Praxis Precision Medicines, Inc. (PRAX) 2026 Q2 法說會逐字稿

Good day and thank you for standing by. Welcome to the Praxis Precision Medicine second quarter 2026 financial results conference call.

大家好，感謝您撥冗等候。歡迎參加 Praxis Precision Medicine 2026 年第二季財務業績電話會議。

(Operator Instructions) Please be advised that today's conference is being recorded. I would now like to hand the conference over to our first speaker today, Daniel Ferry, Managing Director of LifeSci Advisors. Daniel, please go ahead.

(接線員指示) 請注意，今天的會議將被錄音。現在我想把會議交給今天的第一位講者，LifeSci Advisors 董事總經理 Daniel Ferry。Daniel，請開始。

Good morning and welcome to the Praxis Precision Medicine's second quarter 2026 financial results and business update Conference Call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com.

各位早安，歡迎參加 Praxis Precision Medicine 2026 年第二季財務業績與業務更新電話會議。本次會議將進行線上直播，可至 Praxis 官網 www.praxismedicines.com 的投資人專區收看。

Please note that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent Praxis views as of today, they should not be relied upon as representing the company's views in the future.

請注意，本次電話會議中的發言可能包含《1995 年私人證券訴訟改革法》所定義的前瞻性陳述。其中可能包括關於公司未來預期與計畫、臨床開發時程，以及財務預測的陳述。雖然這些前瞻性陳述代表 Praxis 截至今日的觀點，但不應被視為代表公司未來的觀點。

Praxis may update these statements in the future, but is not taking on an obligation to do so. Please refer to Praxis's most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.

Praxis 未來可能會更新這些陳述，但並不承擔必須更新的義務。有關公司業務所面臨之若干風險與不確定性，請參閱 Praxis 最近向美國證券交易委員會提交的文件中的相關討論。

Joining the call today are Marcio Souza, President and Chief Executive Officer of Praxis; and Tim Kelly, Chief Financial Officer. After providing updates on our key programs, we'll move to a brief Q&A session where Marcio and Tim will be joined by Steve Petrou, President of Research and Development; and Megan Sniecinski, Chief Operating Officer.

今天與會者包括 Praxis 總裁暨執行長 Marcio Souza，以及財務長 Tim Kelly。在提供我們主要計畫的最新進展後，我們將進入簡短的問答環節；屆時 Marcio 與 Tim 將與研發總裁 Steve Petrou 及營運長 Megan Sniecinski 一同參與。

With that, it's my pleasure to turn the call over to Marcio. Marcio?

接下來，很高興把電話會議交給 Marcio。Marcio？

Thank you, Dan. Good morning, everyone. Thank you for joining Praxis' second quarter 2026 conference call. Three months ago, I told you this would be the year Praxis become a commercial company. This quarter is the one where that stopped being a plan and started materializing into the organization.

謝謝你，Dan。各位早安。感謝各位參加 Praxis 2026 年第二季電話會議。三個月前我曾告訴各位，今年將是 Praxis 成為商業化公司的年度。而本季正是那個轉捩點：這不再只是計畫，而是開始在組織中具體落地。

We had two NDAs in late-stage review with the FDA, with both approvals expected in about six months. It's extremely exciting to bring both ulixacaltamide to ET patients and relutrigine to SCN2A and 8A patients. We have commercial leadership in place, a field force for the first launch hired and trained, and a distribution network established and inventory being built.

我們有兩項 NDA 正在接受 FDA 的後期審查，兩項核准預期約在六個月內完成。能將 ulixacaltamide 帶給特發性顫抖（ET）患者，以及將 relutrigine 帶給 SCN2A 與 8A 患者，令人非常振奮。我們已建立商業化領導團隊，完成首波上市所需的外勤團隊招募與訓練，並已建立配送網路且正在建立庫存。

I want to spend most of my time today on some key regulatory developments and what we have been building. Let me start with ulixacaltamide.

今天我想把大部分時間用在幾項關鍵的法規進展，以及我們正在打造的能力上。先從 ulixacaltamide 談起。

Essential tremor affects over 7 million Americans and there is still no FDA approved therapy developed specifically to treat the condition. With the potential approval coming up by January next year, ulixacaltamide is poised to change that.

特發性顫抖影響超過 700 萬名美國人，但至今仍沒有任何一款專為治療此疾病而開發、且獲 FDA 核准的療法。隨著可能在明年一月前後獲准，ulixacaltamide 有望改變這一現況。

Speaking about the NDA review, the FDA completed its mid-cycle communications with us and are very pleased with the progress and discussions with the agency. In that meeting, the agency identified no efficacy-related significant issues and stated that he does not plan to request an Advisory Committee meeting. I would characterize the discussion as expected and very forward-looking.

就 NDA 審查而言，FDA 已完成與我們的期中溝通；我們對於與主管機關的進展與討論感到非常滿意。在該次會議中，主管機關未指出任何與療效相關的重大問題，並表示不打算要求召開諮詢委員會（Advisory Committee）會議。我會將這次討論形容為符合預期，且非常著眼於未來。

On the commercial bills itself, leadership is in place, and all core capabilities are where we expect it to be at this stage. We will be ready ahead of PDUFA to launch ulixacaltamide for ET patients. We're set up for a very successful launch and continue to think many years in the future, as we intend to continue to serve patients with ET and other neurological conditions.

在商業化本身方面，領導團隊已就位，所有核心能力在此階段也都達到我們的預期。我們將在 PDUFA 之前做好準備，為 ET 患者推出 ulixacaltamide。我們已為非常成功的上市做好布局，並持續以多年後的長期視角思考，因為我們打算持續服務 ET 以及其他神經系統疾病的患者。

As part of that, you should expect updates from us in the near future about life cycle opportunities for T-type calcium channel inhibitors. One of those steps is the collaboration we just announced with Remagine, which would extend the reach of ulixa further. Their work is about expanding the value for patients and practices way beyond the initial launch year.

作為其中一部分，您應可在不久的將來看到我們就 T 型鈣通道抑制劑的產品生命週期（life cycle）機會提供更新。其中一步是我們剛宣布與 Remagine 的合作，將進一步擴大 ulixa 的觸及範圍。他們的工作著重於在初次上市年度之外，為患者與醫療實務帶來更大的價值。

Turning to relutrigine. SCN2A and SCN8A are amongst the most severe epilepsies we know of, seizure onset in infancy, profound developmental delays and no approved treatments. The addressable population is roughly 10,000 patients in the United States.

接著談 relutrigine。SCN2A 與 SCN8A 是我們所知最嚴重的癲癇類型之一，常在嬰兒期發作，伴隨嚴重的發展遲緩，且目前沒有核准的治療。在美國可觸及的患者族群約為 10,000 人。

As we disclosed last quarter, we submitted additional sensitivity analysis of existing clinical data and the FDA deemed that submission a major amendment. And the review period was extended with a new PDUFA target now off December '27 this year.

如同我們在上季揭露的，我們提交了既有臨床資料的額外敏感度分析，而 FDA 將該提交認定為重大修訂（major amendment）。因此審查期間延長，新的 PDUFA 目標日為今年 12 月 27 日左右。

In the mid-cycle meeting for relutrigine, very similarly to ulixacaltamide as I just discussed, the agents also confirmed they do not intend to hold an Advisory Committee meeting. If approved, relutrigine would be the first therapy for SCN2A and 8A-DEE and would be eligible for a pediatric review voucher.

在 relutrigine 的期中會議中，與我剛才談到的 ulixacaltamide 非常類似，主管機關也確認他們不打算召開諮詢委員會會議。若獲核准，relutrigine 將成為首個用於 SCN2A 與 8A-DEE 的療法，並可符合兒科審查憑證（pediatric review voucher）的資格。

Just like for ulixa, launch preparation here is further along than the calendar might suggest. Commercial and medical teams are fully hired, the supply chain is established and have built a comprehensive patient support program, all pointing to a very structured and successful launch.

與 ulixa 一樣，這裡的上市準備進度也比日曆所顯示的更為超前。商業與醫學團隊已全數到位，供應鏈已建立，並已打造完整的患者支持計畫，這些都指向一個非常有架構且成功的上市。

The broader opportunity keeps getting clearer. Enrollment in EMERALDS, our studying broad DEEs, exceeded its target with approximately 200 patients enrolled spanning more than 50 distinct genetically defined etiology amongst many others not genetically defined.

更廣泛的機會也愈來愈清晰。我們研究廣泛性 DEE 的 EMERALDS 試驗，入組人數已超過目標，約有 200 名患者入組，涵蓋超過 50 種不同的、以基因定義的病因，並包含許多尚未以基因定義的病例。

There is a trial population that did not exist as a cohort even five years ago. Assuming the study will be positive and the initial review for relutrigine in 2A and 8A also positive, EMERALD would serve as the base for our supplemental NDA approval in 2027. It's also worth mentioning a quick regular update that expands both programs.

這是一個即使在五年前也尚未作為一個隊列（cohort）存在的試驗族群。假設研究結果為正向，且 relutrigine 在 2A 與 8A 的初次審查也同樣正向，EMERALDS 將作為我們在 2027 年提交補充 NDA（sNDA）核准的基礎。另外也值得快速提及一項例行更新，將擴展兩個計畫。

During the quarter, the [Praxis] conducted a BIMO inspection of practices as a sponsor for both ulixacaltamide and relutrigine applications.

本季期間，[Praxis] 以贊助商身分，針對 ulixacaltamide 與 relutrigine 兩項申請進行了 BIMO 稽查。

The scope was very comprehensive, including corporate and clinical operations, safety, reporting, data integrity, statistical analysis, and the interim analysis for both programs, amongst other areas of the BIMO program.

稽查範圍非常全面，涵蓋公司與臨床營運、安全性、通報、資料完整性、統計分析，以及兩個計畫的期中分析等 BIMO 計畫中的其他領域。

We are incredibly pleased that the inspections concluded without any findings and therefore no Form 483 was issued. Considering how complex both programs are with multiple studies and the first of its kind decentralized study [402] as well as the interim analysis, we are extremely pleased with the outcome of the inspections.

我們非常高興稽查在沒有任何缺失（findings）的情況下結束，因此未發出 Form 483。考量到兩個計畫都相當複雜，包含多項研究、首創的去中心化研究 [402]，以及期中分析，我們對稽查結果感到非常滿意。

One note on how it communicates from now on. Given the stage of discussions on both applications, we do not intend to provide further regulatory updates until the expected action dates. I would ask you to read our silence between now and January as discipline rather than a signal of any kind.

關於我們接下來的溝通方式補充一點。鑑於兩項申請目前的討論階段，我們不打算在預期的行動日期之前提供進一步的法規更新。我想請各位將從現在到一月之間我們的沉默解讀為紀律，而非任何形式的訊號。

Let me turn to vormatrigine. In June, we reported top-line results from POWER1. In a highly refractory focal onset seizure population. As the study did not meet its primary endpoints of reduction in monthly focal seizures frequency from baseline to week 12.

接下來談 vormatrigine。在六月，我們公布了 POWER1 的主要結果（top-line results）。該研究是在高度難治型的局灶性起始癲癇發作患者族群中進行。由於該研究未達成其主要終點，即從基線至第 12 週每月局灶性發作頻率的降低。

It did meet a key secondary endpoint with a significantly greater proportion of patients on vormatrigine achieving at least 50% reduction in seizure frequency. That result tells you something specific and you have spent the last several weeks making sure we took the right lessons from it rather than the comfortable one.

它確實達成了一項關鍵的次要終點，使用 vormatrigine 的患者中，有顯著更高比例達到癲癇發作頻率至少降低 50%。這個結果傳達了非常具體的訊息，而你們在過去幾週花了很多時間，確保我們從中汲取的是正確的教訓，而不是較令人安心、但未必正確的那一種。

The responder findings say the drug is doing something real in a population where very little works. The prime endpoint myths say our dose and a few elements of our design were not matched to the question we're asking. Those are design problems and therefore fixable.

反應者（responder）的結果顯示，這款藥物在一個幾乎沒有什麼治療有效的人群中，確實正在產生真實的作用。主要終點未達成所帶來的迷思則顯示，我們的劑量以及設計中的幾個要素，並未與我們所要回答的問題相匹配。這些是設計問題，因此是可以修正的。

We are finalizing the plans to amend and revamp both POWER2 and POWER3, informed directly by what POWER1 taught us about the dose and entry criteria, and we intend to have both studies up and running by the fourth quarter of this year.

我們正在敲定修訂並全面改造 POWER2 與 POWER3 的計畫，直接以 POWER1 在劑量與入組標準方面帶給我們的教訓為依據，並且我們打算在今年第四季讓兩項研究都重新啟動並運行。

We will further describe the amendments and impact on the design once they are final in the very near future.

一旦修訂內容定案，我們將在非常近期進一步說明這些修訂以及對研究設計的影響。

Switching gears to elsunersen. In June, the FDA granted us BTD designation for elsunersen for seizures associated with SCN2ADEE caused by gain-of-function variant based on the results of the EMBRAVE Part A study. That's our third breakthrough designation since July next last year, three designations across three different assets on two different platforms. It's basically unheard of for a company like Praxis.

接下來談 elsunersen。6 月，FDA 基於 EMBRAVE A 部分研究的結果，授予我們 elsunersen 用於由功能增強（gain-of-function）變異所致之 SCN2ADEE 相關癲癇發作的突破性療法（BTD）認定。這是自去年 7 月以來我們獲得的第三項突破性認定，三項認定涵蓋三個不同資產、兩個不同平台。對像 Praxis 這樣的公司而言，這基本上是前所未聞的。

We're taking advantage of the access to the FDA that the designation give us and discussing a comprehensive plan with the agency in the near future.

我們正善用該認定所帶來與 FDA 互動的管道，並計畫在不久的將來與主管機關討論一項全面性的方案。

Parallel to that, EMBRAVE3 continues to enroll well with top-line results expected next year. We're incredibly pleased with all the progress made in all fronts this quarter and we look forward for a successful rest of the year.

與此同時，EMBRAVE3 的收案進展仍然良好，預計明年公布主要（top-line）結果。我們對本季在各方面取得的所有進展都感到非常滿意，並期待今年剩餘時間能夠順利成功。

Let me now turn the call to our CFO, Tim Kelly. Tim.

接下來我把電話交給我們的財務長 Tim Kelly。Tim。

Thank you, Marcio, and good morning, everybody. Thank you for joining today's call, where you've heard about the good updates that we have going on. I'll provide a quick summary of our second quarter financials. In Q2, our operating expenses were $96.9 million with $69.4 million of that for R&D and the remaining $27.5 million for G&A which compares to $76 million in operating expenses for the Q2 period in 2025.

謝謝你，Marcio，各位早安。感謝各位參加今天的電話會議，你們也聽到了我們近期的一些正面更新。我將快速摘要我們第二季的財務表現。第二季，我們的營運費用為 9,690 萬美元，其中 6,940 萬美元用於研發（R&D），其餘 2,750 萬美元用於一般及行政（G&A）；相較之下，2025 年第二季的營運費用為 7,600 萬美元。

During the second quarter, Praxis spent $78 million in operating cash compared to $55 million in the second quarter of 2025, with the increase reflecting greater spend in both R&D and G&A. We expect G&A will pick up more on the second half of this year to support our planned upcoming launches. This will be driven by adding two teams at commercial field-facing headcount, rolling out disease state awareness campaigns, building sufficient inventory and ensuring solid business systems and infrastructure.

第二季期間，Praxis 的營運現金支出為 7,800 萬美元，相較於 2025 年第二季的 5,500 萬美元；增加主要反映研發與一般及行政支出均提高。我們預期今年下半年 G&A 將進一步上升，以支援我們規劃中的即將上市（launch）。這將由以下因素驅動：新增兩支面向市場的一線商業團隊人力、推動疾病狀態認知宣導活動、建立足夠庫存，以及確保穩健的商業系統與基礎設施。

We ended the second quarter with $1.4 billion in cash equivalents and marketable securities, compared to $926 million as of December 31, 2025, and we maintain that this is adequate to support our runway into 2028. With that, I will hand the call back over to Marcio.

我們在第二季末持有 14 億美元的現金及約當現金與可出售證券，相較於 2025 年 12 月 31 日的 9.26 億美元；我們仍認為這足以支撐我們的資金跑道延伸至 2028 年。接下來我把電話交回給 Marcio。

Thank you, Tim. Really appreciate it. The updates are now going to move into Q&A later.

謝謝你，Tim。非常感謝。接下來我們將在稍後進入問答環節。

(Operator Instructions)

（接線員指示）

Yasmeen Rahimi, Piper Sandler.

Yasmeen Rahimi，Piper Sandler。

Good morning, team. Congrats to an incredible update that I think was very timely and important to us, especially as some bears have been creating some noise around, [appcom]. So thank you for letting us know that you had a successful mid-cycle review along with inspection.

各位早安，團隊。恭喜帶來一個我認為非常及時且對我們很重要的更新，尤其是在一些看空者一直在針對[appcom] 製造雜音的情況下。因此，謝謝你們讓我們知道你們已成功完成期中週期審查（mid-cycle review）以及查核（inspection）。

Given now that that is behind us, maybe help us understand sort of with the sales team that is being hired for relutrigine, what is the phenotype of the sales force that you have in place? What is the size of it? And how do you see the cadence of hiring for ulixacaltamide?

既然這部分已經告一段落，能否協助我們理解一下：針對 relutrigine 正在招募的銷售團隊，你們目前配置的銷售人員輪廓（phenotype）是什麼？團隊規模多大？以及你們如何看待 ulixacaltamide 的招募節奏？

So Tim, that was really helpful, but if you could dig a little bit deeper around some of the matrix and if you also envision sort of patients have been warehoused as we're getting very close to launch early next year. I appreciate your color and congrats again.

Tim，你剛才的說明很有幫助，但如果你能再更深入談談一些指標（metrics），以及你是否也認為在我們非常接近明年初上市之際，病患可能已被「先行囤積／延後治療」（warehoused）。感謝你的補充說明，也再次恭喜。

I absolutely share the sentiment that you just expressed there, like incredibly complex programs, as we discussed on the remarks, to actually shackle the boxes collaboration with the FCA has been exceptional.

我完全同意你剛才表達的感受：這些計畫確實非常複雜；正如我們在致詞中提到的，與 FCA 的合作一直非常出色，確保把各項要求都落實到位。

The real questions we got throughout have really been, I would say, very straightforward and really very similar to what have been discussed before publicly, so we checked that box quite nicely as well. And of course, the cherry on top, it's always good to get the FDA in the house checking everything, making sure that they agree, we always knew we were doing everything correctly, but that they agree with our assessments that from data integrity, documentation, communications, procedures, safety of subjects, in the studies everything was checked there.

我們一路收到的問題，我會說其實都非常直接，而且與先前公開討論過的內容非常相似，因此這一點我們也處理得相當到位。當然，錦上添花的是，讓 FDA 到現場檢視一切、確認他們同意——我們一直都知道自己做得正確——並且他們也同意我們的評估：從資料完整性、文件、溝通、程序、受試者安全等面向，研究中的各項內容都已逐一查核。

So we turn a page to talk about what we really talked about, like talking about that. The millions and millions of Americans that are not served currently in the United States. We've been very diligent hiring a world-class sales, marketing, market access, medical, of course, at Praxis.

因此我們翻開新頁，回到我們真正想談的重點。也就是在美國目前尚未被充分服務的數以百萬計患者。在 Praxis，我們一直非常審慎地招募世界級的銷售、行銷、市場准入，以及醫療事務團隊。

And I can say this is probably an opportunity of a lifetime if you are in one of those positions to launch these drugs to transform patients' lives, but I'll hand over to Megan to discuss a little bit the phenotype and what we are seeing at the stage we are.

我可以說，如果你身處其中任何一個職位，能夠推出這些藥物、改變患者的生活，這可能是一生一次的機會；不過我先把時間交給 Megan，請她談談我們所看到的人才輪廓，以及目前所處的階段。

Thanks, Marcio. So, yeah, as Marcio is sharing, right, not unexpectedly, these are hot launches upcoming. They each represent the first targeted therapies for indications with huge unmet needs. So it's allowed us from a hiring perspective to be very selective, and we're incredibly pleased with the caliber of the talent.

謝謝，Marcio。是的，正如 Marcio 所分享的，這些即將到來的上市並不意外地都非常受矚目。它們各自代表針對重大未滿足需求適應症的首個標靶治療。因此在招募方面，我們得以非常嚴格篩選，而我們對人才的水準感到非常滿意。

So certainly from the phenotype individuals with multiple launch experience, the rare neuro space, the hunters that are going to go out and really doing a phenomenal job for us. And in the case of relutrigine, now we've got the team hired and trained, so we have the next few months to really be active in doing the account profiling, which will set us up quite well from a launch readiness perspective.

就人員輪廓而言，我們鎖定的是具備多次上市經驗、熟悉罕見神經領域、並且是能主動開拓（hunters）、真正為我們做出卓越成果的人才。以 relutrigine 來說，我們現在已完成團隊招募與訓練，因此接下來幾個月將積極進行客戶／帳戶輪廓分析（account profiling），這將讓我們在上市準備度方面打下非常好的基礎。

And then the ulixa field forest build out is well underway and also on track for where we'll be from a launch perspective.

至於 ulixa 的一線團隊建置也正在順利推進，並且就我們從上市角度所需的進度而言，一切都在軌道上。

Ritu Baral, TD Cowen.

Ritu Baral，TD Cowen。

Good morning, guys. Thanks for taking the question. Marcio, I wanted to dig down into your comment about the mid-cycle review meeting, if you'll let me. You mentioned the word forward-looking. I guess first, could you comment on if there were any surprises during the meeting, any new topics that were unexpected?

各位早安。謝謝讓我提問。Marcio，如果你不介意，我想更深入追問你對期中週期審查會議的評論。你提到了「前瞻性」（forward-looking）這個詞。首先，你能否談談會議中是否有任何意外、是否出現任何先前未預期的新議題？

And two, I guess how do you define what you're calling forward-looking? Have you been able to discuss what we spoke of previously, which is the potential inclusion of alternate titration regimens to improve the ulixa experience.

第二，你如何定義你所稱的「前瞻性」？你們是否已能討論我們先前提過的內容，也就是可能納入替代性的劑量遞增（titration）方案，以改善 ulixa 的使用體驗？

And if I could ask a quick follow-up to that last point, the ulixa experience, what aspects of commercial launch prep are you preparing to optimize that commercial experience to optimize compliance? Thanks.

如果我可以就最後一點再追問一下，關於 ulixa 的經驗，在商業化上市準備方面，你們正在準備優化哪些環節，以優化商業體驗並提升依從性？謝謝。

Yeah, absolutely. And I appreciate the vagueness of what forward-looking might be there. So I'll take that one. But it was not meant to be vague. It was really meant to be when you look into forward-looking here in the context of this application, right? So we are late stage now, approval, labeling, promotion, like making sure these patients have access. I think that that's what I meant by that in the conversation.

是的，當然。我也理解你對於其中可能涉及前瞻性陳述而採取較含糊表述的考量。所以我來回答這題。但那並不是刻意要含糊。我的意思其實是，當你在這個申請案的脈絡下談到前瞻性時，對吧？我們現在已進入後期階段：核准、標示、推廣，以及確保這些病患能夠取得治療。我在對話中所指的就是這些。

I would say, we to the conversation itself in the room, there are it's a rare like fulfilling when you are in a discussion with the FDA, at least in my view, where you actually feel very peaceful. And that's the way I would describe how I felt on that discussion, where they know for a fact that it would be incredibly transparent, like collaborations being incredibly high, and really all the elements that are necessary to make a decision have been on the table.

我會說，就會議室裡的對話本身而言，這種情況很少見——至少在我看來——當你與 FDA 討論時，竟然會覺得非常平靜，甚至有種如釋重負的感覺。那次討論我就是這樣的感受；他們非常清楚整個過程會極其透明，合作程度非常高，而且做出決策所需的所有要素都已攤在檯面上。

So on your sub question about your surprise, I would say none really. Maybe my surprise on the meeting is just how much of the discussion turns into proper use, I'm going to call operator, and by proper use is when you discuss labeling and things like that normally later in the process, all you're really trying to do is proper use, right?

所以針對你提到「是否有驚訝」的子問題，我會說其實沒有。如果要說有什麼驚訝，大概是會議中有相當多的討論都轉向了「正確使用」（我姑且稱之為操作層面），而所謂正確使用，就是在討論標示等通常在流程較後期才會談的事情；但歸根究柢，你們真正想達成的就是正確使用，對吧？

So when you're actually marching towards proper use in conversations like this, I consider exceptionally positive the discussions, the level of collaboration and integration and the understanding of the application, the depth in the graph of the discussion, the number of people in the meeting, the presence of leadership and the support from leadership, all of that, what I meant is, it is an application that matters for them as much as it matters for us, and it was good to see that overall.

因此，當在這樣的對話中實際朝向「正確使用」推進時，我認為這些討論、合作與整合的程度、對申請案的理解、討論的深度與廣度、與會人數、領導層的出席以及其支持——所有這些都非常正面。

The topic of titration did come up to your point, as completely expected, right, it's something we propose to have. And once again, I was positively surprised by how much like further along our alignment is in that regard. While I cannot and should not predict what's going to end up saying on a label, I can tell you right now unequivocally that studies a very good understanding that when patients start to ulixacaltamide, they will sometimes in about 30% of the case have like some tolerability issues that does not transfer to safety issues.

關於你提到的滴定（titration）議題，確實有被提出來，這完全在預期之內，對吧？這也是我們提案中包含的內容。而且我再次正向地感到驚喜的是，我們在這方面的共識其實已經走得更前面了。雖然我不能、也不應該預測最終標示上會怎麼寫，但我現在可以非常明確地告訴你：大家對於一點有很好的理解——病患開始使用 ulixacaltamide 時，大約在 30% 的情況下可能會出現一些耐受性問題，但這並不會轉化為安全性問題。

But if they stay on that that goes away and they have this quite phenomenal, in my view, efficacy that is just not there for any other compounds. And any reasonable person, and I think that is incredibly reasonable and certainly we believe we are, we'll look into that as an opportunity to maximize the suffering on this incredibly difficult indication by figuring out a way for patients to get there. And I think we're really close to figuring that out.

但如果他們能持續用藥，這些問題會消失，而他們會獲得我認為相當驚人的療效，這是其他任何化合物都沒有的。任何理性的人——我認為這非常合理，我們也確信我們是——都會把這視為一個機會：在這個極其困難的適應症上，透過找出讓病患能夠達到那個狀態的方法，來最大程度減輕痛苦。我想我們已經非常接近找到解法了。

How this translates to commercial, and I'm going to head back to Megan on this as well, right? You can imagine that 70% of the patients on 7 million or even 2 million or 3 million at launch, anyone would say plenty for a very, but we want every patient to have the best possible experience. And you want to make sure every patient stay on drug if they desire to and if their physicians believe they should.

至於這如何轉化到商業端，我也會把問題交回給 Megan，對吧？你可以想像，即使上市時在 700 萬、甚至 200 萬或 300 萬的病患中有 70% 能夠使用，任何人都會說這已經很多了；但我們希望每一位病患都能有最佳的體驗。而且你也希望確保每位病患在他們願意、且其醫師認為應該的情況下，能夠持續用藥。

So maybe Megan can talk a little bit about what we are doing there.

所以也許 Megan 可以談談我們在這方面正在做什麼。

Sure, thanks Marcio. So maybe just to recap again, the focus out of the gates for the launch will absolutely be on ensuring the high-quality first experience so that we build a physician confidence and ensure that we have that durable patient persistence.

好的，謝謝 Marcio。我先再簡要回顧一下：上市初期的重點絕對會放在確保高品質的首次用藥體驗，藉此建立醫師信心，並確保病患能夠長期、穩定地持續治療。

I think in the context from the provider's perspective and as we've been doing advisory boards and also engaging with the physicians, I think it starts with them setting up that first conversation with clear expectations. And what they're, as they see that you look at the caltamide data, right, the ability to tell a patient there's going to be a rapid onset of effect, right, with a meaningful change and that there might be some tolerability issues, which as we hear from the neurologists, they're very comfortable with managing the patients through that.

我認為從醫療提供者的角度來看，且我們在進行諮詢委員會（advisory boards）並與醫師互動的過程中，關鍵是由他們先進行第一次對話，並設定清楚的期待。而當他們看到 caltamide 的數據時，對吧？他們可以告訴病患療效起效很快，且會有具意義的改善；同時也可能出現一些耐受性問題——而我們從神經科醫師那裡聽到的是，他們非常有把握能協助病患度過那段期間。

In terms of some patient programs and services that we're building, Tim mentioned in his remarks, we're well underway in establishing the infrastructure we need to support this. We're basically building a hub of the future, which is fully integrated from the front end to receive the prescription all the way pulling through the channel to ensure that we have line of sight to where we are with fulfilling that first RX, but then also having certain programs and services on the SP, the pharmacy side with our integrated network to ensure that we're able to deliver the support to the patient to get them started on treatment as quick as possible and then titrate through those early weeks.

就我們正在建立的一些病患方案與服務而言，Tim 在他的發言中提到，我們正在積極建立支援所需的基礎設施。我們基本上是在打造「未來的服務中樞（hub）」，從前端接收處方開始，到透過通路推進，確保我們能掌握第一張處方（RX）的完成進度；同時也會在專科藥局（SP）與藥局端，透過我們的整合式網絡提供特定方案與服務，確保我們能向病患提供支援，讓他們盡快開始治療，並在最初幾週完成滴定。

So it's absolutely a priority for us, Ritu, and we're feeling really good about where we are with that build. And the excitement and enthusiasm from the physicians is there to get as many patients started.

所以這絕對是我們的優先事項，Ritu，而且我們對目前建置進度感到非常良好。醫師端也確實充滿期待與熱情，希望讓盡可能多的病患開始治療。

Thank you.

謝謝。

Francois Brisebois, LifeSci Capital.

Francois Brisebois，LifeSci Capital。

Hi, thanks for the question. So, just on relutrigine, I was just wondering, I think you mentioned that there's about 50 separate genetic ideologies involved here. Would you say that the study population is relatively enhanced for indications which either have a history of sensitivity to sodium channel blockers or whatnot?

嗨，謝謝讓我提問。關於 relutrigine，我想請教一下：我記得你提到這裡大約涉及 50 種不同的遺傳病因。你會說研究族群是否相對偏向（enriched）那些對鈉通道阻斷劑有敏感史或類似特徵的適應症族群？

Yeah, thanks, Franc, for that. I'll hand over to Steve to discuss a little bit.

是的，謝謝你，Franc。我把這題交給 Steve 來多談一點。

Yes, I mean, looking at the size of the trial, that spread of etiology is precisely what you would think to get when you look at the distribution of prevalence in that group of patients and the precise mix of people that we fully anticipate would be pharmacosensitive to a sodium channel mechanism is represented in that cohort.

是的，我的意思是，從試驗規模來看，那樣的病因分布正是你在檢視該病患族群盛行率分布時所預期會看到的；而我們完全預期對鈉通道作用機轉具有藥物敏感性的那一類人群，也在這個隊列中有所代表。

Okay, great. And then you mentioned at all, can you comment on the powering of EMERALD here? I think based on the study number, is there like a placebo kind of level or median percent change that you're looking for statin?

好的，很好。另外你也提到過，你能評論一下 EMERALD 的統計檢定力（powering）嗎？我想根據研究人數，你們是否有在看某種安慰劑水準或中位數百分比變化，作為要達到統計顯著的目標？

Yeah, but what was the caveat, right, I guess, that's true, like [multile] both genetically diverse and non-genetic diversity. The study has not been run so far, but there are many that we can borrow from. And when you go through that analysis, I think what we know is like there are kind of three levels here.

是的，但前提是，對吧，我想這確實是事實——像是 [multile] 同時具有遺傳多樣性與非遺傳多樣性。這個研究本身尚未完成，但我們可以借鑑許多既有研究。而當你做完那些分析後，我認為我們知道大致可以分成三個層次。

So the first, when you look into the overall response, and let's define whatever 50% that benchmark is very clear. It's very small for placebo. Of course, these patients are so severe. I'll give you a number.

第一個層次是看整體反應率，我們把 50% 反應這個基準定義得很清楚。安慰劑的反應非常低。當然，這些病患的病情非常嚴重。我給你一個數字。

The median baseline countable seizures in EMRALDS is over 50 for 28 days. So imagine that kind of burden and just how little it is, the possibility that these patients are going to naturally regress.

EMRALDS 中位數的基線可計數癲癇發作次數，在 28 天內超過 50 次。所以你可以想像那樣的負擔，以及這些病患自然回歸（regress）的可能性有多低。

But the second is, as we move upwards the latter, like 75% response, 90% response, those numbers become like very ridiculously small for placebo. So as we are looking into the distribution, it was very simple, I would say, to model from a power perspective.

但第二點是，當我們往上看後段，例如 75% 反應、90% 反應時，對安慰劑而言，那些數字會變得非常、非常小，幾乎小到不合理。因此當我們檢視分佈時，從統計效能（power）的角度來建模，我會說是非常簡單的。

And I would say very straightforward, the expectations, as you can imagine, as you heard from me before you hear from Steve now, we're very pleased not only with the a priori powering, but quite importantly, the a posteriori mix of patients that are pharmacosensitive to the mechanism. So stay tuned. Soon to come up the results, but I think we should be as bullish as we are on what we're going to see on the other ends.

而且我會說非常直接的是，如你所想像、也如你先前聽我提過、在你現在聽 Steve 之前，我們不僅對事前（a priori）的效能設計很滿意，更重要的是，對事後（a posteriori）在病患組成上、對該機轉具藥理敏感性的混合比例也相當滿意。所以敬請期待。結果很快就會出來，但我認為我們應該像現在一樣看多我們將在另一端看到的結果。

Great. Thank you very much.

很好。非常感謝。

Kevin Strang of Goldman & Sachs.

高盛（Goldman & Sachs）的 Kevin Strang。

Good morning. I wanted to ask for vormatrigine, you alluded to the design being more important versus the drug itself. Do you mind walking us through sort of some of the specific learnings from Power1 on dose for design that gave you confidence to restart the program?

早安。我想就 vormatrigine 提問，你們提到相較於藥物本身，試驗設計更重要。方便帶我們走一遍 Power1 在「劑量與設計」方面的一些具體學習點，讓你們有信心重啟這個計畫嗎？

Yeah, absolutely. So we're going to reserve it, and I hope you don't see this as hedging because it's not, since we're going to be discussing this a little bit more in the future. But a couple of things that as we look into in a very detailed and at the same time keeping ourselves from seeing things that are not there, but really disciplined approach to what we're going to do next, right?

好的，當然。我們會先保留一些細節，我希望你不要把這視為打太極，因為不是；只是我們未來會再更深入討論。但有幾點是：我們在非常細緻地檢視的同時，也避免看到其實不存在的訊號；而是以非常自律的方式來決定下一步要做什麼，對吧？

Looking about the value right now at least external value for the company vormatrigine for fifth of the value is on the ulixa and relutrigine. So of course, there's a huge potential for upside and we here to residual value for vormatrigine. But we really wants to measure that's one of the reasons why we're not focused today call on format Those clearly play the role.

就目前來看，至少從外部對公司價值的評估，vormatrigine 的價值大概只占 ulixa 與 relutrigine 的五分之一。所以當然，vormatrigine 的剩餘價值有很大的上行潛力。但我們確實想要量化衡量；這也是我們今天不把重點放在 vormatrigine 的原因之一——那些因素顯然都扮演了角色。

Duration added those clear play a role, sometimes say those, it looks like it was only the 20 or the 30, but actually six weeks and six weeks play a role and I would say a pretty significant role on that.

治療期間（duration）也很關鍵；那些因素顯然都扮演了角色。有時候看起來好像只是 20 或 30（的劑量），但其實是六週、而且六週本身就扮演了角色；我會說影響相當顯著。

I think a few other things that are going to be hearing further, including might be number of failures that was extremely high to prior medications that could be tightened up and a few things here and there. But every single parameter, maybe that's the method I'm going to deal with, that we're looking into are very easy to adjust and to fix.

我想還有幾件事之後你們會聽到，包括先前用藥失敗的次數高得異常，這部分可以收緊（納入條件），以及其他零星幾點。但我們正在檢視的每一個參數——也許這就是我處理方式——都非常容易調整與修正。

And then once we do, without overstretching without drinking the [Kool-Aid], without seeing things are not supposed to be seen there. The effects on the other side for Power2 and of course event to the Power3 are X or higher than what I would expect for this drug on those populations.

然後一旦我們做到這些，在不過度延伸、不中「Kool-Aid」的迷思、也不去看那些不該被看見的東西的前提下，Power2 另一端的效果，當然還包括最終到 Power3 的效果，會是我對這個藥在那些族群中所預期的 X 倍或更高。

So great way to look into this. We're finalizing a few things internally and with our key advisors. I'm going to see an update, a fulsome update about that in the near future and restarting of this study.

所以這是一個很好的切入方式。我們正在內部以及與關鍵顧問一起把幾件事定案。不久的將來你會看到一個完整更新，包括這項研究的重啟。

Thiago Fauth, Raymond James.

Raymond James 的 Thiago Fauth。

Great. Thanks for taking the question. Just on EMERALD, right? So, for [Dervay], conditional certain channel blockers are counter-indicated. Sometimes it can make features worse, yet you had really strong clinical data in Dervay models, right? So what does that example tell you about the mechanism relative to conditional certain channel blockers?

很好。謝謝讓我提問。就 EMERALD 而言，對於 [Dervay]，某些鈉通道阻斷劑是禁忌（counter-indicated）的。有時甚至會讓症狀特徵更糟，但你們在 Dervay 模型中卻有非常強的臨床數據，對吧？那這個例子對於你們的機轉、相對於某些鈉通道阻斷劑，代表什麼？

And what does that imply about the potential to work across other DEEs? We've been getting a lot of questions on the enrichment criteria that you have on fission burden DNF to offset some of the unknowns or risks from non-ion channel DEEs that can be in the mix of EMERALD. So how should we think about that overall?

而這又意味著在其他 DEE 上的跨適應症潛力如何？我們收到很多關於你們在 EMERALD 中使用的富集（enrichment）標準的問題：以發作負荷（seizure burden）與 DNF 來抵消一些來自非離子通道型 DEE 可能混入所帶來的未知或風險。所以整體上我們應該怎麼看？

Yeah, absolutely. I'll start where I'm going to hand over to you to see if you're Tiago. The first is, I find a little ironic, I'm going to say to be the classical me in calls like this, that no one asks about how many serotonergic mutations are when this is being discussed, the serotonergic one, but it's very easy to say certain channels for us. So maybe one must revisit their own understanding of neurobiology. But having said that, I'll hand over to the person who really knows neurobiology here. That's not me. That's Steve.

好的，當然。我先說，然後再交給你看看，Tiago。第一點是，我覺得有點諷刺——我會用我在這類電話會議一貫的風格來說——當大家在討論這件事時，沒有人問有多少是血清素相關（serotonergic）的突變；明明這是血清素相關的，但對我們來說卻很容易就被說成是某些通道。所以也許有人需要重新檢視自己對神經生物學的理解。不過話說回來，我把問題交給這裡真正懂神經生物學的人。那不是我。是 Steve。

Thanks, Marcio. I think when you look at the role of sodium channels in determining the behavior of neurons normally and in epilepsy, clearly they are the gatekeepers of excitability in a neuron. And because of that role. If the sodium channels themselves are altered in their behavior as a result of mutations, as we saw in the EMBOLD study, they are a clear target.

謝謝，Marcio。我想當你看鈉通道在正常情況以及癲癇中決定神經元行為的角色時，很明顯它們是神經元興奮性的守門員。而正因為這個角色，如果鈉通道本身因突變而改變其行為——就像我們在 EMBOLD 研究中看到的——它們就是非常明確的標的。

But beyond that, they are also the most downstream element in the etiology of other disorders that result in DEEs, whether it's other genetic mutations or acquired conditions. Because of that very unique role, they are also targets where a lot of the physiology conversion.

但除此之外，它們也是其他導致 DEE 的疾病病因學中最下游的元素，無論是其他基因突變或後天獲得的狀況。因為這個非常獨特的角色，它們同時也是許多生理訊號匯流（conversion）的標的。

So we've got a lot of confidence that it doesn't really matter what the etiology is. Even in the cases of loss of function, and there's always a lot of chatter about that, clearly, even though we've lost sodium channel function as the primary mutation, we still have excitability issues. And the way to control excitability is through modulation of sodium channels. When these loss of function mutations occur, that can result in the upregulation of other elements in the neuron.

因此我們很有信心：病因其實不太重要。即便是在功能喪失（loss of function）的案例——大家對這點總有很多討論——很明顯，即使主要突變造成鈉通道功能喪失，我們仍然會有興奮性問題。而控制興奮性的方式，就是透過調節鈉通道。當這些功能喪失突變發生時，可能會導致神經元內其他元素的上調（upregulation）。

So we're confident that our preclinical data shows that the initial, and this is all because sodium channels are concentrated in a very specific part of the neuron where the axon emerges called the axon initial segment. It's a pretty much crystalline structure of sodium channels and other elements.

所以我們有信心，我們的臨床前數據顯示，最初的——而這一切都因為鈉通道集中在神經元一個非常特定的部位，也就是軸突長出的地方，稱為軸突初始段（axon initial segment）。那裡幾乎是一種晶體般的結構，由鈉通道與其他元素組成。

And that is the little part of the neuron that decides, from my experience, from everything that's upstream. What am I going to do? How am I going to respond to that input? And we know that that program is modulated a lot by sodium channel modulation.

而那個神經元的小區域，依我的經驗、從所有上游訊號來看，會決定：我要做什麼？我要如何回應那些輸入？而我們知道，這個程式在很大程度上會被鈉通道調節所影響。

And one other thing I wanted to say about sodium channels is the manner in which the sodium channel modulator interacts with the actual sodium channels themselves is very important. And we know, we've talked about this a lot, that the mechanism of action and the profile of relutrigine distinguishes from any other agent in the market now. And that was the initial therapeutic hypothesis we started with relutrigine, and we are following that through the trials right now.

另外我還想補充一點：鈉通道調節劑與實際鈉通道本身互動的方式非常重要。而我們也知道——我們談過很多次——relutrigine 的作用機轉與特徵曲線（profile）有別於目前市面上的任何其他藥物。這就是我們一開始以 relutrigine 提出的治療假說，而我們現在也正透過臨床試驗一路驗證下去。

Douglas Tsao, HC Wainwright.

Douglas Tsao，HC Wainwright。

Hi, good morning. Thanks for taking the questions and congrats on the progress. I guess, Marcio, I just want to maybe start with vormatrigine for a minute because it was interesting that you sort of are going to be restarting both POWER2 as well as POWER3. I'm just curious, do you think that those two studies would be enough to support a potential filing, just given the fact that they are going to be very different studies in terms of their design and what they're trying to demonstrate. Thank you.

嗨，早安。感謝讓我提問，也恭喜你們的進展。我想，Marcio，我想先花一分鐘談談 vormatrigine，因為很有意思的是，你們似乎將同時重新啟動 POWER2 以及 POWER3。我只是好奇，你認為這兩項研究是否足以支持潛在的申報？畢竟它們在設計以及試圖證明的內容上會是非常不同的研究。謝謝。

No, thanks, Doug. Yeah, we do. That's maybe the short answer to that there are steps between now and then to have conversations with the agency and to discuss exactly which label potentially that would result. But the bottom line is both from a historical perspective and most importantly, from a policy perspective, as it thumbs up right now. And even considering like the progressive nature of the division that all epilepsy falls within right now as just restructured a couple of weeks ago, I think we feel incredibly bullish about it, but to be seen.

不，謝謝你，Doug。是的，我們認為可以。這也許是簡短的回答；在那之前還有一些步驟，需要與主管機關對話，並討論最終可能對應到的標示（label）會是什麼。但重點是，無論從歷史角度，或更重要的政策角度來看，目前看起來都是正向的。即便考量到癲癇所屬的部門就在幾週前剛完成重組、而且整體趨勢更為進步，我們仍然對此非常看多，但仍有待觀察。

Okay, and if I can ask a follow-up in terms of relutrigine, I'm just curious because obviously that program, or in particular with EMERALD, is enrolling and there's obviously the [befacazarin] program ongoing as well. And I'm just curious if you have heard any feedback in terms from clinicians if there's any kind of sort of pattern in terms of what types of patients they're referring to each particular study?

好的，那我追問一下 relutrigine。我只是好奇，因為很明顯該計畫——特別是 EMERALD——正在收案，另外 [befacazarin] 的計畫也在進行中。我想了解你們是否從臨床醫師那邊聽到任何回饋：在把病人轉介到各個研究時，是否存在某種模式，像是哪些類型的病人會被轉介到哪一個特定研究？

Meaning, is there any kind of sort of subconscious enrichment perhaps ongoing in terms of picking a study in which they think a patient might be best to respond to, just given the different MOAs of the drugs?

我的意思是，是否可能存在某種下意識的富集（enrichment）——也就是在選擇研究時，基於藥物不同的作用機轉（MOA），他們會挑選他們認為病人最可能有反應的那個研究？

Thank you.

謝謝。

I got it. And I would say we always have to take with a grain of salt anecdotal conversations we have with one or two physicians here and there. But it is not unexpected, right, that you would say, oh, now, like, let's say we will start with serotonergics here. There are drugs approved, there are a lot of stuff that's being done on that space, hand-to-hand combat with multiple drugs for Dravet and LGS.

了解。我會說，我們和一兩位醫師零星的軼事性對話，永遠都要保留一些解讀空間。但這並不令人意外，對吧？例如你會說，喔，現在——比方說我們先從血清素能（serotonergics）開始。這個領域已有核准藥物，也有很多事情正在進行，在 Dravet 與 LGS 上有多個藥物正面競爭。

Yeah, if we're going to try another drug, let's try on the ones that I would humbly say. That, yes, that's maybe okay for trial execution. It's a terrible strategy once you get to the markets, but I'll leave it there. I think likewise for us, the EMERALD White, as we said, like about 200 patients finished randomization like a while back.

是的，如果我們要再試另一個藥，我會謙虛地說，就先試那些——這對試驗執行也許還可以。但一旦進到市場，這會是很糟的策略；我就先點到為止。同樣地，對我們而言，EMERALD White 如我們所說，大約 200 名病人在一段時間前就已完成隨機分派。

And it is kind of obvious by what Steve just mentioned that when you look into the final mix, either by chance or not, that this seems to be some of the most potentially active on this mechanism historically. So whether or not there was a conscious or unconscious kind of segmentation when there were sites that were enrolled in both studies, it happens naturally.

而且從 Steve 剛提到的內容來看也很明顯：當你看最終的組成，不論是巧合與否，這看起來是歷史上在這個機轉上可能最具活性的族群之一。因此，當有些中心同時參與兩項研究時，是否存在有意或無意的分流/區隔，這種情況自然就會發生。

You fast forward a few years from now, both mechanisms work, right? I think we know that. And on a market with like anywhere between 2 and 400,000 patients, the discussion is bringing on 10 other mechanisms, right?

把時間快轉到幾年後，兩種機轉都會有效，對吧？我想我們知道這點。而在一個大約 20 萬到 40 萬名病人的市場裡，討論的重點是再引入另外 10 種機轉，對吧？

Like this is number one, should be a dream for anyone on this space. It's an ability to help incredibly sick kids and young adults to control seizures. And any one of us that thinks that one mechanism is going to do this should be institutionalized. So I think it is more than reasonable to expect that multiple mechanisms are going to be not -- I keep going back to the same thematic. You heard me saying this a thousand times. I'm going to do a thousand and one.

就像，這應該是這個領域任何人夢寐以求的第一要務。我們有能力幫助病情非常嚴重的孩子與年輕成人控制癲癇發作。任何一個人若認為單一機轉就能做到這一切，那應該被送去機構收治。所以我認為，合理的期待是多種機轉將會——我又回到同一個主題。你們已經聽我說過一千次了。我現在要說第一千零一次。

The zero-sum game idea in GEs and epilepsy is purely serving to people who don't want patients to get drugs has nothing to do with either drug development or market potential. So if anything else I'm going to say, I'm going to be cheering every day for [LUMBAC] to be incredibly successful, just like you're going to be, so we all can help patients with these conditions.

在廣泛性癲癇（GEs）與癲癇領域，「零和遊戲」的想法純粹是在服務那些不希望病人拿到藥的人，與藥物開發或市場潛力毫無關係。所以如果我還要再說什麼，我每天都會為 [LUMBAC] 的巨大成功而喝采，就像你們也會一樣，這樣我們才能一起幫助這些病人。

Andrew Tsai, Jefferies.

Andrew Tsai，Jefferies。

Hey, team. Good morning. Thanks for all the great sight of updates. Back to essential tremor, there really, to me at least, seems to be a chance maybe ET could be approved earlier. Than expected, especially if this mid cycle review is done, inspections are done. Is it the right thinking that you will be entering final labeling discussion soon? Or if not, can you just remind us what the key steps generally are from here?

嗨，各位團隊。早安。謝謝提供這些很棒的最新進展。回到原發性顫抖（essential tremor），至少對我來說，似乎真的有機會讓 ET 比預期更早獲批。尤其如果這次期中審查（mid-cycle review）完成、查廠（inspections）也完成的話。我的理解是否正確：你們很快就會進入最終標示（final labeling）的討論？或者如果不是的話，你們能否提醒我們，從現在到那時一般有哪些關鍵步驟？

And then how prepared would you guys be to launch in Q4 if there was an early approval? Thank you. I appreciate you might not be able to share too much, but just thought I'd ask. Thank you.

另外，如果真的提前核准，你們在第四季（Q4）上市的準備程度會如何？謝謝。我知道你們可能不能分享太多，但我還是想問問。謝謝。

I appreciate it. So the next formal steps here are the quick late cycle discussion. I'll tell you that's in the books. Labor negotiations, that's in the books. So the reason why we mentioned my preferred remarks is that we're not going to be giving updates because you can imagine that this discussion as we move forward is very dynamic, right? So there's a lot of back and forth. There's a lot of really cool discussions there.

謝謝。所以接下來的正式步驟是快速的期末週期討論（late-cycle discussion）。我可以告訴你，那已經排進行程了。勞資協商（labor negotiations）也已經排進行程了。我們之所以在我準備的發言中提到，是因為你可以想像，隨著我們往前推進，這些討論非常動態，對吧？所以會有很多來回。也會有很多非常有意思的討論。

We set the goal to be ready for launch way ahead of the PDUFA for multiple reasons. One, it's the right thing to do. Two, thanks to a lot of you listening to this call, we have the capital to do it. Three, I would challenge absolutely everyone in this call to name one market with millions of Americans. That don't have a treatment right now that are getting every single day requests from physicians and patients to when is this drug going to be available.

我們設定的目標是要在 PDUFA 之前很早就把上市準備做好，原因有好幾個。第一，這是正確的事。第二，感謝今天收聽電話會議的許多各位，我們有資本可以做到。第三，我想請在座每一位說出一個市場：有數以百萬計的美國人，現在沒有治療選項，且每天都收到醫師與病人詢問「這個藥什麼時候能用」。（這樣的市場）

So it's just a responsible thing to do. So, we'll be ready. We are basically ready, and we're going to continue to be ready to maximize in the case of the great fortune that the agents finished the review earlier, and we are blessed with that approval earlier than the PDUFA.

所以這就是一件負責任該做的事。因此，我們會準備好。我們基本上已經準備好了，而且我們會持續保持準備狀態，以便在非常幸運的情況下，若主管機關提前完成審查、我們也因此在 PDUFA 之前更早獲得核准時，能把效益最大化。

Thank you. Fingers crossed. Thank you.

謝謝。祈禱一切順利。謝謝。

Yatin Suneja, Guggenheim.

Yatin Suneja，Guggenheim。

Hey guys, thank you for taking my questions and again, excellent updates today. So just staying with the essential summer, could you maybe talk a little bit about the payer work you have done? I see you in the past have talked about pricing, love to get the feedback that you are hearing from the payer perspective.

嗨，各位，謝謝回答我的問題，也再次恭喜今天的更新非常出色。那我就繼續談原發性顫抖（essential tremor），你們能否談談你們已經做過的支付方（payer）工作？我看到你們過去談過定價，也很想聽聽你們從支付方角度收到的回饋。

And in terms of the step at it, how should we think about it? I mean, most people are on generic stuff, so they should not pretty much love to sort of understand all of those dynamics. And in terms of the commercial build out, could you maybe outline for us when is that plan in terms of, how big of the sales force you would need, all of that stuff? Thank you so much.

那麼就加階治療（step at it）而言，我們應該如何看待？我的意思是，多數人都在使用學名藥，所以他們大概不太會想去理解所有那些動態。另外就商業化建置而言，您是否可以為我們概述一下該計畫的時程、需要多大規模的銷售團隊，以及所有相關事項？非常感謝。

Yeah, absolutely. And so from a payer perspective, very active, so we did a lot of pre-work to shape like our general understanding, of course, that is a lot of analytical work that can be done with that benchmarking work, and we moved on the last several weeks to a different phase where both proactively we want to talk to some of those plan administrators, but I would say the latest wave is that they want to talk to us.

是的，當然可以。因此從付款方（payer）的角度來看，我們非常積極；我們做了大量前期工作來形塑我們的一般理解，當然其中包含很多可透過基準比較（benchmarking）完成的分析工作。過去幾週我們進入了不同階段：一方面我們主動想與部分計畫管理者（plan administrators）交流，但我想最新一波是他們也想跟我們談。

And I would say there was a lot of those interactions. I would even argue I was positively surprised with one. They are understanding that absolutely there's a need here and that they're not going to put a lot of stuff, not a lot of blocks in the way.

而且我會說這類互動很多。我甚至可以說其中有一次讓我正向地感到驚喜。他們理解這裡確實有需求，而且他們不會設置太多障礙、不會在路上放太多阻礙。

The second is just like they want to be right at day one, just like we want to be right at day one. So that's good news. Our planning assumptions includes step-addits through ProPanel. Not at all, by the way, what we're hearing across the board is going to happen. It's just a prudent thing to do, or look into this.

第二點是，他們希望從第一天就把事情做對，就像我們也希望從第一天就做對一樣。所以這是好消息。我們的規劃假設包含透過 ProPanel 的加階治療（step-addits）。不過順帶一提，我們從各方聽到的並不是一定會發生這種情況。這只是審慎起見，或是值得納入評估的一件事。

Now, we know what we did extensive work here from a medical perspective and claims and so on that a lot of these patients, they're just super adicardial or something else that it prevents them from ever going into a beta blocker. So about half of the market cannot magically take ProPanel.

現在，我們從醫療端、理賠（claims）等方面做了大量工作後知道，許多這類病患有非常嚴重的心動過緩（bradycardia）或其他狀況，使他們根本無法使用 β 阻斷劑。因此大約有一半的市場不可能憑空就能服用 ProPanel。

One can call that low-hanging fruits, but I guess you call a million patients low-hanging fruits a little bit oxymoronic, so I'm not going to do that. So that is a very clear part of the market. I think the other parts, they just had exposed to that. I'll remind everyone on the stratified predefined use of ProPanel on the Essential3 study showing that on top of ProPanel, ulixacaltamide is incredibly efficacious, right?

有人可能會稱之為「低垂的果實」，但我想把一百萬名病患稱為低垂的果實有點自相矛盾，所以我不會這麼說。因此那是一個非常明確的市場區隔。我認為其他部分則是他們只是曾經接觸過那個治療。我也提醒大家，在 Essential3 研究中，依預先分層（stratified）且預先定義的 ProPanel 使用情境顯示：在 ProPanel 基礎上加用 ulixacaltamide 的療效非常顯著，對吧？

And so there is really no restrictions here one way or another. And welcome, do we believe that in the long run that's going to be needed to stay on both? No, but that's a belief.

因此在這裡並沒有任何單向或雙向的限制。而且我們也歡迎；我們是否相信長期而言需要同時維持兩者治療？不，但那是一種信念（看法）。

We welcome all the patients that they want to hear and physicians are incredibly excited about hearing that, which is normally what payers actually want to hear. So a lot of work has been done on the payer space. I know you asked about pricing. I think the more we talk to payers, the more we realize that our initial pricing assumptions are very well, I would say, grounded.

我們歡迎所有病患的需求，而醫師對於聽到這些也非常興奮；而這通常正是付款方其實也想聽到的。所以在付款方領域已經做了大量工作。我知道你問到定價。我認為我們與付款方談得越多，就越發現我們最初的定價假設非常——我會說——有根據。

We talked about a little bit over maybe $50,000 to $100,000 per year. There was a lot, as from clients of yours and from people we talked to, a little bit of pushback and you have to go that high. I think right now, while we're not going to disclose the price specifically, I think we're actually very confident that that's the right range to operate in general.

我們曾提到每年大約略高於 50,000 美元到 100,000 美元。從你們的一些客戶以及我們交流過的人那裡，曾有不少反饋，認為你們不必定到那麼高。我想目前雖然我們不會具體披露價格，但我們其實非常有信心，整體而言那就是合適的操作區間。

Kambiz Yazdi, US Bancorp, BTIG.

Kambiz Yazdi，美國合眾銀行（US Bancorp），BTIG。

Thank you for the question. How are you thinking about the relutrigine efficacy in EMERALD relative to what was observed and involved? From a biological level, how should we think about relutrigine performance in broader DEEs compared to the SDN2A and 8A population? Thank you.

謝謝讓我提問。你們如何看待 relutrigine 在 EMERALD 中的療效，相較於先前觀察到以及所涉及（involved）的結果？從生物學層面，我們應該如何看待 relutrigine 在更廣泛的 DEE（發育性與癲癇性腦病）中的表現，相較於 SDN2A 與 8A 族群？謝謝。

Yeah, so thanks, Kambiz. Good to hear from you. I would start with what is necessary and then what is possible. And I think those are two completely different things here, right? I mentioned earlier in the call on the background of seizure burden for these patients, right?

好的，謝謝你，Kambiz。很高興聽到你的聲音。我會先從「必要」與「可能」來談。我認為這兩者在這裡是完全不同的概念，對吧？我在電話會議前面提過這些病患的癲癇發作負擔背景，對吧？

Like it is absolutely insane. I cannot even imagine as a parent to have to deal with something like that. These patients tried and these parents tried everything they could possibly imagine on those. So logically, no matter what it wants to believe, reducing consistently a part of those seizures and therefore statistical significance when you think about a study, that should be a bar, right?

那真的是極其嚴重。我甚至無法想像身為父母要如何面對那樣的情況。這些病患以及他們的父母，已經嘗試了他們所能想到的一切方法。所以從邏輯上講，不管你願意相信什麼，若能持續降低其中一部分發作，並因此在研究中達到統計顯著性，那應該就是一個門檻，對吧？

So the bar here is significance on this study. But of course, we want to go above much higher than the bar, right? So bar for success, no doubt whatsoever physicians, patients are saying help me control a little bit better. Let me give a little bit more hours without being on top of these kids nonstop, afraid of complications to that, you name it. And that would be a big win.

因此這項研究的門檻是達到顯著性。但當然，我們希望遠遠高於這個門檻，對吧？毫無疑問，成功的門檻是：醫師與病患都在說，請幫我把控制做得更好一點。讓我能多一些小時不用一直守在孩子身邊、時時刻刻擔心併發症等等，你能想到的都有。那就會是很大的勝利。

Biologically, though, by what Stephen just discussed, there are reasons to believe that it could be similar, if not better, than what he was saying. I think it's hard to imagine, right, being better than both, but we need to stay true to the science and to what you're seeing so far. We're going to talk a lot more about this in the near future as well, but again, going to have to stay true to what is possible. Not necessary, but I will love nothing more than help these patients to an extreme.

但從生物學角度來看，依 Stephen 剛才討論的內容，有理由相信結果可能相近，甚至可能更好。我想很難想像會比兩者都更好，但我們必須忠於科學，也忠於目前看到的資料。我們在不久的將來也會就此談更多，但同樣地，我們必須忠於「可能」的範圍。不是「必要」，但我最希望的莫過於能在很大程度上幫助這些病患。

Jay Olson, Oppenheimer.

Jay Olson，Oppenheimer。

Oh, hey, congrats on all the progress and thanks for taking our questions. We have another relutrigine question and just wanted to follow-up on something that you've commented on in the past, Marcio, that you've seen in the pooled mask data from EMERALD that you've observed dynamics are profoundly different from what a meta-analysis of the stored DEE placebo groups could accommodate.

嗨，恭喜你們取得所有進展，也謝謝回答我們的問題。我們還有一個關於 relutrigine 的問題，想追問你過去曾評論過的一點，Marcio：你在 EMERALD 的合併盲態（pooled mask）資料中觀察到的動態，與對既有 DEE 安慰劑組所做的統合分析（meta-analysis）所能解釋的情況有顯著不同。

Can you talk about the most important factor behind this observation, and how would you compare the information in proportion of patients with a 50% reduction versus 75% reduction versus 100% freedom from seizures? Thank you.

你能談談造成這項觀察背後最重要的因素是什麼嗎？另外，你會如何比較不同資訊：病患中達到 50% 減少、75% 減少，以及 100% 無發作（seizure freedom）的比例？謝謝。

Yeah, no, thank you very much. I think that's all those parameters you mentioned, right? These continuous of response, 50%, 70%, 75%, 90%, 95%, whatever you want, 100% are incredibly important. And we've been tracking and we've been, I would say, quite pleased about the entire distribution. Maybe one point here that we haven't discussed as much.

好的，非常感謝。我認為你提到的那些參數都很重要，對吧？這些連續性的反應指標——50%、70%、75%、90%、95%，不管你要哪個，乃至 100%——都極其重要。我們一直在追蹤，而且我會說，我們對整體分布相當滿意。這裡也許有一點我們還沒有談那麼多。

It is quite interesting as well to see what happens when they transition to the open label. And studies have been going on for a bit and we enrolled relatively fast. So there is a very large proportion of patients that have multiple moms now in the open label.

同樣也很有意思的是，觀察他們轉入開放標籤（open label）後會發生什麼。研究已進行了一段時間，而我們的入組相對快速。因此有相當大比例的病患現在在開放標籤階段已經有多個月（multiple months）的資料。

So when you put all of that together, the initial response of the double blinds, the information we are able to get from the open label, I would say. They depart a lot from what historical expectations would be. And hey, who here hasn't been burned by applying the data, right, for the first rock.

所以把這些全部綜合起來，雙盲試驗的初步反應、以及我們能從開放標籤中取得的資訊，我會這麼說。它們與歷史上的預期相差很大。而且，嘿，這裡有誰沒有因為套用數據而吃過虧呢，對吧，第一次就踩雷。

So I'm not saying this is like completely proof of any possibilities of not being misread, but it is just very hard to believe that we was reinstating correctly considering how severe this disease is and how high the seizure burden is. So very happy across the boards, but we're going to stay vigilant until the end of the study.

所以我不是說這就完全證明了任何「不會被誤讀」的可能性，但考量到這個疾病有多嚴重、癲癇發作負擔有多高，要相信我們其實是在正確地「回復」是非常困難的。所以整體來說我們非常高興，但在研究結束前我們會保持警覺。

Super helpful. Thank you.

非常有幫助。謝謝。

Ami Fadia, Needham & Company.

Ami Fadia，Needham & Company。

Hi, good afternoon. Thank you for taking my question and congrats on all the positive updates this morning. I had one question on ulixa and one follow-up on EMERALD. As you think about the uptake of ulixa, can you talk about the mix of patients that you expect across maybe the commercial Medicare, Medicaid setting? And where do you see the initial patients coming from? Is it sort of all the patients that have been sort of, suffering with ET for a very long time or do you also expect younger patients to start to take ulixa earlier in the launch?

嗨，下午好。謝謝你回答我的問題，也恭喜今天早上所有正面的更新。我有一個關於 ulixa 的問題，以及一個關於 EMERALD 的追問。在你們思考 ulixa 的採用/滲透時，能否談談你們預期的病患組合，可能涵蓋商業保險、Medicare、Medicaid 等不同情境？以及你們認為初期病患會從哪裡來？是那些已經長期受 ET 困擾的病患為主，還是你們也預期較年輕的病患會在上市初期就更早開始使用 ulixa？

And then with regards to the EMERALD study, across the 50 etiologies that you talked about, from a mechanistic perspective, is there a reason to believe that the response rates would be similar or could it be varied across the different etiologies. Thank you.

另外，關於 EMERALD 研究，在你提到的 50 種病因之間，從機轉角度來看，有理由相信反應率會相近嗎？還是可能會因不同病因而有所差異？謝謝。

Yeah, no, absolutely. I mean, so forth, this launch is going to likely have like several states. If you look into the -- I believe we've been quite responsible defining the addressable population at the time of launch around 2 million patients.

是的，當然。我的意思是，這次上市很可能會有好幾個階段。如果你看——我相信我們在上市時對可觸及族群的界定相當審慎，大約是 200 萬名病患。

And that is mostly, I would say, three-quarters or so of those patients would be the medicaid, medicare advantage, like arguably is likely older patients there. Maybe the phenomena that we are seeing more and more is the family members, right?

而其中大多數，我會說大約四分之三的病患會是 Medicaid、Medicare Advantage 這類，某種程度上可能是年紀較大的病患。我們看到越來越多的一個現象是家屬，對吧？

The interests of those patients. And so, I would say for the Phase II, very likely we're going to see is like a migration continue to increase these patients on the 65 plus. That was a lot of the 40s to 65 patients there. Of course, there's a different Bayer mix. There's different dynamic on those patients. Maybe the parts we don't talk as much about.

這些病患的需求/關注。所以我會說，在第二期（Phase II）方面，我們很可能會看到一個持續的移動趨勢：65 歲以上的病患占比會繼續提高。那邊有很多是 40 多歲到 65 歲的病患。當然，保險支付方（payer）的組合不同。這些病患的動態也不同。也許有些部分我們談得沒那麼多。

We kept this number static, but it's not static, right? The population demographics in the United States, and globally, but particularly in the United States, is shifting quite a lot. And when you're looking to the prevalence of essential tremor in the overall population, it's a little bit about like 2%, 2.5%.

我們把這個數字維持不變，但它其實不是靜態的，對吧？美國的人口結構，以及全球的人口結構——但特別是美國——正在相當明顯地改變。而當你看原發性顫抖（essential tremor）在整體人口中的盛行率，大約是 2% 到 2.5%。

When you get to 60s, that is about 2.5 times the overall prevalence and then about every 10 years after that, it doubles. So we haven't discussed, but we're going to hear discussing a lot more exactly the completely organic growth of these markets that is about double-digit and we just don't have drug launch on multi-million patient markets growing organically as a market, the positions are moving forward. So that changed a little bit the mix.

到了 60 多歲時，大約是整體盛行率的 2.5 倍，之後大概每過 10 年就會再翻倍。所以我們之前沒有談到，但接下來會談得更多：這些市場完全由人口結構帶來的自然成長，大約是雙位數，而我們很少看到在數百萬病患規模的市場中，市場本身還能以自然方式成長，且滲透率持續往前推進。所以這會讓病患組合有些改變。

I know you had an EMERALD question there as well. The efficacy across the etiologist? Oh, the efficacy across the etiologist. Thanks, Tim. Of course, it's not going to be the same. I think it would be actually, I think my math teacher would tell me would remove my diplomas if I say it's going to be the same on an heterogeneous population. But we do expect that it would be consistently positive. And I think that that's what we should be expecting at this point in time.

我知道你也有一個 EMERALD 的問題。不同病因之間的療效？喔，不同病因之間的療效。謝謝，Tim。當然，不會是一樣的。我想如果我說在異質族群中會完全一樣，我的數學老師大概會把我的文憑收回去。但我們確實預期它會呈現一致的正向結果。我認為在這個時間點，我們應該期待的就是這樣。

Brian Skorney, Baird.

Brian Skorney，Baird。

Hey, good morning, guys. Thanks for taking the question. Maybe if I could just kind of ask you to characterize some of the areas of the focus for the agency in the mid-cycle review meeting for you. Like who took the most time on the side of the FDA? Was it like the clinical review team, the stats group, the safety group? Is it mostly handed by the lead reviewer, like are [ Emily Freilich] and [Teresa Barraccio] in the meeting?

嘿，早安，各位。謝謝讓我提問。也許我想請你們描述一下，在期中審查（mid-cycle review）會議上，主管機關對你們而言的重點關注領域有哪些。像是 FDA 哪一方花最多時間？是臨床審查團隊、統計團隊、還是安全性團隊？主要是由主審查員主導嗎？像是 [ Emily Freilich] 和 [Teresa Barraccio] 也有出席會議嗎？

And I don't know if there's something that comes across in the context of a mid-cycle review meeting, but any insight into FDA's thinking about whether or not they're going to look for scheduling here?

另外我不確定這是否屬於期中審查會議的討論範圍，但你們是否能分享一些對 FDA 想法的洞見：他們是否會在這裡要求列管（scheduling）？

Yeah, so I'll say those meetings are comprehensive, right? This is not exactly like all they stayed quiet for several months and they come and then by meeting on us, quite the opposite, right? So it's been dialogue and overall it's an opportunity as you might recall when senate with heavy lobby from the industry requested a mid cycle meetings to be implemented as part of a P2 for reauthorization was to actually give us as the applicants an opportunity to have that discussion on how things are going.

好的，我會說這些會議是全面性的，對吧？這不是那種他們沉默好幾個月，然後突然來開會「轟炸」我們；恰恰相反。一直都有對話，而整體而言，這是個機會——你可能記得，當時在產業強力遊說下，參議院要求在 P2（再授權）的一部分中導入期中審查會議——目的其實是讓我們這些申請方有機會討論目前進展如何。

And I would say very little on areas that are off, I would say interest for people that don't have an interest on this drug getting to the markets like some of your clients. A lot of the interest here was actually how to actually get this drug to help patients. All the errors were represented that you named there as normally the case.

我會說，幾乎沒有什麼偏離軌道的議題——我想對那些不關心這個藥能否上市的人（像你的一些客戶）來說可能才會特別在意。這裡很多關注點其實是：如何讓這個藥真正到達市場去幫助病患。你剛剛提到的那些領域通常都會有代表出席。

Of course, senior leadership was represented since this is not only an important application, but that's one with breakthrough designation, no drug approved mechanistically for essential treatment ever, only one approved. So you would imagine that that's exactly the agenda for the FDA from a public health perspective in the United States.

當然，資深領導層也有出席，因為這不只是重要的申請案，還具有突破性療法認定；而且在機轉上，針對原發性顫抖（essential tremor）從未有藥物獲批——目前也只有一個藥獲批。所以你可以想像，從美國公共衛生的角度，這正是 FDA 的議程重點。

And what I would say is, and as we said in the prepared remarks, which, by the way, were legally obliged to be complete, as so I find some of the questions, to be honest, a little bit annoying, is that there was no major comments here, or there. So we see this as overall incredibly positive that we are. It's not over yet. It's never over.

我想說的是，正如我們在事先準備的講稿中所說——順帶一提，那些內容在法律上有義務必須完整——所以老實說，我覺得有些問題有點惱人：這裡沒有任何重大意見或重大疑慮。因此我們整體上認為這是非常正面的。但還沒結束。永遠都不算結束。

But one must take at the stage we are the questions before this call were what happened in the mid-cycle. Is the FDA going to have an advisory committee? Is this, and that? So maybe it's time to flip the page towards how large of an opportunity the essential term is and burn the chips, as one say in [cartaga] and start moving forwards, upwards, conquering your words.

但在我們目前這個階段，這通電話之前大家的問題是：期中審查到底發生了什麼？FDA 會不會召開諮詢委員會？會不會怎樣、會不會那樣？所以也許現在該翻篇了，轉而去看原發性顫抖（essential tremor）到底是多大的機會，然後像在 [cartaga] 那句話說的那樣「燒掉籌碼」，開始往前、往上推進，去征服你們的話語。

Danielle Brill, Truist.

Danielle Brill，Truist。

Hey guys, this is Alex on for Danielle. Thanks for taking the question. Another question on the mid-cycle reviews. Just given that you have these two mid-cycle reviews in close proximity, any noticeable differences in the tenor, pushback, body language, et cetera, between the FDA reviews for ulixa versus relutrigine? Thanks so much.

各位好，我是 Alex，代 Danielle 發言。感謝讓我提問。再問一題關於期中審查（mid-cycle reviews）。鑑於你們兩個期中審查時間很接近，在 FDA 對 ulixa 與 relutrigine 的審查之間，在語氣、反對力道、肢體語言等等方面，有沒有任何明顯差異？非常感謝。

I would say no on the body language, I think we're all -- That is a very collegial discussion throughout the group at the agents and ourselves, and exemplified by the fact that we are really the only company that probably know every person on that room by name and actually have a trust and rapport with each one of them because there are multiple INGs and multiple NGAs under review.

我會說沒有，肢體語言方面沒有差異。我想我們大家——整個討論在審查人員與我們之間都非常融洽、很有同事情誼；這也體現在一點上：我們大概是唯一一家可能能叫得出那個會議室裡每個人名字的公司，而且我們與他們每一位都建立了信任與默契，因為目前有多個 ING 與多個 NGA 正在審查中。

Much larger, right, on the -- as you can imagine, the application for ulixacaltamide is so much larger, so there is a lot more people involved on that, but if anything, I'm a paranoid by nature person, so I never expect people to be very happy on meetings like this, but I will venture to say that, I think it's very common. It's very peaceful, and body language is incredibly positive across the board. And it reflects the collaboration throughout the review, as one would expect.

當然，ulixacaltamide 的申請資料規模要大得多——如你所想像的——因此牽涉的人也更多。但如果真要說的話，我天性比較多疑，所以我從不期待在這種會議上大家會表現得很開心；不過我可以說，我覺得這很常見。整體氣氛非常平和，且各方面的肢體語言都非常正向。這也反映了審查過程中的合作程度，正如大家所預期的那樣。

David Hoang, Deutsche Bank.

David Hoang，德意志銀行。

Hi there. Thanks for the updates and taking my questions. So I want to go back to ulixa's potential commercial launch. Could you talk a little bit about the prescriber base for the drug and remind us that this will be primarily neuro's writing for it or would a primary care doc, let's say, feel comfortable to write for this drug?

你好。感謝更新並回答我的問題。我想回到 ulixa 潛在的商業上市。你們能否談談這個藥的處方醫師基礎（prescriber base），並提醒我們主要會是神經科醫師開立，還是說例如基層醫療（primary care）的醫師也會覺得可以放心開立這個藥？

And what size of sales force would you need to support a successful launch? And then if you could just remind us of your latest assumptions on peak sales for ulixa. Thank you.

另外，為了支持成功上市，你們需要多大規模的銷售團隊？最後也請提醒我們，你們對 ulixa 峰值銷售（peak sales）的最新假設。謝謝。

Sounds good. We start with the last part and I hand over to Megan. The big sales here, I think we've been very conservative on when you look into the size of the opportunities, in general, from number of patients, from not really having anything else. The growth we just mentioned, there have not been adding in general feedback from physicians, you name it, we set steps floor into around $10 billion.

好的。我先從最後一部分開始，然後交給 Megan。關於銷售規模，我認為我們一直非常保守；當你看這個機會的規模——不論是病患人數，或是幾乎沒有其他替代選項——再加上我們剛提到的成長，以及來自醫師的整體回饋等等，我們把門檻（floor）設在大約 100 億美元。

And I would say the more we move forward, I think the more we feel comfortable that that's really a fairly conservative number. Let me hand over to Megan to discuss the other topics.

而且我會說，隨著我們持續推進，我想我們越來越覺得這其實仍是相當保守的數字。我把其他主題交給 Megan 說明。

Yes, absolutely. Thanks, David, for the question. So from a target perspective, you're right. Neurologists are our focus coming out for the launch with us targeting them primarily because of their strong ET influence and just the patient volume. So with sort of call target sizing in the 13,000 to 15,000 range, that puts us in a place of having a field force around 300.

好的，當然。David，謝謝你的問題。從目標客群的角度來看，你說得對。上市初期我們的重點會放在神經科醫師，主要鎖定他們，因為他們在 ET 領域影響力很強，而且病患量也大。因此以拜訪目標（call target）規模約 13,000 到 15,000 名來估算，這會讓我們的外勤團隊（field force）大約在 300 人左右。

And as I shared earlier at the start of the Q&A, we're well underway with our hiring. And again, the context we're heading into with the first targeted therapy, huge unmet need and just the opportunity to have the most successful launch here in neurology, we're definitely attracting top caliber talent that want to be a part of this.

正如我在 Q&A 一開始較早前分享的，我們的招募已經進行得很順利。再強調一次，在我們即將面對的是第一個標靶治療、巨大的未被滿足需求，以及在神經科領域達成最成功上市的機會這樣的背景下，我們確實吸引到希望參與其中的一流人才。

And again, the focus for the build-out will allow us to be out in the field doing the account profiling, so we're very well prepared upon PDUFA.

同樣地，這次的團隊建置重點會讓我們能夠走到第一線進行帳戶輪廓分析（account profiling），因此在 PDUFA 時點到來時，我們會準備得非常充分。

Leonid Timashev, RBC CM.

Leonid Timashev，RBC CM。

Hey, guys, Josh on for Leo. Thanks for taking my question. So for the initial patient population that you'll be targeting for relutrigine, are you planning on going after the most severe patients, or do you think you'll go more broadly earlier? And how might that play with how clinicians typically may use a novel seizure agent? Thanks.

各位好，我是 Josh，代 Leo 提問。謝謝讓我提問。關於你們 relutrigine 初期要鎖定的病患族群，你們計畫先從最嚴重的病患著手，還是會更早就採取更廣泛的推進？而這會如何影響臨床醫師通常對新型抗癲癇藥物（novel seizure agent）的使用方式？謝謝。

Yeah. I would say to call any patient with this condition on severe. It's probably something I'm never going to be able to do it. So the population is the population here, right? We still represented us into the SCN2A Family Foundation meeting last week.

是的。我會說，要把任何患有這種疾病的病人稱作「不嚴重」，我大概永遠做不到。所以這裡的族群就是這個族群，對吧？我們上週也出席了 SCN2A Family Foundation 的會議。我們上週也出席了 SCN2A Family Foundation 的會議。

And we had several updates after that and discussions with them. And many clinicians gave us the feedback basically on how they are waiting for this. Some of these hospitals in America centers of excellence have like very largest either the largest or second largest cohorts of GEs they have.

之後我們也有幾次更新與討論。許多臨床醫師給我們的回饋基本上是，他們一直在等待這個治療。美國有些卓越中心（centers of excellence）的醫院，手上有非常大的 GE 病患隊列——不是最大就是第二大。

Why we should never be suffering is suffering and we shouldn't compare, but when you look into other GEs that there are three or four companies going after. They are way less severe, and the majority of the patients are being treated there. So we don't see a segmentation per se here, but really careful use.

我們不應該拿痛苦去比較，痛苦就是痛苦；但當你看其他有三、四家公司在追逐的 GE，那些其實嚴重程度低得多，而大多數病患也都在那裡接受治療。我們不應該拿痛苦去比較，痛苦就是痛苦；但當你看其他有三、四家公司在追逐的 GE，那些其實嚴重程度低得多，而大多數病患也都在那裡接受治療。因此我們不太看到這裡有所謂的分層（segmentation），而是更強調謹慎使用。

I don't think we would want, or like everyone should just start right away without doing the proper assessments of these patients, making sure their background medications are optimized before getting into relutrigine.

我不認為我們會希望——或是說——大家在沒有做適當評估的情況下就立刻開始；在使用 relutrigine 之前，應先確保這些病患的背景用藥已經最佳化。

So that is what's going to dictate the launch. I think our medical education exchange discussions are going to focus on proper use because proper use is what leads to maximum penetration and maximum retention and of course maximum benefit for patients and the other parts that we are all interested is maximum revenue that can return to all of us and get more drugs to the market. So that is the strategy here.

所以這將會決定上市推進的方式。我認為我們的醫學教育與交流（medical education exchange）討論會聚焦在正確使用，因為正確使用才能帶來最大的滲透率（penetration）與最高的留存率（retention），當然也能為病患帶來最大的效益；而我們大家也都關心的另一部分是最大化營收，讓資金能回流給我們所有人，並把更多藥物帶到市場上。這就是這裡的策略。

I couldn't be more pleased to the feedback we're getting from physicians and patient groups.

我對我們從醫師與病友團體那裡得到的回饋感到非常滿意。

Rudy Li, Wolfe Research.

Rudy Li，Wolfe Research。

Thanks for taking my question. For ulixa, so what gives you confidence that titration can help improve discontinuation in practice? Like what data evidence you have to support your titration proposal? And how should we think about discontinuation rates in the real world? Thanks.

謝謝讓我提問。關於 ulixa，你們為什麼有信心認為劑量滴定（titration）能在實務上改善停藥（discontinuation）？你們有哪些數據證據支持你們的滴定方案？我們應該如何看待真實世界（real world）的停藥率？謝謝。

Yeah, so that is a fantastic question and one that we spent a lot of time. Ourselves and of course discussing with the agency. That is why I can't possibly go through every line of evidence here. One thing that is quite key that we haven't, and I'll take full responsibility for not actually discussing this properly publicly before, is if the patients stay the odds of staying on drug and responding, if you just stay a day or two more after a rise in tolerability are disproportionate.

是的，這是個非常好的問題，也是我們花了很多時間思考的問題——我們自己也當然與主管機關討論過。也因此我不可能在這裡逐條走完所有證據。有一點相當關鍵，而我們之前沒有——我也願意為此負全責，因為我過去沒有在公開場合好好說明——就是：如果病患能撐住，隨著耐受性改善後，只要再多撐一兩天，繼續用藥並產生反應的機率會呈現不成比例的提升。有一點相當關鍵，而我們之前沒有——我也願意為此負全責，因為我過去沒有在公開場合好好說明——就是：如果病患能撐住，隨著耐受性改善後，只要再多撐一兩天，繼續用藥並產生反應的機率會呈現不成比例的提升。

So that essence and the mathematical essence is very clear. Imagine a study, when we conducted these studies, we wanted to make sure we're not biasing these patients.

所以其本質與數學上的本質都非常清楚。想像一下，在我們進行這些研究時，我們希望確保不會對這些病患造成偏差。

When a patient goes to an office to discuss with their physician, it's very different conversations, like this is the possible benefits and this is the possible risks, right? But the benefit question is there. In a clinical study, the benefit question is not there.

當病患到診間與醫師討論時，對話會非常不同，例如「可能的效益」與「可能的風險」，對吧？但效益這個問題是存在的。在臨床試驗中，效益這個問題並不存在。

So that is a key driver. So we have a fair bit of data showing that if patients stay on the drug and if they stay a little bit longer, not a lot longer, they're going to be able to tolerate and get fantastic, in my words benefits on the other side of that. Our proposal in the label, notwithstanding the fact that label has to be approved by the agents and so on and so forth, is that physicians are instructed to if they have concerns because they know their patients that chronically don't respond so well in terms of vulnerability, they can keep the patients up for a little bit longer, right?

所以那是一個關鍵驅動因素。因此我們有相當多的數據顯示，如果病人持續用藥，而且多撐一段時間——不需要長很多——他們就能夠耐受，並在度過那段期間後獲得非常出色、用我自己的話說的益處。我們在標籤上的提案——當然標籤必須經主管機關核准等等——是指示醫師：如果他們有疑慮，因為他們了解自己的病人中有些在脆弱性方面長期反應不佳，他們可以讓病人多維持一段時間，對吧？

It is important because they're going to see 70% of the patients doing really well. And then their desire is going to turn into like, I want to get all my patients to do really well. And that's the bridge we want to. What Megan mentioned before about the hub of the future, right?

這很重要，因為他們會看到有70%的病人表現得非常好。然後他們的想法就會變成：我想讓我所有的病人都表現得非常好。而那就是我們想要搭起的橋樑。就像Megan先前提到的未來的樞紐（hub），對吧？

It is really, and we're going to be talking about in our commercial day coming up soon, going to be announcing, it is really a state-of-the-art way to help the practice manage the patients and getting all the tools to maximize tolerabilities.

這確實是——我們也會在即將到來的商業日（commercial day）上談到並宣布——這是一種最先進的方法，協助診所管理病人，並提供所有工具以最大化耐受性。

We could be here saying, why do we care about those patients, right? It's completely irrelevant from a big revenue perspective, but it's not because we know this drug works and we want to make sure it's there with each one of those patients.

我們也可以在這裡說，我們為什麼要在意那些病人，對吧？從龐大營收的角度看似乎完全無關，但其實不是，因為我們知道這個藥有效，我們想確保每一位病人都能用得到。

So I really appreciate it. It is something very close to our hearts. Our team worked incredibly hard to make sure every percent point is not only a percent point in revenue, it's a lot more patients that are being able to get benefits. That they cannot get any other way.

所以我真的很感謝。這是非常貼近我們內心的一件事。我們團隊非常努力，確保每一個百分點不只是營收上的一個百分點，而是更多病人能夠獲得益處。而那些益處是他們無法透過其他方式得到的。

Ben Burnett, Wells Fargo.

Ben Burnett，富國銀行（Wells Fargo）。

Hi, good morning, Tim. This is [Orpheus] on for Ben. Congrats on over-enrolling, EMERALD. I had one question on value and one on your cash runway. First on value, are you able to share what proportion of animal patients are on or another blocker baseline? And what are your expectations for incremental efficacy in the patients?

嗨，早安，Tim。我是代替Ben的[Orpheus]。恭喜EMERALD超額入組。我有一個關於價值的問題，以及一個關於你們現金續航期（cash runway） 的問題。先談價值：你們能否分享在基線時，有多少比例的動物病人正在使用或使用另一種阻斷劑？以及你們對這些病人增量療效（incremental efficacy）的預期是什麼？

Then secondly, your cash runway, given that both are eligible for pediatric vouchers, are your current plans to monetize those on approval and is that contemplating your cash runway? Thank you very much.

第二個是關於你們的現金續航期：鑑於兩者都符合兒科代金券（pediatric vouchers）的資格，你們目前的計畫是在核准後將其變現嗎？這是否已納入你們對現金續航期的考量？非常感謝。

Yeah, so I think we've got a very representative distribution of what the background meds are here. Very happy. I'll tell you, discontinuation, for example, it's a good surrogate. They are being extremely low on this study, to our ability being very good.

是的，所以我認為我們這裡的背景用藥分布非常具有代表性。我們非常滿意。我可以告訴你，例如停藥率（discontinuation）是一個很好的替代指標。在這項研究中停藥率極低，顯示我們的耐受性表現非常好。

We know, and unfortunately, like a lot of these patients failed pretty much everything. So you name a drug, I'm going to tell you they failed or they are on it, but we're confident not only on the effects, which is important, but on the safety as well to get to a positive benefit-risk. And then I'll leave the last question to Tim, who is being anxiously waiting for a financial question for the call.

我們知道——不幸的是——這些病人大多幾乎什麼都失敗過。你隨便說一個藥，我都會告訴你他們不是用過失敗了，就是正在用，但我們不僅對療效有信心（這很重要），對安全性也有信心，能達到正向的效益-風險（benefit-risk）。最後一個問題我就交給Tim，他一直很期待這通電話裡能有個財務問題。

Thanks for the question about the runway. And I think part of what we talked about with the runway is it gives us this great flexibility and ability to launch into these launches, the way we're investing with field force and all the activities that Marcio and Megan have taken us through. With respect to the PRV, because we do anticipate approval for [vormatrigine] for 2A and 8A, where we do have work in the designation and are eligible for a PRV, we would expect to receive that as well.

謝謝你關於續航期的提問。我想我們談到續航期的一部分，是它讓我們在推進這些上市（launch）時具備很大的彈性與能力，能以我們正在投入的方式來推動，包括前線團隊（field force）以及Marcio和Megan帶大家走過的所有活動。至於PRV（優先審查代金券），因為我們預期[vormatrigine]在2A與8A會獲得核准，而我們在該適應症的認定（designation）上已有工作並符合PRV資格，我們也預期會取得該PRV。

It is not a meaningful impact to our runway, but it does ensure that we can continue to invest in these launches. And you're right also about elsunersen down the road because that also has elsunersen designation. We believe that would be our second product if you could be eligible for a PRV. But thank you for the question.

它對我們的續航期不會造成重大影響，但確實能確保我們可以持續投資於這些上市活動。而你提到未來的elsunersen也沒錯，因為它也有elsunersen的認定（designation）。我們相信那會是我們第二個產品，若符合資格也可能取得PRV。不過謝謝你的提問。

Thank you. This concludes the question-and-answer session. I would now like to turn it back to Marcio for closing remarks.

謝謝。問答環節到此結束。我現在想把時間交回給Marcio做結語。

Yeah, thank you so much. I appreciate it. I hope you seem to try to be very comprehensive today, giving updates on -- it's just absolutely just amazing, palpable energy that we get every single day here in the office. With all the now sales team as well and being there and talking to physicians, giving us a lot more information.

好的，非常感謝。我很感激。我希望大家今天覺得我們已盡量做到非常全面，提供各項更新——我們每天在辦公室都能感受到那種令人驚嘆、非常強烈的能量。現在也包括銷售團隊，他們在外面與醫師交流，帶回更多資訊給我們。

I would say as we move this page towards a commercial, a lot of you helped us along the way to make a successful clinical development for this drug, as we discussed less and less.

我想說，當我們把這一頁推向商業化時，你們很多人一路以來都幫助我們，讓這個藥物的臨床開發能夠成功；正如我們討論的，臨床與法規相關的內容會越來越少。

The clinical and regulatory, I just want to take a moment to thank all of you who are certainly my biggest critics and my biggest supporters when we got into certain conversations and I appreciate every feedback that's been given to the company made us to where we are right now couldn't be prouder on behalf of patients.

關於臨床與法規，我想花點時間感謝各位：在某些對話中，你們既是我最大的批評者，也是我最大的支持者。我很感謝每一個回饋；這些回饋讓公司走到今天的地步。站在病人的立場，我再自豪不過。

When we get these stories every single day, and trust me, we got them every single day, from the patients who transitioned on EMERALDs to the open label, or the ones who are involved, or the ones who are on emergency access of one of our medicines, or particularly these days, for the ones wanting to be on ulixacaltamide. That's what keeps us going.

我們每天都會聽到這些故事——相信我，真的是每天——來自那些從EMERALD轉入開放標籤（open label）的病人，或是那些參與其中的病人，或是那些透過緊急使用（emergency access）取得我們某個藥物的病人；尤其是最近，那些想要使用ulixacaltamide的病人。這就是支撐我們繼續前進的動力。

Thanks enormously for your support and really looking forward to the conversations later today and in the near future.

非常感謝你們的支持，也很期待今天稍晚以及不久的將來能再與各位交流。

Thank you for your participation in today's conference. This does conclude the program and you may now disconnect.

感謝您參與今天的會議。本次議程到此結束，您現在可以斷線。