Xenon Pharmaceuticals Inc. (XENE) 2026 Q2 法說會逐字稿

Ladies and gentlemen, thank you for standing by. My name is Angela, and I will be your conference operator today. At this time, I would like to welcome everyone to the second-quarter 2026 Xenon Pharmaceuticals, Inc. earnings conference call. I'd like to remind everyone that this call is being recorded. (Operator Instructions)

各位女士、先生，感謝您耐心等候。我叫 Angela，今天將擔任本次電話會議的接線員。此刻，我謹代表主辦方歡迎各位參加 Xenon Pharmaceuticals, Inc. 2026 年第二季財報電話會議。提醒各位，本次通話將被錄音。（接線員指示）

I would now like to turn the call over to Ms. Colleen Alabiso, Senior Vice President of Corporate Affairs at Xenon Pharmaceuticals, Inc. You may begin.

現在我將把電話交給 Xenon Pharmaceuticals, Inc. 企業事務資深副總裁 Colleen Alabiso 女士。您可以開始了。

Good afternoon. Thank you for joining us on our call and webcast to discuss Xenon's second-quarter 2026 financial and operating results. Joining me today are Ian Mortimer, President and Chief Executive Officer; Dr. Chris Kenney, Chief Medical Officer; Darren Cline, Chief Commercial Officer; and Tucker Kelly, Chief Financial Officer.

各位下午好。感謝各位參加我們的電話會議與網路直播，一同討論 Xenon 2026 年第二季的財務與營運成果。今天與我一同出席的有：總裁兼執行長 Ian Mortimer、首席醫療長 Chris Kenney 醫師、首席商務長 Darren Cline，以及首席財務長 Tucker Kelly。

After completing our prepared remarks today, we will open the call up for your questions. 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 in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners' product candidates, the strength of our clinical trial designs, our ability to successfully develop and achieve milestones in our clinical development programs, including the anticipated filing of INDs or equivalent and NDAs.

在我們完成今天的事先準備發言後，將開放提問。請注意，在本次通話中，我們將做出若干前瞻性陳述，包括有關臨床試驗時程及潛在結果的陳述、我們及合作夥伴產品候選藥物的潛在療效、安全性特徵、於現有及預期適應症的未來開發計畫、可觸及市場、法規核准成功與商業化潛力、我們臨床試驗設計的強度，以及我們成功開發並達成臨床開發計畫里程碑的能力（包括預期提交 IND 或同等申請及 NDA）。

The timing and results of those filings and our interactions with regulators, our ability to successfully obtain regulatory approvals, anticipated timing of top line data readouts for our clinical trials of Azetukalner and other candidates and our expectation that we will have sufficient cash to fund operations into 2029.

亦包括上述申請的時程與結果、我們與主管機關的互動、我們成功取得法規核准的能力、Azetukalner 及其他候選藥物臨床試驗主要（top line）數據讀出之預期時程，以及我們預期現金足以支應營運至 2029 年。

Today's press release summarizing Xenon's second quarter financial results and the 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 SEDAR+.

今日發布、彙總 Xenon 第二季財務結果的新聞稿，以及 Form 10-Q 季度報告，將於 xenon-pharma.com 網站的「投資人」專區提供，並向 SEC 與 SEDAR+ 提交。

I'll now turn the call over to Ian.

現在我把電話交給 Ian。

Thanks, Colleen, and good afternoon to everyone joining us today. We are excited to recap another productive quarter for Xenon as we work toward our goal of becoming a fully integrated neuroscience company, delivering life-changing medicines to patients. In the second quarter, we remain focused on three key areas: First, preparing our new drug application for Azetukalner or AZK for focal seizures as well as sharing our exciting Phase 3 X-TOLE2 results with healthcare providers and preparing our go-to-market strategy.

謝謝你，Colleen，也向今天加入我們的各位致上下午好。我們很高興回顧 Xenon 又一個成果豐碩的季度；我們正朝著成為一家全面整合的神經科學公司邁進，為病患帶來改變人生的藥物。在第二季，我們持續聚焦三個關鍵領域：第一，為 Azetukalner（或 AZK）用於局灶性癲癇發作（focal seizures）的新藥申請（NDA）做準備，同時與醫療照護提供者分享令人振奮的第三期 X-TOLE2 結果，並擬定上市策略。

Second, advancing five additional Phase 3 studies of AZK in epilepsy and neuropsychiatry indications, which may help significantly expand the addressable patient population. And third, advancing and expanding our pain programs, including the Phase 1 studies of XEN1120 targeting Kv7 and XEN1701 targeting Nav1.7 as well as initiating clinical development of an additional Nav1.7 molecule, XEN1720, demonstrating our belief in and the importance of this target.

第二，推進 AZK 在癲癇與神經精神科適應症的另外五項第三期研究，這些研究可能有助於大幅擴大可觸及的病患族群。第三，推進並擴展我們的疼痛研發計畫，包括針對 Kv7 的 XEN1120 與針對 Nav1.7 的 XEN1701 之第一期研究，同時啟動另一個 Nav1.7 分子 XEN1720 的臨床開發，展現我們對此標的的信心與其重要性。

I'll provide a bit more detail of our recent achievements before passing the call over to Chris, Darren and Tucker. First, we are making great progress towards submitting our NDA for AZK and preparing for launch. I'm happy to share that we've completed a successful pre-NDA meeting with the Food and Drug Administration, and we're on track for a submission later this quarter.

在把電話交給 Chris、Darren 與 Tucker 之前，我先更詳細說明我們近期的成果。首先，我們在提交 AZK 的 NDA 與上市準備方面進展非常順利。我很高興分享，我們已與美國食品藥物管理局（FDA）完成一次成功的 NDA 前會議，並按計畫於本季稍晚提交申請。

We have continued to share our X-TOLE2 data with HCPs, including two important meetings for the epilepsy community. First, at the American Academy of Neurology meeting in April, where many of you will recall that the X-TOLE2 results were featured as a late-breaking science abstract and podium presentation.

我們也持續向醫療照護專業人員（HCP）分享 X-TOLE2 數據，包括癲癇領域兩場重要會議。首先是 4 月的美國神經學學會（American Academy of Neurology）年會，許多人應該記得，X-TOLE2 結果在該會議中以「最新突破科學」（late-breaking science）摘要與口頭報告形式發表。

Then in June, we had another opportunity to present the top line X-TOLE2 results at the Epilepsy Foundation Pipeline Conference. This is attended by HCPs, researchers, industry and patient advocates. Beyond these congresses, our MSLs have been out in the community responding to HCP requests to learn more about our data.

接著在 6 月，我們又有機會在癲癇基金會（Epilepsy Foundation）Pipeline Conference 上發表 X-TOLE2 的主要（top line）結果。該會議匯集 HCP、研究人員、產業界與病友倡議者。除上述學術會議外，我們的醫學科學聯絡員（MSL）也持續在社群中回應 HCP 的需求，協助其進一步了解我們的數據。

Overall, we continue to hear very positive feedback and excitement for both the X-TOLE2 results including the best placebo-adjusted efficacy in FOS to our knowledge and AZK's differentiated profile, including a novel mechanism of action, rapid onset of effect, once-daily dosing with no titration and no need for dose adjustments with other ASMs. We feel increasingly confident in AZK's potential to become a preferred add-on therapy for the significant number of patients who do not achieve seizure freedom with initial treatment.

整體而言，我們持續聽到非常正面的回饋與高度期待，涵蓋 X-TOLE2 的結果（據我們所知，在局灶性發作（FOS）中具備最佳的安慰劑校正後療效）以及 AZK 的差異化特徵，包括新穎作用機轉、快速起效、每日一次給藥且無需滴定（titration），並且與其他抗癲癇藥物（ASM）併用時無需調整劑量。我們對 AZK 成為加用治療（add-on therapy）的首選方案之潛力愈發有信心，特別是對於相當多在初始治療後仍無法達到無發作（seizure freedom）的病患。

Darren will share a bit more on the excitement from the epilepsy community later in the call as well as the progress we continue to make on preparing for the launch of AZK. We also continue to focus on expanding the opportunity for Azetukalner, including through the X-TOLE3 study in FOS to support potential regulatory submissions outside the US as well as the X-ACKT study in primary generalized tonic-clonic seizures to support regulatory submissions for an additional epilepsy indication.

Darren 將在稍後的通話中，進一步分享癲癇社群的熱烈反應，以及我們在 AZK 上市準備方面持續取得的進展。我們也持續聚焦擴大 Azetukalner 的機會，包括透過在 FOS 的 X-TOLE3 研究，以支持美國以外地區的潛在法規申請，以及在原發性全身性強直—陣攣性發作（primary generalized tonic-clonic seizures）的 X-ACKT 研究，以支持新增一項癲癇適應症的法規申請。

Through our ongoing Phase 3 X-NOVA2, X-NOVA3 and X-CEED studies, we continue to advance our work to broaden Azetukalner's opportunity to neuropsychiatry. There is strong rationale for Kv7 openers in major depressive disorder and bipolar depression, and AZK could deliver a novel mechanism where innovative treatments are urgently needed, especially treatments that may also impact anhedonia and that could offer differentiated tolerability profiles as well as rapid onset of action.

透過持續進行的第三期 X-NOVA2、X-NOVA3 與 X-CEED 研究，我們持續推進將 Azetukalner 的機會拓展至神經精神科領域。Kv7 開啟劑（openers）在重度憂鬱症（MDD）與雙相憂鬱方面具有強而有力的科學理據，而 AZK 有望提供一種新穎機轉；在亟需創新治療的領域中，尤其是可能同時改善快感缺失（anhedonia）、並可提供差異化耐受性特徵以及快速起效的治療。

We continue to expect our first Phase 3 MDD study results in the first half of 2027, and we will narrow that guidance as we get closer to the top line readout.

我們仍預期在 2027 年上半年取得首項第三期 MDD 研究結果，並將在更接近主要數據讀出時進一步縮小該時程指引。

Additionally, we're excited about the progress of our early clinical pipeline for pain. We are nearing completion of our Phase 1 studies for both XEN1701 and XEN1120, and data generated to date supports the initiation of Phase 2 proof-of-concept studies in acute pain for both programs.

此外，我們對早期臨床疼痛研發管線的進展也感到振奮。我們的 XEN1701 與 XEN1120 兩項第一期研究即將完成；迄今產生的數據支持兩個計畫皆可在急性疼痛領域啟動第二期概念驗證（proof-of-concept）研究。

We have also recently advanced a second Nav1.7 candidate for pain into a Phase 1 clinical trial. So, this will give us multiple shots on goal for this important pain target. Success in any one of these three novel non-opioid pain programs would meaningfully increase value for Xenon and our opportunity to impact the lives of millions who live with chronic or acute pain.

我們近期也已將第二個用於疼痛的 Nav1.7 候選藥物推進至第一期臨床試驗。因此，針對這個重要的疼痛標的，我們將擁有多次成功機會。在這三項新穎的非鴉片類（non-opioid）疼痛計畫中，任何一項成功都將為 Xenon 帶來顯著的價值提升，並擴大我們影響數以百萬計慢性或急性疼痛患者生活的機會。

In line with our continued commitment to epilepsy, we also continue to invest in multiple high-quality candidates targeting various ion channels. This includes our preclinical Nav1.1 program for Dravet syndrome, where we are in IND-enabling studies with the intent of putting the best candidate into the clinic. It also includes our partnered program with Neurocrine, NBI-921355, an investigational selective inhibitor of Nav1.2 and Nav1.6 in development for the potential treatment of certain types of epilepsy, which continues to advance through a Phase 1b study with data expected in 2027.

秉持我們對癲癇領域的持續承諾，我們也持續投資多項高品質候選藥物，鎖定不同的離子通道。其中包括我們針對 Dravet 症候群的臨床前 Nav1.1 計畫；目前正進行 IND 支持性研究（IND-enabling studies），目標是將最佳候選藥物推進臨床。也包括我們與 Neurocrine 的合作計畫 NBI-921355；該藥為一項研究性（investigational）選擇性 Nav1.2 與 Nav1.6 抑制劑，正開發用於某些類型癲癇的潛在治療，並持續推進至第一期 b（Phase 1b）研究，預計於 2027 年取得數據。

So, with that, now I'll turn over the call to Chris, who will provide additional clinical and regulatory updates. Chris?

因此，接下來我將把電話交給 Chris，由他提供更多臨床與法規方面的最新進展。Chris？

All right. Thanks, a lot. It continues to be a very exciting time here at Xenon as we prepare the NDA for Azetukalner and share our data with the community through scientific exchange opportunities. The interactions our team has had at recent meetings as well as out in the field have been incredibly affirming of our belief in AZK's potential to meaningfully impact the FOS treatment paradigm and provide a therapeutic option with appeal to epilepsy specialists, general neurologists and advanced practice providers alike.

好的。非常感謝。在 Xenon，我們正準備為 Azetukalner 提交 NDA，並透過科學交流機會與社群分享我們的數據，這段時間持續令人振奮。我們團隊近期在會議以及實地與各方的互動，極大地印證了我們對 AZK 潛力的信心：它有望對 FOS 的治療典範帶來實質影響，並提供一項對癲癇專科醫師、一般神經科醫師以及高階執業醫療人員同樣具吸引力的治療選擇。

As Ian mentioned, we have completed a productive and positive in-person pre-NDA meeting with FDA, where we gained alignment with the agency on components of the NDA package. We, therefore, remain on track to submit our NDA this quarter as planned and are encouraged by our continued engagement with the agency.

如 Ian 所提到，我們已與 FDA 完成一次富有成效且正面的面對面 pre-NDA 會議，並就 NDA 套件的組成要素與主管機關取得一致。因此，我們仍按計畫在本季提交 NDA，並對與主管機關持續互動所取得的進展感到鼓舞。

Completing the NDA submission is our team's top priority, and I'm very pleased with our progress and look forward to updating you in the coming months. We also continue our focus on presenting and educating on our exceptional X-TOLE2 data and recently presented at two important conferences for the epilepsy community.

完成 NDA 送件是我們團隊的首要任務；我對目前的進度非常滿意，並期待在未來幾個月向各位更新。我們也持續聚焦於展示並教育市場了解我們卓越的 X-TOLE2 數據，並且近期在癲癇社群兩個重要會議上進行發表。

First is a late-breaking science abstract and platform presentation at the AAN meeting in Chicago and second, at the EF Pipeline Conference in Leesburg, Virginia. In these presentations, we highlighted the following key points from our X-TOLE2 data.

第一是在芝加哥舉行的 AAN 年會上，以 late-breaking science 摘要與口頭平台報告形式發表；第二是在維吉尼亞州利斯堡舉行的 EF Pipeline Conference。在這些發表中，我們強調了 X-TOLE2 數據的以下幾個重點。

One, with regards to efficacy, the study met its primary endpoint and demonstrated what we continue to believe is the best placebo-adjusted response of any pivotal focal seizure study, which was highly significant and outperformed our Phase 2b X-TOLE study. This is even more meaningful when you consider the level of treatment resistance in the X-TOLE2 study population, which had failed a median of five prior antiseizure medications and 60% of those patients were on or had already tried and stopped cenobamate.

第一，就療效而言，本研究達成主要終點，並展現出我們持續認為是所有關鍵性局灶性發作（focal seizure）研究中、經安慰劑校正後最佳的反應幅度，具高度統計顯著性，且優於我們的第 2b 期 X-TOLE 研究。考量到 X-TOLE2 受試族群的治療抗性程度，這一點更具意義：受試者先前抗癲癇藥物失敗的中位數為 5 種，且其中 60% 的患者正在使用或曾嘗試後停用 cenobamate。

Second, we also observed early dose-dependent MPC reductions in weekly FOS from baseline to week 1, reinforcing AZK's rapid and sustained antiseizure activity.

第二，我們也觀察到從基線到第 1 週，每週 FOS 出現早期且具劑量依賴性的 MPC 降幅，進一步支持 AZK 具快速且持續的抗癲癇活性。

Third, we observed dose-dependent increases in the proportion of patients with at least 75%, 90% and 100% reductions in monthly seizure frequency through the double-blind period as well as evidence of efficacy building over time as evidenced by improvements in the 100% responder rate in the last eight, six, and four weeks of the study.

第三，在雙盲期間，我們觀察到達到每月發作頻率至少降低 75%、90% 與 100% 的患者比例呈現劑量依賴性上升；同時也看到療效隨時間累積的證據，表現在研究最後 8 週、6 週與 4 週的 100% 反應者比例有所改善。

Fourth, with regards to safety, AZK continued to demonstrate a generally well-tolerated profile, which was consistent with the X-TOLE study. The most common treatment-emergent adverse events across both studies in the AZK dose groups were dizziness, somnolence, headache and fatigue.

第四，就安全性而言，AZK 持續展現整體耐受性良好的特徵，且與 X-TOLE 研究一致。在兩項研究中，AZK 各劑量組最常見的治療期間新發不良事件為頭暈、嗜睡、頭痛與疲勞。

With more than 800 patient years of safety and exposure data, we're comfortable that this profile is consistent with other well-tolerated antiseizure medications and with a drug that is potent and active in the central nervous system.

累計超過 800 個病人年（patient-years）的安全性與暴露數據後，我們有信心此一特徵與其他耐受性良好的抗癲癇藥物一致，也符合一種在中樞神經系統具高效力且具活性的藥物所呈現的樣貌。

We also had a tremendous opportunity to interact with general neurologists at AAN, where we highlighted our 48-month X-TOLE open-label extension data, demonstrating a 91% reduction in monthly seizure frequency for those treated for at least 48 months. In the same group, almost 40% were seizure-free for at least 12 months and one in four were seizure-free for at least two years.

我們也在 AAN 與一般神經科醫師進行了非常深入的交流，並重點展示我們 48 個月的 X-TOLE 開放標籤延伸研究數據：接受治療至少 48 個月者，其每月發作頻率降低 91%。在同一族群中，近 40% 至少 12 個月無發作，且每 4 人就有 1 人至少 2 年無發作。

This is truly remarkable considering the level of treatment resistance in seizure frequency in the overall patient population at baseline. Now as we look ahead, we're excited to continue to share the AZK data at the 16th European Epilepsy Congress, or EEC, taking place between September 5 and 9 in Athens, Greece and at the Annual American Epilepsy Society or AES meeting taking place December 4 through 8 in Denver.

考量到整體受試者在基線時的發作頻率與治療抗性程度，這確實非常令人矚目。展望未來，我們很期待在第 16 屆歐洲癲癇大會（EEC）上持續分享 AZK 數據；該會議將於 9 月 5 日至 9 日在希臘雅典舉行；此外也將在 12 月 4 日至 8 日於丹佛舉行的美國癲癇學會（AES）年會上發表。

With regards to EEC, our X-TOLE2 top line results are among the six abstracts accepted and planned for presentation. Also accepted is a new abstract that will highlight the mechanistic characterization of Azetukalner, including Kv7 binding, enhanced channel opening and rational polytherapy potential. In this presentation, we plan to share in vivo data demonstrating the potential additive effects of Azetukalner when used in combination with commonly prescribed antiseizure medications, reinforcing its opportunity to enhance seizure control through the application of rational polytherapy in clinical practice.

就 EEC 而言，我們的 X-TOLE2 主要結果（top line results）是獲選並預計發表的 6 篇摘要之一。另有一篇新摘要也已獲接受，將聚焦於 Azetukalner 的作用機轉特性描述，包括 Kv7 結合、增強通道開啟，以及合理多重治療（rational polytherapy）的潛力。在該發表中，我們計畫分享體內（in vivo）數據，顯示 Azetukalner 與常用抗癲癇藥物合併使用時可能具有加成效果，進一步強化其在臨床實務中透過合理多重治療提升發作控制的機會。

Looking ahead, we're planning to have a significant Xenon presence at AES in December and multiple new AZK data presentations, including additional data from the X-TOLE2 study and continued follow-up from the X-TOLE open-label extension study.

展望未來，我們計畫在 12 月的 AES 會議上大幅提升 Xenon 的參與度，並安排多項新的 AZK 數據發表，包括 X-TOLE2 研究的更多補充數據，以及 X-TOLE 開放標籤延伸研究的持續追蹤結果。

Moving on to neuropsychiatry. We continue to enroll patients in our three ongoing Phase 3 studies of AZK for Major Depressive Disorder or MDD and Bipolar Depression or BPD. Depression remains an area where the differentiated profile of AZK, including its novel mechanism of action, rapid onset of action and potential benefits on anhedonia could meaningfully benefit patients in a second category with a much larger patient population who continue to have unmet medical needs.

接著談神經精神領域。我們持續在三項進行中的第 3 期研究中招募患者，評估 AZK 用於重度憂鬱症（MDD）與雙相憂鬱（BPD）。憂鬱症仍是一個領域：AZK 的差異化特徵（包括新穎作用機轉、快速起效，以及對快感缺失 anhedonia 的潛在益處）有望在第二個、患者人數更龐大的族群中為病患帶來實質幫助，而該族群仍存在未被滿足的醫療需求。

There's a strong rationale for Kv7 openers in MDD and BPD. Several preclinical and clinical studies, including our own X-NOVA study have shown promising signals of antidepressive effects for the Kv7 mechanism. Additionally, in BPD, specifically, there are genetic links with Kv7, including evidence of Kv7 downregulation.

Kv7 開啟劑（openers）在 MDD 與 BPD 具有強而有力的科學依據。多項臨床前與臨床研究（包括我們自己的 X-NOVA 研究）已顯示 Kv7 機轉具有具前景的抗憂鬱效果訊號。此外，特別是在 BPD 中，Kv7 亦存在遺傳學上的關聯，包括 Kv7 下調（downregulation）的證據。

AZK would deliver a novel mechanism to the MDD and BPD treatment paradigms where innovative treatments are urgently needed, especially those that may also impact anhedonia and that have the potential to offer differentiated tolerability profiles and rapid onset of action. Our clinical team has made great progress with X-NOVA2 and X-NOVA3 in MDD and X-CEED in BPD. Enrollment remains on track, and we anticipate sharing top line data from X-NOVA2 in the first half of 2027.

AZK 將為 MDD 與 BPD 的治療典範帶來一項新穎機轉；在此領域迫切需要創新療法，尤其是可能同時改善快感缺失、並有機會提供差異化耐受性特徵與快速起效的治療。我們的臨床團隊在 MDD 的 X-NOVA2 與 X-NOVA3，以及 BPD 的 X-CEED 方面已取得重大進展。收案進度仍符合規劃，我們預期於 2027 年上半年分享 X-NOVA2 的主要數據（top line data）。

Turning now to our pain portfolio. There remains a critical unmet need for non-opioid therapies given the limited efficacy of current options and substantial risk of abuse independency tied to opioids. At Xenon, we have more than 20 years of experience, both through collaborations and our own discovery research on novel pain targets, most notably the sodium channel, Nav1.7, which we view as the best genetically validated pain target.

接著談我們的疼痛產品組合。鑑於現有選項療效有限，且與鴉片類藥物相關的濫用與依賴風險相當高，非鴉片類療法仍存在關鍵且未被滿足的需求。在 Xenon，我們在新型疼痛標的方面累積超過 20 年經驗，包含透過合作以及我們自身的探索性研究；其中最重要的是鈉離子通道 Nav1.7，我們認為它是遺傳學驗證最充分的疼痛標的。

There's striking genetic data in patients with loss of function mutations that have no ability to feel pain and gain of function mutations have also been identified that drive pain disorders, further underscoring the critical role Nav1.7 plays in pain signaling.

患者的遺傳數據非常醒目：具有功能缺失（loss of function）突變者完全無法感受疼痛；同時也已辨識出功能增益（gain of function）突變會驅動疼痛疾病，進一步凸顯 Nav1.7 在疼痛訊號傳遞中的關鍵角色。

Our Phase 1 study of XEN1701, which targets Nav1.7 continues to advance. Consistent with what we shared earlier this year, we've seen exposures in both the single and multiple ascending dose portions of the study that are predictive of efficacy. Recall that nociceptive sensory neurons have processes that extend into peripheral tissue as well as behind the blood-brain barrier, such that channels are expressed in both peripheral and central compartments.

我們針對 Nav1.7 的 XEN1701 第 1 期研究持續推進。與我們今年稍早分享的內容一致，我們在單次與多次遞增劑量（single and multiple ascending dose）兩個部分均觀察到可預測療效的暴露水準。請記得，傷害感受（nociceptive）感覺神經元的突起一方面延伸至周邊組織，另一方面也延伸至血腦障壁後方，因此這些通道同時在周邊與中樞區室表達。

Central Nav1.7 target engagement is therefore core to our therapeutic hypothesis. And in this Phase 1 study, we have confirmed central drug exposure via cerebrospinal fluid collection in healthy volunteers. Based on this, we believe we are achieving both peripheral and central receptor occupancies that exceed what is needed for efficacy based on our modeling and on human genetic data.

因此，中樞 Nav1.7 的標的結合（target engagement）是我們治療假說的核心。在此第 1 期研究中，我們已透過健康受試者的腦脊髓液採集，確認藥物在中樞的暴露。基於此，我們相信依據模型推估與人類遺傳數據，我們正達到周邊與中樞兩端的受體占有率（receptor occupancy），且其水準高於達成療效所需。

We're looking forward to completing the Phase 1 study this year. In addition to advancing XEN1701, we've continued our discovery around Nav1.7 given our deep experience with the target and strong belief in its therapeutic potential. We've been working on several preclinical Nav1.7 compounds, continuing to refine our understanding of the biology and to develop novel chemistries.

我們期待在今年完成第一期研究。除了推進XEN1701之外，基於我們在Nav1.7靶點上的深厚經驗以及對其治療潛力的高度信心，我們也持續推進圍繞Nav1.7的探索性研究。我們一直在開發多個Nav1.7的臨床前化合物，持續精進對其生物學機制的理解，並開發新穎的化學結構。

We're pleased to announce that we recently received CTA approval of XEN1720, which also targets Nav1.7 and have initiated a Phase 1 SAD/MAD study. XEN1720 provides us with an additional clinical candidate that further strengthens our leading position in Nav1.7, an important pain target with compelling genetic validation.

我們很高興宣布，我們近期已獲得XEN1720的CTA核准；該藥物同樣以Nav1.7為靶點，且我們已啟動第一期SAD/MAD研究。XEN1720為我們提供了另一個臨床候選藥物，進一步鞏固我們在Nav1.7領域的領先地位；Nav1.7是重要的疼痛靶點，並具有強而有力的遺傳學驗證。

Beyond Nav1.7, our Phase 1 SAD/MAD study of XEN1120, which targets Kv7 also continues to advance. Kv7 modulates neuronal hyperexcitability at multiple points along the pain pathway, and we believe Kv7 potentiators have the potential to treat a range of pain conditions. This is supported by high levels of Kv7 expression throughout the pain pathway and our preclinical data shows that Kv7 is enriched in the C and A delta pain subtypes of sensory neurons. In addition, Kv7 openers can block action potential firing in both DRG and spinal cord neurons, thereby significantly inhibiting pain signals from reaching the brain and evidence supports that dysfunction or downregulation of Kv7 activity has been observed in altered pain states.

除Nav1.7之外，我們針對Kv7靶點的XEN1120第一期SAD/MAD研究也持續推進。Kv7可在疼痛傳導路徑的多個節點調節神經元過度興奮性，我們相信Kv7增效劑有潛力治療多種疼痛狀況。這一點受到多項證據支持，包括Kv7在整個疼痛路徑中具有高表達量，以及我們的臨床前數據顯示Kv7在感覺神經元的C纖維與Aδ疼痛亞型中更為富集。此外，Kv7開啟劑可阻斷DRG與脊髓神經元的動作電位放電，從而顯著抑制疼痛訊號傳至大腦；亦有證據顯示，在改變的疼痛狀態中可觀察到Kv7活性功能失調或下調。

We've been pleased to see drug concentrations in both the single and multiple ascending dose portions of the study that are consistent with pain reduction in preclinical models. Like Nav1.7, exposure in both the peripheral and central nervous system is likely critical to success for a Kv7 opener in pain, and data so far support that we are achieving Kv7 target engagement in both compartments. We look forward to completing the Phase 1 study this year and continuing to lead on Kv7 science and its application to pain in addition to epilepsy and depression.

我們很高興看到，在研究的單次與多次遞增劑量部分，藥物濃度與臨床前模型中觀察到的疼痛降低效果一致。與Nav1.7類似，對於用於疼痛的Kv7開啟劑而言，同時在周邊與中樞神經系統達到足夠暴露量很可能是成功關鍵；目前數據支持我們在兩個區室皆達成Kv7靶點結合（target engagement）。我們期待在今年完成第一期研究，並持續在Kv7科學及其於疼痛（以及癲癇與憂鬱症）上的應用方面保持領先。

With that, I'll turn it over to Darren to provide an update on our path to commercialization.

接下來，我將把時間交給Darren，請他就我們的商業化路徑提供最新進展。

Thank you, Chris, and good afternoon, everyone. We're making strong progress as we prepare for a potential launch of AZK, our first commercial product and bring an important new treatment option to patients living with focal seizures.

謝謝你，Chris，各位下午好。在為AZK（我們第一個商業化產品）潛在上市做準備的同時，我們正取得強勁進展，並為局灶性發作患者帶來一項重要的新治療選擇。

During the second quarter, we continued to execute our commercial build-out, adding key leaders across marketing, sales and field strategy and commercial operations. We've assembled an exceptional team that brings decades of epilepsy experience and successful launch execution. Their expertise, combined with a strong belief in AZK's potential, gives us confidence that we are building the capabilities needed to realize the significant commercial and patient impact opportunity ahead for AZK.

在第二季期間，我們持續推進商業化團隊建置，於行銷、銷售與外勤策略以及商業營運等領域增聘關鍵領導人才。我們已組建一支卓越團隊，具備數十年的癲癇領域經驗與成功上市執行實績。他們的專業能力，加上對AZK潛力的堅定信念，使我們有信心正在建立所需能力，以實現AZK在商業與患者端的重大影響機會。

Additionally, we continue to advance our launch readiness and refine our launch strategy informed by deep insights into the treatment landscape, prescribing dynamics and the healthcare professionals we expect to serve in both primary research and in advisory discussions with general neurologists, epilepsy specialists and advanced practice providers, we consistently hear strong enthusiasm for AZK and the recognition of the unmet needs that AZK would address, including compelling efficacy, a well-understood safety profile, rapid onset of action and ease-of-use attributes, all of which could make AZK a go-to add-on therapy.

此外，我們持續提升上市準備度並精進上市策略；該策略建立在對治療環境、處方動態以及我們預期服務之醫療專業人員的深度洞察之上。透過主要研究以及與一般神經科醫師、癲癇專科醫師與進階實務提供者的顧問討論，我們一再聽到對AZK的高度熱忱，並認同AZK可滿足的未被滿足需求，包括具說服力的療效、充分被理解的安全性概況、快速起效以及易用性等特點；上述因素皆可能使AZK成為首選的加用治療（add-on therapy）。

While we expect epilepsy specialists to lead early adoption of AZK, our market research supports the view that general neurologists can move to AZK sooner than historically has been the case for newly launched epilepsy therapies. To support these efforts, we continue to refine and validate our brand positioning, sharpen our key points of differentiation and develop tailored engagement strategies designed to resonate with specific customer segments.

雖然我們預期癲癇專科醫師將引領AZK的早期採用，但我們的市場研究支持一項觀點：一般神經科醫師採用AZK的速度，可能會比過往新上市癲癇療法的情況更快。為支持這些工作，我們持續精煉並驗證品牌定位，強化關鍵差異化要點，並制定量身打造的互動策略，以與特定客戶族群產生共鳴。

We also are increasingly focused on introducing payers to Xenon and communicating the potential value proposition of AZK through the lens of the unmet medical need. We've engaged with payers through several key conferences this year, helping to refine our market access strategy and strengthen our overall launch readiness. We also have started to build out our payer-facing field team with the expectation to fill all roles by the end of the year and deploy them in the field early next year.

我們也日益聚焦於向支付方介紹Xenon，並從未被滿足的醫療需求角度溝通AZK的潛在價值主張。今年我們透過數個重要會議與支付方互動，協助精進市場准入策略並強化整體上市準備度。我們也已開始建置面向支付方的外勤團隊，預期在年底前補齊所有職位，並於明年初投入第一線部署。

An important component of the AZK launch will be our distribution approach, and we continue to work to identify, engage our channel partners on the distribution and access side. We also continue to build awareness of Xenon as an emerging leader and committed partner to the epilepsy community between our customer engagement, MSL and patient advocacy teams as well as our presence at congresses, regional meetings, community events, we're making new connections, raising awareness of Xenon and the AZK data we've generated and deepening our relationship each day.

AZK上市的一個重要組成部分將是我們的配送策略；我們持續努力識別並與通路夥伴就配送與可近性（access）面向進行接洽。我們也持續透過客戶互動、MSL與病友倡議團隊，以及我們在學術年會、區域會議與社區活動中的參與，提升Xenon作為新興領導者與癲癇社群承諾夥伴的能見度；我們正在建立新的連結、提升對Xenon與我們所產生之AZK數據的認知，並日復一日加深彼此關係。

As we move forward, I look forward to sharing more details on our go-to-market strategy and how we plan to bring innovation to the epilepsy landscape with a best-in-class antiseizure medication, enhanced channel and patient services and a strong value proposition for payers. We believe the strategy, capabilities and team we are assembling position us well for a successful launch, pending FDA approval and ultimately, the opportunity to improve outcomes for patients living with epilepsy.

展望未來，我期待分享更多我們的上市策略細節，以及我們計畫如何以同級最佳（best-in-class）的抗癲癇發作藥物、強化的通路與患者服務，以及對支付方具吸引力的價值主張，為癲癇治療版圖帶來創新。我們相信，我們正在打造的策略、能力與團隊，使我們在取得FDA核准的前提下具備成功上市的良好條件，並最終有機會改善癲癇患者的治療結果。

With that, I'll now turn the call over to Tucker to review our financial results and upcoming milestones. Tucker?

接下來，我將把電話會議交給Tucker，請他回顧我們的財務結果與即將到來的里程碑。Tucker？

Thanks, Darren, and good afternoon, everyone. We ended Q2 with cash, cash equivalents and marketable securities of $1.2 billion, which, based on our current operating plans, provides cash to fund operations into 2029.

謝謝你，Darren，各位下午好。我們在第二季末的現金、約當現金與有價證券為12億美元；依據我們目前的營運計畫，該資金可支應營運至2029年。

Given our strong balance sheet, we are well positioned to support AZK's US launch, multiple AZK registrational programs, the continued maturation of our pain pipeline and the advancement of other early-stage research and development programs. I would refer you to our press release and our 10-Q filed today for further details on our financial results.

憑藉我們強健的資產負債表，我們具備良好條件以支持AZK在美國上市、多項AZK註冊性（registrational）計畫、疼痛產品線的持續成熟，以及其他早期研發計畫的推進。關於財務結果的更多細節，請參閱我們的新聞稿以及今日提交的10-Q。

Overall, it's a very exciting time at Xenon as we continue to build momentum toward our first commercial launch and across our promising pipeline. As we head into the back half of the year, we remain focused on our upcoming NDA submission expected this quarter as well as the advancement of our commercial readiness activities to support a strong launch in FOS.

整體而言，對Xenon來說這是一個令人振奮的時刻；我們正持續累積動能，朝向首次商業化上市邁進，並同步推進我們具前景的產品線。進入下半年之際，我們仍聚焦於預計於本季提交的NDA，以及推進商業化準備活動，以支持在FOS適應症上的強勁上市表現。

We are also working to broaden the therapeutic opportunities for AZK beyond epilepsy, and we continue to make progress enrolling our studies in MDD and BPD. We look forward to the readout of our X-NOVA2 study in MDD anticipated in the first half of 2027. And lastly, we're excited about the progress we're making in pain with two Phase 1 studies for XEN1701 and XEN1120 approaching completion and now one additional Phase 1 study for XEN1720 underway and believe Xenon is well positioned to become a scientific leader in the development of novel non-opioid pain therapeutics. We remain very optimistic about the opportunity ahead as we transition to a fully integrated commercial stage company.

我們也正致力於將AZK在癲癇之外的治療機會擴大，並持續在MDD與BPD研究的受試者招募方面取得進展。我們期待於2027年上半年取得X-NOVA2在MDD的研究讀出結果。最後，我們對疼痛領域的進展感到振奮：XEN1701與XEN1120的兩項第一期研究接近完成，且目前另有一項針對XEN1720的第一期研究正在進行中；我們相信Xenon具備良好條件，成為開發新型非鴉片類疼痛治療藥物的科學領導者。隨著我們轉型為一家完整整合的商業化階段公司，我們對未來機會仍保持高度樂觀。

And with that, we can open the call for questions. Operator?

接下來，我們可以開放提問。接線員？

(Operator Instructions) Paul Matteis with Stifel.

(接線員指示) Stifel的Paul Matteis。

One quick one on AZK and one on pain. On AZK, maybe just recap for us this FDA pre-NDA meeting and if anything notable came out of it? And then second, on the pain program, maybe talk a little bit about the safety profile you've seen so far. Have you seen any cardiac AEs or anything noteworthy that has been dose-limiting for prior Nav1.7, not Kv7. And then just for Nav1.7, what's the rationale behind advancing a second product now?

我有一個關於AZK的簡短問題，以及一個關於疼痛的問題。關於AZK，能否請你們為我們回顧一下這次FDA的pre-NDA會議，以及是否有任何值得注意的重點？第二個，關於疼痛計畫，能否談談你們目前看到的安全性概況？你們是否觀察到任何心臟相關不良事件（AE），或任何值得注意、在先前Nav1.7（非Kv7）計畫中曾造成劑量限制的情況？另外，就Nav1.7而言，現在推進第二個產品的理由是什麼？

Thanks, Paul. Chris, do you want to take the, maybe a little bit of color and commentary on the pre-NDA meeting, and then I'm happy to answer the pain questions.

謝謝你，Paul。Chris，你要不要先就 pre-NDA 會議補充一些背景與評論，然後我也很樂意回答關於疼痛的問題。

Sure. Happy to do so, Ian. Thanks for the question, Paul. So we've had the pre-NDA meeting, as mentioned in the prepared remarks, it was an in-person meeting. It was very productive. We continue to appreciate the collaborative nature of the interactions with FDA. We covered the main questions that we wanted to cover with FDA as it pertains to the submission. We continue to believe that we have a very strong package and that overall, it's a pretty straightforward package that we're bringing to the agency. So we're in good shape at this point in time. We're on target to submit this quarter.

當然。很樂意這麼做，Ian。謝謝你的提問，Paul。如同在事先準備的發言中提到的，我們已經完成 pre-NDA 會議，而且是面對面的會議。會議非常有成效。我們持續感謝與 FDA 互動時所展現的合作精神。我們也就提交申請相關、我們希望與 FDA 討論的主要問題都做了涵蓋。我們仍然相信我們的資料包非常強，而且整體而言，我們帶給主管機關的是一個相當直接明確的資料包。因此就目前而言，我們的進度狀況良好。我們也按計畫在本季提交。

Thanks, Chris. And then, Paul, I think I've got all your pain questions down here, but if I miss one, just jump back in. So, as we think about, and your questions were related to Nav1.7, let's just focus on that target for a second. We had said earlier this year that based on some of the SAD data, we already thought that we were getting or we had profiled that we were getting up to enough exposures that we would see based on our predictions kind of that level of receptor occupancy that should show an analgesic effect. I would say we have even more confidence today because we're really nearing the completion of the study.

謝謝你，Chris。然後，Paul，我想我已經把你所有關於疼痛的問題都記在這裡了，但如果我漏掉任何一個，請再插話提醒。所以，針對你的問題（與 Nav1.7 相關），我們先聚焦在這個標的。我們今年稍早曾說過，基於部分 SAD 數據，我們已經認為我們達到、或已描繪出我們達到足夠的暴露量；依照我們的預測，這樣的受體佔有率應該會呈現鎮痛效果。我會說，今天我們更有信心，因為研究已接近完成。

So, we've gone through multiple SAD and MAD cohorts. And again, all of our modeling predicts that we're going to have enough exposure to have the receptor occupancy that is being taught by human genetics. So I think we feel like we're in a really good spot from the XEN1701 profile. There was a new piece of information that Chris disclosed today that I just don't want to miss, which is we've looked at CSF as well. So our hypothesis is that we want to get exposure both in the peripheral nervous system as well as the central nervous system.

因此，我們已經完成多個 SAD 與 MAD 隊列。同樣地，我們所有的模型都預測，我們將有足夠的暴露量，以達到由人類遺傳學所指引的受體佔有率。所以我認為，就 XEN1701 的特徵而言，我們覺得處在非常好的位置。Chris 今天揭露了一個新的資訊，我不想漏掉：我們也檢視了 CSF。因此，我們的假設是，我們希望在周邊神經系統以及中樞神經系統都能達到暴露。

We can kind of model that based on our animal work and kind of predict what it's going to be in humans, but we did take extra cohorts just to actually do CSF and to make sure that we were getting central exposure. So I think that's another box that we've checked that, again, feel comfortable that we're getting this global receptor occupancy of the target. We haven't finished yet.

我們可以根據動物研究來做模型推估，並預測在人類中的情況，但我們確實另外納入了額外隊列，實際進行 CSF 檢測，以確認我們取得了中樞暴露。所以我認為這是我們又勾選完成的一項要點；同樣地，我們對於能達到該標的的整體受體佔有率感到放心。我們尚未完全結束。

So I'm not going to go into specific safety data. You asked around the cardiovascular effect. Again, today, what we see in the data is that it's a profile that we're very comfortable moving ahead into a Phase 2 proof-of-concept study. So that's taking everything into consideration. So I'm not going to go into very specific details, but we feel very comfortable on what we've seen so far, getting close to completion. (multiple speakers)

因此我不會深入到具體的安全性數據。你問到心血管方面的影響。同樣地，就目前我們在數據中看到的結果而言，這是一個我們非常有信心推進到第 2 期概念驗證（proof-of-concept）研究的特徵。這是綜合所有因素後的判斷。所以我不會談非常細的細節，但就目前所見、且研究接近完成之際，我們感到非常安心。(多位發言者)

Yes. Yes. Once we're complete, then I think we have an opportunity to just give you a little bit more information when we have all of the data unblinded and we can see both the placebo and the active groups.

是的。是的。等我們完成之後，我想當所有數據解盲、而且我們能同時看到安慰劑組與用藥組時，我們就有機會再提供你更多一些資訊。

I think your last one was just around XEN1720 kind of the next molecule. Is that right?

我想你最後一個問題是關於 XEN1720，也就是下一個分子。對嗎？

Yes. I don't know if you dropped off, Paul. But yes, I think you had a question just around 1720. So we have taken a second molecule into Phase 1 clinical development. When we think about the Nav1.7 program, and if you go back to the webinar we did almost a year ago, we've made a number of advancements that have overcome some of the limitations we've seen historically.

是的。Paul，我不確定你是不是掉線了。不過是的，我想你有一個問題是關於 1720。所以我們已經把第二個分子推進到第 1 期臨床開發。當我們思考 Nav1.7 計畫時，如果你回顧我們將近一年前做的線上說明會，我們已經取得多項進展，克服了過去歷來看到的一些限制。

So those were around selectivity and potency, around protein binding and around the kind of this PK or biodistribution and exposure both in the periphery as well as in the central nervous system. So when we look at 1720, it has some different analysis of those components that we're looking for when we compare it to 1701 and a differentiated chemistry profile.

這些限制包括選擇性與效力、蛋白結合，以及這類 PK 或生體分布與暴露（在周邊以及中樞神經系統）。因此當我們看 1720 時，與 1701 相比，它在我們關注的這些構面上有一些不同的表現分析，並且具有差異化的化學特徵。

So I think that this is such a high-value target. We're going to continue to do preclinical work. We're going to continue to advance novel chemistries and move multiple molecules into the clinic just to get more opportunities to see what's the best molecule at the end of the day. Nothing changes with the lead molecule 1701. This is really just around a second molecule that has somewhat of a differentiated profile.

所以我認為這是一個價值非常高的標的。我們會持續進行臨床前工作。我們會持續推進新穎化學結構，並將多個分子推進到臨床，讓我們有更多機會在最後判斷哪一個分子是最佳的。以 1701 這個領先分子而言，沒有任何改變。這主要是關於第二個分子，它具有某種程度上差異化的特徵。

Tessa Romero, JPMorgan.

Tessa Romero，摩根大通（JPMorgan）。

Ian, Chris, can you maybe talk a little bit about how you are thinking about what you would still like to get out into the public domain about the profile of Azetukalner in your Phase 3 X-TOLE2 trial and what the specific publication strategy looks like? I know there's a small epilepsy conference at the end of the year, but any other color you'd give us?

Ian、Chris，你們能否談談你們如何思考：在第 3 期 X-TOLE2 試驗中，關於 Azetukalner 的特徵，你們還希望有哪些資訊能對外公開，以及具體的發表策略會是什麼樣子？我知道年底有一個小型癲癇會議，但你們還能提供其他補充說明嗎？

Thanks, Tessa. I'm happy to start, and Chris, you can add. So I think we've given a fair bit of information on X-TOLE2 already. So you've seen top line data. You've seen all of the key efficacy endpoints, including some that were outside of the statistical hierarchy. And you've seen kind of the broad safety profile. So we were able to show those data at AAN at the EF pipeline. We're going to have more data in Encore at EEC and then more, as you mentioned, at AES.

謝謝你，Tessa。我先開始回答，Chris 你也可以補充。我想我們已經就 X-TOLE2 提供了相當多資訊。你已經看到主要（top line）數據。你也看到所有關鍵療效終點，包括一些不在統計階層（statistical hierarchy）之內的終點。你也看到大致的安全性概況。因此我們能在 AAN 的 EF pipeline 上展示這些數據。我們會在 EEC 的 Encore 提供更多數據，然後如你所提，AES 也會有更多。

If we look back to the X-TOLE data, we looked at certain different analyses that we're still going through, different seizure subtypes, different types of patients. So all of that work kind of ongoing, and you'll see that over time.

如果回頭看 X-TOLE 的數據，我們做了一些不同的分析，目前仍在持續進行中，例如不同的發作亞型、不同類型的病人。所以這些工作都在進行，你會隨著時間逐步看到。

The publication strategy is critical. So we have peer-reviewed publication of the X-TOLE and X-TOLE OLE data, and we are working hard to get the peer review of the X-TOLE2 data as well because we think that's really going to be important for the epilepsy community that we not only presented at congresses, but it's also peer reviewed.

發表策略非常關鍵。因此，我們已經有 X-TOLE 與 X-TOLE OLE 數據的同儕審查（peer-reviewed）論文發表；我們也正努力推進 X-TOLE2 數據的同儕審查發表，因為我們認為這對癲癇社群非常重要：不僅在學術會議上報告，也要經過同儕審查。

Chris, anything to add on kind of details on some of the other analyses you're looking at?

Chris，你要不要補充一下你們正在看的其他分析細節？

In the prepared remarks, we had talked about the fact that 60% of patients in X-TOLE2 were either on or had failed cenobamate. And so you may see data on that down the road.

在事先準備的發言中，我們提到 X-TOLE2 中有 60% 的病人不是正在使用 cenobamate，就是曾經使用失敗。因此你們之後可能會看到關於這部分的數據。

Andrew Tsai, Jefferies.

Andrew Tsai，Jefferies。

Congrats on the progress this quarter. This is Matthew Barcus on for Andrew Tai. Now you provided more color today on the progress of your Phase 1 SAD/MAD studies in pain. Can you just remind us like what additional data you plan on sharing later this year for those programs? And then at that time, will you be prepared to delineate which acute pain indications you'll be pursuing next for these studies as well?

恭喜本季的進展。我是代替 Andrew Tai 的 Matthew Barcus。你們今天對疼痛領域第 1 期 SAD/MAD 研究的進展提供了更多補充。你們能否提醒我們：今年稍晚你們計畫就這些計畫再分享哪些額外數據？另外，到那個時候，你們是否會準備好說明接下來這些研究將會追求哪些急性疼痛適應症？

And then our understanding is that X-CEED started maybe 6 to 8 months after X-NOVA2. And with X-NOVA2 data in the first half of next year, how should we be thinking about the interim look from X-CEED, if you have any color on the timing for that?

然後我們的理解是，X-CEED 可能是在 X-NOVA2 之後約 6 到 8 個月才啟動。那麼在明年上半年會有 X-NOVA2 數據的情況下，對於 X-CEED 的期中分析（interim look），我們應該如何看待？如果你能就時間點提供一些補充說明的話。

Sure. I think Matt, I got them all. I'm happy to kind of walk through time lines and the pain stuff. Tucker, do you want to do the X-NOVA timelines? And then I'll, why don't I jump in on the data from the pain programs and the types of acute pain PoC studies?

當然。我想，Matt，我都收到了。我很樂意大致帶大家走一遍時間線以及疼痛相關的部分。Tucker，你要不要先講一下 X-NOVA 的時間線？然後我再補充疼痛項目的數據，以及急性疼痛 PoC（概念驗證）研究的類型？

Sure. So we've said on the call in the press release is that we'll have the X-NOVA2 data in the first half of next year. We haven't provided any guidance yet on either X-NOVA3, right, the second Phase 3 study in MDD. And I think you asked about the X-CEED study in bipolar depression. And again, as you said, both of those started after X-NOVA2, but we're still not far enough along in the enrollment curve to provide an updated time line for when those might read out, but they'll certainly be after, obviously, the first half readout for the MPD study, X-NOVA2.

好的。我們在電話會議與新聞稿中都提到，X-NOVA2 的數據會在明年上半年出來。我們目前尚未就 X-NOVA3（對，MDD 的第二個第三期研究）提供任何指引。我想你問的是雙相憂鬱症的 X-CEED 研究。同樣地，如你所說，這兩個研究都是在 X-NOVA2 之後才啟動，但我們在收案曲線上仍未進展到足以提供更新時間線、說明何時讀出結果；不過它們肯定會在（顯然）MDD 研究 X-NOVA2 明年上半年讀出之後。

And then on the pain stuff, yes. As I mentioned in the first question, we're getting close to completion of those Phase 1 studies, then we'll have the complete data package and then we can really talk about what we provide publicly. These are competitive targets. And so I think we may be balanced in terms of how much information we provide publicly. But I think we'll be able to at least walk you through kind of our decision process on why we believe we have enough exposure and the appropriate safety profile to move into a proof-of-concept study.

至於疼痛部分，是的。如我在第一個問題中提到的，我們已接近完成那些第一期研究，之後我們會拿到完整的數據包，然後才能真正討論我們會對外公開哪些內容。這些是競爭性標的。因此我想我們在對外提供資訊的多寡上會保持平衡。但我認為我們至少能帶大家了解我們的決策流程：為什麼我們相信已經有足夠的暴露量（exposure）以及合適的安全性概況，可以推進到概念驗證研究。

The proof-of-concept studies are still being designed right now for both XEN1120, the Kv7 drug as well as 1701, the Nav1.7 drug, but these will be acute proof-of-concept studies, so things like a bunionectomy or an abdominoplasty study. We'll have the final trial designs for those in the coming months. And I think part of that rollout, we'll be able to talk about the specific indication in the acute pain proof of concept, but importantly, the trial design as well.

概念驗證研究目前仍在設計中，涵蓋 XEN1120（Kv7 藥物）以及 1701（Nav1.7 藥物）；但這些都會是急性疼痛的概念驗證研究，例如拇囊炎切除術（bunionectomy）或腹部整形（abdominoplasty）研究。我們會在接下來幾個月內確定最終的試驗設計。我想在那次對外說明時，我們也能談到急性疼痛 PoC 的具體適應症，更重要的是試驗設計本身。

Brian Skorney, Baird.

Brian Skorney，Baird。

My question is on the anticipated Phase 2 proof of concept in acute pain. How are you thinking about design right now? If we look at the path Vertex, they went head-to-head with low-dose oxycodone and placebo, but restricted rescue to ibuprofen, the TiVo program which was published the other week. We also went against low-dose oxycodone and placebo, but allowed use as Percocet as rescue and maybe because of Percocet's efficacy showed a pretty disparate result. Do you see any better value in one versus the other design in terms of using an opioid as a rescue? Or are you thinking about something completely different?

我的問題是關於預期在急性疼痛領域進行的第二期概念驗證。你們目前如何思考試驗設計？如果看 Vertex 的路徑，他們採用低劑量羥考酮（oxycodone）與安慰劑的頭對頭比較，但將救援用藥限制為布洛芬（ibuprofen），也就是前陣子發表的 TiVo 計畫。我們也曾與低劑量羥考酮和安慰劑比較，但允許以 Percocet 作為救援用藥，可能因為 Percocet 的療效而呈現相當不同的結果。在是否使用鴉片類藥物作為救援用藥方面，你認為哪一種設計更有價值？或者你們在考慮完全不同的做法？

Thanks, Brian. I'm happy to start and then, Chris, if you've got anything to add. So Brian, we're not quite there yet, as I just kind of answered on the last question. I know you've been thinking about this a lot and you and I have had conversations about just the right design for a Phase 2 proof of concept.

謝謝，Brian。我先回答，然後 Chris 如果有補充也請加入。Brian，我們目前還沒到那一步，正如我剛才在上一題所回答的。我知道你對這件事想了很多，而且你我也討論過第二期概念驗證要採用什麼才是合適的設計。

I'll take it a step further. You're looking at both what active comparators as well as kind of rescue. We also have to think just about how many active dose arms of the experimental medicine as we kind of really understand dose range finding and identifying doses to move forward in the future clinical development. So there's a number of things that we kind of want to answer within that Phase 2 proof-of-concept study. We're still in the design phase. I don't think that there's going to be anything in this study that's going to be unusual.

我再往前推一步說。你需要同時考量主動對照（active comparators）以及救援用藥（rescue）的安排。我們也必須思考實驗藥物要設置多少個有效劑量組（active dose arms），以便真正理解劑量範圍探索（dose range finding），並找出未來臨床開發要推進的劑量。因此在那個第二期概念驗證研究中，我們希望回答的問題其實有好幾個。我們仍在設計階段。我不認為這個研究會有任何不尋常之處。

So I think it would be reasonably standard. But as you said, a few different sponsors have taken slightly different approaches here. But I think we're only a few months away being able to kind of walk you through what the trial design is and why we've made certain decisions in the trial design.

所以我想它會是相當標準的設計。但如你所說，幾家不同的贊助方在這裡採取了略有不同的方法。不過我想再過幾個月，我們就能帶大家了解試驗設計是什麼，以及我們為何在設計上做出某些決定。

Chris, anything to add right now from your perspective?

Chris，從你的角度現在有什麼要補充的嗎？

I'll just say that we're following the field closely. And of course, the studies that have been done recently will serve as guides for what we do eventually. The advantage of using the opioid as a rescue is that you can show data with opioid sparing. So we're looking at that, but it's still in the works, Brian.

我只想說，我們正密切追蹤這個領域。當然，近期已完成的研究會成為我們最終要做什麼的參考指引。使用鴉片類藥物作為救援用藥的優點是，你可以呈現「減少鴉片用量」（opioid sparing）的數據。所以我們正在評估這點，但目前仍在規劃中，Brian。

Joseph Thome, TD Cowen.

Joseph Thome，TD Cowen。

On the progress. Maybe first on depression. Can you remind us the powering assumptions on HAM-D for X-NOVA2? And maybe any changes in the baseline depression severity versus the patients that you were enrolling for X-NOVA? And then for AZK, this adoption by general neurologists seems to be a unique exciting opportunity. Can you go into a little bit more detail on when you expect general neurologists to start adopting the therapy and maybe specific education efforts you can do to make sure they have a good initial experience?

關於進展。也許先談憂鬱症。你能提醒我們 X-NOVA2 在 HAM-D 上的檢定力（powering）假設嗎？以及相較於你們在 X-NOVA 收案的病人，基線憂鬱嚴重度是否有任何變化？另外就 AZK 而言，一般神經科醫師的採用似乎是一個獨特且令人振奮的機會。你能更詳細說明你們預期一般神經科醫師何時會開始採用這項治療，以及你們可能會做哪些具體教育工作，以確保他們有良好的初期使用體驗嗎？

Thanks, Joe. Okay. Why don't we do, I'm happy to start just on the powering assumptions. And then, Chris, why don't we broaden that out? I mean, Joe's question is just on the HAM-D entry criteria from Phase 2 to Phase 3, but I think it might be helpful just to walk through a bunch of the changes that we've made from Phase 2 to Phase 3 because I think we learned a lot in the X-NOVA study that we're applying into X-NOVA2.

謝謝，Joe。好。不如我先從檢定力假設開始回答。然後 Chris，我們再把範圍擴大一些？Joe 的問題是關於從第二期到第三期的 HAM-D 入組標準，但我想也許有幫助的是，帶大家走一遍我們從第二期到第三期做了哪些改變，因為我認為我們在 X-NOVA 研究中學到很多，並把這些應用到 X-NOVA2。

And then Darren, jump in on your thoughts on general neuros and both adoption, but also, I think some of the profile of AZK that is really the feedback you're getting from the general neuro interaction, and I know you've done some ad boards on the general neuro side as well.

然後 Darren，也請你補充你對一般神經科醫師的看法：包括採用時點，以及我想 AZK 的一些特徵輪廓（profile）——這些其實是你從與一般神經科互動中收到的回饋；我也知道你在一般神經科端做過一些顧問委員會（ad boards）。

But Joe, just to kick off on the HAM-D17, so we're appropriately powered for a Phase 3 study. So think about that kind of 90% for about a 2, 2.5 point separation in that range based on our expectation in terms of standard deviation. So I think we have really good powering in the study. It's 450 subjects. X-NOVA2 and X-NOVA3 are the same, meaning they're designed exactly the same as monotherapy studies, but I think well powered to see that separation between active and placebo.

不過 Joe，先從 HAM-D17 開始，我們的第三期研究有適當的檢定力。可以把它想成：在我們對標準差的預期之下，約 90% 的檢定力，用來偵測大約 2 到 2.5 分左右的差異（separation）。所以我認為這個研究的檢定力非常充足。樣本數是 450 位受試者。X-NOVA2 和 X-NOVA3 是相同的，也就是說它們的設計完全一致，都是單藥治療（monotherapy）研究；而且我認為其檢定力足以看到活性治療組與安慰劑之間的差異。

Chris, do you want to go through the X-NOVA to X-NOVA2 changes?

Chris，你想帶大家回顧一下 X-NOVA 到 X-NOVA2 的變更嗎？

Yes, sure. Happy to. So obviously, one of the things that we changed is we're including a larger sample size, so the power is higher. We decreased the number of active treatment arms from two to one, which in general, saves you about one point on the placebo response. So that's favorable. We increased the cutoff a little bit so that we're collecting a little bit more of a slightly more impaired population with more depressive symptoms in Phase 3 relative to Phase 2.

是的，當然。很樂意。很明顯地，我們做的其中一項改變是納入更大的樣本數，因此統計檢定力更高。我們把主動治療組的數量從兩組降為一組，整體而言，這通常能讓安慰劑反應大約降低一個百分點。所以這是有利的。我們也把納入門檻稍微提高一些，讓第三期相較於第二期能收納到功能受損稍重、憂鬱症狀更多的族群。

We're focusing on adherence by using an app that captures adherence and allows for real-time feedback for subjects who aren't adhering. And then just overall, we're scrutinizing patient randomization even closer in Phase 3 than we were in Phase 2, using the safer criteria and then keeping a real close eye on the data in real time to make sure that there isn't anything unexpected happening. But yes, we don't share baseline characteristics as the study is unfolding. As you know, every patient that's added changes that. So we'll share that once the study is complete.

我們透過使用一個可記錄依從性並允許對未依從受試者提供即時回饋的 App，來聚焦在依從性。此外，整體而言，我們在第三期對病人隨機分派的審視會比第二期更嚴格，採用更安全的標準，並且即時密切監看資料，以確保沒有任何意外狀況發生。不過是的，在研究進行期間我們不會分享基線特徵。如你所知，每新增一位病人都會改變那些數據。所以我們會在研究完成後再分享。

Yes, Joe, regarding the general neuro, yes, we think it's a pretty exciting opportunity. If you look historically at the most successful antiseizure medications, Kv those were really embraced by the general neurologists. And we spent a lot of time understanding that history, but also then where does Azetukalner fit in with its unique characteristics.

是的，Joe，關於一般神經科醫師（general neuro），是的，我們認為這是一個相當令人振奮的機會。如果你回顧歷史上最成功的抗癲癇藥物，Kv7 這類藥物確實很受一般神經科醫師的青睞。我們花了很多時間去理解那段歷史，同時也思考 Azetukalner 以其獨特特性，應該如何定位。

And Joe, you know better than anyone. It's a novel mechanism. We have ease of use attributes, really stellar safety and efficacy profile. So we've talked to a lot of general neurologists about this. And as Ian highlighted, through advisory boards and other one-on-ones. And when you couple the efficacy safety along with our open-label extension seizure freedom data, it really is a package that they're really compelled by.

而且 Joe，你比任何人都更清楚。這是一個新穎的作用機轉。我們具備易用性的特點，以及非常出色的安全性與療效表現。因此我們和許多一般神經科醫師談過這件事。如 Ian 所強調的，透過諮詢委員會（advisory boards）以及其他一對一交流。當你把療效與安全性，再加上我們開放標籤延伸試驗（open-label extension）的無發作（seizure freedom）資料結合起來，這整體方案確實非常能打動他們。

I think we have this opportunity to do that. We're doing a lot of work now kind of targeting, understanding where we're going to have our focus at launch. And so as you've noted, kind of how do we expedite that utilization, that's something we're tremendously highly focused on. The other piece of it is also how do you use the expression, make it a good experience for them.

我認為我們有機會做到這一點。我們目前正在做大量工作，鎖定並理解上市時我們要把重點放在哪些地方。所以如你所提到的，如何加速使用量的提升，這是我們高度聚焦的事項。另一個面向是，你要怎麼說呢，就是讓他們有良好的使用體驗。

I think this is where we're trying to be and thinking about really being a little bit disruptive or innovative here because I think traditional antiseizure medication launches have gone a certain distribution route, have not really assisted the general neurologists in different things like prior authorization and helping patients get through obtaining the therapy.

我認為這正是我們想達到的方向；我們也在思考是否能在這裡更具顛覆性或更創新一些，因為我認為傳統抗癲癇藥物的上市通常走的是某種既定的通路模式，並沒有在事前授權（prior authorization）等不同環節上真正協助一般神經科醫師，也沒有幫助病人順利取得治療。

And also on the patient side, where they may show up at a retail pharmacy, for example, and really struggle there. So we're really evaluating a service that we can wrap around both the general neurologists and the patient to make that experience a good one out of the gate. We think that based on our research and discussions, those have been some of the barriers that they've encountered and that we hope to overcome. And so again, we still have a lot of work to do and over the next several quarters, but I think that we're in a really good position to really bend the curve if we can with the general neurologists.

另外在病人端，例如他們可能到零售藥局領藥時，會在那裡遇到很大的困難。因此我們正在認真評估一套服務，能同時包覆一般神經科醫師與病人，讓他們從一開始就有良好的體驗。我們認為根據研究與討論，這些一直是他們遇到的一些障礙，而我們希望能加以克服。所以再次強調，我們仍有很多工作要做，接下來幾個季度也會持續推進，但我認為如果我們能在一般神經科醫師端把曲線「扭轉」過來，我們的位置會非常好。

Brian Abrahams, RBC Capital Markets.

RBC Capital Markets 的 Brian Abrahams。

Two for me. First, can you characterize your payer conversations and just the latest views on the potential pricing benchmarks for Azetukalner and receptivity to potential premium pricing, just given all of its profile advantages? And then secondly, how might your commercial strategy be affected if there looks like there could be a Kv7 focal onset seizure fast follower competitor emerging?

我有兩個問題。第一，能否描述一下你們與支付方（payer）的對話情況，以及對 Azetukalner 潛在定價基準（pricing benchmarks）的最新看法；考量到它在各方面的優勢，支付方對可能的溢價定價（premium pricing）的接受度如何？第二，如果看起來可能會出現一個 Kv7 局灶性起始發作（focal onset seizure）的快速跟進者（fast follower）競品，你們的商業策略可能會如何受到影響？

Yes. Well, yes, both of them. Maybe I can start on a little bit, Darren, I'll start on the competitive landscape and then you can go into kind of the specific question from Brian on kind of a fast follower as well as on the payer stuff because I know you guys have done a huge amount of work already.

是的。嗯，是的，兩個問題都是。也許我可以先談一點，Darren，我先從競爭格局談起，然後你再針對 Brian 的具體問題補充，包括快速跟進者以及支付方的部分，因為我知道你們已經做了大量工作。

Yes, Brian, look, there's more than 20 antiseizure medicines available. Patients do kind of cycle through drugs. We do see drugs. If you look at like sodium channel inhibition, multiple drugs of the same mechanism. And as Darren just talked about in the last answer, you have a drug like Vimpat, which is the same mechanism and did incredibly well, and there were attributes of that medicine that I think we’re really important specifically with the general neurologists. I think where we are today is we've set an incredibly high bar. So obviously, we will be the first Kv7 drug on the market.

是的，Brian，你看，目前市面上有超過 20 種抗癲癇藥物。病人確實會在不同藥物之間輪替使用。我們也看到同機轉的藥物並存。例如鈉離子通道抑制（sodium channel inhibition），同一機轉就有多個藥物。而且如 Darren 在上一題所說，你有像 Vimpat 這樣同機轉的藥物表現非常出色，而我認為那個藥物的一些特性，對一般神經科醫師而言尤其重要。我認為我們目前的狀態是，我們把門檻設得非常高。所以很明顯地，我們將會是市場上第一個 Kv7 藥物。

I think we have an incredible profile. And when you look at the four doses on label that we're talking to the agency about, you've got a clear dose response. You've got 10 and 15 milligrams that show separation, but quite frankly, have a really benign safety profile, very similar to placebo, a little bit higher in dizziness at the 15-milligram dose.

我認為我們的產品特性非常出色。當你看我們正在與主管機關討論、標籤上可能會有的四個劑量時，你會看到清楚的劑量反應關係。10 與 15 毫克顯示出差異性（separation），但坦白說，安全性輪廓非常溫和，與安慰劑非常相近；在 15 毫克劑量時頭暈略高一些。

And then if you go up to 20 and 25 milligrams, you get the opportunity in that dose response to see even better efficacy and seizure reduction. So, I think we've set an incredibly high bar, but we do see in the epilepsy space that this isn't a zero-sum game that multiple molecules can be successful together and even multiple molecules within the same mechanistic class. But I really like the setup for where we are right now. But Darren, happy for you to add your comments to that and then specifically on the payer side.

然後如果你往上到 20 與 25 毫克，在這個劑量反應中，你有機會看到更好的療效與更大的發作降低幅度。所以我認為我們把門檻設得非常高，但我們也看到在癲癇領域這並不是零和遊戲（zero-sum game），多個分子可以一起成功，甚至同一機轉類別內的多個分子也能同時成功。不過我真的很喜歡我們目前的布局。但 Darren，也歡迎你補充你的看法，然後特別談談支付方那一端。

No, I think you've covered it on the potential other mechanisms. So, Brian, regarding payer and price, as I remind folks, by the time we're approved and commercializing, it will be almost a decade since the last focal onset seizure medication was approved. And so regarding the payer audience, our kind of our initial discussions really anchor around re-educating them about, A, focal seizures and B, most importantly, the unmet medical need.

不，我認為你已經把其他可能機轉的部分涵蓋到了。所以，Brian，關於支付方與價格，我提醒大家，等到我們獲批並開始商業化時，距離上一個局灶性起始發作藥物獲批，將近已經過了十年。因此就支付方受眾而言，我們初期的討論重點，主要是重新教育他們：A，什麼是局灶性發作；以及 B，更重要的是，未被滿足的醫療需求（unmet medical need）。

When we put the product profile in front of them, they're very impressed. They understand the difficulty in managing these patients, all the antiseizure medications that patients cycle through. And quite frankly, with Azetukalner and the new mechanism of action are excited. So, I think from that perspective, and we'll continue that dialogue with them as we get closer to launch.

當我們把產品特性（product profile）呈現給他們時，他們印象非常深刻。他們理解管理這些病人的困難，也理解病人會在各種抗癲癇藥物之間輪替。坦白說，對於 Azetukalner 以及這個新的作用機轉，他們感到興奮。所以我認為從這個角度來看，我們會在接近上市時持續與他們對話。

But I think it leads to the second part of your question is, okay, what's the value then that they perceive of this new antiseizure medication. So we have kicked off our pricing work. It's still ongoing. I think that I would characterize it that if you look at where we are today when we launch, the efficacy and safety that Azetukalner provides, meeting still a tremendous unmet medical need.

但我認為這也引出你問題的第二部分：也就是說，支付方對這個新抗癲癇藥物所感受到的價值是什麼。因此我們已經啟動定價工作。目前仍在進行中。我會這樣描述：如果你看我們上市時的狀況，Azetukalner 所提供的療效與安全性，仍是在滿足一個非常巨大的未被滿足醫療需求。

We feel early days that there is an opportunity to ensure we get the value out of Azetukalner, while also, though, ensuring that patients can access the drug and physicians feel confident writing it. So it's one of these things. We'll assemble all that data. And when we ultimately launch it, we'll price it, but we'll have a good idea as we learn more as we continue our work.

我們在早期就覺得有機會確保能從 Azetukalner 中取得其價值，同時也要確保病患能取得這個藥物，並讓醫師有信心開立處方。所以這是其中一個面向。我們會彙整所有這些資料。而當我們最終推出時，我們會訂價；但隨著我們持續推進工作、了解更多，我們也會對價格有更清楚的掌握。

Myles Minter, William Blair.

Myles Minter，William Blair。

Just a confirmatory one. In the pre-NDA meeting, did you confirm that you've got a sufficient amount of data for review in some of the lower doses that I think you're going to go on label with alongside the 25 milligram. That's the first one.

我只是想確認一下。在 pre-NDA 會議中，你們是否確認在一些較低劑量上已經有足夠的資料可供審查？我想你們會把這些劑量與 25 毫克一起納入標籤。這是第一個問題。

And then the second one is actually on the X-CEED trial in bipolar. I know you're certainly getting patients in that have depressive episodes on type 1 and type 2. The type 1 patients, like there is always a reasonable chance that there may be some mania in the trial and you have a year open-label extension. How are you dealing with a patient that may experience mania? Do they drop out of the trial? Or do they go to like rescue medications like cariprazine?

第二個問題其實是關於雙相情感障礙的 X-CEED 試驗。我知道你們確實正在納入第一型與第二型、且有憂鬱發作的病患。第一型病患在試驗中一向有相當合理的機率可能出現躁期，而且你們還有一年的開放標籤延伸期。你們如何處理可能出現躁期的病患？他們會退出試驗嗎？還是會使用像 cariprazine 之類的救援用藥？

Chris, these are, I think, all for you. Do you want to start with the pre-NDA and just our plan for four doses on label. Obviously, Myles, as you know, I think that's kind of where the question is coming from is that we have 10 milligrams was in the X-TOLE study, 15 in X-TOLE 2, 20 in X-TOLE and then 25 in both. So we do have different safety exposures at different doses, but obviously, a lot of open-label data at these kind of higher doses that would provide that coverage. But Chris, provide your perspective there. And then if you can go into the bipolar in terms of the patients that cycle into mania as well.

Chris，我想這些問題都給你。你要不要先從 pre-NDA 開始，以及我們在標籤上規劃四個劑量的計畫。顯然，Myles，如你所知，我想問題的來源在於：10 毫克是在 X-TOLE 研究中、15 毫克在 X-TOLE 2、20 毫克在 X-TOLE，而 25 毫克在兩個研究中都有。所以我們在不同劑量上確實有不同的安全性暴露資料，但顯然也有大量在這些較高劑量下的開放標籤資料可提供涵蓋。不過 Chris，請你從你的角度補充。然後也請你談談雙相那邊，關於病患也可能轉入躁期的情況。

Yes. I mean, Myles, thanks for the question. A lot of this stuff will be dealt with in the review, but there were no concerns from the agency specifically about inadequate exposures in any way. So the details of that will be kind of discussed as we kind of go through the review process. But we think we have a pretty robust package for all these different doses that supports getting all four doses approved.

是的。我是說，Myles，謝謝你的問題。很多這類內容會在審查中處理，但主管機關並沒有特別對任何劑量的暴露不足提出疑慮。所以相關細節會在我們進入審查流程時再進一步討論。但我們認為，針對這些不同劑量，我們有相當扎實的資料包，足以支持四個劑量都獲得核准。

I mean the 10-milligram dose was studied in a double-blind study, and it did separate from active, and it showed a really quite remarkable tolerability profile similar to placebo. So we think we're in pretty good shape as far as all the different doses go. It remains to be seen. We'll have to see how the review goes.

我是說，10 毫克劑量是在一項雙盲研究中評估的，而且它確實與對照藥物拉開差異，並呈現相當顯著、接近安慰劑的耐受性表現。所以就各個不同劑量而言，我們認為狀況相當不錯。至於最終結果如何，還得看審查進展。

The other topic, X-CEED BPD. I mean, that's starting to get into details about the protocol, but I'll just share with you that in general, most protocols deal with mania by defining it with a certain cutoff on the YMRS. And then if that's met, patients are discontinued. So we're taking kind of a standard approach to that.

另一個主題是 X-CEED BPD。這開始涉及方案細節，但我可以跟你分享的是，一般而言，多數試驗方案會用 YMRS 的某個切點來界定躁期。一旦達到該標準，病患就會被停止試驗。所以我們採取的是一種相對標準的作法。

Paul Choi, Goldman Sachs.

Paul Choi，Goldman Sachs。

This is Kevin Strang on for Paul. Just had a quick one on MDD. You talked about potential differentiation for AZK and sort of the rationale for Kv7 there. Can you just sort of book in what specific efficacy signals you might be looking for or thresholds when that trial reads out next year?

我是代替 Paul 的 Kevin Strang。我有一個關於 MDD 的簡短問題。你們談到 AZK 可能的差異化，以及 Kv7 的一些研發理據。你能否具體說明一下，明年試驗讀出時，你們會特別關注哪些療效訊號或門檻？

Sure. I'm happy to start. And Darren, maybe you can provide your perspective commercially as well. Kevin, in terms of the work that we've done with prescribers is obviously, there's a significant medical need here and they want different options for their patients. And so drugs that are approved, i.e., they've shown statistical data in clinical development, what we find it's less around a specific separation on HAM-D17 or MADRS or even kind of drug to drug, but much more about the profile of the patient and what therapy may be prescribed. And as we've talked a lot, the feedback that we're getting is where AVK could really stand apart is a novel mechanism.

當然。我很樂意先回答。Darren，也許你也可以從商業面補充你的看法。Kevin，就我們與處方醫師所做的工作而言，很明顯這裡有顯著的醫療需求，他們希望能為病患提供不同的選擇。因此，對於已獲核准的藥物，也就是在臨床開發中展現統計學數據的藥物，我們發現重點較少在於 HAM-D17 或 MADRS 的特定差距，甚至也不是藥物對藥物的比較，而更多在於病患的特徵輪廓，以及可能會開立何種治療。而如我們多次討論的，我們收到的回饋是 AVK 真正能脫穎而出的地方在於其新穎機轉。

So most of these patients will have exposure to standard SSRIs or SNRIs atypicals, but it would be exposure to a novel mechanism. It would have the opportunity, what we've seen for this mechanism is to have an impact on anhedonia, which other mechanisms don't seem to have that impact. And so we are looking that as a key secondary endpoint in the study, looking at the SHAP scale.

因此，多數這些病患都曾使用過標準的 SSRI 或 SNRI、非典型藥物，但這將是接觸一種新穎機轉。就我們對此機轉的觀察，它有機會對快感缺失（anhedonia）產生影響，而其他機轉似乎沒有這樣的效果。因此我們把它作為研究中的一個關鍵次要終點，使用 SHAP 量表來評估。

It does, what we see both across the epilepsy program as well as the psychiatry program is the rapid onset of effects. You do see the separation, whether it be in depression or epilepsy between active and placebo. at week one. And so for, again, some of the mechanisms in depression that takes some time to work, this would work more quickly. And then a different tolerability profile. We don't, to date, haven't seen any notable sexual dysfunction or weight gain.

另外，我們在癲癇計畫以及精神科計畫中看到的是起效迅速。無論是在憂鬱或癲癇，你都會在第一週就看到治療組與安慰劑之間的差異。因此，對於憂鬱症中某些需要一段時間才起效的機轉，這個藥物可能會更快發揮作用。再來是不同的耐受性特徵。截至目前，我們尚未看到任何明顯的性功能障礙或體重增加。

So I think it's the kind of that package that the prescribers are talking to when we do DPP and market research to get the feedback and less around a specific efficacy measure. But Darren, I'm happy for you to provide your perspective as well.

所以我認為，當我們做 DPP 與市場研究、向處方醫師蒐集回饋時，他們談論的是這整套特性，而不是某一個特定的療效指標。不過 Darren，我也很樂意請你補充你的看法。

Ian, I think you went through all the kind of the attributes other than it is still a tremendous unmet need. It's a big market, roughly 22 million Americans, a little bit more than half are treated with some kind of pharmacotherapy and one out of three of those are not adequately managed. So, and would be available for a branded and particularly a novel mechanism, which, again, most of these are SSRIs. So it's really, really a great opportunity. And there is a lot when we go talk to docs and do some market research, a lot of excitement around a new mechanism in this space.

Ian，我想你已經把除了「仍然存在巨大的未被滿足需求」之外的各項特性都講到了。這是一個很大的市場，大約有 2,200 萬名美國人，略多於一半接受某種藥物治療，而其中三分之一的病患控制並不理想。因此，對於品牌藥，特別是新穎機轉的藥物而言，這些病患是可觸及的；而且再次強調，目前多數仍是 SSRI。所以這真的是一個非常、非常好的機會。而且當我們與醫師交流並做市場研究時，大家對於這個領域出現新機轉有很高的期待。

David Hoang, Deutsche Bank.

David Hoang，Deutsche Bank。

So I just wanted to ask about some of these two questions. So for focal epilepsy for the adolescent population there, what additional work would be required to get a label and extend down to adolescent patients? And then to what extent is the PGTCS indication and label important for AZK's overall profile? And what would that contribute to the overall revenue opportunity?

我想問兩個問題。第一，針對局灶性癲癇的青少年族群，若要取得標籤並將適應症延伸到青少年病患，還需要做哪些額外工作？第二，PGTCS 的適應症與標籤對 AZK 的整體產品定位有多重要？它對整體營收機會會帶來什麼貢獻？

Thanks, David. Chris, why don't we start with just the our pediatric plans, maybe I know David's question was around adolescents, but we could probably just expand to kind of the pediatric development that we've negotiated with FDA and EMA. And then Darren, can you address the patient population for PGGCS and how you see that commercially? Yes, sure. Chris, to start?

謝謝你，David。Chris，我們先從兒科計畫開始吧；我知道 David 的問題聚焦在青少年，但我們也可以擴大談談我們與 FDA 與 EMA 協商的整體兒科開發規劃。然後 Darren，你能否說明一下 PGGCS 的病患族群，以及你在商業面如何看待？好的，當然。Chris，你先開始？

Yes, sure. So we have agreement on the pediatric plans for focal onset seizures with both FDA and EMA, as Ian has said. For those of you who aren't familiar with that, you're basically capturing data that pertains to safety and PK, not efficacy. And you sort of start at the older patients, the adolescents and then work your way down to patients who are younger over time based upon your being comfortable with the safety and the PK data. So we have all that agreed upon. That's exactly what we're intending to do to get sort of the extrapolation for the label down to a younger age than 18, which is what the studies are currently studying at least in focal onset seizures.

是的，當然。如 Ian 所說，我們已就局灶性起始癲癇發作的兒科計畫，與 FDA 與 EMA 皆達成一致。對於不熟悉這點的各位，基本上你是在蒐集與安全性與藥物動力學（PK）相關的資料，而非療效。你會先從年紀較大的患者開始，也就是青少年，然後隨著你對安全性與 PK 資料的信心提升，逐步往更年幼的患者推進。因此這些我們都已經談妥。這正是我們打算採取的做法，以便將標籤的外推適用年齡延伸到 18 歲以下；而目前這些研究至少是在局灶性起始癲癇發作的適應症上進行。

Darren?

Darren？

Yes. So regarding focal and then generalized, just to step back, there's roughly three million adults or folks with epilepsy in the US, about 1.8 million have focal and then roughly almost another one million have generalized seizures. From a development perspective, if you look at the most successful ASMs that I referenced earlier, focal is the entry and then you follow on with a generalized. I think in the marketplace, you do get some use in the generalized.

是的。關於局灶性以及接著的全身性，我先退一步說明：美國大約有三百萬名成人或癲癇患者，其中約 180 萬為局灶性，另外大約將近 100 萬為全身性發作。從開發角度來看，如果你看我先前提到最成功的抗癲癇藥物（ASM），通常是先以局灶性作為切入點，之後再延伸到全身性。我認為在市場上，確實也會有一些用於全身性。

But I think our development plan fits nicely with, if you think about Azetukalner being a broad-spectrum antiseizure medication, having that supplemental label expansion will be quite helpful, particularly down the road for general neurologists who want to treat their patients and want to have the comfort that it can cover a broad spectrum. So it's important. I know the development plan is going well. There's a lot of excitement for Azetukalner in this space, and it will be very beneficial for us.

但我認為我們的開發計畫非常契合：如果你把 Azetukalner 視為一種廣效型抗癲癇發作藥物，取得那個補充性的標籤擴增將非常有幫助，特別是長期來看，對於希望治療其患者的一般神經科醫師而言，能夠安心它可涵蓋廣泛譜系。所以這很重要。我知道開發計畫進展順利。Azetukalner 在這個領域引起很多期待，對我們將非常有利。

Ben Burnett, Wells Fargo.

Ben Burnett，富國銀行。

One question on X-TOLE3, just as this is enrolling, I think you've mentioned this has expanded to include Japanese patients. I guess what are you seeing in terms of baseline characteristics? Or what are you expecting in terms of baseline characteristics? Any differences that we should expect relative to X-TOLE2? Really just asking if the different geographies being included are associated with maybe different treatment paradigms. And of course, could that lead to differences in these characteristics and maybe a different effect on the drug?

關於 X-TOLE3 有一個問題：在這項試驗正在收案之際，我想你們提到已擴大納入日本受試者。我想問你們在基線特徵方面看到了什麼？或你們預期基線特徵會是什麼樣？相較於 X-TOLE2，我們應該預期有任何差異嗎？我主要是想了解，納入不同地理區域是否可能對應到不同的治療模式。當然，這是否可能導致這些特徵出現差異，並可能對藥物效果造成不同影響？

Thanks, Ben. Chris, do you want me to start and then you can jump in as well. So Ben, I wasn't sure if you were referring to do we expect with the inclusion of Japanese subjects whether the baseline characteristics would change or just generally X-TOLE3 versus X-TOLE2. Was there something specific on the Japanese side you wanted to understand?

謝謝你，Ben。Chris，你希望我先開始，然後你也可以補充嗎？所以 Ben，我不確定你是指：因納入日本受試者，我們是否預期基線特徵會改變；還是更一般地在問 X-TOLE3 相對於 X-TOLE2。你在日本這一端有沒有特別想了解的點？

No, more just generally.

沒有，比較是一般性的。

Okay. Yes. I mean, as the study, I'll start and then Chris can provide additional detail. As these studies are ongoing, we don't comment and we didn't on X-TOLE or X-TOLE2 on baseline characteristics as we go along. Similarly, I think Chris answered this question as it relates to a different question earlier is that these things are changing all the time. Each patient has an impact on that. So we're not going to go into the specific details.

好的。是的。我的意思是，這些研究仍在進行中，我先說，之後 Chris 可以補充更多細節。在研究進行期間，我們不會評論基線特徵；我們在 X-TOLE 或 X-TOLE2 進行時也沒有這麼做。同樣地，我想 Chris 先前在回答另一個相關問題時也提到，這些數據一直在變動。每位受試者都會對此產生影響。因此我們不會深入到具體細節。

As a reminder, X-TOLE2 and X-TOLE3 are an identical protocol. So by that definition, we expect a similar patient population in both. Once we unblind the data and we're done, would they maybe be slightly different depending on the jurisdiction and different sites? Yes, they might be. But I think generally, the expectation is that the patient baseline characteristics would be somewhat similar to X-TOLE2.

提醒一下，X-TOLE2 與 X-TOLE3 的試驗方案（protocol）是完全相同的。因此按此定義，我們預期兩者的受試者族群會相似。等到我們解盲並完成後，是否可能因不同司法管轄區與不同試驗中心而略有差異？是的，可能會。但整體而言，我們的預期是患者的基線特徵會與 X-TOLE2 大致相近。

Chris, anything to add to that?

Chris，還有要補充的嗎？

Well, just that the inclusion exclusion criteria were pretty similar between X-TOLE and X-TOLE2 and the baseline characteristics were nearly identical. So Ben, that's sort of the direction that we think we're heading in, but it's changing over time.

嗯，補充一點：X-TOLE 與 X-TOLE2 的納入與排除標準相當類似，而基線特徵幾乎完全一致。所以 Ben，這就是我們認為將會前進的方向，但它會隨時間而變動。

Okay. So you're not really expecting major differences in sort of background medication with XCOPRI and other medications that can maybe influence the drug profile?

好的。所以你們其實不太預期在背景用藥方面會有重大差異，例如 XCOPRI 以及其他可能影響藥物特徵的藥物？

Well, from Phase 2 to Phase 3, the concomitant use of cenobamate went up because its usage went up within the medical community. But X-TOLE3 and X-TOLE 2 have been run in parallel. So I don't predict any significant differences between those studies.

嗯，從第二期到第三期，cenobamate 的併用比例上升了，因為它在醫療社群中的使用增加了。但 X-TOLE3 與 X-TOLE2 是平行進行的。因此我不預期這兩項研究之間會有任何顯著差異。

That concludes our question-and-answer session. I will now turn the conference back over to Mr. Ian Mortimer for closing remarks.

問答環節到此結束。接下來我將把電話會議交回給 Ian Mortimer 先生作結語。

Thanks, operator, and thanks to everyone for joining us today. If we didn't get a chance to get to your questions during the allotted time, happy to reach out directly and connect. And we look forward to continuing to provide updates as we advance our programs and deliver on important milestones through the remainder of the year.

謝謝主持人，也謝謝各位今天加入我們。如果在既定時間內我們未能回答到各位的問題，我們很樂意直接聯繫並進一步交流。我們也期待在推進各項計畫、並在今年剩餘時間達成重要里程碑的過程中，持續提供最新進展。

So operator, we can now end the call.

所以，主持人，我們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.

各位女士、先生，今天的電話會議到此結束。感謝各位參與。您現在可以掛線。