Stoke Therapeutics, Inc. (STOK) 2026 Q3 法說會逐字稿

Good day, and thank you for standing by. Welcome to Stoke Therapeutics’ third-quarter 2026 business update conference call. At this time, all participants are in a listen-only mode. After the speaker’s presentation, there will be a question-and-answer session. (Operator Instructions) Please be advised today’s conference may be recorded.

大家好，感謝您稍候等候。歡迎參加 Stoke Therapeutics 2026 年第三季業務更新電話會議。此刻，所有與會者皆處於僅收聽模式。在講者簡報結束後，將進行問答環節。(接線員指示) 請注意，今日會議可能會被錄音。

I will now hand the conference over to our first speaker for today, Thomas Leggett, Chief Financial Officer. Please go ahead, sir.

現在我將把會議交給今天的第一位講者，Thomas Leggett，財務長。先生，請開始。

Good evening, and welcome to Stoke Therapeutics’ third quarter 2026 business update conference call. I am Thomas Leggett, the Chief Financial Officer at Stoke Therapeutics. Joining me on today’s call, Ian Smith, our Chief Executive Officer, Dr. Barry Ticho, Chief Medical Officer, and Jason Hoitt, Chief Patient Officer. As a reminder, today’s webcast presentation is available in the Investors section of our website.

各位晚安，歡迎參加 Stoke Therapeutics 2026 年第三季業務更新電話會議。我是 Thomas Leggett，Stoke Therapeutics 財務長。今天與我一同參與電話會議的還有：執行長 Ian Smith、醫務長 Barry Ticho 醫師，以及首席病患長 Jason Hoitt。提醒各位，今日網路直播簡報可於我們官網的投資人專區取得。

This webcast is being recorded and will be available for replay later this evening. Before we begin, please note that today’s discussion includes forward-looking statements. These forward-looking statements are subject to risks and uncertainties, and actual results may differ materially. Please refer to our filings with the SEC for additional information.

本次網路直播將進行錄製，並將於今晚稍後提供重播。在開始之前，請注意今日討論包含前瞻性陳述。這些前瞻性陳述存在風險與不確定性，實際結果可能出現重大差異。更多資訊請參閱我們向美國證券交易委員會（SEC）提交的文件。

With that, I will turn the call over to Ian.

接下來，我將把電話會議交給 Ian。

Thank you, Thomas, and thank you to everyone joining us this evening. It has been a busy quarter at Stoke. Tonight, we will discuss our recent progress, including an update on the advancement of patients through key time points in the EMPEROR Phase 3 registrational study of zorevunersen, our recent discussion with the FDA related to our NDA planning, and the latest on our commercial readiness activities. I will start with some highlights from our Phase 3 study.

謝謝你，Thomas，也感謝今晚加入我們的各位。對 Stoke 而言，這是一個忙碌的季度。今晚我們將討論近期進展，包括：zorevunersen 於 EMPEROR 第 3 期註冊性研究中，病患在關鍵時間點的推進更新；我們近期與 FDA 就 NDA 規劃相關的討論；以及我們商業化就緒活動的最新進度。我將先從第 3 期研究的一些重點開始。

To date, approximately 110 of 162 enrolled patients have completed their week 28 visit. This is the time point at which data for the primary endpoint of change in major motor seizure frequency is captured. Approximately 20 patients have also completed their week 52 visit, marking the end of the study treatment period and the time point at which key secondary endpoint data will be captured.

截至目前，約 162 名入組病患中的 110 名已完成第 28 週回診。此時間點會收集主要終點「重大運動性癲癇發作頻率變化」的數據。另約有 20 名病患已完成第 52 週回診，這標誌著研究治療期結束，也是將收集關鍵次要終點數據的時間點。

All of these patients are continuing into the open-label portion of the study. Notably, there have been no treatment discontinuations to date. Barry will provide some additional metrics and context in a few moments.

所有這些病患都將持續進入研究的開放標籤部分。值得注意的是，截至目前尚無任何治療中止。Barry 將在稍後提供更多指標與背景說明。

Next, I will highlight our recent interaction with the FDA that gave us the opportunity to discuss our five years of clinical data for zorevunersen, including our Phase 1/2, and OLE studies, and to align on key aspects of our planned 2027 US NDA submission.

接下來，我將重點說明我們近期與 FDA 的互動；這讓我們有機會討論 zorevunersen 的五年臨床數據，包括第 1/2 期與 OLE（開放標籤延伸）研究，並就我們計畫於 2027 年在美國提交 NDA 的關鍵面向達成一致。

We were pleased with the agency’s engagement, responsiveness, and interest in zorevunersen. An important outcome of our meeting was the FDA’s willingness to accept a multicomponent assessment of Vineland-3 data for purposes of evaluating the key secondary endpoint related to changes in cognition and behavior. This is a positive outcome because we believe a multicomponent approach acknowledges the complexity of the disease and the fact that each patient’s experience with Dravet syndrome is different, especially when it comes to impacts on cognition and behavior.

我們對主管機關的投入、回應速度以及對 zorevunersen 的興趣感到滿意。本次會議的一項重要成果是，FDA 願意接受以 Vineland-3 數據的多組成（multicomponent）評估方式，用於評估與認知與行為變化相關的關鍵次要終點。這是一項正面成果，因為我們認為多組成方法能反映疾病的複雜性，以及每位病患的德拉維特症候群（Dravet syndrome）經驗皆不相同，尤其是在對認知與行為的影響方面。

Coming out of the discussion, we are reiterating our timelines for a data readout in Q3 2027, followed by a planned NDA submission in the second half of next year. Clarity on these timelines is important as we scale our organization and capabilities to deliver zorevunersen to patients following a potential US approval in early 2028. Our medical affairs team has done an incredible job over the past two years establishing a foundation of awareness and understanding of Dravet syndrome and the data to support the disease-modifying potential of zorevunersen. We are continuing to expand our educational efforts, moving to reach more clinicians and other stakeholders, including payers, with the recent addition of our field market access team.

基於此次討論，我們重申時程：預計於 2027 年第三季（Q3 2027）進行數據揭露，並計畫於明年下半年提交 NDA。在我們擴大組織與能力、以便在 2028 年初若於美國獲得核准後將 zorevunersen 交付給病患之際，這些時程的明確性相當重要。過去兩年，我們的醫學事務團隊在建立對德拉維特症候群的認知與理解，以及建立支持 zorevunersen 具疾病修飾潛力的數據基礎方面，表現非常出色。隨著近期新增外勤市場准入團隊，我們持續擴大教育推廣，觸及更多臨床醫師與其他利害關係人，包括支付方。

We continue to learn as much as we can about Dravet syndrome and the opportunity through ongoing research. These efforts have given us additional confidence in the addressable patient population and are guiding our organizational build.

我們也透過持續研究，盡可能深入了解德拉維特症候群及其治療機會。這些努力讓我們對可觸及的病患族群更具信心，並正在引導我們的組織建置。

At the same time, the field is continuing to evolve, and we see growing awareness of the needs of patients with Dravet syndrome and other genetic epilepsies. We are encouraged by the actions of stakeholder organizations such as American Epilepsy Society’s Presidential Task Force on preparing for disease-modifying therapies and education and advocacy related to the need for genetic testing. Jason Hoitt will share more on these efforts in a few minutes.

同時，該領域也在持續演進，我們看到對德拉維特症候群及其他遺傳性癲癇病患需求的認知正在提升。我們也受到利害關係組織行動的鼓舞，例如美國癲癇學會（American Epilepsy Society）的總統工作小組，致力於為疾病修飾療法做準備，以及就基因檢測需求所進行的教育與倡議。Jason Hoitt 將在幾分鐘後分享更多相關內容。

We see haploinsufficient diseases as a clear and unique opportunity for our platform, which is why we are excited to advance STK-002. Autosomal dominant optic atrophy, or simply ADOA, is a rare genetic disease that is primarily caused by a haploinsufficiency that results in 50% of functional protein production. STK-002 is designed to increase naturally occurring, fully functional OPA1 protein production to address the underlying cause of this disease.

我們認為半量不足（haploinsufficient）疾病對我們的平台而言是一個明確且獨特的機會，因此我們很期待推進 STK-002。常染色體顯性視神經萎縮（autosomal dominant optic atrophy），簡稱 ADOA，是一種罕見遺傳疾病，主要由半量不足所致，導致功能性蛋白產量僅約 50%。STK-002 的設計目標是提高天然存在、完全具功能的 OPA1 蛋白產量，以處理此疾病的根本原因。

In addition to our preclinical data, recent data from the field supports the potential of the OPA1 targeting hypothesis. Dosing is now underway in the third cohort of our Phase 1 OSPREY study, and we expect to initiate the fourth dose cohort in early 2027. Initial safety and efficacy data are anticipated in the first half of next year, which will inform future development. As we expand our research efforts, we will continue to focus on severe genetic diseases driven by haploinsufficiency with an emphasis on the CNS, given our experience in Dravet syndrome.

除我們的臨床前數據外，近期來自該領域的數據也支持 OPA1 標的假說的潛力。我們第 1 期 OSPREY 研究的第三個劑量隊列目前已開始給藥，並預期於 2027 年初啟動第四個劑量隊列。預計於明年上半年取得初步安全性與有效性數據，這將為後續開發提供依據。隨著我們擴大研究工作，我們將持續聚焦於由半量不足驅動的嚴重遺傳疾病，並以中樞神經系統（CNS）為重點，因為我們在德拉維特症候群方面已有相關經驗。

With that, I would summarize by saying that Stoke has made great progress throughout 2026, and we are well-positioned heading into the end of this year. With that, I will turn the call over to Barry Ticho.

總結來說，Stoke 在 2026 年期間取得了顯著進展，並在邁向今年年底之際處於有利位置。接下來，我將把電話會議交給 Barry Ticho。

Thank you, Ian. I will start by expanding on our Phase 3 progress that Ian mentioned. EMPEROR is a global, double-blind, sham-controlled Phase 3 study of zorevunersen in patients with Dravet syndrome. The study is designed as a 52-week treatment period in which patients receive two loading doses plus two maintenance doses of either zorevunersen or sham, followed by an open-label extension period in which all patients receive zorevunersen.

謝謝你，Ian。我將先就 Ian 提到的第 3 期進展做進一步說明。EMPEROR 是一項全球性、雙盲、假處置對照的第 3 期研究，評估 zorevunersen 用於德拉維特症候群病患。本研究設計為 52 週治療期，病患將接受兩次負荷劑量加上兩次維持劑量的 zorevunersen 或假處置，之後進入開放標籤延伸期，所有病患皆接受 zorevunersen。

The primary endpoint is percent change from baseline in log transformed major motor seizure frequency at week 28. All secondary endpoints are measured at week 52. To protect the integrity of the study, we will not review or analyze any data until all patients reach week 52.

主要終點為第 28 週時，相較基線之對數轉換後重大運動性癲癇發作頻率的百分比變化。所有次要終點皆於第 52 週測量。為維護研究的完整性，在所有病患皆達到第 52 週之前，我們不會檢視或分析任何數據。

The study is progressing very well. All 162 patients enrolled in the US, UK, and Japan are through week 8 of the study, which means that they have received either the two loading doses of 70 milligrams of zorevunersen or sham.

本研究進展非常順利。在美國、英國與日本入組的全部 162 名病患皆已完成研究第 8 週，這表示他們已接受兩次 70 毫克 zorevunersen 的負荷劑量或假處置。

Approximately 130 patients are through week 24, and therefore have only one of the four doses left in the 52-week treatment period. Approximately 110 patients have also completed their week 28 visit, the time point at which the primary endpoint of change in major motor seizure frequency is measured. Approximately 65 patients are through week 40 and have therefore received all four doses of zorevunersen or sham. Approximately 20 patients have reached the end of the 52-week treatment period.

約有130名患者已完成至第24週，因此在52週治療期間四次給藥中僅剩最後一次尚未完成。約有110名患者亦已完成第28週回診，此時間點用於測量主要終點：重大運動性癲癇發作頻率的變化。約有65名患者已完成至第40週，因此已接受zorevunersen或安慰劑（sham）的四次給藥。約有20名患者已達到52週治療期末。

All of these patients are continuing into the open-label extension period. No patients have discontinued treatment in EMPEROR.

所有這些患者都將持續進入開放標籤延伸期。EMPEROR試驗中沒有患者中止治療。

When we originally designed EMPEROR, we set an enrollment target of 150 patients. This was based on a goal of 128 evaluable patients at the end of the study with an assumed 15% discontinuation rate. We ultimately enrolled 162 patients, and as I mentioned, there have been no discontinuations to date. These metrics reflect a well-designed trial, the need for better treatments, and a deeply committed community of investigators, site teams, and caregivers.

在我們最初設計EMPEROR時，設定的收案目標為150名患者。此目標係基於研究結束時希望有128名可評估患者，並假設15%的中止率。最終我們共收納162名患者，且如我所提及，迄今尚無任何中止。這些指標反映了試驗設計完善、對更佳治療的迫切需求，以及研究者、試驗中心團隊與照護者社群的高度投入。

The primary endpoint of EMPEROR is change in major motor seizure frequency at week 28. There is no doubt that anti-seizure medications are providing benefit for patients. Even still, seizure control remains the number one goal for new treatments. Demonstrating a disease-modifying impact on cognition and behavior is expected to take longer, which accounts for the year-long treatment period and evaluation of the Vineland results at week 52.

EMPEROR的主要終點為第28週重大運動性癲癇發作頻率的變化。毫無疑問，抗癲癇藥物正為患者帶來益處。即便如此，發作控制仍是新療法的首要目標。要證明對認知與行為具有疾病修飾（disease-modifying）影響，預期需要更長時間；這也解釋了為期一年的治療期間，以及在第52週評估Vineland結果的安排。

As Ian mentioned, for the purposes of our US NDA, we plan to use a multicomponent assessment that combines four pre-specified Vineland-3 sub-domains: expressive communication, receptive communication, interpersonal relationships, and personal skills. We believe the multicomponent assessment is the most appropriate way to evaluate changes in cognition and behavior due to the variability in how the disease affects patients.

如Ian所提及，為了我們的美國NDA申請，我們計畫採用一項多組成評估（multicomponent assessment），結合四個預先指定的Vineland-3子領域：表達性溝通、接受性溝通、人際關係，以及個人技能。我們認為，多組成評估是評估認知與行為變化最合適的方法，因為疾病對患者的影響具有變異性。

To generate a multicomponent score, we first calculate the individual treatment effect for each subdomain using a multivariate mixed model for repeat measures, or MMRM. We then average all four scores to produce a single number that reflects the overall treatment effect. I will show you what that looks like in a minute. Before I do that, I want to remind you of an analysis that we performed back in 2024 to inform the design of the Phase 3 study, and specifically to help us prioritize the selection of Vineland sub-domains.

為產生多組成分數，我們首先使用重複量測之多變量混合模型（multivariate mixed model for repeat measures，MMRM）計算各子領域的個別治療效果。接著將四個分數取平均，得到一個反映整體治療效果的單一數值。我稍後會向各位展示其呈現方式。在此之前，我想提醒各位我們在2024年所做的一項分析，用以支持第三期研究的設計，並特別協助我們優先選擇Vineland子領域。

On the left side, you see data from a subset of patients treated in our Phase 1/2 and OLE studies. These patients received a total cumulative dose of zorevunersen that was consistent with our plans for Phase 3.

左側顯示的是我們第一/二期與OLE研究中一部分接受治療患者的資料。這些患者接受的zorevunersen累積總劑量與我們第三期的規劃一致。

On the right, you see data from patients followed in our natural history study whose baseline characteristics were matched to the treated patient population. Week 68 was used for these analyses because it was the most proximal to a 52-week study design when accounting for the pause in dosing between the last Phase 1/2 dose and the first OLE dose.

右側顯示的是我們自然病程研究中追蹤的患者資料，其基線特徵與治療組患者族群相匹配。本分析採用第68週作為時間點，因為在考量第一/二期最後一次給藥與OLE第一次給藥之間的暫停後，第68週最接近52週的研究設計。

Selection of these sub-domains was further supported by feedback from clinicians and caregivers. Now, with an additional two years of data and in light of our recent discussion with the FDA, we generated a multicomponent analysis using propensity score weighting to calculate a treatment effect. Use of propensity score weighting mimics randomization by adjusting for baseline differences between treated and natural history groups.

這些子領域的選擇亦獲得臨床醫師與照護者回饋的進一步支持。目前在新增兩年的資料，並結合我們近期與FDA的討論後，我們使用傾向分數加權（propensity score weighting）產生多組成分析以計算治療效果。傾向分數加權可透過調整治療組與自然病程組之間的基線差異，來模擬隨機分派（randomization）。

This is the closest we can come to replicating a randomized trial. This analysis demonstrates the overall treatment effect across the four sub-domains using a multicomponent average as well as the contributions of each of the four selected sub-domains. Even with small numbers of patients, a highly statistically significant multicomponent score was demonstrated. With five years of clinical data, an assumption of 150 evaluable patients, and the change to a multicomponent assessment of the Vineland-3 for our US NDA, we have run a calculation of the minimum treatment effect to achieve a P value of 0.05 to 0.01.

這是我們最接近重現隨機試驗的方法。此分析以多組成平均值呈現四個子領域的整體治療效果，同時也顯示所選四個子領域各自的貢獻。即使患者人數不多，仍可觀察到在統計上高度顯著的多組成分數。基於五年的臨床資料、150名可評估患者的假設，以及我們為美國NDA將Vineland-3改為多組成評估的變更，我們已計算達到P值0.05至0.01所需的最低治療效果。

The study has 90% power to detect a treatment difference between treatment arms of 46% to 53% relative reduction in seizure frequency at a two-sided significance level of 0.05 to 0.01, respectively, at weeks 28 and week 52. For the second key secondary endpoint measured by Vineland-3, the study has 90% power to detect a treatment difference of approximately 1.8 to 2.1 raw score points in the multicomponent assessment at week 52, using the same two-sided significant levels of 0.05 to 0.01, respectively.

本研究在雙側顯著水準0.05至0.01下，於第28週與第52週分別具有90%的檢定力（power），可偵測治療組間癲癇發作頻率相對降低46%至53%的治療差異。對於以Vineland-3衡量的第二個關鍵次要終點，本研究在相同的雙側顯著水準0.05至0.01下，於第52週具有90%的檢定力，可偵測多組成評估約1.8至2.1個原始分數點（raw score points）的治療差異。

We are often asked to explain the real-world meaning of these Vineland scores. What I can say is that even small changes can have meaningful impacts for patients and their families. This has been documented in the literature and is evident in the video case study that was included as supplemental to our data published in the New England Journal of Medicine earlier this year. We will continue to keep you updated as we progress the study, and we look forward to our data readout in Q3 of next year.

我們經常被要求說明這些Vineland分數在真實世界中的意義。我能說的是，即使是很小的變化，也可能對患者及其家庭帶來有意義的影響。這點已在文獻中有所記載，並且也可從我們今年稍早發表於《新英格蘭醫學期刊》的資料所附補充影片個案研究中看出。隨著研究推進，我們將持續向各位更新，並期待於明年第三季（Q3）進行資料揭盲/讀出（data readout）。

Let me turn to our second clinical stage program, STK-002. Momentum and awareness of this program are increasing. Earlier this month at the American Academy of Ophthalmology Annual Meeting, our teams delivered two presentations of data that support the potential of STK-002 as a disease-modifying treatment for ADOA.

接下來我將談到我們第二個臨床階段計畫STK-002。此計畫的動能與關注度正在提升。本月稍早在美國眼科學會（American Academy of Ophthalmology）年會上，我們的團隊發表了兩場報告，呈現支持STK-002作為ADOA疾病修飾治療潛力的資料。

ADOA is a rare genetic disease that leads to progressive degeneration of the optic nerve and vision loss starting in the first decade of life. It is the most common inherited optic nerve disorder, affecting approximately 13,000 in the US, UK, EU4, and Denmark. The majority of cases are caused by mutations in one copy of the OPA1 gene, resulting in haploinsufficiency and reduced functional OPA1 protein. Approximately half of people living with ADOA will progress to legal blindness. There are currently no approved treatments for ADOA.

ADOA是一種罕見遺傳疾病，會導致視神經進行性退化，並在生命的第一個十年開始出現視力喪失。它是最常見的遺傳性視神經疾病，在美國、英國、EU4與丹麥約影響13,000人。多數病例由OPA1基因其中一個拷貝的突變所致，造成單倍體不足（haploinsufficiency）並降低功能性OPA1蛋白。約有一半的ADOA患者將進展至法定失明。目前尚無任何獲核准的ADOA治療。

STK-002 is designed to increase OPA1 protein expression with the aim of improving vision in people with ADOA. We are encouraged by our preclinical data as well as emerging data from the field demonstrating that upregulation of OPA1 protein has disease-modifying potential. In ADOA patient-derived cells with different OPA1 variants, STK-002 significantly increased OPA1 protein expression and improved mitochondrial function compared with healthy controls.

STK-002旨在提高OPA1蛋白表現，以期改善ADOA患者的視力。我們對臨床前資料以及領域內新出現的證據感到鼓舞，這些證據顯示上調OPA1蛋白具有疾病修飾潛力。在具有不同OPA1變異的ADOA患者來源細胞中，相較於健康對照，STK-002可顯著提高OPA1蛋白表現並改善粒線體功能。

On the next slide, you see that after a single intravitreal dose in non-human primates, STK-002 was also shown to reach retinal ganglion cells and increase retinal OPA1 protein. On the left side, staining shows STK-002 in red in retinal ganglion cells with increased signal correlating with increased dose. In the center, immunofluorescence staining with an OPA1 antibody, again in red, shows an increase in OPA1 protein in the retinal ganglion cell layer.

在下一張投影片中，各位可看到在非人靈長類接受單次玻璃體內注射（intravitreal）後，亦證實STK-002可到達視網膜神經節細胞，並提高視網膜OPA1蛋白。左側的染色顯示視網膜神經節細胞中STK-002以紅色呈現，且訊號增強與劑量增加相關。中間的免疫螢光染色使用OPA1抗體，同樣以紅色呈現，顯示視網膜神經節細胞層中的OPA1蛋白增加。

OPA1 protein levels increased at all doses by week four by 44% to 47% at the 0.3 milligram and 1 milligram doses, respectively. The Phase 1 OSPREY study in people with ADOA is ongoing in the UK and Europe. The study aims primarily to evaluate the safety, tolerability, and exposure of single ascending doses of STK-002 following a standard dose escalation design. OSPREY will also assess clinical activity, including changes in visual function and patient quality of life, as well as retinal mitochondrial dysfunction. Data from our natural history study show higher levels of mitochondrial stress strongly correlate with decreased visual acuity.

OPA1 蛋白水準在所有劑量下於第 4 週均上升，其中 0.3 毫克與 1 毫克劑量分別增加 44% 與 47%。針對 ADOA 患者的第 1 期 OSPREY 研究目前正在英國與歐洲進行中。該研究主要目標是依照標準劑量遞增設計，評估 STK-002 單次遞增劑量的安全性、耐受性與暴露量。OSPREY 亦將評估臨床活性，包括視覺功能與患者生活品質的變化，以及視網膜粒線體功能障礙。我們的自然病程研究數據顯示，較高的粒線體壓力水準與視力（視覺敏銳度）下降呈高度相關。

OSPREY is designed to provide clinical proof of concept by testing whether increasing OPA1 protein expression with STK-002 translates into measurable effects on visual function in patients with ADOA. The study is progressing well. We recently completed dosing of the first two cohorts of patients, and dosing the third cohort is underway, with completion expected by year-end. Subject to ongoing safety assessments, we expect to begin dosing of the fourth cohort in early 2027. We expect Cohorts 3 and 4 to reach dose levels that may produce measurable effects on visual function.

OSPREY 的設計旨在提供臨床概念驗證，藉由測試以 STK-002 提升 OPA1 蛋白表達是否能轉化為 ADOA 患者視覺功能上可量測的效果。研究進展順利。我們近期已完成前兩個患者隊列的給藥，第三隊列正在給藥中，預計於年底完成。在持續的安全性評估前提下，我們預期將於 2027 年初開始第四隊列的給藥。我們預期第 3 與第 4 隊列將達到可能產生可量測視覺功能效果的劑量水準。

Initial safety and efficacy data from these higher dose cohorts are expected in the first half of 2027. With that, I will turn the call over to Jason Hoitt.

來自這些較高劑量隊列的初步安全性與療效數據，預計將於 2027 年上半年取得。接下來我將把電話會議交給 Jason Hoitt。

Thank you, Barry. Shifting back to Dravet, I will start by sharing an overview of the patient population. While we have shared these data previously, our latest market research continues to validate our assumptions and strengthen our confidence in the numbers. There are an estimated 38,000 patients with Dravet syndrome across the seven major markets where we are running the EMPEROR study, the US, UK, EU4, and Japan, including approximately 16,000 in the US alone. Of those 16,000 in the US, we estimate 6,000 are under the age of 25 and likely under the care of a pediatric provider. These are the patients who would be immediately addressable at the time of a potential US launch.

謝謝你，Barry。回到 Dravet（德拉維特症候群）議題，我將先分享患者族群概況。雖然我們先前已分享過這些數據，但我們最新的市場研究持續驗證我們的假設，並強化我們對這些數字的信心。在我們進行 EMPEROR 研究的七大主要市場（美國、英國、EU4 與日本）中，估計共有 38,000 名 Dravet 症候群患者，其中僅美國約 16,000 名。在美國這 16,000 名患者中，我們估計有 6,000 名年齡低於 25 歲，且很可能由兒科醫療提供者照護。這些患者將是在潛在美國上市時可立即觸及的族群。

Pediatric neurologists and epileptologists tend to follow the field closely and are typically the most well-informed about the disease and current treatment options. An ICD-10 code was established in 2020 and is used to track confirmed Dravet diagnoses. With the increasing awareness of Dravet syndrome and the importance of genetic testing, we are seeing 40 to 50 new patients entering these claims databases every month, equating to 500 to 600 every year, including newly identified younger patients and older patients finally arriving at a diagnosis.

兒科神經科醫師與癲癇專科醫師通常密切追蹤該領域發展，並且往往對疾病與現行治療選項最為了解。ICD-10 代碼於 2020 年建立，並用於追蹤已確認的 Dravet 診斷。隨著對 Dravet 症候群的認知提升以及基因檢測重要性增加，我們看到每月有 40 至 50 名新患者進入這些理賠資料庫，約等於每年 500 至 600 名，包含新辨識的年幼患者，以及終於獲得診斷的年長患者。

As a result, we anticipate the total number of immediately addressable patients to increase between now and the time of launch. We are confident that we know where 80% of the 6,000 immediately addressable patients are being cared for today. In the US, the Dravet population is highly concentrated around centers of excellence and other key treatment centers. Approximately half of identified US patients are cared for by the top 50 sites.

因此，我們預期從現在到上市時，可立即觸及的患者總數將會增加。我們有信心知道目前 6,000 名可立即觸及患者中，有 80% 正在哪些地方接受照護。在美國，Dravet 患者高度集中於卓越中心（centers of excellence）及其他關鍵治療中心周邊。約有一半已辨識的美國患者由前 50 個據點照護。

All 50 of those sites are experienced in administering intrathecal medicines, and over half of these sites have participated in a zorevunersen study. There is a high level of awareness of zorevunersen in anticipation for the Phase 3 readout and potential approval. The Dravet community has been involved in this program since its earliest days, and sites are anticipating strong demand upon a potential US approval. Several of the top treatment centers have proactively reached out to us asking what they can do to be ready to deliver zorevunersen.

這 50 個據點皆具備施用鞘內（intrathecal）藥物的經驗，且其中超過一半曾參與 zorevunersen 研究。在第 3 期讀出與潛在核准之前，對 zorevunersen 的認知度很高。Dravet 社群自本計畫最早期即參與其中，各據點預期在潛在美國核准後將出現強勁需求。數個頂尖治療中心已主動聯繫我們，詢問他們能做些什麼以準備好提供 zorevunersen。

Our teams are beginning to engage with sites to help them prepare the infrastructure protocols and staff expertise necessary to administer zorevunersen with appropriate capacity. The Dravet community has been waiting years for a medicine like zorevunersen. Our job is to do everything we can to ensure they do not have to wait a day longer than they need to.

我們的團隊正開始與各據點互動，協助其準備所需的基礎設施流程與人員專業，以在具備適當量能的情況下施用 zorevunersen。Dravet 社群多年來一直在等待像 zorevunersen 這樣的藥物。我們的工作是竭盡所能，確保他們不必多等任何一天。

To that end, we are adding resources and capabilities with an emphasis on people who have launched high science new medicines, particularly for rare genetic diseases, and are committed to delivering excellence in patient care and overall experience.

為此，我們正在增加資源與能力，重點延攬曾成功上市高科學含量新藥的人才，特別是針對罕見遺傳疾病，並致力於提供卓越的病患照護與整體體驗。

Our head of patient services recently joined Stoke. She is in the initial stages of designing a patient support program that reflects the unique needs of this patient community and enables timely access. Our goal is to make the process between prescription and treatment as simple and easy as possible. Co-creation sessions with caregivers, clinicians, and office administrators are underway to design a program that meets their needs.

我們的病患服務負責人近期加入 Stoke。她正處於設計病患支持計畫的初期階段，該計畫將反映此患者社群的獨特需求並促進及時取得治療。我們的目標是讓從處方到治療之間的流程盡可能簡單、容易。我們正與照護者、臨床醫師與診所行政人員進行共同創作會議，以設計符合其需求的計畫。

On the payer side, we recently deployed our payer account team, who will start their educational efforts with medical directors at insurers across the country. These educational efforts build upon the years-long effort of our medical affairs team, who have supported our clinical teams and have done an exceptional job of education and awareness with healthcare providers and treating physicians around the world. Our latest HCP market research shows a high conviction in the data and in the disease-modifying potential of zorevunersen.

在支付方（payer）方面，我們近期部署了支付方客戶團隊，將開始對全國各保險公司的醫療主管進行教育推廣。這些教育工作建立在我們醫藥事務團隊多年來的努力之上；該團隊支持我們的臨床團隊，並在全球對醫療照護提供者與治療醫師的教育與認知提升方面表現卓越。我們最新的醫療照護專業人員（HCP）市場研究顯示，對數據以及 zorevunersen 具疾病修飾潛力的信念度很高。

We are also making progress among the broader neurology community, who may be less familiar with the latest advances in the treatment of Dravet syndrome. We are very encouraged by the growing awareness and interest we experienced at the recent Child Neurology Society meeting.

我們也在更廣泛的神經科社群中取得進展；這些人可能對 Dravet 症候群治療的最新進展較不熟悉。我們對近期兒童神經學會（Child Neurology Society）年會上所見到的認知提升與興趣增加感到非常鼓舞。

As recently as three years ago, very few people at this meeting knew about Dravet, zorevunersen, or Stoke. Today, there is a far greater appreciation among general neurologists and epileptologists for the genetic drivers of Dravet syndrome and the reclassification of genetic epilepsies as DEEs. The ability to genetically diagnose these diseases is also prompting physicians and medical societies to rethink the treatment paradigm.

就在三年前，該會議上知道 Dravet、zorevunersen 或 Stoke 的人仍然很少。如今，一般神經科醫師與癲癇專科醫師對 Dravet 症候群的遺傳驅動因素，以及將遺傳性癲癇重新分類為 DEEs（發展性與癲癇性腦病）的理解大幅提升。對這些疾病進行基因診斷的能力，也正促使醫師與醫學學會重新思考治療典範。

One such example is the American Epilepsy Society’s new Presidential Task Force on disease-modifying therapies. The intent behind this new initiative is to prepare those who treat these diseases for the arrival of genetically targeted treatments. We are encouraged by initiatives like this one, which complement the work we are doing, signaling a shared commitment to improve outcomes for patients, and recognition of the potential for a new class of medicines.

其中一個例子是美國癲癇學會（American Epilepsy Society）新成立的「疾病修飾療法」總統任務小組。這項新倡議的目的，是讓治療這些疾病的醫師為基因標靶治療的到來做好準備。我們對這類倡議感到鼓舞；它們與我們正在進行的工作相輔相成，顯示出改善患者預後的共同承諾，並認可一個新藥物類別的潛力。

Beyond our educational efforts, we are preparing to initiate two additional clinical studies of zorevunersen by the end of this year. This includes a study in adult patients, which is intended to support access and reimbursement, as well as a study in infants and toddlers. The primary objective of these studies is to evaluate the safety of zorevunersen in these populations.

除了教育推廣之外，我們正準備在今年年底前啟動另外兩項 zorevunersen 的臨床研究。其中包括一項成人患者研究，旨在支持取得治療與給付/報銷（reimbursement），以及一項針對嬰幼兒（infants and toddlers）的研究。這些研究的主要目標是評估 zorevunersen 在這些族群中的安全性。

These are not registrational studies. Consistent with our Breakthrough Therapy Designation, we believe we can achieve a broad label without an upper age limit. Taken together, the strength of the clinical package, the continued positive feedback from payers and providers, and how we are preparing our organization and the treating community give us confidence that we will be able to deliver zorevunersen to families quickly at the time of a potential US launch in early 2028.

這些並非註冊性研究（registrational studies）。依據我們獲得的突破性療法認定（Breakthrough Therapy Designation），我們相信可在不設上限年齡的情況下取得廣泛適應症標示（broad label）。綜合而言，臨床資料組合的強度、支付方與醫療提供者持續正向的回饋，以及我們為組織與治療社群所做的準備，使我們有信心在潛在美國於 2028 年初上市時，能迅速將 zorevunersen 交付給家庭。

With that, I will turn it over to Thomas.

接下來我將交給 Thomas。

Thank you, Jason. I will remind you that full financial results can be found in today’s press release and our 10-Q that we file next week. Today, I will focus on the strength of our balance sheet position. We ended the quarter with $358.8 million in cash equivalents, and marketable securities. This excludes restricted cash of $3.2 million. Our net loss for the three months ended September 30 was $73.6 million, which include $11 million of non-cash stock-based compensation expense.

謝謝你，Jason。我提醒各位，完整的財務結果可在今天的新聞稿以及我們將於下週提交的 10-Q 中查閱。今天我將聚焦於我們資產負債表部位的強勁表現。本季結束時，我們持有 3.588 億美元的現金約當物及有價證券。此數字不包含 320 萬美元的受限制現金。截至 9 月 30 日止三個月，我們的淨虧損為 7,360 萬美元，其中包含 1,100 萬美元的非現金股票基礎薪酬費用。

Our priorities at Stoke have not changed. Advancing our Phase 3 study of zorevunersen, preparing the organization for potential US commercialization, and investing in our pipeline while maintaining a strong financial position. Along with the reimbursement we received from Biogen for zorevunersen related expenses and a potential development milestone payment, we expect our cash position to fund our operations into early 2028.

Stoke 的優先事項並未改變。推進 zorevunersen 的第 3 期研究、為潛在的美國商業化做好組織準備，並在維持強健財務狀況的同時投資我們的產品線。連同我們自 Biogen 收到的 zorevunersen 相關費用補償以及潛在的開發里程碑付款，我們預期現金部位可支應營運至 2028 年初。

Thank you. I will now ask for the line to be open for Q&A.

謝謝。我現在請開放電話線進行問答。

(Operator Instructions) Kevin Helfrich, Goldman Sachs.

(接線員指示) Kevin Helfrich，高盛。

Great, thanks. Just a question on the design for EMPEROR in terms of data quality monitoring. Can you walk us through how you designed the trial with that in mind in terms of the Vineland-3 subdomain scores, how you could consistently collect that across different time points, across different sites? That would be helpful. And then as just a brief follow-up on the multicomponent analysis plan that you have in place now, are there any meaningful differences between this plan with the FDA and what you have planned in Europe? Thanks.

很好，謝謝。我想問一個關於 EMPEROR 試驗設計、就資料品質監測方面的問題。能否帶我們了解一下，你們在設計試驗時如何把這點納入考量：就 Vineland-3 分量表分數而言，如何在不同時間點、不同研究中心之間一致地收集？這會很有幫助。另外簡短追問一下，關於你們目前採用的多組成分析計畫，這個與 FDA 的計畫，和你們在歐洲規劃的之間，有沒有任何實質差異？謝謝。

Thanks, Kevin, for the question. This is Barry. So the collection of the data for the Vineland in the study is vitally important. What we have put into place are several measures. One important one is that there is a trained central rater who collects all the data and puts together the scores, so that is uniformity across all the different sites.

謝謝你，Kevin，這個問題。我是 Barry。因此，在研究中收集 Vineland 的資料至關重要。我們已經建立了幾項措施。其中一項重要措施是由受訓的中央評分員收集所有資料並彙整分數，確保所有不同研究中心之間的一致性。

Second is that we encourage the same family member to be the reporter on the questionnaire. So at every time that the questionnaire is asked, it’s the same person giving the response. Then we also do have an internal spokesperson who is reviewing on nearly a daily basis to make sure that the Vineland tests are being collected and done appropriately at every site.

第二，我們鼓勵由同一位家庭成員擔任問卷的填答者。因此每次施測問卷時，都是同一個人提供回覆。此外，我們也有內部負責人幾乎每日審查，以確保每個研究中心都以適當方式收集並完成 Vineland 測驗。

Kevin, it’s Ian here. I’ll take the US versus Europe question. Correct, and I’m sure we’ll talk about it more on this call. The MC4, as we call it now, that’s for the US, but in Europe, they still have what’s called a net treatment benefit for individual Vineland sub-domains, and there’s five of them, in a similar way that we had before we got to the MC4. Biogen is in control of that filing in Europe, and we’ll wait to see how they proceed with those authorities overseas.

Kevin，我是 Ian。我來回答美國與歐洲的問題。沒錯，而且我相信我們在這通電話中會再多談一些。我們現在所稱的 MC4 是用於美國；但在歐洲，他們仍採用所謂針對個別 Vineland 分量表的「淨治療效益」，共有五個分量表，方式與我們在採用 MC4 之前相似。Biogen 負責歐洲的申報，我們將觀察他們如何與海外主管機關推進。

Great. Thank you.

很好。謝謝。

Laura Chico, Wedbush.

Laura Chico，Wedbush。

Good afternoon. Thank you very much for taking the question. Just two from me. I guess, following the interactions with the FDA, I’m wondering if you could elaborate if there’s been any change on the potential for an advisory committee meeting. How have the expectations there changed? And just a point of clarification, what remaining areas need to be resolved prior to the rolling submission?

午安。非常感謝讓我提問。我有兩個問題。我想在與 FDA 互動之後，想請你們進一步說明：是否就召開諮詢委員會會議（advisory committee meeting）的可能性有任何變化？相關預期有何改變？另外釐清一下，在滾動式提交（rolling submission）之前，還有哪些剩餘事項需要解決？

And I’m sorry, one last one for Barry, perhaps. You recently presented some data at the CNS meeting on the OLE data. Could you just remind us on how the protocol there handles discontinuations of preexisting ASMs? I guess maybe said it differently. I’m trying to remember whether patients are coming off some of their baseline ASMs when they were on at study entry. Thanks.

抱歉，最後再問一個，可能給 Barry。你最近在 CNS 會議上發表了一些 OLE 資料。能否提醒我們，該研究的方案如何處理既有 ASM 的停用？換句話說，我想確認病人在入組時使用的一些基線 ASM，是否會在研究期間停用？謝謝。

Laura, I will take the first two, and then Barry can take the question regarding maybe a change in medicines or ASM medicines through to week 28. Firstly, AdCom. We do not anticipate an AdCom. There was absolutely no discussion relating to an AdCom when we had our FDA interaction a month or so ago. As far as submitting data for the NDA, we anticipate submitting data throughout the first half of 2027 with a completion of the submission in the second half of 2027.

Laura，前兩個我來回答，然後 Barry 可以回答關於到第 28 週期間藥物或 ASM 藥物是否變更的問題。首先，AdCom。我們不預期會有 AdCom。大約一個月前我們與 FDA 互動時，完全沒有討論到 AdCom。至於 NDA 的資料提交，我們預期在 2027 年上半年持續提交資料，並在 2027 年下半年完成提交。

What we want to do is we want to submit that data to give the FDA the option to review early. There are no guarantees they will review early until they actually confirm that they are doing a rolling review. and so we will await that. But we will be submitting the data to the FDA to give them the option.

我們想做的是提交這些資料，讓 FDA 有機會提早開始審查。在他們實際確認採用滾動式審查之前，並無保證他們會提早審查。因此我們會等待其確認。但我們會把資料提交給 FDA，讓他們保有這個選項。

We will be continuing to work with the FDA to talk about the importance of what our medicine has shown, basically through our Phase 1/2 and our OLE data. We have had multiple meetings outside just this meeting with the FDA to show the importance of our data and the urgent need to move fast through our submission and potentially through our approval.

我們將持續與 FDA 合作，討論我們藥物所展現結果的重要性，基本上是基於我們的第 1/2 期與 OLE 資料。除了這次會議之外，我們也與 FDA 進行了多次會議，說明我們資料的重要性，以及在提交、乃至於潛在核准流程上加速推進的迫切需求。

Then Barry, do you want to talk about how we treat change in ASM medicines through week 28?

那麼 Barry，你要不要談談到第 28 週期間我們如何處理 ASM 藥物的變更？

Sure. Thanks, Laura, for the question. So the background anti-seizure medications, the patients, are monitored for the first six weeks before treatment with the background anti-seizure medications kept stable. Then they are supposed to stay stable through at least the first six months to the week 28 endpoint.

好的。謝謝你，Laura，這個問題。因此，關於背景抗癲癇藥物，病人在治療前的前六週會被監測，且背景抗癲癇藥物需維持穩定。接著理論上應維持穩定至少到前六個月，也就是第 28 週的終點。

And again, the background medications are continued, so any effects that we are going to see with zorevunersen will be on top of the baseline anti-seizure medications that they are already on. This is the way we saw in Phase 1/2, that the improvements that we saw in terms of, or the reductions that we saw in seizures, seizure frequency, were on top of background standard of care anti-seizure medications.

再者，背景用藥會持續使用，因此我們將在病人既有的基線抗癲癇藥物之上，觀察 zorevunersen 所帶來的任何效果。這也與我們在第 1/2 期所見一致：我們看到的改善，或我們在癲癇發作、發作頻率方面看到的降低，都是在既有標準照護的背景抗癲癇藥物之上發生的。

Laura, could I just also add, it is a great question. One actually Barry and I frequently talk about. I want to remind everyone that there is an eight-week screen period before you come into the EMPEROR study. That eight-week screen period, there are a number of things, but one of the things it does is it allows you to assess that these patients are already on a stable background of medicines.

Laura，我也想補充一下，這是個很好的問題。其實是我和 Barry 經常討論的一個。我想提醒大家，在進入 EMPEROR 研究之前有一個八週的篩選期。這八週篩選期包含多項目的，其中之一就是讓你能評估這些病人是否已經處於穩定的背景用藥狀態。

And so when they enter the study, whether they are going to sham or active drug arm, they are on a stable background of anti-seizure medicine. So we would anticipate there to be small changes in terms of anti-seizure medicines. But there probably will be changes, and we will assess week 28, and we will look at the data with and without the changes of those background seizure medicines.

因此當他們進入研究時，不論分派到假手術（sham）或有效藥物組，他們都處於穩定的背景抗癲癇用藥狀態。所以我們預期抗癲癇藥物的變動會很小。但可能仍會有變動；我們會在第 28 週進行評估，並在分析資料時同時檢視有無背景抗癲癇藥物變更的情況。

Thank you very much.

非常感謝。

Pete Stavropoulos, Cantor Fitzgerald.

Pete Stavropoulos，Cantor Fitzgerald。

Hello, Ian and team. Congrats on the progress and thanks for taking our questions. A couple from me.

你好，Ian 以及團隊。恭喜你們取得進展，也謝謝你們回答我們的問題。我這邊有兩個問題。

For the Vineland-3 sub-domains, you showed a very impressive forest plot compared to natural history. You mentioned on the call that even small changes can be meaningful. Just help us understand what those treatment effects sort of translate to, with examples.

關於 Vineland-3 的子領域，你們展示的森林圖相較於自然病程資料非常亮眼。你們在電話會議中提到，即使是很小的變化也可能具有意義。能否協助我們理解這些治療效果大致可轉化為什麼樣的實際改變，並舉例說明？

Also, that was also at 18 months. What gives you confidence that the one-year time point is sufficient to capture differences between the two different arms under the current multicomponent assessment of the four pre-specified sub-domains?

另外，那也是在 18 個月的時間點。在目前針對四個預先指定子領域所採用的多組分評估之下，什麼讓你們有信心一年（12 個月）的時間點足以捕捉兩個不同治療組之間的差異？

Yeah, Pete, this is Barry. Thanks for that question. Very important.

好的，Pete，我是 Barry。謝謝你的問題。非常重要。

So when we look at the treatment effect of the Vineland changes, we know that even small changes can be reflected in impact on the families, and we’ve heard that from many families. The measures of the Vineland are scores of zero, one, and two, for instance. That means that a score of zero would mean for a particular activity, that child would never do that, and a score of one would be usually.

當我們看 Vineland 分數變化的治療效果時，我們知道即使是很小的變化，也可能反映在對家庭的影響上，我們也從許多家庭那裡聽到這點。Vineland 的量表例如是以 0、1、2 來計分。這表示，對於某一項特定活動，0 分代表那個孩子從不會做，1 分代表通常會。

So if you ask the question, for instance, does the child respond to their own name or be able to say their own name? Those are questions. If you can imagine a child never being able to say their own name, as opposed to sometimes being able to say their own name, that’s a change of 1 point, which, as you can imagine, is quite meaningful for a family.

例如你問：孩子是否會對自己的名字有反應，或是否能說出自己的名字？這些都是題目。你可以想像，一個孩子從來不能說出自己的名字，相較於有時候能說出自己的名字，這就是 1 分的改變；如你所想，對家庭而言相當有意義。

Another would be following a simple instruction of one action. Again, zero being they never can do that, or one meaning they can. So as you can imagine, these are effects that are having a huge impact both on the quality of life of the child as well as the family.

另一個例子是能否遵循一個動作的簡單指令。同樣地，0 分代表他們從來做不到，1 分代表他們做得到。所以如你所想，這些效果對孩子以及家庭的生活品質都會帶來巨大的影響。

Pete, I’ll just add to that. I’m not sure how familiar people are with Vineland-3. To be honest, it sits on my desk. I look at it most days of the week, and I look at the questions, and as Barry gives some good examples. It also includes things like, do you recognize your name? Never, you get a zero. Sometimes you get a one. Usually, you get a two.

Pete，我再補充一下。我不確定大家對 Vineland-3 有多熟悉。老實說，它就放在我桌上。我一週大多數日子都會看它，並閱讀那些問題；Barry 也舉了一些很好的例子。它也包含像是：你是否認得自己的名字？從不，就得 0 分。有時候，就得 1 分。通常，就得 2 分。

That’s how it works. There’s a long list of these type of questions that you add up in terms of total score at baseline. You then do it at week 52 in our study, and same questions, and you add it all up. Let’s say there’s a total score of 150, but then at baseline. You’d get a total score of 154. That would be four Vineland points, four extra points. That would be what maybe the drug is contributing towards. So that’s how the scoring works.

運作方式就是這樣。有一長串這類問題，你把它們加總成基線時的總分。然後在我們研究的第 52 週再做一次，同樣的問題，再把它們加總。假設總分是 150，在基線時。到了之後你得到總分 154。那就是 Vineland 多了 4 分，多出 4 分。那可能就是藥物所帶來的貢獻。所以計分方式就是如此。

To Barry’s point, you shift somebody that never does something to a patient that does something sometimes. That’s a 1-point score, and therefore, meaningful. I would advise people to take a look at the Vineland scoring or the questions, and you’ll get a good feel for the type of questions that are asked.

呼應 Barry 的觀點，你把一個「從不做某事」的人，轉變成「有時候會做某事」的病人。那就是 1 分，因此具有意義。我建議大家去看看 Vineland 的計分方式或題目內容，你就會對所問問題的類型有更直觀的感受。

As far as your question regarding the 12-month, yes, we did put up the forest plot for the 18-month data. Interestingly, what we’re trying to show here is that I would start with saying, when you take the basket of endpoints approach, you have multiple ways to measure disease modification. And contrast that to a hierarchical assessment of individual Vineland domains, there is sometimes a little bit of a lottery there if you can hit the first one, so you can go to the second one and hit the second one to go to the third one.

至於你關於 12 個月的問題，是的，我們確實展示了 18 個月資料的森林圖。有趣的是，我們想在這裡說明：我會先從這點開始——當你採用「終點籃子（basket of endpoints）」的方法時，你有多種方式來衡量疾病修飾。相較之下，如果採用對單一 Vineland 領域的階層式（hierarchical）評估，有時候會有點像抽籤：你得先在第一個達標，才能進到第二個，再達標才能進到第三個。

With the multicomponent assessment, we remove that hierarchical assessment, the need for hierarchical assessment. What you’re doing is you’re assessing four domains equally as a basket to get an average score. That’s a much better way in a disease that manifests itself with multiple comorbidities that frankly do manifest at different variations within each patient.

透過多組分評估，我們移除了那種階層式評估、也就是對階層式評估的需求。你所做的是把四個領域同等看待，作為一個籃子來取得平均分數。在一種會伴隨多重共病、而且坦白說在不同病人身上表現差異各異的疾病中，這是更好的方式。

What it also does, which is a really nice outcome, it’s a statistical outcome. Because you’ve got more valuable data, you’re measuring an endpoint 4 times. You actually get more powering. You asked about the 12-month data and scoring if we ran the same assessment. We did. Interestingly, in those four domains, we missed P values on three out of the four, but we hit one out of the four. Overall, our MC4 score, so our multicomponent score, achieved an overall P value of less than 0.001.

它另外帶來的一個很好的結果是統計上的結果。因為你有更多有價值的資料，你等於把同一個終點量測了 4 次。你實際上會得到更高的檢定力（power）。你問到 12 個月資料，以及如果我們用同樣的評估來計分會如何。我們做了。有趣的是，在那四個領域中，我們有三個的 P 值沒有達標，但有一個達標。整體而言，我們的 MC4 分數，也就是多組分分數，整體 P 值小於 0.001。

Just to give you an idea of how much it enhances the powering, because you’ve got more valuable data and you’re assessing four endpoints equally. Those three endpoints that missed, they did have trends, and they were close to 0.05, so understand that. Then there was one that was below 0.05. Overall, the MC4 P value was 0.001 or 0.01, sorry. So less than.

這只是讓你了解它在提升檢定力方面的效果有多大，因為你有更多有價值的資料，且四個終點被同等評估。那三個未達標的終點其實也呈現趨勢，而且接近 0.05，請理解這點。然後有一個低於 0.05。整體而言，MC4 的 P 值是 0.001 或 0.01，抱歉。所以是小於（該數值）。

What we’re trying to show here is that we’ve enhanced the powering of the study, but as a principle, it’s enhanced and it’s more appropriate of how to measure the cognition and behavioral benefits our medicine may be providing to these patients because it is a basket approach.

我們想在這裡表達的是：我們提升了研究的檢定力；但從原則上來說，這種方式也更合適，用來衡量我們的藥物可能為這些病人帶來的認知與行為方面的效益，因為它是一種籃子式的方法。

All right. Well, thanks very much, Ian, and congratulations again on the progress and looking forward to the data.

好的。非常感謝你，Ian，也再次恭喜你們的進展，期待看到資料。

Thanks, Pete.

謝謝你，Pete。

Andrew Tsai, Jefferies.

Andrew Tsai，Jefferies。

Hey, guys. Congrats on all the great execution. This is John on for Andrew. Thanks so much for taking our question. Earlier this week, your partner, Biogen, made a comment about how they think differentiation and differential pricing, especially for ex-US, is for the zorevunersen to have an impact on cognition. Just curious how you guys think about their comments and whether there’s an alignment on the underlying value proposition. Thanks.

嗨，各位。恭喜你們執行得非常出色。我是 John，代 Andrew 發問。非常感謝你們回答我們的問題。本週稍早，你們的合作夥伴 Biogen 提到，他們認為差異化與差異化定價，特別是在美國以外市場，將取決於 zorevunersen 是否能對認知產生影響。想請教你們如何看待他們的評論，以及你們在底層的價值主張上是否一致。謝謝。

Well, I think Biogen can give you their best answer. I don’t mean to speak for Biogen. But I’ve been involved with rare disease, genetic diseases, and readouts in the single-payer markets within Europe, for example, which is what I think you’re asking about, John. I will tell you that it is more challenging in those markets than it is in the US.

我想 Biogen 可以給你他們最好的答案。我不想代表 Biogen 發言。但我曾參與罕見疾病、遺傳疾病，以及例如歐洲單一支付者市場中的數據解讀，我想你問的是這部分，John。我可以告訴你，那些市場確實比美國更具挑戰。

In the US, I would say the approach, and I’m very comfortable talking about the US, because those are our territories. But in the US, it is about the totality of the data. We’ve been sharing four-year OLE data, New England Journal of Medicine, various peer-reviewed presentations with the payers, and they understand the value of the medicine. Jason will probably comment on that later.

在美國，我會說我們的做法——而且我很放心談美國，因為那是我們的市場——在美國，重點在於資料的整體性（totality of the data）。我們一直與支付方分享四年的 OLE（開放標籤延伸）資料、《新英格蘭醫學期刊》發表，以及各種同儕審查的報告與簡報，而他們理解這項藥物的價值。Jason 之後可能也會對此再補充。

Whereas in the EU, for example, they do hold you closer to the label in terms of valuing a medicine. They have a whole scoring system in certain countries. But overall, it is more challenging over there. But Biogen should be able to provide you more understanding of that. But it is more challenging in Europe.

例如在歐盟，他們在藥品定價評估上，確實會更嚴格地依照標籤（label）所載內容來衡量。在某些國家，他們有一整套評分系統。但整體而言，那邊的挑戰更大。不過 Biogen 應該能讓你更了解這方面的情況。但在歐洲確實更具挑戰性。

Thanks so much. Then maybe just one quick follow-up, if I may. I was curious, besides the Vineland-3 adjustment and the recent FDA meeting, what other topics may have come up in the meeting with the FDA? Or was Vineland-3 the main focus? Thanks.

非常感謝。那如果可以的話，我再快速追問一個問題。我想了解，除了 Vineland-3 的調整以及最近與 FDA 的會議之外，這次與 FDA 的會議還討論了哪些其他主題？還是 Vineland-3 是主要焦點？謝謝。

There was a few other things. So I think Vineland-3, getting to the multicomponent four assessment was the priority focus. The submission of data to the NDA was important. We did ask the question regarding the OLE data, the four-year OLE data, which will be five-year OLE data by the time that we submit our data. We asked them whether that can be included in the label, and we got a clear answer from them, which is it will be a review issue, which is a good answer for us.

還有幾個其他事項。所以我認為 Vineland-3、以及推進到多組成（multicomponent）的四項評估，是優先的重點。將資料提交到 NDA 也很重要。我們也詢問了關於 OLE 資料、也就是四年的 OLE 資料；等到我們提交資料時，將會是五年的 OLE 資料。我們問他們這些資料是否可以納入標籤，他們給了我們明確答覆：這會是審查（review）議題；對我們來說這是個好的回答。

This is a chronically dosed medicine. By the time we file, we are going to have five years worth of data to show how these children may have compounded benefits year one to year two to year three to year four to year five. We believe that is important. The regulations for labeling is that you put clinical study data on the label that is supportive of an understanding of the benefits a medicine may provide.

這是一種需要長期、持續給藥的藥物。等到我們遞交申請時，我們將有五年的資料可用來展示：這些孩子可能從第一年到第二年、第三年、第四年、第五年，累積（compounded）獲益。我們認為這很重要。標籤法規的要求是：在標籤上放入臨床研究資料，以支持對藥物可能帶來之效益的理解。

Overall, the interaction with the FDA is always a great opportunity to continue to educate on our medicine. That is where we started with the OLE data, because it is a chronic disease, and we are dosing a chronic medicine. We have come a long way with the FDA over the last two years. I think that was one of the reasons it drove the outcome to the multicomponent assessment, where we are assessing cognition and behavior on a basket of endpoints now.

整體而言，與 FDA 的互動一直都是持續向其說明我們藥物的一個很好的機會。因此我們從 OLE 資料談起，因為這是慢性疾病，而我們給的是慢性用藥。過去兩年我們與 FDA 的溝通已經走了很長一段路。我認為這也是促成多組成評估結果的原因之一；我們現在用一籃子（basket）的終點來評估認知與行為。

Understood. Thanks so much, and congrats again on all the progress.

了解。非常感謝，也再次恭喜你們取得的所有進展。

Thank you.

謝謝。

Sumant Kulkarni, Canaccord.

Sumant Kulkarni，Canaccord。

Good afternoon. Thanks for taking our questions. This is again related to the Vineland scale and the multicomponent assessment used as a key secondary endpoint. Does the relative contribution of the subdomain to the average score assume importance, and would high deviations from the mean on sub-domains make a difference to being able to support a disease modifying claim on the label?

下午好。感謝回答我們的問題。這個問題同樣與 Vineland 量表以及作為關鍵次要終點（key secondary endpoint）的多組成評估有關。各子領域（subdomain）對平均分數的相對貢獻是否重要？如果某些子領域相對於平均值的偏離很大，是否會影響在標籤上支持疾病修飾（disease modifying）主張的能力？

I guess asked another way, would an average that meets the definition of clinical relevance still be viewed that way if one or two sub-domains drive most of the difference, even if the others may take away from the effect?

換個方式問：即使平均值符合臨床相關性（clinical relevance）的定義，但如果差異主要由一到兩個子領域所驅動，而其他子領域反而削弱效果，這樣的平均值仍會被視為具有臨床相關性嗎？

Thanks for the question, Suman. The way it does work, and I’ll keep this simple, which is you do assess equally, each subdomain. So there’s four sub-domains you assess equally.

謝謝你的問題，Suman。它的運作方式是這樣，我會簡單說明：你會對每個子領域做同等權重的評估。所以有四個子領域，都是等權重評估。

Let’s say you score a 3, a 3; a 2, and a 2. Make the numbers easy. Divide that by 4, and that gives you a MC4 score of 2.5. That’s what you then assess the P value. One of the things I want to be very clear on, what we’re trying to help you with these forest plots that we’ve showed today, that 2.5, if you score it, because you’re assessing Vineland four different ways and you’ve got more valuable data, you get more power to that score.

假設你得到 3、3、2、2。用簡單的數字來說明。把它除以 4，就得到 MC4 分數 2.5。接著你就用這個分數去評估 P 值。我想非常清楚地說明一點：我們今天展示的這些森林圖（forest plots）想幫助大家理解的是，這個 2.5 的分數，因為你用四種方式評估 Vineland、取得更有價值的資料，因此這個分數會有更高的統計力（power）。

And that’s why when I referred to the 12-month or even the 18-month scoring of MC4, we got a lower P value than we did in any individual domain. What it really translates to is you could miss on one of the domains in terms of a P value, but still achieve a significantly low P value of potentially 0.01, as we saw on the 12-month data.

這也是為什麼我提到 12 個月、甚至 18 個月的 MC4 評分時，我們得到的 P 值比任何單一領域（domain）都更低。這實際上代表：你可能在某一個領域的 P 值上沒有達標，但仍可能達到顯著偏低的 P 值，例如我們在 12 個月資料中看到可能到 0.01。

And I’ll just take this opportunity. When I say we missed on one on the 12-month data, I want to be clear, and Barry was in his remarks earlier on this call. The 12-month data was suboptimal dose. There was a 6- to 7-month gap in dosing, and they did not get the level of dosing that we’re dosing in our Phase 3. I do want to remind people of that, but I’m giving you the example that we still hit a very low P value, less than 0.01, even on the 12-month data. So it is a simple kind of average, but because you’ve got more valuable data, you get greater power.

我也藉此機會補充一下。當我說我們在 12 個月資料中有一項沒有達標時，我想講清楚；Barry 先前在本次電話會議的發言也提到。12 個月的資料使用的是次最佳劑量（suboptimal dose）。給藥中間有 6 到 7 個月的空窗期，而且他們沒有達到我們在第三期（Phase 3）所使用的給藥劑量水準。我想提醒大家這點；但我舉這個例子是要說明：即便在 12 個月資料下，我們仍達到非常低的 P 值，小於 0.01。所以它確實是一種簡單的平均，但因為你有更有價值的資料，因此統計力更強。

I’ll just add, Sumant. This is Barry. What Ian was talking about also, the 12-month data, those were with a relatively small number of patients, quite small number of patients. So obviously, we’re going to have more. Addressing your question a little bit more specifically, of the four sub-domains, there is no one that is more important than the other when we do this calculation.

我再補充一下，Sumant。我是 Barry。Ian 也提到的 12 個月資料，是在病人數相對較少、相當少的情況下得到的。所以很明顯，我們之後會有更多病人數。更直接回應你的問題：在這四個子領域中，當我們做這個計算時，沒有任何一個比其他更重要。

The other thing, the advantage of doing this multicomponent is that it smooths out the variability and the differences between the different sub-domains. So even if there is one that is extreme, extremely high, for instance, or extremely low, the multicomponent will take that into account and average it out.

另外，多組成作法的優點之一，是它能平滑（smooth out）不同子領域之間的變異性與差異。因此即使其中一個子領域非常極端，例如特別高或特別低，多組成指標也會把它納入考量並加以平均化。

Got it. Thank you.

了解。謝謝。

Yaron Werber, TD Cowen.

Yaron Werber，TD Cowen。

Great. Thanks so much and really nice progress. So Barry, on the last point on the MMRM is a big deal on the composite, right? Because essentially, it uses the entire curve in every visit. You’re not just doing baseline against at the end. As you mentioned, it really helps reduce heterogeneity and ultimately really boosts the power. And also, I believe that when you use MMRM, the way you handle dropouts is you don’t have to impute. Can you comment on that?

很好。非常感謝，進展也很不錯。Barry，關於你剛才提到的最後一點：在複合指標（composite）上使用 MMRM 是很關鍵的，對吧？因為基本上它會使用每次訪視（visit）的整條曲線資料。你不只是做基線（baseline）對照期末。如你所說，它確實有助於降低異質性（heterogeneity），並最終提升統計力。而且我相信使用 MMRM 時，對於退組（dropouts）的處理方式是不需要做插補（impute）。你能評論一下嗎？

And also, the second question, are you doing the MMRM, the multiplicity at the same time, or is each score still hierarchical of the four domains? Thank you.

另外第二個問題：你們是在做 MMRM 的同時處理多重性（multiplicity）嗎？還是四個領域的每個分數仍然採用階層式（hierarchical）檢定？謝謝。

Yaron, thanks. This is Barry. So as far as the MMRM, yes, we’re using the MMRM for the Vineland. And the advantage of that is that it takes into account all of the data collected up to that time point. So as you mentioned, it’s not just at week 52.

Yaron，謝謝。我是 Barry。就 MMRM 而言，是的，我們在 Vineland 上使用 MMRM。其優點是它會把截至該時間點所收集的所有資料都納入考量。所以如你所提到的，它不只是看第 52 週。

We do have a collection of the Vineland, for instance, at six months in the study. That would be combined with the data that we have at the 52-week endpoint. And it does allow then for any missing data and could then impute for missing data or take that into account. As far as the hierarchy, the multicomponent endpoint will be assessed as all four of the sub-domains together.

例如，在研究進行到六個月時，我們確實會收集 Vineland 的資料。這些資料會與我們在第 52 週終點所取得的資料合併。如此一來，就能處理任何缺失資料，並可對缺失資料進行插補或將其納入考量。就層級而言，多組成分終點將以四個子領域合併一起評估。

So there is no need to put together any hierarchy. That was part of what we had in agreement with FDA, that we can measure just that as a second key endpoint. We will just use the multicomponent and not have to do any ranking of the sub-domains. So that obviously is an advantage in terms of having power for that endpoint.

因此不需要建立任何層級。這是我們與 FDA 達成一致的一部分，也就是我們可以將其作為第二個關鍵終點來衡量。我們將僅使用多組成分，而不必對各子領域進行任何排序。因此，這顯然在該終點的統計檢定力方面是一項優勢。

Thank you. Super useful.

謝謝。非常有幫助。

Joseph Stringer, Needham.

Joseph Stringer，Needham。

Hi, thanks for taking our question. Just a follow-up question on the statistical analysis. Just given the change to the multicomponent analysis from the individual component, can you speak to how this affects the alpha allocation? Does this change the split across the primary endpoint, the week 28 endpoint, and the seizure endpoint at week 52 in this new MC4 assessment?

嗨，謝謝你們回答我們的問題。我想就統計分析再追問一下。鑑於分析方式從單一組成分改為多組成分分析，你們能否談談這對 alpha 分配有何影響？在新的 MC4 評估下，這是否會改變主要終點、第 28 週終點，以及第 52 週癲癇發作終點之間的分配？

So Joe, it’s Ian. I think Barry referred to these endpoints and how they’re measured, the primary, given this change with MC4. In the prepared remarks, we gave you the updated powering. So let me just remind you of that.

Joe，我是 Ian。我想 Barry 已提到這些終點以及在 MC4 這項變更下它們如何被衡量。在事先準備的發言中，我們已提供更新後的檢定力估算。我先提醒大家一下。

Firstly, we do have more patients that are being retained in this study than we initially anticipated. Just to remind you of the initial expectations, we thought this would be a 150-patient study with potentially a 15% dropout. That gave us an estimate of needing 128 patients to power the study.

首先，這項研究中留在試驗內的受試者人數比我們最初預期的更多。提醒一下最初的預期，我們原本認為這會是一項 150 名受試者的研究，且可能有 15% 的退出率。因此我們估算需要 128 名受試者才能讓研究具備足夠的檢定力。

But if we bring it all the way forward, as of today, we’ve got 162 patients in the study, of which zero dropouts and 110 of those are already through the primary endpoint. We believe there is going to be more evaluable patients. What we showed you today is we’re making an assumption. That’s all it is.

但如果把時間推進到今天，截至目前我們研究中共有 162 名受試者，其中退出為零，且其中 110 名已經完成主要終點的評估。我們相信可評估的受試者人數會更多。我們今天展示的是一項假設。僅此而已。

But maybe there’s going to be 150 evaluable patients. Assuming there’s 150 evaluable patients, and with these new assessments, we anticipate that we need a 46%-53% treatment effect for seizure reductions just to achieve P values of 0.05 or 0.1.

但也許會有 150 名可評估的受試者。假設有 150 名可評估受試者，並在這些新的評估方式下，我們預期癲癇發作減少需要達到 46%–53% 的治療效果，才能使 P 值達到 0.05 或 0.1。

For that Vineland endpoint, it’s now 1.8 to 2.1 to achieve a P value of 0.05 to 0.1. The evaluable patients that are still in the study and this change has really enhanced the overall powering of the study. I do want to continue to echo, I will say, or repeat. The real benefit here is this is a disease with many comorbidities. They evolve at different rates within different patients. Being able to measure these endpoints in a basket approach is the real win here, because that is the way you should be measuring disease modification.

至於 Vineland 終點，現在需要達到 1.8 到 2.1，才能使 P 值達到 0.05 到 0.1。仍在研究中的可評估受試者，以及這項變更，確實提升了研究整體的檢定力。我也想再次強調，或者說重申。真正的好處在於，這是一種伴隨許多共病的疾病。不同患者的共病以不同速度演變。能以「籃式」方式衡量這些終點才是關鍵勝利，因為這才是衡量疾病修飾效果應採用的方法。

I will just add, Joe, to your question. In terms of split, there is no alpha split. The seizure reduction at 28 weeks is the primary endpoint. 52-week seizure reduction is the first secondary, and the Vineland is the second secondary. Sp alpha is not split between those.

另外補充一下，Joe，針對你問的問題。就分配而言，沒有 alpha 分割。第 28 週的癲癇發作減少是主要終點。第 52 週的癲癇發作減少是第一個次要終點，而 Vineland 是第二個次要終點。這些之間不會分割 alpha。

Jessica Fye, JPMorgan.

Jessica Fye，JPMorgan。

Hey, guys. Good afternoon. Thanks for taking my question. I was curious, what do experts tell you is a clinically meaningful drop in seizures?

嗨，各位。下午好。謝謝你們回答我的問題。我想了解的是，專家告訴你們癲癇發作下降多少才具有臨床意義？

Clinically meaningful drop in seizures? Actually, Jason, why don’t you take that again? You spend a lot of time in the field.

癲癇發作下降多少才具有臨床意義？其實，Jason，你要不要再回答一次？你在第一線花了很多時間。

Yeah, it’s a great question, Jess. When we talk to healthcare providers in market research, I think the first thing they talk about when you talk about what the unmet need is in Dravet, it is the persistent seizure burden that exists today with the anti-seizure medications and the strong desire to ultimately get as close as possible, if not, to seizure freedom itself.

是的，Jess，這是個很好的問題。當我們在市場調查中與醫療照護提供者交流時，我認為他們在談到 Dravet 的未被滿足需求時，首先提到的是：即使已有抗癲癇藥物，當前仍存在持續的癲癇發作負擔；並且大家強烈希望最終能盡可能接近、甚至達到無發作。

Any additional reduction in seizures on top of the best standard of care medicines is considered an advance. But I think most are expecting something in the neighborhood of 40%-50% additional reduction over what you would see in the control arm.

在最佳標準治療用藥的基礎上，任何額外的癲癇發作減少都被視為一種進步。但我認為多數人期待的是，相較於對照組所看到的結果，能再額外降低約 40%–50%。

To be clear, is that an expectation for the trial, or is the threshold for clinical meaningfulness, really, 40%?

我想確認一下，這是對試驗結果的期待，還是臨床意義的門檻其實就是 40%？

It’s more what their expectation is of a disease-modifying treatment versus clinically meaningful. I think if you ask them what’s clinically meaningful, fewer seizures is always clinically meaningful relative to more seizures.

這更像是他們對「疾病修飾」治療的期待，而不是臨床意義的定義。我想如果你問他們什麼是具有臨床意義的，癲癇發作更少相對於更多，永遠都具有臨床意義。

Okay. And just last one for me. Is success in EMPEROR defined by achieving stat sig with a P value less than 0.05 or less than 0.01?

好的。那我最後一個問題。EMPEROR 的成功是以達到統計顯著、P 值小於 0.05，還是小於 0.01 來定義？

Jess, this is Barry. Yeah. The answer is 0.05. So this is a standard assessment that we have put into the protocol, so that 0.05 for the primary, as well as the key secondaries would be statistically significant.

Jess，我是 Barry。是的，答案是 0.05。這是我們納入試驗方案中的標準評估，因此主要終點以及關鍵次要終點，只要達到 0.05 就會被視為具有統計顯著性。

Great. Thank you.

很好。謝謝。

Marc Goodman, Leerink.

Marc Goodman，Leerink。

Yeah. The comment around the five-year data being a review issue, did that refer to if the study just misses, then the FDA would consider the longer-term five-year data a review issue? Is that what you were saying?

是的。你提到五年期資料會是審查議題（review issue）的那段評論，是指如果研究結果只是些微未達標，那 FDA 會把較長期的五年資料視為審查議題嗎？你是這個意思嗎？

When it comes to misses, it always depends on how close you are on the miss. And it is always a discussion. There are many drugs that have had P values that miss on the 0.05 but have been close. When you take into the totality of the primary and secondary endpoints and tertiary endpoints, you can absolutely have a discussion with the FDA.

談到未達標時，總是取決於你未達標的幅度有多接近。而且這永遠都需要討論。有許多藥物的 P 值未達 0.05，但非常接近。當你把主要與次要終點以及第三終點的整體證據一併納入考量時，你絕對可以與 FDA 進行討論。

I do feel as though we are in a good position with the OLE data, which will be five years of OLE data, or effectively six years of OLE data by the time we file. It does put you in a good position. But we did not discuss with them about missing.

我確實覺得，憑藉 OLE 資料我們處於有利位置；到我們申報時，將會有五年的 OLE 資料，或實際上接近六年的 OLE 資料。這確實讓你處於有利位置。但我們並沒有和他們討論「未達標」的情境。

Right.

了解。

It was more of an education of the disease. We started there, just as we did this time last year when we asked if they would support an NDA submission on the basis of the OLE in Phase 1 data. This continuous education, certainly over the last two years, has really brought the FDA forward to be in a really good spot of understanding the disease and how our medicine affects that disease. It will be the totality of the data that will drive the label.

那更多是關於疾病的教育。我們從那裡開始，就像去年這個時候一樣，當時我們詢問他們是否會支持基於第一期 OLE 資料來提交 NDA。這種持續的教育，尤其在過去兩年，確實讓 FDA 在理解該疾病以及我們的藥物如何影響該疾病方面，進展到一個非常好的狀態。最終將由整體資料來決定標籤內容。

I guess, Ian, one of the other analysts was asking about at the FDA meeting, and you mentioned three things, and the third thing was they asked about the four-year data, and you talked about the five-year data, and you said it was a review issue. What did you mean exactly when you said it would be a review issue? Referring to the five-year data serving as what?

我想，Ian，另一位分析師在問 FDA 會議的事，你提到了三件事，第三件是他們問到四年期資料，而你談到五年期資料，並說那是審查議題（review issue）。你說它會是審查議題時，具體是什麼意思？你指的是五年期資料將作為什麼用途？

Oh, okay. Yes. Thanks for clarifying, Marc. So when you go to the FDA, the process is you submit a briefing book. That briefing book has questions in it.

哦，好。是的。謝謝你釐清，Marc。所以當你去 FDA 時，流程是你會提交一份簡報資料（briefing book）。那份簡報資料裡面會包含問題。

One of the questions that we put in that briefing book specifically was, would you support putting the OLE data within our label? Section 14, it’s known as. Would you support putting that data in our label if we were to have approval? As you probably know, the FDA doesn’t say yes at this point in time, but they did say it would be a review issue, which is a very clear answer, which is it’s the totality of data.

我們在那份簡報資料中放入的一個問題，特別是：你們是否會支持把 OLE 數據放進我們的標籤（label）裡？也就是所謂的第 14 節。如果我們獲得核准，你們是否會支持把那些數據放進我們的標籤？如你可能知道的，FDA 在這個時間點不會直接說「是」，但他們確實表示這會是一個審查議題（review issue），這其實是非常明確的回答，也就是要看全部數據的整體性（totality of data）。

Right.

對。

That’s what I meant by it being a review issue.

這就是我所說它會是一個審查議題的意思。

Got it. Then just secondly, just to be clear on this MC4, it can be positive even if the benefit is concentrated in one or two sub-domains, the way you’ve described it, right? That discussion is, you’ve had that with FDA. If you hit your Vineland secondary endpoint with the P value, you’re going to be good, right? Even if it’s driven by one or two of these sub-domains. Is that fair to say?

了解。那第二點，為了把 MC4 講清楚，依你描述的方式，即使效益集中在一到兩個子領域（sub-domains），它也可以是正向的，對吧？你們已經和 FDA 討論過這點。如果你們在 Vineland 的次要終點（secondary endpoint）達到 P 值，你們就會沒問題，對吧？即使它是由其中一到兩個子領域所驅動。這樣說公平嗎？

That is correct. They’ve absolutely gone far with us in the discussion to advise us that they would like to see it as a forest plot because they want to understand what drives the MC4 score. The example you just gave, Marc, is a good one. The example where you say you miss or you get a zero in one of the domains, but if you hit on the others, yes, as long as you hit your P value on MC4, yes, acceptable.

沒錯。他們在討論中確實和我們談得很深入，並建議我們他們希望以森林圖（forest plot）的方式呈現，因為他們想了解是什麼在驅動 MC4 分數。你剛剛舉的例子，Marc，是個很好的例子。你說某一個領域沒達到或拿到零分，但如果其他領域達到，是的，只要你在 MC4 的 P 值達標，是的，可以接受。

Thank you.

謝謝。

Rudy Li, Wolfe Research.

Rudy Li，Wolfe Research。

Hey, thanks for taking my question. Maybe a question for Barry. For upcoming ADOA readout in first half, what is the bar for visual retinal benefits to support your dosing selection. I mean, making sure you are reaching the therapeutic levels. Are you measuring OPA1 protein levels, and do you need further dose-finding study before a pivotal? Thanks.

嗨，謝謝讓我提問。可能是問 Barry 的問題。針對上半年即將公布的 ADOA 讀出結果，在視覺／視網膜效益方面，要達到什麼門檻才能支持你們的劑量選擇？我的意思是，確保你們達到治療濃度。你們有在測量 OPA1 蛋白水平嗎？在進入關鍵性試驗（pivotal）之前，是否需要進一步的劑量探索研究？謝謝。

Yeah, Rudy, thanks for the question. Yeah, so the ADOA program is a very important program for us, and we do have quite a bit of preclinical data and data from the field that supports the premise that increasing OPA1 protein levels in the cell can have a beneficial effect and potentially even improve vision in ADOA patients.

好的，Rudy，謝謝你的問題。是的，所以 ADOA 計畫對我們非常重要，我們確實有相當多的臨床前數據以及來自實務領域的數據，支持這樣的前提：提高細胞內 OPA1 蛋白水平可能帶來有益效果，甚至可能改善 ADOA 患者的視力。

So the Phase 1 study is designed primarily as a safety study, which will be an important readout, but we are also looking at visual acuity as well as a biomarker measure of mitochondrial function. So those will be important endpoints for us to analyze in terms of the decision to make to go forward. But again, improvement in vision would be something that we would be looking for as well as the safety effects.

因此，第 1 期研究主要設計為安全性研究，這將是一個重要的讀出結果，但我們也會觀察視力（visual acuity），以及一項反映粒線體功能的生物標記（biomarker）測量。因此，這些將是我們在決定是否繼續推進時要分析的重要終點。但同樣地，視力改善也是我們會尋找的訊號之一，連同安全性效果一起評估。

Yeah. So it sounds like you need another dose-ranging study to determine the right dose moving forward. Is that fair?

好的。聽起來你們需要另一個劑量範圍研究（dose-ranging study）來決定後續正確的劑量。這樣說公平嗎？

I would say that we’ll wait and see what the data are. We are considering different ways to potentially accelerate the program because this is a disease where there is no approved medicine for this patient.

我會說，我們會先等看看數據結果如何。我們正在考慮不同方式來加速這個計畫，因為這是一種目前沒有任何已核准藥物可用的疾病。

And patients are progressively losing vision. So there’s a tremendous amount of interest, both on the part of the patient advocates as well as the clinicians to see this sort of medicine. So we’re going to look for the way that we can most quickly get the medicine to the patients.

而且患者的視力正在逐步喪失。因此，無論是病友倡議者或臨床醫師，都對這類藥物抱有極大的興趣。所以我們會尋找能夠最快把藥物送到患者手上的方式。

Got it.

了解。

To your other question, in terms of the OPA1 protein level, that’s not something we’re measuring, but as I mentioned, we have this biomarker for mitochondrial function. So that would be an important way that we could look at the basis for the mechanism of action of the medicine.

至於你另一個問題，關於 OPA1 蛋白水平，那不是我們正在測量的項目；但如我提到的，我們有這個用於粒線體功能的生物標記。因此，這會是我們用來觀察該藥物作用機轉（mechanism of action）基礎的一個重要方式。

Very helpful. Thank you.

非常有幫助。謝謝。

Yatin Suneja, Guggenheim.

Yatin Suneja，Guggenheim。

Hey, guys. Thank you for taking my question. Maybe just one more on ADOA. Could you maybe articulate for us a little bit more on what the learnings were from the first two cohorts? How would you characterize the cohort later this year? That is the first part.

嗨，各位。謝謝讓我提問。可能再問一個關於 ADOA 的問題。你們能否再多說一點，前兩個隊列（cohorts）有哪些學習與收穫？你們會如何描述今年稍晚的那個隊列？這是第一部分。

The second is on the spend side. Could you maybe also comment on how should I model the spend in Q4 in 2027? Any sort of color you guys could provide would be great. Thank you.

第二部分是關於支出。你們能否也評論一下，我應該如何建模 2027 年第 4 季的支出？你們能提供的任何補充說明（color）都會很有幫助。謝謝。

Yatin, thanks for that important question. This is Barry. In terms of progressing the study, as I mentioned before, the primary endpoint is safety. We do have a safety monitoring committee that reviews the results, and they did review the results of the first two cohorts, and so that recommendation to move forward to the third cohort was part of the safety review.

Yatin，謝謝這個重要的問題。我是 Barry。就研究推進而言，如我先前提到，主要終點是安全性。我們確實有一個安全性監測委員會會審查結果，他們也已審查前兩個隊列的結果，因此，建議推進到第三個隊列的決定，是安全性審查的一部分。

I would just add, Yatin, to what Barry’s saying. As we move into the third and fourth cohort, at doses of 0.3 milligrams and 0.5 milligrams, we are starting to move into the therapeutic dosing level, and that’s why we anticipate seeing safety and efficacy results in the first half of 2027. Tommy?

我再補充一下，Yatin，針對 Barry 所說的。當我們進入第三與第四個隊列、劑量為 0.3 毫克與 0.5 毫克時，我們開始進入治療劑量水準，這也是為什麼我們預期在 2027 年上半年看到安全性與有效性結果。Tommy？

Yatin, this is Tommy here. Thanks for the question. Just to help you, just to get you straight there in terms of how to guide forward to Q4 2026, I think you should look at Q3 2026. You saw the increase we saw quarter-to-quarter, and I think you could assume a similar number going forward.

Yatin，我是 Tommy。謝謝你的問題。為了協助你釐清、並就如何指引到 2026 年第 4 季，我認為你應該參考 2026 年第 3 季。你看到我們季度對季度的增幅，我想你可以假設往後也是類似的數字。

Thank you. I am showing no further question. I will now turn the call back over to Ian Smith for any closing comments.

謝謝。我這邊顯示沒有其他提問。我現在把電話交回給 Ian Smith，請他做結語。

Oh, thank you. Just want to thank everybody for their time tonight. We approach this call, thank you for submitting questions to us beforehand. It gives us good clarity. Fortunately, we were in position to help you understand this technical analysis of the primary and secondary endpoints and the powering of the study. All very important and all very good questions, so I appreciate your time and your patience of listening to us, and look forward to catching up with you very soon. Thank you.

哦，謝謝。只想感謝今晚各位撥冗參與。我們在準備這通電話會議時，也謝謝大家事先提交問題給我們。這讓我們能更清楚掌握重點。很幸運地，我們也能協助各位理解主要與次要終點的技術性分析，以及研究的檢定力（powering）。這些都非常重要，也都是很好的問題，所以感謝各位的時間，以及耐心聆聽我們的說明；也期待很快能再與各位交流。謝謝。

Ladies and gentlemen, that does end our conference for today. Thank you for your participation. You may now disconnect.

各位女士先生，今天的電話會議到此結束。感謝各位的參與。您現在可以掛線。