 可以談談。我知道克里斯在準備好的發言中提到的市場研究實際上是在尋找解決憂鬱症和癲癇共病的機會。但我們之前也與精神科醫生做了很多工作，我認為機會作為一個差異化特徵，正如你提到的 azetukalner 與快感缺失一樣，很重要。克里斯，也許你想在那裡提供你的觀點？

Yeah. Ian, I was going to jump in and say exactly that. When we've conducted market research in the past, thinking about the profile of azetukalner, physicians clearly latch onto a number of elements, the novel mechanism of action, the lack of sexual dysfunction or weight gain. But we hear very clearly, the unmet medical need that exists with anhedonia and really the desperation for alternatives that offer a compelling efficacy profile in this component of the disease. And [that's driven] because SSRIs and SNRIs don't offer benefit along that dimension. So we view it as a really important component of the commercial differentiation for azetukalner and MDD. And we're hopeful as Chris and Ian both mentioned that this is something ultimately will be incorporated in the label as we move forward.

是的。伊恩，我本來想插話來說這句話的。當我們過去進行市場研究時，考慮到 azetukalner 的概況，醫生清楚地抓住了許多因素，新穎的作用機制，沒有性功能障礙或體重增加。但我們非常清楚地聽到，快感缺乏症存在著未被滿足的醫療需求，並且迫切需要能夠在該疾病的這一組成部分中提供令人信服的療效的替代方案。[這是驅動的]因為 SSRI 和 SNRI 不能在這方面提供益處。因此，我們將其視為 azetukalner 和 MDD 商業差異化的一個非常重要的組成部分。我們充滿希望，因為克里斯和伊恩都提到，隨著我們的前進，這最終將被納入品牌中。

Great. Thanks, guys.

偉大的。多謝你們。

Thank you.

謝謝。

Brian Skorney, Baird.

布萊恩·斯科尼，貝爾德。

This is Luke on for Brian. We were just wondering, were there any notable changes that FDA suggested for the Phase 3 MDD program, endpoints, enrollment criteria, or any other aspects? Are they largely on board with your proposed designs?

這是盧克為布萊恩代言的。我們只是想知道，FDA 對第 3 期 MDD 計畫、終點、入組標準或任何其他方面是否有任何顯著變化建議？他們在很大程度上同意您提出的設計嗎？

Yeah. Thanks, Luke. Yeah, they were largely -- they are on board with our design. Actually, if you go back to our Q4 results script of a couple of months ago and the prepared remarks there, we kind of walked through at least the high level how you are thinking about it and Chris did it again today in terms of the design, the primary endpoint, and other things that we would be looking at. So no, you'll have seen in today's remarks when you compare to our remarks last time, nothing has changed there. So as we mentioned, we have good alignment with the agency and no major adjustments needed as we move forward.

是的。謝謝，盧克。是的，他們很大程度上支持我們的設計。實際上，如果您回顧幾個月前的第四季度結果腳本以及那裡準備好的評論，我們至少大致了解了您的想法，克里斯今天在設計方面再次做到了這一點、主要終點以及我們要關注的其他事項。所以不，當你與我們上次的言論相比時，你會在今天的言論中看到，那裡沒有任何變化。正如我們所提到的，我們與該機構保持良好的一致性，在我們前進的過程中不需要進行重大調整。

Okay. Thank you.

好的。謝謝。

Tess Romero, JPMorgan.

苔絲‧羅梅羅，摩根大通。

Hey. Good afternoon, Ian and team, and thanks for taking our questions. So first one is probably a fairly quick one. I'm just wondering a little bit of clarity on, is the ASCP presentation more of an encore of what we've already seen. Are there new analyses that we should be preparing for?

嘿。下午好，伊恩和團隊，感謝您提出我們的問題。所以第一個可能是相當快的。我只是想知道一點，ASCP 演示是否更像是我們已經看到的內容的重演。我們是否應該準備新的分析？

And then second one is when you might think you will be able to come and more definitively outline where you might like to take XEN1101 and what types of internal work you are doing to decide on where the most derisked or compelling potential opportunities might be? Thanks.

第二個是當您可能認為您能夠來更明確地概述您可能希望在哪些方面採用 XEN1101 以及您正在做什麼類型的內部工作來決定最危險或最引人注目的潛在機會可能在哪裡？謝謝。

Tess, just for clarification. So the second question on indication expansion outside of epilepsy in MDD?

苔絲，只是為了澄清。那麼第二個問題是關於 MDD 癲癇以外的適應症擴展嗎？

That's right. Exactly.

這是正確的。確切地。

Okay. Great. Chris, do you want to answer the first question on the data that we're going to be presenting from X-NOVA later this month? And then I'm happy to just talk about indication expansion.

好的。偉大的。Chris，您想回答有關我們將於本月稍後從 X-NOVA 提供的數據的第一個問題嗎？然後我很高興談論適應症擴展。

Yeah, hi, Tess. So regarding ASCP, if you're referring to the poster that was shared in the scientific exhibit at AES, it will be largely an Encore. There will be one set of new analyses in there.

是的，嗨，苔絲。因此，關於 ASCP，如果您指的是 AES 科學展覽中分享的海報，那麼它很大程度上將是一次 Encore。那裡將會有一組新的分析。

Thanks, Chris. And then, Tess, in terms of indication expansion, I mean, we've talked about it in prior calls, we did a really significant lifecycle management project between our medical team and our commercial team last year, a lot of really great ideas on where we could potentially take both azetukalner, but also other Kv molecules. And we've made really good progress on some of those preclinical assets as we've talked about.

謝謝，克里斯。然後，苔絲，就適應症擴展而言，我的意思是，我們在之前的電話中討論過這一點，去年我們的醫療團隊和商業團隊之間做了一個非常重要的生命週期管理項目，有很多非常好的想法我們可以同時使用 azetukalner 和其他 Kv 分子。正如我們所討論的，我們在一些臨床前資產方面取得了非常好的進展。

So you'll hear from us later this year. So obviously, we're committed to the Phase 3 program in epilepsy in the Phase 3 program in major depressive disorder. We think there is an opportunity to expand additionally for azetukalner in other neuropsych areas. And so I'm sure you can kind of think about the ones that bubble up to the top of that list. But we've done a fair bit of work. We want to do a little bit more, and then we'll come back with a plan that's more fully fleshed out.

所以今年晚些時候您會收到我們的消息。顯然，我們致力於在重度憂鬱症第三階段計畫中開展癲癇第三階段計畫。我們認為 azetukalner 有機會在其他神經心理學領域進一步擴展。所以我相信你可以想想那些排在清單頂部的內容。但我們已經做了相當多的工作。我們想做更多一點，然後我們會帶著一個更充實的計劃回來。

Thank you.

謝謝。

Paul Choi, Goldman Sachs.

保羅‧崔，高盛。

Thanks for taking our question. This is Khalil calling in for Paul. I guess a quick one for me. If you could just provide a little bit of color on your Phase 3 X-ACKT study in PGTCS. Has that study completed enrollment and do you have any color on the timing of when you expect that to read out? Thank you so much.

感謝您提出我們的問題。我是卡里勒來找保羅。我想這對我來說很快。您能否就 PGTCS 中的第 3 階段 X-ACKT 研究提供一些資訊。該研究是否已完成註冊？太感謝了。

Thanks, Khalil. Sherry, do you want to address milestones for the X-ACKT study?

謝謝，卡里爾。Sherry，您想談談 X-ACKT 研究的里程碑嗎？

Yes, absolutely. And so the X-ACKT study is ongoing. We started it last year and were actively recruiting patients in that study. As a reminder, we're actually leveraging the sites from X-TOLE2 and X-TOLE3 for the X-ACKT study. So investigators can actually -- epileptologists or neurologists who have patients, who have the primary diagnosis of PGTCS can be directed into the X-ACKT study.

是的，一點沒錯。因此 X-ACKT 研究正在進行中。我們去年開始這項研究，並積極招募患者參與研究。提醒一下，我們實際上正在利用 X-TOLE2 和 X-TOLE3 的網站進行 X-ACKT 研究。因此，研究人員實際上可以將患有 PGTCS 初步診斷的患者的癲癇科醫生或神經科醫生納入 X-ACKT 研究。

PGTCS, just to take a step back, is less prevalent than FOS. So the patient population overall is smaller and just to have a different phenotype, right, patients have more severe seizures, but generally a lower seizure burden. And so in general, if you think about just fewer patients in this PGTCS population versus FOS. These studies do take a little bit longer to recruit and enroll.

退一步來說，PGTCS 不如 FOS 普遍。因此，患者群體總體較小，只是具有不同的表型，對吧，患者癲癇發作更嚴重，但癲癇發作負擔通常較低。因此，總的來說，如果您考慮與 FOS 相比，PGTCS 族群中的患者數量較少。這些研究的招募和註冊確實需要更長的時間。

And that's very consistent with what we've seen historically with PGTCS studies from other study sponsors. So we're continuing to make progress again, leveraging the sites from X-TOLE2 and X-TOLE3. X-ACKT is continuing to actively recruit patients. We will absolutely give guidance on this study. We're just not quite there yet today.

這與我們歷史上看到的其他研究贊助商的 PGTCS 研究非常一致。因此，我們將繼續利用 X-TOLE2 和 X-TOLE3 的站點再次取得進展。X-ACKT 正在繼續積極招募患者。我們絕對會對這項研究給予指引。只是今天我們還沒有完全做到這一點。

Okay.

好的。

And Sherry, just to add, this was already stated in the prepared remarks. But I think it's really important to keep in mind that we're positioning X-TOLE as the first pivotal trial in focal onset seizures, and it's really the completion of X-TOLE2 that will drive the initial NDA submission. So not to be dismissive of the PGTCS question, but I just wanted to be clear that where the priority is in the short term. Thanks.

雪莉補充一下，這已經在準備好的發言中闡明了。但我認為重要的是要記住，我們將 X-TOLE 定位為局部癲癇發作的第一個關鍵試驗，而 X-TOLE2 的完成將推動最初的 NDA 提交。因此，並不是要忽視 PGTCS 問題，但我只是想明確短期內的優先事項。謝謝。

Of course. Thank you.

當然。謝謝。

Absolutely. Thanks, Chris.

絕對地。謝謝，克里斯。

Danielle Brill, Raymond James.

丹妮爾·布里爾，雷蒙德·詹姆斯。

Hey, guys. This is Alex on for Danielle. Just another question on MDD. Could you walk us through your rationale for running three distinct Phase 3 trials as opposed to say two potentially larger more well-powered trial? And is it your intention that these trials will be philosophically identical in trial design? Thanks.

大家好。這是亞歷克斯為丹妮爾代言。這是關於 MDD 的另一個問題。您能否向我們介紹一下進行三個不同的 3 期試驗而不是進行兩個可能更大、效果更佳的試驗的理由？您的意圖是這些試驗在試驗設計上在理念上是​​相同的嗎？謝謝。

Thanks, Alex. Chris, I can start, you can add in? So Alex, we haven't given sample size numbers for the Phase 3 program yet; that's to come. But I think when you -- when we do have those numbers out, you'll see that we believe each of these Phase 3 studies is well powered. So they're going to be significantly larger than the X-NOVA in terms of number of patients per arm.

謝謝，亞歷克斯。克里斯，我可以開始了，你可以加入嗎？亞歷克斯，我們還沒有給出第三階段計劃的樣本數；那即將到來。但我認為，當我們確實公佈這些數據時，您會發現我們相信每一項第三階段研究都是有力的。因此，就每臂的患者數量而言，它們將明顯多於 X-NOVA。

The real reason to do three studies, I think we all know that the subjectivity and variability that you can see in depression studies. And so we believe this is the right thing to do from a risk mitigation point of view to run three studies.

進行三項研究的真正原因，我想我們都知道憂鬱症研究中的主觀性和可變性。因此，我們認為從風險緩解的角度來看，進行三項研究是正確的做法。

They'll be yes, they'll be very similar. I think as we get into the more granular details if there's any real differences or nuances we can communicate at that time. But yeah, essentially you can think about them as similar studies, three ongoing. First one to start later this year. And as Chris mentioned in his remarks, we've kind of mapped out already for you, the primary endpoint, the trial design, and some of the other details, including sample size to come over the next number of months as we just finalized the protocol. Obviously, we need to submit it to the IND and then get ready to get sites initiated and patients enrolled.

他們會是的，他們會非常相似。我認為，當我們了解更詳細的細節時，如果存在任何真正的差異或細微差別，我們可以在那時進行溝通。但是，是的，本質上你可以將它們視為類似的研究，其中三個正在進行中。第一個項目將於今年稍後開始。And as Chris mentioned in his remarks, we've kind of mapped out already for you, the primary endpoint, the trial design, and some of the other details, including sample size to come over the next number of months as we just finalized the協定.顯然，我們需要將其提交給 IND，然後準備啟動站點並招募患者。

Chris, anything else to add in terms of some details there?

克里斯，還有什麼需要補充的細節嗎？

Sure. You know, I mean, obviously, the question about how many studies we should do is something that we've intensely thought about over the past several months, really over the past few years. And, it wasn't like we were weighing two scenarios like, oh let's partially power three studies versus really power two studies. We were going into it with a mindset that every study we conduct will be meticulously conducted to the extent that we can control variables. And then it's just a question of, okay, we're going to do that, how many times. And so it is Ian's already that I think when you see the size of these studies coming out I think you're going to see that we're not taking any shortcuts here. Thanks.

當然。你知道，我的意思是，顯然，關於我們應該做多少研究的問題是我們在過去幾個月，實際上是在過去幾年裡一直在認真思考的問題。而且，我們並不是在權衡兩種情況，例如，哦，讓我們部分支持三項研究，而不是真正支持兩項研究。我們的心態是，我們進行的每項研究都將在我們可以控制變數的範圍內一絲不苟地進行。然後這只是一個問題，好吧，我們要這樣做多少次。因此，我認為當你看到這些研究的規模時，我想你會發現我們在這裡沒有走任何捷徑。謝謝。

Great. Thanks so much.

偉大的。非常感謝。

Marc Goodman, Leerink.

馬克‧古德曼，萊林克。

Hi, good afternoon. This is Basma on for Mark. Can you remind us again of the food effect of XEN1101? And what kind of food is it, like is it fatty food or just any type of food?

嗨，下午好。這是馬克的巴斯馬。您能再提醒我們XEN1101的食物效應嗎？它是什麼類型的食物，是脂肪食物還是任何類型的食物？

Also we have another question. So even though XEN1101 has been developed as monotherapy for MDD, there's a high likelihood that it's going to be used in combination with other antidepressants in later lines if the drug is successful in the indication. So are you paying to run any DDI studies just to confirm the safety of the combination of XEN1101 with other antidepressants? Thank you. That's it for us.

我們還有另一個問題。因此，儘管 XEN1101 已被開發為 MDD 的單一療法，但如果該藥物在適應症上取得成功，它很可能會在後續產品線中與其他抗憂鬱藥物聯合使用。那麼，您是否付費進行任何 DDI 研究只是為了確認 XEN1101 與其他抗憂鬱藥物聯合用藥的安全性？謝謝。我們就這樣了。

Thank you. I can -- I'll do the first one, Chris, maybe a little bit of that background on the food effect and what we're doing in all of the efficacy studies. And then if you want to comment just on some comments on DDI and monotherapy versus adjunctive MDD.

謝謝。我可以——我會做第一個，克里斯，也許有一點關於食物影響的背景知識以及我們在所有功效研究中所做的事情。然後，如果您只想評論一下關於 DDI 和單一療法與輔助 MDD 的一些評論。

So we know from our Phase 1 work, that XEN -- or azetukalner has a marked food effect. And so all of our efficacy studies have been completed in the presence of food and so the drug is taken with the evening meal. That's important because we usually see maximal concentration of the drug. We do have obviously patient to patient variability, but we see the maximal concentration of the drug during sleeping hours in the middle of the night. There isn't -- so the protocols talk about come, it being administered or taking the drug with the evening meal, we don't have to specify on what type of food the drug is taken with.

因此，我們從第一階段的工作中得知，XEN（或 azetukalner）具有顯著的食物效應。因此，我們所有的功效研究都是在食物存在的情況下完成的，因此藥物是在晚餐時服用的。這很重要，因為我們通常會看到藥物的最大濃度。我們確實有明顯的患者差異，但我們在半夜的睡眠時間內看到了藥物的最大濃度。沒有——所以方案談到了，它是與晚餐一起服用或服用藥物，我們不必具體說明該藥物與哪種類型的食物一起服用。

So hopefully that addresses the food question. Chris, do you want to talk about our thinking around DDI and injunctive?

希望這能解決食物問題。Chris，您想談談我們對 DDI 和禁令的看法嗎？

Sure. So in terms of DDIs, I mean, things have evolved over the past couple of decades or so. I think from the standpoint where even if you didn't predict a specific DDI, you would sometimes do a drug-drug interaction study with the drug and another drug, say, an antiseizure medication or antidepressant that's used quite a bit.

當然。因此，就 DDI 而言，我的意思是，在過去幾十年左右的時間裡，事情已經改變了。我認為，從這樣的角度來看，即使您沒有預測特定的 DDI，您有時也會對該藥物和另一種藥物（例如，經常使用的抗癲癇藥或抗憂鬱藥）進行藥物交互作用研究。

The field has kind of gone away from that because we've gotten pretty good at predicting drug-drug interactions. And so as it pertains specifically to antidepressants, we don't foresee any major issues whatsoever in terms of drug-drug interactions with any of the antidepressants used. So the current -- so we don't see any need to do those additional NDA enabling studies and we haven't had any regulatory feedback to suggest that there was disagreement.

這個領域已經遠離了這個領域，因為我們已經非常擅長預測藥物之間的相互作用。因此，由於它專門涉及抗憂鬱藥，因此我們預計在與所使用的任何抗憂鬱藥物之間的藥物交互作用方面不會出現任何重大問題。因此，目前我們認為沒有必要進行額外的新藥申請授權研究，而且我們也沒有收到任何監管回饋表明存在分歧。

Thank you. That's very helpful.

謝謝。這非常有幫助。

Thanks, Chris.

謝謝，克里斯。

Andrew Tsai, Jefferies

安德魯蔡，杰弗里斯

Hey, thanks. Good afternoon. Thanks for taking my question. Can you just remind us how long it took X-NOVA to start up and generate the top line data and whether you think the Phase 3s should also have a similar timing? Thank you.

嘿，謝謝。午安.感謝您提出我的問題。您能否提醒我們 X-NOVA 啟動並產生頂線資料需要多長時間？謝謝。

Thanks, Andrew. Sherry, do you want to go through the X-NOVA timing?

謝謝，安德魯。Sherry，你想體驗一下 X-NOVA 時間嗎？

Yeah, absolutely. So yeah, just as a reminder, X-NOVA took us about 18 months, I would say from start to finish. As a reminder, we randomized just over 160 patients in that study. As Ian mentioned earlier, these Phase 3 trials are going to be powered well for Phase 3. So we're going to see multiples of the number of patients that we saw per arm in a one-to-one randomization. So think about a study size that's 2x to 3x the size of X-NOVA?

是的，絕對是。所以，是的，提醒一下，X-NOVA 從開始到完成花了我們大約 18 個月的時間。提醒一下，我們在研究中隨機分組了 160 多名患者。正如伊恩之前提到的，這些第三階段試驗將為第三階段提供良好的支持。因此，我們將在一對一隨機化中看到每個手臂看到的患者數量的倍數。那麼考慮一下 X-NOVA 大小 2 到 3 倍的研究規模嗎？

These studies do take, I would say, generally less time to enroll than epilepsy versus more patients out there that meet the enrollment criteria. So we do expect that the timing will be not too dissimilar X-NOVA. So probably some somewhere kind of in the two year range. I would say, Andrew, if you think about start to finish for the each of the Phase 3 studies.

我想說的是，這些研究的入組時間通常比癲癇患者少，而符合入組標準的患者則更多。所以我們確實預期時間不會與《X-NOVA》有太大不同。所以可能是在兩年範圍內的某個地方。我想說，安德魯，如果你考慮一下每個第三階段研究的開始到結束。

We're not going to start them all, practically. These studies are typically staggered a little bit. So as we said, the first study will initiate later this year, practically there will be a little bit of a stagger, a number of months to the second study and then again, a number of months to the third study. Hopefully that helps.

實際上，我們不會啟動所有這些。這些研究通常會稍微錯開。正如我們所說，第一項研究將於今年稍後啟動，實際上會有一點錯開，第二項研究需要幾個月的時間，第三項研究需要幾個月的時間。希望有幫助。

Very helpful. Thank you.

很有幫助。謝謝。

Peyton Bohnsack, TD Cowen

佩頓·博恩薩克，TD·考恩

Hi. Good afternoon and thank you for taking our questions. Just a quick one from us. Can you remind us on what you're doing to control placebo rates in the MDD program in Phase 2 trials and highlighting any changes that may have come from the learnings from the X-NOVA trial and the interactions with the FDA. Thank you.

你好。下午好，感謝您回答我們的問題。我們只是簡單介紹一下。您能否提醒我們，您在第 2 期試驗中正在採取哪些措施來控制 MDD 項目中的安慰劑比例，並強調從 X-NOVA 試驗中學到的知識以及與 FDA 的互動可能帶來的任何變化。謝謝。

Great. Thank you, Peyton. Chris, do you want to walk through both what we had done, and we'll maybe focus more on what we expect to do to continue to keep an eye on placebo rate in the Phase 3 MDD program?

偉大的。謝謝你，佩頓。Chris，您想回顧一下我們所做的事情嗎？

Yeah, absolutely. So I mean, X-NOVA -- we're quite pleased with the results that we saw with the X-NOVA study and so in terms of trying to control placebo effect, to the extent that we could, we really focused on choosing a CRO that was highly experienced and major depressive disorder. We use the safer criteria to make sure that appropriate patients were getting into the study. So that's an external group that has no skin in the game in terms of whether a patient is enrolled or not.

是的，絕對是。所以我的意思是，X-NOVA——我們對 X-NOVA 研究的結果非常滿意，因此在試圖控制安慰劑效應方面，在我們可以的範圍內，我們真正專注於選擇一個CRO 經驗豐富，患有嚴重憂鬱症。我們使用更安全的標準來確保合適的患者參與研究。因此，這是一個外部團體，在患者是否入組方面沒有參與權。

We also obviously chose really high-quality sites with lots of experience in MDD, make sure that the training on the skills was done appropriately. So -- and then there's a bunch of ways that you can keep an eye on data in real time to make sure that you're not seeing anything unusual either in a patient or a site level or of course, at the study level. Obviously, you keep an eye on the baseline demographics and make sure that you're putting together a population that you expect.

顯然，我們也選擇了在 MDD 方面擁有豐富經驗的高品質站點，確保技能培訓得到適當的完成。因此，您可以透過多種方法即時關注數據，以確保您沒有在患者或網站層級（當然，在研究層級）中看到任何異常情況。顯然，您要密切注意基線人口統計數據，並確保您收集的人口符合您的預期。

And then going forward, one thing that's absolutely clear in this studies is that a handful of patients can really have an untoward effect on all of the results. And one of the things that we've seen as a common theme in successful MDD studies is a real focus on making sure that patients with mild -- on the milder end of the spectrum don't get into the study. And so as we shared these design elements, you'll see that we're using a slightly higher cutoff on the HAM-D. That's one thing. And then we're doing some other things too, that we'll share publicly when the time is right.

展望未來，這項研究中絕對清楚的一件事是，少數患者確實會對所有結果產生不良影響。我們認為成功的 MDD 研究的一個共同主題是真正專注於確保輕度患者（處於譜系較輕的一端）不參與研究。因此，當我們分享這些設計元素時，您會發現我們在 HAM-D 上使用了稍高的截止值。這是一回事。然後我們也在做其他一些事情，我們會在適當的時候公開分享。

So we're really focused on trying to minimize the placebo effect to the extent that we can. I mean the only other thing I will say is that compliance is a major issue and so that we're in this in the psychiatric population. And so we're going to be doing as much or more as we transition to Phase 3 to ensure compliance to the extent that you can.

因此，我們真正專注於盡可能減少安慰劑效應。我的意思是，我要說的唯一一件事是，依從性是一個主要問題，因此我們在精神病人群中處於這種情況。因此，在過渡到第三階段時，我們將採取盡可能多或更多的措施，以盡可能確保合規性。

Thanks, Chris. And the only other one that I would add to Chris's list that we've talked about publicly is in the Phase 2 program, we had two active arms versus placebo. And in Phase 3, as we've talked about, will go to a one-to-one randomization. And so literature teaches us that should have an impact on the placebo rate by lowering the placebo rate in terms of expectation bias.

謝謝，克里斯。我要添加到克里斯的清單中的唯一另一個我們公開討論過的項目是在第二階段計劃中，我們有兩個主動組與安慰劑組。正如我們所討論的，在第三階段，將進行一對一的隨機化。因此文獻告訴我們，應該透過降低預期偏差方面的安慰劑率來影響安慰劑率。

Great. Makes a lot of sense. Thanks for taking our questions.

偉大的。很有道理。感謝您回答我們的問題。

Thank you.

謝謝。

Tim Lugo, William Blair.

提姆·盧戈，威廉·布萊爾。

And again for MDD. I know there's been a lot of questions on MDD, but you mentioned a higher cutoff of the HAM-D to try and manage the placebo effect, but also given the anhedonia effect and the differentiation versus the existing modalities that the FDA kind of give you any guidance during the meeting on how heavily pretreated the population should be or how many therapies maybe failed or cycled through prior to enrollment?

再次是MDD。我知道關於 MDD 有很多問題，但您提到了 HAM-D 的較高截止值來嘗試控制安慰劑效應，但也考慮到快感缺失效應以及與 FDA 提供的現有模式的區別會議期間是否有關於應對人群進行何種程度的預處理或在入組前可能失敗或循環進行多少種治療的指導？

Thanks, Tim. Chris?

謝謝，蒂姆。克里斯？

Yes. I mean the feedback they provided wasn't so much in terms of medications failed or anything like that or the resistance of the population, per se. They did provide some feedback on cutoffs that can be used to optimize the patient population. And of course, we're going to implement those recommendations. I promise you will hear more -- you'll hear specifics on all of that before too long.

是的。我的意思是，他們提供的回饋並不是關於藥物治療失敗或類似的事情或人口本身的抵抗力。他們確實提供了一些關於可用於優化患者群體的截止值的回饋。當然，我們將實施這些建議。我保證你會聽到更多——不久之後你就會聽到所有這些的細節。

Okay. Thank you so much. And actually, one last question. Since we expect the Mount Sinai Phase 2 results? Is that something we're still expecting this year?

好的。太感謝了。實際上，還有最後一個問題。既然我們期待西奈山第二階段的結果？今年我們仍然期待這一點嗎？

Yeah, just as a reminder, there is an IST ongoing for azetukalner in an MDD study being run by Mount Sinai and Baylor, this is looking at 20 milligrams of the drug versus placebo. The primary endpoint of that is a functional endpoint. It's a functional MRI endpoint, but then there are secondary endpoints and clinical scales of depression and anhedonia.

是的，提醒一下，西奈山大學和貝勒大學正在進行一項 MDD 研究，正在對 azetukalner 進行 IST 試驗，比較 20 毫克的藥物與安慰劑。其主要終點為功能終點。這是一個功能性 MRI 終點，但還有次要終點以及憂鬱症和快感缺乏的臨床量表。

Tim, we don't have specific guidance on that. And we do know based on obviously, we have a close relationship with the physicians running that study. We fully expect that the patient enrollment will complete this year and then it will be a conversation with the physicians in terms of where those data may be presented. So we still don't have that information yet. As that information's available, then we'll be able to communicate it to you.

提姆，我們對此沒有具體指導。我們確實知道，顯然，我們與進行這項研究的醫生有著密切的關係。我們完全預計患者登記將於今年完成，然後將與醫生就這些數據的呈現位置進行對話。所以我們還沒有這些資訊。當該資訊可用時，我們將能夠將其傳達給您。

All right. Thank you.

好的。謝謝。

Mohit Bansal, Wells Fargo.

莫希特·班薩爾，富國銀行。

Great. Thank you very much for taking my question. I just wanted to ask, I think about -- and your thought process on the depression market in general. There's a lot of development in mid to late stage. Recently, we have seen Kappa-opioid receptor, we have seen AMPA potentiator. Interesting data on depression scale, but I mean there could be some effect on anhedonia and Sidonia as well. So just wanted to see like how do you compare and contrast with XEN1101 and these other mechanisms also look really safe. So how do you think about the market evolving with these multiple drugs out there?

偉大的。非常感謝您回答我的問題。我只是想問，我想一下——以及您對蕭條市場的整體思考過程。中後期有很大的發展。最近，我們看到了Kappa鴉片受體，我們看到了AMPA增效劑。關於憂鬱量表的有趣數據，但我的意思是對快感缺乏和西多尼亞也可能有一些影響。所以只是想看看如何與 XEN1101 進行比較和對比，這些其他機制看起來也非常安全。那麼，您如何看待這些多種藥物的市場演變？

Thanks, Mohit. Yeah, excellent question, we think about a lot. Chris Von Seggern, do you want to walk through how we just think about the overall medical need and where azetukalner would fit in, especially considering that there are other drugs that are in development?

謝謝，莫希特。是的，很好的問題，我們想了很多。Chris Von Seggern，您是否想了解我們如何考慮整體醫療需求以及 azetukalner 的適用範圍，特別是考慮到其他藥物正在開發中？

Yeah, absolutely. I think first and foremost, if you take a step back and you think about the major depressive market and we're talking about an addressable population that is measured in the multi, multi-millions. And as we all know, the mainstay of therapy in that spaces is SSRIs and SNRIs of which there are many. And patients typically cycle through a couple of those options before they transition into what we consider the more of the branded market.

是的，絕對是。我認為首先也是最重要的，如果你退後一步，想想主要的蕭條市場，我們談論的是數以百萬計的可尋址人口。眾所周知，該領域的主要治療方法是 SSRI 和 SNRI，其中有很多。在進入我們認為更多的品牌市場之前，患者通常會循環選擇幾個選項。

We think there's ample opportunity for a number of products to fill a void in the need for patients who don't have inadequate response to an SSRI or SNRI or importantly have greater need as it pertains to an adverse events associated with either weight gain or sexual dysfunction. So we do appreciate that the competitive landscape in this space is quite a bit more than what we see in the focal onset seizure arena. But from a profile as it pertains to azetukalner, clinicians are really excited and have continued to express enthusiasm about that profile.

我們認為，對於對 SSRI 或 SNRI 反應不充分的患者，或者重要的是，由於與體重增加或性行為相關的不良事件有關，因此有更大的需求，許多產品有足夠的機會填補其需求空白。功能障礙。因此，我們確實意識到這個領域的競爭格局比我們在局部癲癇發作領域看到的要多得多。但從 azetukalner 的個人資料來看，臨床醫生非常興奮，並繼續表達對該個人資料的熱情。

Kv7 potentiation has really strong linked to the depressive state. The efficacy and safety profile that we've seen coming out of the X-NOVA study has really resonated with clinicians reaching for a novel mechanism of action. And then importantly, other attributes of rapidity of onset, the potential to address in anhedonia are things that clinicians are really hungry for. So the emergence of competition around us and will further bolster some of those attributes. But there's still plenty of opportunity for multiple successful products from a branded standpoint, given the residual unmet need that is so substantial in the major depressive market.

Kv7 增強與憂鬱狀態確實有強烈的關聯。我們從 X-NOVA 研究中看到的療效和安全性確實引起了尋求新作用機制的臨床醫生的共鳴。然後重要的是，起效快的其他屬性以及解決快感缺乏的潛力是臨床醫生真正渴望的東西。因此，我們周圍競爭的出現將進一步增強其中一些屬性。但從品牌的角度來看，鑑於主要蕭條市場中剩餘的未滿足需求如此之大，多種成功產品仍有許多機會。

Super helpful. Thank you.

超有幫助。謝謝。

David Huang, Citigroup.

黃大衛，花旗集團。

Hi there. Thanks for taking my question and fitting me in. I just wanted to ask about your, I guess, latest thoughts on given everything we know about 1101 clinical profile, which now obviously includes a mood benefit? Does that impact how you think about the peak sales opportunity for the product in epilepsy and MDD? And are there any, I guess, analogues out there historically in the market that we could think about as potential comps for 1101? I know products such as Vimpat have come up in discussions before but just wanted to get a sense of what your current and latest thinking was on that?

你好呀。感謝您提出我的問題並讓我適應。我只是想問一下您對 1101 臨床概況的最新想法，我猜您對 1101 臨床概況的最新想法現在顯然包括情緒益處？這是否會影響您對癲癇和重度憂鬱症產品的高峰銷售機會的看法？我想，歷史上市場上是否有類似的產品可以作為 1101 的潛在競爭產品？我知道像 Vimpat 這樣的產品之前已經在討論中出現過，但只是想了解一下你們目前和最新的想法是什麼？

Thanks, David. Yes, some will I'll pass the call to Chris Von Seggern, because we've done a lot of work now on really understanding having a mood benefit of azetukalner in epilepsy and we've done even more market research just over the last few months. So Chris talked about that a little bit in his prepared remarks, but I think he can go into a little bit more detail now in terms of that as a differentiator and as an opportunity from a commercial perspective?

謝謝，大衛。是的，有些人會，我會把電話轉給Chris Von Seggern，因為我們現在已經做了很多工作，真正了解azetukalner 對癲癇症的情緒益處，並且在過去的幾年中我們做了更多的市場研究幾個月。克里斯在他準備好的發言中談到了這一點，但我認為他現在可以更詳細地闡述這一點，將其作為差異化因素和從商業角度來看的機會？

Yeah, happy to, Ian. So prior to the X-NOVA results, we felt very strongly based on the research that had been conducted to date but these azetukalner product profile, should the product be approved is really a market-leading profile. So again, the attributes we've historically discussed novel mechanism of action, rapidity of onset, and ease of use attributes are really, really, really compelling when you think about the dozens of alternatives that exist in the focal onset seizure market.

是的，很高興，伊恩。因此，在 X-NOVA 結果之前，我們根據迄今為止進行的研究感到非常強烈，但這些 azetukalner 產品概況（如果產品獲得批准）確實是市場領先的概況。再說一遍，當您考慮局部癲癇發作市場中存在的數十種替代方案時，我們歷史上討論過的新穎作用機制、起效速度和易用性等屬性確實非常非常引人注目。

And you're right, historically, we've talked about Vimpat, the most recent blockbuster in our category as being a product that we tend to think about as having really occupying that first branded opportunity where we feel azetukalner is positioned well, should it come to market.

你是對的，從歷史上看，我們已經討論過 Vimpat，我們類別中最新的重磅產品，我們傾向於認為它真正佔據了第一個品牌機會，我們認為 azetukalner 定位良好，如果它來到市場。

I think what we've learned with the market or the recent market research in the backbone of the X-NOVA data is that it really changes the profile of this product and clinicians are even more enthusiastic. When you think about the potential benefit in depression, and that's driven by a couple of factors. The first of which is the mainstay of treatment in our category levetiracetam is known to exacerbate mood related conditions. And we often see clinicians choosing their antiseizure medication based on the existence or emergence of mood related disorders.

我認為我們從市場或最近的 X-NOVA 數據骨幹市場研究中了解到的是，它確實改變了該產品的概況，臨床醫生甚至更加熱情。當您考慮憂鬱症的潛在益處時，這是由幾個因素驅動的。第一個是我們類別中的主要治療方法，已知左乙拉西坦會加劇情緒相關疾病。我們經常看到臨床醫生根據情緒相關疾病的存在或出現來選擇抗癲癇藥物。

The other component is there's great evidence in the literature that suggests that as patients progress through lines of therapy, the rate of depression increases and the outcomes for those patients who experienced depression, get worse or compliance in poor seizure management and control. That unmet medical need is amplified in these patients who have co-morbid depression and when presented with a profile of azetukalner that includes a potential benefit in the mood related category, clinicians are just expressing a really significant enthusiasm.

另一個組成部分是，文獻中有大量證據表明，隨著患者接受治療的進展，憂鬱症的發病率會增加，那些經歷過憂鬱症的患者的結果會變得更糟，或者癲癇發作管理和控制依從性差。在這些患有憂鬱症共病的患者中，未被滿足的醫療需求被放大，當向臨床醫生展示azetukalner 的概況（其中包括情緒相關類別的潛在益處）時，臨床醫生只是表達了真正巨大的熱情。

And when we think about the market, this sort of moves the thinking from a product like Vimpat which was exceptionally successful in this market to a product like lamotrigine, which from a category standpoint, is the second most utilized product in our category and clinicians often point to lamotrigine beyond seizure benefit derived from a perception of mood benefit in the epilepsy population.

當我們考慮市場時，這種思維方式從像Vimpat 這樣在這個市場上非常成功的產品轉移到像拉莫三嗪這樣的產品，從類別的角度來看，拉莫三嗪是我們類別中使用第二多的產品，臨床醫師常指出拉莫三嗪除了癲癇發作的益處外，也源自於對癲癇族群情緒益處的認知。

So from the recent research and our continued evolution of thinking here, the data emerging from X-NOVA really do change the nature of the opportunity for azetukalner in the focal onset market.

因此，從最近的研究和我們不斷演變的思維來看，X-NOVA 中出現的數據確實改變了 azetukalner 在焦點發病市場中機會的性質。

Thank you. And that completes our question-and-answer session. I will now turn the call back over to Sherry Aulin for closing remarks.

謝謝。我們的問答環節就這樣結束了。現在，我將把電話轉回給雪莉·奧林 (Sherry Aulin)，讓其致閉幕詞。

Thank you all very much for joining us on our Q1 2024 call today. Operator, you may now end the call.

非常感謝大家今天參加我們的 2024 年第一季電話會議。接線員，您現在可以結束通話了。

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

女士們、先生們，今天的電話會議到此結束。感謝大家的加入。您現在可以斷開連線。