Praxis Precision Medicines Inc (PRAX) 2025 Q2 法說會逐字稿

Good day, and welcome to the Praxis Precision Medicine's RADIANT top line results and second-quarter 2025 financial results conference call. (Operator Instructions) As a reminder, this call may be recorded.

大家好，歡迎參加 Praxis Precision Medicine 的 RADIANT 頂線業績和 2025 年第二季財務業績電話會議。（操作員指示）提醒一下，此通話可能會被錄音。

I would now like to turn the call over to Dan Ferry of LifeSci Advisors. Please go ahead.

現在我想把電話轉給 LifeSci Advisors 的 Dan Ferry。請繼續。

Good morning, and welcome to the Praxis Precision Medicine's RADIANT top line results and second quarter 2025 financial results conference. This call is being webcast live and can be accessed on the Investors section of the Praxis website at www.praxismedicines.com.

早安，歡迎參加 Praxis Precision Medicine 的 RADIANT 頂線業績和 2025 年第二季財務業績會議。本次電話會議正在進行網路直播，您可以透過 Praxis 網站 www.praxismedicines.com 的投資者部分觀看。

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 time lines 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，本次電話會議中的言論可能包含《1995 年私人證券訴訟改革法案》所定義的前瞻性陳述。這些可能包括有關公司未來預期和計劃、臨床開發時間表和財務預測的聲明。雖然這些前瞻性陳述代表了 Praxis 目前的觀點，但不應將其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' most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.

Praxis 將來可能會更新這些聲明，但不承擔這樣做的義務。請參閱 Praxis 向美國證券交易委員會提交的最新文件，以了解與公司業務相關的某些風險和不確定性。

Joining the call today are Marcio De'Souza, President and Chief Executive Officer of Praxis; Tim Kelly, Chief Financial Officer; and Steve Petrou, Chief Scientific Officer. After our prepared remarks, there will be a brief question-and-answer session.

今天參加電話會議的有 Praxis 總裁兼執行長 Marcio De'Souza、財務長 Tim Kelly 和首席科學長 Steve Petrou。在我們準備好的發言之後，將有一個簡短的問答環節。

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

說完這些，我很高興將電話轉給馬西奧。馬西奧？

Good morning, everyone, and welcome to the RADIANT's top line results presentation. We're incredibly excited to share this Best-in-disease results with all of you. Before we begin, I would like to note that today's presentations contain forward-looking statements. For complete disclosures, please refer to our latest SEC filings. Praxis is in an incredible position to bring innovative drugs to patients with CNS disorders.

大家早安，歡迎參加 RADIANT 的頂線業績示範。我們非常高興與大家分享這最佳疾病結果。在我們開始之前，我想指出今天的演示包含前瞻性陳述。如需完整揭露，請參閱我們最新的 SEC 文件。Praxis 在為中樞神經系統疾病患者提供創新藥物方面具有得天獨厚的優勢。

We have four late-stage assets, 1 of which we are discussing here today, and we expect five clinical [readouts] within the next year. There is no small feat. This progress is powered by our two robust platforms, enabling current developments and future CNS drug innovation. Our cash runway extends into 2028, supporting our ambitious clinical agenda.

我們有四項後期資產，其中一項我們今天在這裡討論，我們預計明年將有五項臨床[讀數]。這絕非易事。這項進步得益於我們兩個強大的平台，支持當前的發展和未來的中樞神經系統藥物創新。我們的現金流延伸至 2028 年，以支持我們雄心勃勃的臨床計劃。

Today, we'll discuss the RADIANT results for Vormatrigine. But it's worth taking a few moments to remind everyone of the rich and zip pipeline we have with multiple readouts coming out in the next several quarters, which will enable Praxis to stay at the forefront of CNS drug development.

今天，我們將討論沃馬三嗪的 RADIANT 結果。但值得花點時間提醒大家，我們擁有豐富且快速的研發管道，未來幾季將發布多份報告，這將使 Praxis 始終處於中樞神經系統藥物開發的前沿。

Focal Epilepsy a very serious medical condition impacting about 3 million US patients. Contrary to common belief, most of the patients are now doing well. Over 60% of those patients require multiple antiseizure medications, highlighting the inadequacy of existing therapies. Patients need effective, tolerable, fast-acting and durable treatments to avoid a constant ASM cycling, and we believe Vormatrigine can deliver on that.

局部性癲癇是一種非常嚴重的疾病，影響約 300 萬美國患者。與普遍的看法相反，大多數患者現在情況良好。超過 60% 的患者需要多種抗癲癇藥物，凸顯了現有療法的不足。患者需要有效、可耐受、快速起效且持久的治療方法來避免持續的 ASM 循環，我們相信 Vormatrigine 可以實現這一點。

Starting with today's results, Vormatrigine is showing best-in-disease efficacy in the RADIANT study. That should be enough to be excited. We should not minimize the further differentiation of vormatrigine with current and in development therapies being the only drug to combine, once daily administration, fast action, no food effect ideal tolerability and no meaningful drug-drug interactions, which importantly do not interfere with common contraceptive agent.

從今天的結果開始，沃馬三嗪在 RADIANT 研究中顯示出最佳的疾病療效。這應該足以讓人興奮。我們不應低估沃馬三嗪的進一步區分，沃馬三嗪是目前和正在開發的療法中唯一的結合藥物，每日一次給藥，快速起效，不受食物影響，耐受性理想，沒有有意義的藥物相互作用，重要的是不會幹擾常見的避孕藥。

Before I hand over the call to Steve to discuss the details of the RADIANT study results, I want to take a step back and talk about execution. We have executed the RADIANT study exceptionally well, initially setting an enrollment target of 35 patients with focal epilepsy and 15 have generalized epilepsy. The strong demand for focal, even after we announced the closing of the enrollment to the site, demonstrate the effectiveness of our recruitment capabilities. The same engine is already at play for the POWER1 and soon to be for the POWER2 and POWER3 studies.

在我將電話交給史蒂夫討論 RADIANT 研究結果的細節之前，我想先退一步談談執行情況。我們非常出色地執行了 RADIANT 研究，最初設定的招募目標是 35 名局部癲癇患者和 15 名全身性癲癇患者。即使在我們宣佈網站招生結束之後，對焦點的需求仍然強勁，這證明了我們招募能力的有效性。相同的引擎已在 POWER1 研究中發揮作用，並且很快就會用於 POWER2 和 POWER3 研究。

We have so far completed screening of 99 patients in those 61 as of July 25. We expected to complete the study in the near future with approximately 75 patients dosed. Today, we will review data from 37 focal patients who completed [VA] study for efficacy so far. We also review the safety for the overall (technical difficulty) -- the 61 patients who have been dosed.

截至 7 月 25 日，我們已完成對這 61 名患者中的 99 名患者的篩檢。我們預計在不久的將來完成這項研究，大約有 75 名患者接受治療。今天，我們將回顧迄今為止完成 [VA] 療效研究的 37 名局部患者的數據。我們也檢視了整體（技術難度）的安全性——已服藥的 61 名患者。

We present more details from this initial cohort of patients at the upcoming International Epilepsy Conference in Lisbon later this month. The full study results are expected to be presented during the American Epilepsy Society Conference later in the year.

我們將於本月稍晚在里斯本舉行的國際癲癇會議上介紹這批首批患者的更多詳細資訊。完整的研究結果預計將在今年稍後的美國癲癇協會會議上公佈。

Let me now hand over the call to Steve to discuss the results. Steve?

現在，我將把電話交給史蒂夫來討論結果。史蒂夫？

Thanks, Marcio. Let me walk you through the design of the RADIANT study. We began with a 28 day observation period during which patients stayed on their existing antiseizure medications while we monitor seizure activity. Following that, participants received 30 milligrams of vormatrigine once daily for eight weeks. An optional two week safety follow-up was also available at the end of the treatment phase.

謝謝，馬西奧。讓我帶您了解 RADIANT 研究的設計。我們從 28 天的觀察期開始，在此期間患者繼續服用現有的抗癲癇藥物，同時我們監測癲癇發作活動。隨後，參與者每天服用一次 30 毫克的伏馬三嗪，持續八週。治療階段結束時還可以進行為期兩週的可選安全追蹤。

We're proud to have enrolled a representative sample of the Refractory Epilepsy population here in the US, predominantly female with a high baseline seizure burden. The median monthly seizure count was 12 and most participants were on multiple antiseizure medications.

我們很榮幸能夠在美國招募具有代表性的難治性癲癇患者樣本，其中大多數為女性，且基線癲癇發作負擔較高。每月癲癇發作次數中位數為 12 次，大多數參與者服用多種抗癲癇藥物。

Looking ahead, we expect the population in our upcoming POWER1 study to closely reflect what we've seen here in RADIANT. That alignment gives us a strong foundation and confidence in how we're approaching the next phase of development.

展望未來，我們預計即將進行的 POWER1 研究中的人口將與我們在 RADIANT 中看到的情況密切相關。這種協調為我們進入下一階段的發展奠定了堅實的基礎和信心。

Now let's turn to the part of that we're most excited about, the results. Vormatrigine delivered a truly remarkable performance in the RADIANT study. We observed a median seizure reduction of over 56%. And importantly, that effect came on quickly and was sustained throughout the treatment period. Even more compelling, 60% of patients achieved at least a 50% reduction in seizures.

現在讓我們來談談最讓我們興奮的部分，即結果。沃馬三嗪在 RADIANT 研究中表現出了真正卓越的表現。我們觀察到癲癇發作的平均減少量超過 56%。重要的是，這種效果出現得很快，並且在整個治療期間持續存在。更令人信服的是，60% 的患者癲癇發作次數減少了至少 50%。

That's one of the highest responder rates we've seen in recent epilepsy trials, and it speaks to the potential impact vormatrigine could have for this community.

這是我們在最近的癲癇試驗中看到的最高反應率之一，它說明了沃馬三嗪可能對該群體產生的潛在影響。

What's especially striking is how quickly these responses emerged and how they continue to improve over time. By just week one 54% of patients had already responded. That number climbed to 67% by week eight showing a clear and encouraging trend of improvement. Even more notable, over 22% of patients, more than one in five were completely seizure-free during the second month of treatment. That kind of outcome not only underscores vormatrigine's potential but also sets the stage for what we hope to see in the longer 12-week POWER1 and POWER2 studies.

尤其引人注目的是這些反應出現得如此之快，並且隨著時間的推移而不斷改進。光是第一周，54% 的患者就已經產生反應。到第八週，這一數字攀升至 67%，顯示出明顯且令人鼓舞的改善趨勢。更值得注意的是，超過 22% 的患者（超過五分之一的患者）在治療的第二個月內完全沒有癲癇發作。這種結果不僅凸顯了沃馬三嗪的潛力，而且為我們希望在為期 12 週的 POWER1 和 POWER2 研究中看到的結果奠定了基礎。

Looking more closely at the data, for vormatrigine efficacy held strong across all patient subgroups, regardless of baseline seizure burden. We specifically analyzed outcomes by splitting patients at the median baseline seizure frequency to explore whether those with a higher or lower seizure loads responded differently.

更仔細地觀察數據，我們發現無論基線癲癇發作負擔如何，沃馬三嗪對所有患者亞群具有很強的療效。我們透過按中位基線癲癇發作頻率對患者進行分組來專門分析結果，以探討癲癇發作負荷較高或較低的患者是否有不同的反應。

As you can see in the figure, the drug performed consistently well across both groups. That kind of robust and uniform response is a strong signal of reliability in a heterogeneous epilepsy population.

如圖所示，該藥物在兩組的表現均良好。這種強勁而統一的反應對於異質性癲癇患者群體來說是一個強烈的可靠性訊號。

Taking a step back, it's important to remember what treatments these patients were already receiving when they entered the study. The bar in RADIANT was especially high. This was the first epilepsy study launched and reported in the US following widespread adoption of Cenobamate--. In fact, 30% of RADIANT participants were already Cenobamate-- meaning vormatrigine had to demonstrate efficacy on top of an already aggressive background regimen. That context makes the results even more compelling.

退一步來說，重要的是要記住這些患者在進入研究時已經接受了哪些治療。RADIANT 的標準特別高。這是 Cenobamate 廣泛採用後在美國啟動並報告的首個癲癇研究。事實上，30% 的 RADIANT 參與者已經接受了 Cenobamate 治療——這意味著沃馬三嗪必須在已經很積極的背景治療方案的基礎上證明其有效性。這種背景使得結果更加引人注目。

When we looked at response rates based on the most commonly used background ASMs, the results are consistently strong. Patients showed excellent responses, whether they were on one or more sodium channel blockers, SV2A modulators or even Cenobamate.

當我們查看基於最常用的背景 ASM 的回應率時，結果始終強勁。無論患者使用一種或多種鈉通道阻斷劑、SV2A 調節劑或 Cenobamate，他們都表現出了良好的反應。

This level of consistency in both efficacy and tolerability and across different treatment backgrounds speaks to vormatrogene's versatility. It reinforces the idea that this is a therapy with broad applicability, not limited by the complexity of background regimens. --

這種療效和耐受性以及不同治療背景下的一致性體現了 vormatrogene 的多功能性。它強化了這樣一種觀點，即這是一種具有廣泛適用性的治療方法，不受背景療法複雜性的限制。--

Turing now to safety and tolerability. Vormatrigine demonstrated a favorable overall profile. Most adverse events were mild to moderate and tended to resolve over time. We did observe a 23% discontinuation rate, which, in many cases, was linked to a lack of background ASM dose adjustment despite protocol guidance.

現在轉向安全性和耐受性。沃馬三嗪表現出良好的整體療效。大多數不良事件都是輕度至中度的，並且往往會隨著時間的推移而消退。我們確實觀察到了 23% 的停藥率，在許多情況下，這與儘管有方案指導但缺乏背景 ASM 劑量調整有關。

Importantly, -- in 6 instances where investigators proactively reduced background ASMs, both adverse events and discontinuations were avoided entirely. We see this not as a safety signal related to vormatrigine itself but rather a manageable interaction dynamic that can be addressed with appropriate background therapy management.

重要的是，在 6 個研究人員主動減少背景 ASM 的案例中，不良事件和停藥都完全避免了。我們認為這不是與沃馬三嗪本身相關的安全訊號，而是一種可控的相互作用動態，可以透過適當的背景治療管理來解決。

I'll close by saying how proud we are to share these results today. RADIANT was a high bar study in a complex and underserved patient population. We believe the data clearly support Vormatrigine potential to make a real difference for people living with Refractory Epilepsy.

最後，我想說，我們今天能夠分享這些成果，我們感到非常自豪。RADIANT 是針對複雜且服務不足的患者群體進行的一項高標準研究。我們相信，數據清楚證明了沃馬三嗪對難治性癲癇患者有真正的治療潛力。

With that, I'll now hand the call back to Marcio.

說完這些，我現在將電話交還給馬西奧。

I'm sure you are as excited as I am about the strength of the RADIANT data Steve just reviewed. As we move forward, we must remember that one of the key motivations to conduct RADIANT was to better inform the final design of POWER2. In that regard, one of the key aspects Steve did not discuss was the preliminary modeling for dosing and efficacy.

我相信您和我一樣對史蒂夫剛剛審查的 RADIANT 數據的強度感到興奮。在我們前進的過程中，我們必須記住，進行 RADIANT 的主要動機之一是更了解 POWER2 的最終設計。在這方面，史蒂夫沒有討論的一個關鍵方面是劑量和功效的初步建模。

We have concluded that it would be beneficial to add a dose arm of 40 milligrams to the POWER2 study, bringing to life the potential of even greater efficacy. We also intend to be more deliberate in our instruction CPI on how to dose reduce the background ASM for even better management of patients.

我們得出的結論是，在 POWER2 研究中添加 40 毫克的劑量組將是有益的，從而實現更大療效的潛力。我們也打算在指導 CPI 中更加慎重地說明如何減少背景 ASM 劑量，以便更好地管理患者。

Another incredibly interesting piece of inflationary learns in the RADIANT study is the reported positive impact in moods observed in patients. With that in mind, we decided to include a depression and mood endpoints to the POWER2 design.

RADIANT 研究中另一個非常有趣的通貨膨脹研究結果是，患者情緒受到了正面影響。考慮到這一點，我們決定在 POWER2 設計中加入憂鬱和情緒端點。

We're ready to start rolling out POWER2, and it goes without saying that the full force of the practice recruitment engine would be at it. The final design of POWER2 enroll approximately 400 refractory epilepsy patients, testing vormatrigine dose of 20, 30 or 40 milligrams against placebo over 12 weeks. The enrollment is expected to complete in 2026. I want to now focus the next few minutes into a very important and often neglected part of drug development in Epilepsy.

我們已準備好開始推出 POWER2，毋庸置疑，實踐招募引擎的全部力量都將投入其中。POWER2 的最終設計招募了大約 400 名難治性癲癇患者，在 12 週內測試 20、30 或 40 毫克的沃馬三嗪劑量與安慰劑的療效。預計招生將於2026年完成。接下來的幾分鐘我想集中討論一下癲癇藥物開發中一個非常重要但經常被忽略的部分。

As you can see here, we're presenting some data from a very large US claims analysis in patients with focal epilepsy conducted by practice, which covers almost 0.5 million patients worth of data.

正如您在此處看到的，我們展示了美國局部癲癇患者索賠分析的一些數據，該分析涵蓋了近 50 萬名患者的數據。

The message is very clear. The majority of the patients are not doing okay, and virtually 2/3 of them fail their first-line treatment. And after that, very improvised layering of multiple agents begin. This is not good for patients or the health care system.

訊息非常明確。大多數患者的病情都不太好，其中幾乎三分之二的患者一線治療失敗。此後，就開始即興地對多個代理人進行分層。這對患者或醫療保健系統來說都不是好事。

Clearly, there's a critical need for simpler, more effective treatments vormatrigine, ones that combine the fast acting mechanism with minimum restrictions and high effectiveness.

顯然，我們迫切需要更簡單、更有效的伏馬三嗪治療方法，這種治療方法將快速起效的機制與最少的限制和高效的效果結合起來。

With that in mind, we'll be launching POWER3, which aims to establish vormatrigine as stand-alone therapy, enrolling role refractory plastic patients transitioning off currently ASM. This study leveraged historical understanding benchmarks and safety matters to protect the integrity of the patients and the results of it. And we plan to initiate POWER3 in early 2026.

考慮到這一點，我們將推出 POWER3，旨在將沃馬三嗪確立為獨立療法，招募目前正在從 ASM 過渡的難治性整形患者。本研究利用歷史理解基準和安全事項來保護病患的完整性及其結果。我們計劃在 2026 年初啟動 POWER3。

To wrap up the call about vormatrigine, it's incredibly exciting to be the point where we can confidently say it has emerged as Best-in-disease ASM, distinguished by rapid seizure reduction, favorable safety, ease of use and sustained effectiveness across diverse patient group. The RADIANT results significantly bolster our confidence in the ongoing and upcoming studies for Vormatrigine.

總結關於沃馬三嗪的電話會議，我們非常興奮地可以自信地說，它已經成為最佳疾病 ASM，其特點是快速減少癲癇發作、安全性高、易於使用以及在不同患者群體中持續有效。RADIANT 的結果極大地增強了我們對沃馬三嗪正在進行和即將進行的研究的信心。

Before we move to Q&A, and reminding that today's results is about celebrating Vormatrigine, I want to emphasize that practice remains deeply committed to revolutionize epilepsy treatments from common focal epilepsy to rare conditions. I'm sure we have seen the fantastic news of Relutrigine being granted breakthrough designation here in the US, which will allow us to move even faster towards registration in patients with SCN2A and SCN8A.

在我們進入問答環節之前，我想提醒大家，今天的結果是為了慶祝沃馬三嗪，我想強調的是，實踐仍然致力於徹底改變癲癇治療方法，從常見的局部癲癇到罕見疾病。我相信我們已經看到了 Relutrigine 在美國獲得突破性認證的好消息，這將使我們能夠更快地在 SCN2A 和 SCN8A 患者中註冊。

Lastly, we extend our sincere thanks to our investigators, patients, site staff and practice team for their contribution to the success of the Epilepsy program in overall.

最後，我們向研究人員、患者、現場工作人員和實踐團隊表示誠摯的感謝，感謝他們為整個癲癇計畫的成功所做的貢獻。

We now open the call to Q&A. Operator?

我們現在開始問答環節。操作員？

(Operator Instructions) Yasmeen Rahimi, Piper Sandler.

（操作員指示）Yasmeen Rahimi、Piper Sandler。

Team, congrats really to the outstanding data, both in treatment response as well as seizure free, especially at the majority of the patients are on background therapy. I guess the first question is, have you looked in terms of the background therapies, were you able to look at if there was a difference in response rate if they were on different products. That's sort of question number one.

團隊，真的祝賀你們取得瞭如此出色的數據，無論是在治療反應方面還是在無癲癇發作方面，特別是大多數患者都在接受背景治療。我想第一個問題是，您是否研究過背景療法，您是否能夠研究不同產品的反應率是否有差異。這是第一個問題。

And then a question for number two is just given the incredible execution into Radian and that and you provide a color around POWER2 reading out in -- POWER2 finishing in the back half of 2026, could you maybe help us understand sort of, I think we get the question a lot, what were sort of the nuggets that leads you to execute really strongly through the study?

然後第二個問題是，鑑於 Radian 令人難以置信的執行力，並且您提供了有關 POWER2 的解讀 - POWER2 將在 2026 年下半年完成，您能否幫助我們理解，我想我們經常會問到這個問題，是什麼樣的關鍵因素促使您在研究中表現得如此強勁？

And then the timing of POWER1, I think a lot of -- it sounded like you're on track to finish POWER1 at year-end, but if you could just reconfirm guidance around timing of POWER1, that would be very helpful.

然後是 POWER1 的時間安排，我認為很多——聽起來您有望在年底完成 POWER1，但如果您可以重新確認有關 POWER1 時間安排的指導，那將非常有幫助。

Thanks, Yas, like incredibly enthusiastic, right, as we come out here, when you look into [Pocola] Lapse background in general I think your question is exactly on the specifics. The first question on the specifics for the background. If you look across Keppra or any of the -- it's on our slide 13 as and our team, right? We sell incredibly robust effects on sudden general blockers in general, some patients were in one, some patients were on two like you wouldn't expect much of an effect there. I think that was some of these ceptism before, and we're seeing incredibly robust effect as well with over 57% of patients having a response. -- But maybe the most striking result on that same slide is patients on this study over 30% of them were on 300 milligrams or even more, sometimes 400, 450 of cenobamate, this was not our mildly treated like a run-of-the-mill Epilepsy patient.

謝謝，Yas，你太熱情了，對吧，當我們來到這裡，當你總體上了解 [Pocola] Lapse 背景時，我認為你的問題正是關於具體細節的。第一個問題是關於背景的具體內容。如果您看一下 Keppra 或任何 - 它就在我們的第 13 張投影片上，以及我們的團隊，對嗎？我們銷售的突發性全身阻斷劑通常具有極其強大的效果，有些患者只使用一種，有些患者使用兩種，就像您不會期望有太大效果一樣。我認為這是之前的一些懷疑，我們也看到了令人難以置信的強勁效果，超過 57％ 的患者有反應。 - 但也許同一張投影片上最引人注目的結果是在這項研究中超過 30％ 的患者服用了 300 毫克甚至更多，有時是 400、450 毫克的 cenobamate，這不是我們像普通癲癇患者那樣進行輕度治療。

And on those patients, we're seeing over 55% of response. So if there is any doubt on the placements in terms of refractory, I think that should be no more. We did talk as well on what we believe to be the proper way for this drug to be used is really moving towards first therapy and first line. And that's why we're starting the POWER3 study, but I'm sure you can discuss that soon.

對於這些患者，我們看到了超過 55% 的反應率。因此，如果對於耐火材料的放置有任何疑問，我認為應該沒有了。我們也確實討論了我們認為使用這種藥物的正確方法，即真正走向首選療法和一線治療。這就是我們開始 POWER3 研究的原因，但我相信你們很快就能討論這個問題。

So going back to your question, right? We set up to recruit a smaller group of patients than we end up recruiting. That should be a big check mark on our ability to recruit this population that as you've seen on the demographics slide, as your classical refractory seizing a lot multi treated patient population in the United States and in Europe.

那麼回到你的問題，對嗎？我們最初計劃招募的患者群體比最終招募的患者群體要小。這應該是我們招募這一人群的能力的一個重大檢查標記，正如您在人口統計幻燈片上看到的那樣，作為經典的難治性疾病，在美國和歐洲吸引了大量接受過多種治療的患者群體。

So I'm pretty happy with that. Not happy for the patients on being treated with those drugs but happy on the fact that we can recruit them well, it's already happening on POWER1, the acceleration we did in our corporate release or Form 10-Q, which should be filed right now, and you can refer to like reinforce the guidance that we previously gave on finalizing POWER1 this year.

所以我對此非常滿意。我們不為接受這些藥物治療的患者感到高興，但很高興我們能夠很好地招募他們，這已經在 POWER1 上發生了，我們在公司發布或 10-Q 表中所做的加速，應該立即提交，您可以參考強化我們之前在今年完成 POWER1 時給出的指導。

POWER2 is not off the ground yet. So one should always be careful on making predictions of studies that have not started, but based on our engine, particularly here in the US, we are really able to get high-quality sites and to help the sites with their own recruitment efforts with our own recruitment efforts to get more patients, we believe more patients in a site is a good thing because then they have more experience, the qualities higher, the overall operations went smoother.

POWER2 尚未啟動。因此，人們在對尚未開始的研究進行預測時應該始終保持謹慎，但基於我們的引擎，特別是在美國，我們確實能夠獲得高質量的站點，並通過我們自己的招募工作幫助站點進行自己的招募工作，以獲得更多患者，我們相信站點中更多的患者是一件好事，因為這樣他們就有了更多的經驗，質量更高，整體運營更順暢。

So that is going incredibly well. So we're going to transfer that enthusiasm towards POWER2, and pretty soon in the future POWER3 as well. So it's on and all -- it's not only a phenomenal result as we see for patients today.

一切進展非常順利。因此，我們將把這種熱情轉移到 POWER2 上，並且很快也會轉移到 POWER3 上。所以這一切都是——這不僅僅是我們今天為患者看到的驚人結果。

But in general, it brings us a step closer or an inch closer to completing POWER1 and to getting POWER3 and getting that registrational. It's particularly sad as others struggle here to recruit on the same population and one must ask why. But on our case, we are incredibly happy of our execution and our team's focus on getting these patients on these studies.

但總的來說，它使我們離完成 POWER1 和獲得 POWER3 以及獲得註冊更近了一步或一英寸。這尤其令人傷心，因為其他人也難以在同一人群中招募人才，人們不禁要問為什麼。但就我們而言，我們對我們的執行情況以及我們團隊致力於讓這些患者參與這些研究感到非常高興。

Ritu Baral, TD Cowen.

Ritu Baral，TD Cowen。

Congratulations on this on this really good data. I've gotten a bunch of questions this morning. Just being driven by this 22% seizure free rate and the sort of large percentage of patients that responded very rapidly. Marcio and Steve, what do you think is driving this increase in efficacy on all these measures. Even after steady-state plasma is achieved in a new patients -- and is your -- do you have any exposure response analysis done, which is contributing to the 20-milligram dose that you now plan on including in POWER2? And then I've got just a quick housekeeping follow-up.

恭喜您獲得如此好的數據。今天早上我收到了很多問題。只是因為 22% 的無癲癇發作率和很大比例的患者反應非常迅速。馬西奧和史蒂夫，你們認為是什麼推動了所有這些措施的有效性的提升。即使在新患者體內達到穩態血漿後 - 您是否進行過任何暴露反應分析，這有助於您現在計劃在 POWER2 中納入 20 毫克劑量？然後我只需要進行一些簡單的後續工作。

Yes. The -- so we do have the exposures, and I would say that the raw exposures are already quite well processed and the preliminary exposure response well underway as well. So I'll make a couple of comments about that, and then I'll hand over to Steve to talk about why we are -- we were expecting and we are seeing this phenomenal results. So we do see steady state being reached quite quickly here between the first and the second week of treatment.

是的。所以我們確實有曝光，我想說原始曝光已經處理得相當好，初步曝光反應也在順利進行中。因此，我將對此發表幾點評論，然後我將交給史蒂夫來談談為什麼我們——我們期待並且看到了這一非凡的結果。因此，我們確實看到在治療的第一周和第二週之間很快就達到了穩定狀態。

As you've seen on the slides, off the gate to get very good results, it did -- quite considerably. We thought the most scientifically relevant way to present was actually fitting the lowest to the charts because we know Epilepsy is not a weekly process, right? Like the patients don't sense otherwise, we'll observe them for a week and then just for a week or two afterwards. And it's the overall month. I think the matter here.

正如您在幻燈片上看到的，一開始就取得了非常好的結果，確實如此——相當可觀。我們認為最科學的呈現方式實際上是將最低的擬合到圖表中，因為我們知道癲癇不是每週發生的過程，對嗎？就好像病人沒有其他感覺一樣，我們會觀察他們一周，然後再觀察一兩週。這是整個月份。我認為事情就在這裡。

But we do see less -- I think the overall concept is that less seizures leads to last seizures. So we see this deepening over time, which bodes incredibly well for POWER1, which is 12 weeks long. And POWER2 is going to be 12 weeks long as well on that regard. The 20 milligram dose that we are using for the first six weeks of POWER is rising to the range where you are seeing this incredible efficacy, clearly in the 30 as well. But what you've seen is a potential for a fairly significantly higher when you go to the much higher side of the exposure of these patients to get an even bigger results here.

但我們確實看到的癲癇發作較少——我認為總體概念是，癲癇發作較少會導致癲癇發作較多。因此，我們看到這種情況隨著時間的推移而不斷加深，這對於為期 12 週的 POWER1 來說是一個非常好的預兆。從這方面來看，POWER2 也將持續 12 週。我們在 POWER 治療的前六週中使用的 20 毫克劑量正在上升到您可以看到這種驚人功效的範圍，顯然在 30 毫克劑量下也是如此。但是，您已經看到，當您對這些患者的暴露程度進行更高程度的評估時，獲得更大結果的可能性相當高。

Now that we need it, not like this is the highest seizure reduction ever seen on an Epilepsy study. Not that we need anymore, but I think these patients do deserve more and they're going to drive that. And that's why we added the 40-milligram. So in a sense, it's good to be stepping in into POWER2, expecting all 3 dose to be quite effective and giving this flexibility for the patients.

現在我們需要它，這並不像癲癇研究中見過的最高癲癇發作減少率。並不是說我們需要更多，但我認為這些病人確實值得更多，而且他們會推動這一點。這就是我們添加 40 毫克的原因。因此從某種意義上說，加入 POWER2 是件好事，預計所有 3 種劑量都會非常有效，並為患者提供這種靈活性。

But maybe Steve can talk about why we think the (technical difficulty) -- is granted.

但也許史蒂夫可以談談為什麼我們認為（技術難度）是理所當然的。

Just speaks to the issue you raised, Marci, about fuel seizures causing fuel seizures. And the same thing -- the old saying in epilepsy is seizures beget seizures, and that's a process of really resetting the activity level of a neuron. That's a molecular process that takes time to occur conversely, when you give an agent like relutrigine vormatrigine, you immediately decrease activity, and that's actually starting to reset the level of neuronal activity.

馬西，剛才談到了你提出的問題，關於燃料扣押導致燃料扣押。同樣的事情——關於癲癇的古老說法是癲癇發作會導致癲癇發作，這是一個真正重置神經元活動水平的過程。這是一個需要時間發生的分子過程，相反，當你給予像瑞妥金和沃馬金這樣的藥物時，你會立即減少活動，這實際上是開始重置神經元活動的水平。

So that process takes time to unwind as it took time to wind up -- so we just think it's really the opposite corral of increasing seizures as a patient first presents. And there's well-known physiological mechanisms, homeostatic plasticity at that are known to underlie this phenomenon.

因此，這個過程需要時間來結束，就像它需要時間來結束一樣——所以我們只是認為，這實際上與患者首次出現癲癇發作增加的情況相反。眾所周知，這種現象的根本原因在於其生理機制，即穩態可塑性。

Super helpful. And then, Marcio, you knew this was coming. The upcoming POWER1 data, you mentioned you would finish enrollment and have data by end of year. Is there any more granularity that you can give us around where enrollment currently stands? And will you announce completion of enrollment for that study?

非常有幫助。然後，馬西奧，你知道這會發生。即將到來的 POWER1 數據，您提到您將在年底前完成註冊並獲得數據。您能否向我們詳細介紹一下目前的入學情況？您會宣布該研究的招生工作已經完成嗎？

Yes, we probably will announce the completion. And I would say, at this point today is the day to celebrate RADIANT. But yes, I could see this coming. I appreciate your processing with that. The enrollment is incredibly strong.

是的，我們可能會宣布完成。我想說，今天是慶祝 RADIANT 的日子。但是是的，我可以預見到這一點。我很感謝您的處理。報名人數非常多。

I just had a call this morning with most investigators and enthusiasm of everyone that is on POWER1 is really great to see. I know it was in these lines, and I reinforce it, but the rate -- one of the things on rates that we are not expecting was really this overwhelming feedback from patients and investigators on their improvements in moods on their ability to call better with their day.

我今天早上剛與大多數調查人員進行了通話，看到 POWER1 上每個人的熱情真是太好了。我知道情況就是這樣，而且我強調了這一點，但是這個比率——關於比率，我們沒有想到的一件事是，患者和研究人員對他們情緒的改善以及他們一天中打電話的能力的改善給予瞭如此強烈的反饋。

And I think investigators like that a lot as well, and that is certainly helping with even more patients being funneled towards this study versus other things going on out there.

我認為研究人員也非常喜歡這一點，而且與其他正在進行的研究相比，這無疑有助於吸引更多的患者參與這項研究。

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

Congrats on the beta for taking our question. Can you elaborate a little bit more on this discontinuation rates in the RADIANT and how that was imputed into the seizure reduction data, if at all? And also for the forthcoming POWER1, would it be fair to assume that placebo rates will be lower than those reported for cenobamate and drug given the more refractory population in POWER1.

恭喜測試版回答了我們的問題。您能否詳細說明一下 RADIANT 中的停藥率以及如何將其計入癲癇發作減少數據中？對於即將推出的 POWER1，考慮到 POWER1 中的難治性人群較多，是否可以公平地假設安慰劑率將低於報告的 cenobamate 和藥物的安慰劑率。

So why we are -- we think we can do better on the discontinuation, right? Like if you look into competitively our other studies, it's fairly similar. As I'm sure you've already done the comparison in overall. So not but completely satisfied are there yet because we've seen what happens when investigators like actually follow the bills they had on the protocol, it doesn't happen, right? Or it happens at a variable rate.

那為什麼我們認為我們可以在停產方面做得更好，對嗎？如果你仔細研究我們的其他研究，你會發現它們非常相似。我相信您已經進行了整體比較。所以還沒有完全滿意，因為我們已經看到當調查人員真正按照他們在協議上所提出的法案行事時會發生什麼，但這種情況並沒有發生，對吧？或者它以可變的速率發生。

And I think that's why we're going to see moving forward. Having talked with some of them already over the weekend and so on, I think some regrets they would then have removed some of the drug. So not as much on the impact to your question on the ability to reduce seizure, but just that is a lot on top of these patients, and I think that that's what is leading primarily here for patients don't want to stay.

我認為這就是我們能夠繼續前進的原因。我已經在周末等時間與其中一些人進行了交談，我認為他們可能會後悔當初停止使用一些藥物。因此，對於您的問題而言，其對減少癲癇發作的能力的影響並不大，但這對這些患者來說影響很大，我認為這是患者不想留下來的主要原因。

Because that's what needs to study to come out as well, right? When you are in the open-label setting, it's certainly more reports of side effects in general and easier to discontinue. So I'm not completely surprised a little bit higher than we expected, but it's still lower than Cenobamate competitive to other drugs in the market with lower efficacy.

因為這也是需要研究才能得出的結論，對吧？當您處於開放標籤設定時，肯定會有更多關於副作用的報告，並且更容易停止治療。因此，我並不完全驚訝於它比我們預期的要高一點，但它仍然低於與市場上其他療效較低的藥物競爭的 Cenobamate。

And you mentioned what we should be expecting for POWER1. I agree on -- in general, what you're seeing in this patient population are two things, right? So one is the background, as you mentioned, very difficult, very refractory in general and then the second is really the quality of the sites, the quality of the patients are coming in. The stability of these patients on their seizures beforehand.

您也提到了我們對 POWER1 的期望。我同意——總的來說，您在這個患者群體中看到的是兩件事，對嗎？因此，正如您所說，首先是背景，非常困難，總體來說非常難治；其次是治療場所的質量，即患者的質量。這些患者事先對癲癇發作的穩定性進行了研究。

So I think when you get like higher number of patients per site higher quality of assessment, good level of stability in terms of the seizures beforehand. That all contributes to lower potential placebo rates.

因此我認為，當每個站點的患者數量較多時，評估品質會更高，事先癲癇發作的穩定性會更好。所有這些都有助於降低潛在的安慰劑率。

Douglas Tsao, H.C. Wainwright.

Douglas Tsao、H.C. Wainwright。

Congrats on the data. I guess as a starting point, in terms of the added effect of the increasing efficacy that we see over time, that was something that we saw with the [Lucene] as well. And I'm just curious, the two molecules are similar in many respects. Do you think that, that is a function of sort of how they interact with the sodium channel uniquely that you sort of get this detindling effect, which sort of I think Steve sort of talked to I think in response to Ritu's question, and then I have a follow on.

恭喜數據。我想作為一個起點，就我們隨著時間的推移所看到的功效不斷提高的附加效果而言，這也是我們在 [Lucene] 中看到的。我只是好奇，這兩種分子在很多方面都很相似。您是否認為，這是它們與鈉通道獨特相互作用的一種功能，從而產生這種消光效果，我想史蒂夫在回答 Ritu 的問題時也談到了這一點，然後我有一個後續問題。

Yes, maybe just to further what I said before, Doug, yes, that's very specific and different to how any other molecule interacts with the sodium channel, their biophysical profile. And we think that's got a lot to do with this effect because they target the activity more than the target normal function. They target the epileptic activity. I think that profile leads to this rapid and then it's growing because we're having such good acute efficacy that encourages this longer-term efficacy to grow over time. So very much associated with our physical character.

是的，也許只是為了進一步說明我之前所說的，道格，是的，這是非常具體的，並且與任何其他分子與鈉通道相互作用的方式以及它們的生物物理特徵不同。我們認為這與這種效果有很大關係，因為它們針對的是活動而不是正常功能。它們針對的是癲癇活動。我認為這種概況導致了這種快速增長，因為我們擁有如此良好的急性功效，從而鼓勵這種長期功效隨著時間的推移而增長。這與我們的體質特徵密切相關。

Okay. Great. And I guess on the side effect profile, I'm just curious Marcio or to the extent that you've been able to sort of detangle the effect that some of these side effects were or AEs were related to vormatrogene versus the background therapy. -- And as you look to the POWER studies, sort of thinking about enabling some sort of reduction in dosing in background ASMs, which obviously probably contribute to many of the side effects experienced by patients.

好的。偉大的。關於副作用概況，我只是好奇 Marcio，或者您是否能夠理清這些副作用或不良事件與 vormatrogene 和背景療法之間的關係。 —當您查看 POWER 研究時，您可能會考慮在背景 ASM 中減少某種劑量，這顯然是患者出現許多副作用的原因。

Yes. So absolutely right. But maybe before they all ground us on the table on our slide 23, -- The vormatrogene treatment emerging as with over 20% lower than any other drug out there, 20% less patients. But if you're talking about any other therapeutic area, this is like 100 miles from anything else. On CNS related, it's about 20% as well.

是的。絕對正確。但也許在他們將我們全部放在第 23 張幻燈片上之前，vormatrogene 療法的出現，其成本比其他任何藥物都低 20% 以上，患者人數也減少了 20%。但如果你談論的是其他治療領域，那麼這與其他任何領域都相距 100 英里。就中樞神經系統 (CNS) 而言，這一比例也約為 20%。

So we're already at other like universe when it comes to these other drugs that are unfortunately in the background, right? So we this intent. These other things are doing. But what we know because we run the experiment is it gets reduced or removes when the background drugs are reduced, which ultimately is what these patients do, right, in what the physicians there. So we see that it's incredibly positive not only for patients continuing RADIANT since we have significant more now and for open-label extension as well.

因此，當談到這些不幸隱藏在幕後的其他藥物時，我們已經處於類似的境地了，對嗎？所以我們有這個意圖。這些其他的事情正在做。但是，透過實驗我們知道，當背景藥物減少時，副作用也會減少或消除，這最終就是這些患者所做的，對吧，也是那裡的醫生所做的。因此，我們看到，這不僅對繼續使用 RADIANT 的患者俱有極其積極的意義，因為我們現在有了更多的患者，而且對開放標籤擴展也具有同樣積極的影響。

But for the POWER1 and POWER2 and potentially POWER3 I studies as well. So yes, I think the trajectory, while we should ground on the numbers and be happy about being best-in-class and here in Best-in-disease that is a space to get better. That's why we're moving forward.

但對於 POWER1、POWER2 以及潛在的 POWER3，我也進行了研究。所以是的，我認為我們應該以數字為基礎，為成為一流而感到高興，而在最佳疾病領域，這是一個可以變得更好的空間。這就是我們不斷前進的原因。

Okay. And if I can, one follow-up. I'm just curious on the mood benefits that you saw. I'm just curious, is that based on sort of anecdotal feedback? Or was there any kind of sort of inventory on emotional state taken?

好的。如果可以的話，請再跟進一次。我只是好奇您所看到的情緒益處。我只是好奇，這是基於某種軼事回饋嗎？或是否對情緒狀態進行過某種調查？

Yes. So you will start systematically reported by sites. But unfortunately, we have not designed an instrument to collect that from the very beginning. And that's where we are incorporating the power to design. It's not completely unexpected, right?

是的。因此您將開始有系統地透過網站進行報告。但不幸的是，我們從一開始就沒有設計出一種儀器來收集這些資訊。這就是我們融入設計力量的地方。這並不完全出乎意料，對吧？

I think there's other drugs in this class that have approval for like bipolar, for example, like vormatrigine, but they just can't be used probably because of the other issues, including like the allergic reactions to the drug. So not -- again, not completely than expected, but you all a very welcome comments that we got across the board from investigators.

我認為該類別中還有其他藥物已獲批准用於治療躁鬱症，例如伏馬三嗪，但它們可能由於其他問題而無法使用，包括對該藥物的過敏反應。所以不是——再說一次，不是完全超出預期，但你們都非常歡迎我們從調查人員那裡得到的評論。

Yatin Juneja, Guggenheim.

古根漢美術館的亞廷·朱內賈（Yatin Juneja）。

Let me add my congratulations. Very nice results, again, congratulations to the team. So a couple for me. So the first one is, could you talk about the kinetics of responses in the sense that are you seeing improvement in efficacy over time for most patients. And then when you do a 12 week study, you'd probably get more benefit.

讓我也表達我的祝賀。非常好的結果，再次恭喜團隊。對我來說這是一對。所以第一個問題是，您能否談談反應動力學，即您是否看到大多數患者的療效隨著時間的推移而提高。然後，當你進行 12 週的研究時，你可能會獲得更多益處。

And the reason I ask is because I couldn't really figure out from the chart that you have, are you seeing sort of deepening of this efficacy throughout the period. So that's first.

我之所以問這個問題，是因為我無法從您的圖表中真正弄清楚，您是否看到這種功效在整個期間有所加深。這是第一步。

Second one is what should be the read-through to generalized data that you will have for the same asset? What should be the expectation there? And then finally, on the safety, which I'll ask, I mean you should be very comfortable with the safety, especially the call it ability if you are going with the 40-milligram in the future studies. Those are the two questions.

第二個問題是，對於同一資產，您應該如何解讀通用資料？那裡應該期待什麼？最後，關於安全性，我想問的是，您應該對安全性非常放心，特別是如果您在未來的研究中採用 40 毫克的話，這種安全性就更加可靠了。這是兩個問題。

On the kinetics of the response it is very clear, if we thought it would be this ingenuous just get a straight line there to fit like a linear. But if that was the case, and you can do yourself since the data, you would see a very significant -- between the first month and the second month, which we expect to continue as we treat this patient further.

關於反應動力學，這非常清楚，如果我們認為它會如此巧妙，那麼只需在那裡畫一條直線就可以像線性一樣擬合。但如果情況確實如此，而且您可以自行根據數據進行觀察，您會發現在第一個月和第二個月之間有非常顯著的變化，我們預計隨著我們進一步治療該患者，這種變化將會持續下去。

So for POWER1, the translation should be even deeper response there. Of course, going to have to wait for that study to read out, but that is the expectation based on the data we have. And that is kind of the read-through that was the second part of your question.

因此對 POWER1 來說，翻譯應該有更深層的回應。當然，還得等待研究結果出來，但這是基於我們掌握的數據的預期。這就是對你的問題的第二部分的解釋。

We're looking to safety as we're very comfortable going to 40 milligrams. We really see this association being a lot more related to the time and type of management by the investigators than the drug itself. And we do see, as I mentioned, one of the previous questions, on the higher end of the exposure response we see even further efficacy response or deepening.

我們尋求的是安全，因為我們非常放心地將劑量控制在 40 毫克。我們確實看到這種關聯與研究人員的時間和管理類型比藥物本身更相關。正如我之前提到的，我們確實看到，在暴露反應的高端，我們看到了進一步的功效反應或深化。

So when you combine that, we form with another month of treatment, we should expect significantly better results here, not once again, not that it's needed, right? This is already the best results in epilepsy study.

因此，當你將其與另一個月的治療結合時，我們應該期待明顯更好的結果，而不是再一次，不是那樣的，對吧？這已經是癲癇研究中最好的結果了。

David Hoang, Deutsche Bank.

德意志銀行的 David Hoang。

Congrats on the data. So I just wanted to ask about some of these other work that you mentioned you're doing with the program here in terms of I guess, mood endpoint and port looking at a role for monotherapy. How do you envision some of these other endpoints and additional studies here could -- are you looking, I guess, to enhance the label or get some label differentiation versus what's currently available and what else is in the pipeline?

恭喜數據。因此，我只是想詢問一下您提到的您正在通過該計劃進行的一些其他工作，我想，就情緒終點和端口而言，看看單一療法的作用。您如何設想這些其他終點和附加研究？我想，您是否希望增強標籤或獲得一些標籤差異，以區別於當前可用的標籤和正在籌備中的其他標籤？

So on the moods benefits, right, I mentioned a couple of minutes back, that is an expectation that a drug that reduces the seizures make these patients feel like more leave from the hyperexcitable activity and with this mechanism that is known for -- in a specific way to improve load in general, to be positive.

因此，關於情緒方面的好處，對的，我幾分鐘前提到過，這是一種期望，即一種減少癲癇發作的藥物可以讓這些患者感覺更遠離過度興奮的活動，並且通過這種已知的機制 - 以特定的方式改善總體負荷，從而產生積極的影響。

So we are looking for adding that as an endpoint, potentially a label claim, of course, pace on the results there. On the POWER3, switch to monotherapy study, I think that's a game changer, right? We haven't really had a drug for many years that is able to move to those 100% of the patients there at the beginning versus the 30% on the bottom.

因此，我們希望將其添加為一個終點，可能是一個標籤聲明，當然，還要根據結果進行調整。在 POWER3 上，切換到單一療法研究，我認為這會改變遊戲規則，對嗎？多年來，我們一直沒有一種藥物能夠一開始就惠及 100% 的患者，而只惠及最低的 30% 的患者。

So when you're talking about the refractory -- hyper refractory patients like fourth or fifth line, as we show on the chart on this slide, we're talking about a $2 billion to $3 billion market opportunity there. When you move up to the first line, second line, we're talking about several folds that potential.

因此，當您談論難治性 - 超難治性患者（例如第四線或第五線）時，正如我們在這張投影片的圖表中所示，我們談論的是 20 億至 30 億美元的市場機會。當你移動到第一行、第二行時，我們談論的是潛力的幾倍。

So from a market opportunity perspective, it makes a lot of sense, number one. But for a drug profile is the only drug that makes sense. Well, let me remind everyone that Keppra, which is now the drug that people use of the gate showed an efficacy of like 30%, basically no seizure freedom and with very similar pharmacological properties and overall toxicological properties or for vormatrigine. So we're not talking about a high bar to replace there.

因此，從市場機會的角度來看，這非常有意義，這是第一點。但對於藥物概況來說，這是唯一有意義的藥物。好吧，讓我提醒大家，現在人們使用的藥物 Keppra 顯示出 30% 的有效率，基本上沒有癲癇發作，並且具有與沃馬三嗪非常相似的藥理特性和整體毒理學特性。所以我們不是在談論要取代的高標準。

We're just talking about the fact that no other drug we're able to. So that is expected to get off the ground pretty soon and to if completed before the NDA submission beyond the NDA, potential NDA, if not to be a quick add-on to the label there.

我們只是在談論這樣一個事實：我們沒有其他藥物可以治療。因此，預計這項工作將很快啟動，如果在提交保密協議 (NDA) 之前完成，則可能是保密協議 (NDA)，如果不是，則可能是標籤的快速附加部分。

Ami Fadia, Needham & Company.

Ami Fadia，Needham & Company。

Congratulations on this really strong and impressive data. I wanted to sort of better understand the discontinuation rates. If the physicians were allowed to discontinue any background therapies, why did they not do that?

恭喜您獲得如此強勁且令人印象深刻的數據。我想更了解停藥率。如果允許醫生停止任何背景治療，為什麼他們不這樣做呢？

And for the six or so patients where they were discontinued, was there any change? Or can you kind of talk about the change in the efficacy as well as the safety adverse events that were noted after the background therapies are removed.

對於停藥的六名左右的患者來說，有什麼改變嗎？或者您能否談談在去除背景療法後觀察到的療效變化以及安全不良事件。

And then maybe a related question on -- what additional data do you think you need to generate perhaps in an open label portion to convince physicians to switch out patients from their existing background therapies and then move patients through vormatrigine?

然後也許有一個相關的問題——您認為需要在開放標籤部分產生哪些額外數據來說服醫生將患者從現有的背景療法中轉換出來，然後讓患者接受沃馬三嗪治療？

Yes, absolutely. So Ami, on why people haven't done something, it's going to be kind of speculation on a bit on my end, right? But it informed the speculation since we had that conversation. And I'll refer to one conversation, for example, I had with an investigator in the last few days, who was a little bit slow to start reducing. And I think his point to us was, and to me, particularly.

是的，絕對是。所以阿米，至於為什麼人們沒有採取行動，這只是我的一點猜測，對嗎？但自從我們進行了那次談話後，它就為猜測提供了依據。例如，我引用最近幾天我與一位調查員的一次談話，他開始減少的速度有點慢。我認為他的觀點對我們，尤其是對我而言，是這樣的。

Well, we're so used about keep adding and just doing nothing and then cycling these patients on that the reaction time for some of them. This is a big key opinion leader, someone is very important for the space and the number of patients in the trial.

好吧，我們已經習慣了不斷添加，什麼也不做，然後循環這些病人，這是他們中的一些人的反應時間。這是一位重要的關鍵意見領袖，對於試驗的空間和患者數量來說非常重要。

And then when you realize was the first few patients that was not the case and that for the following ones. -- was able to and worked really well. So I think it's a timing thing and really people learning other with the drug at the end of the day, that's why we did the study as well.

然後，當您意識到前幾個病人的情況並非如此，而對於接下來的幾個病人來說——能夠並且效果非常好。所以我認為這是時間問題，實際上人們最終會透過藥物來學習其他知識，這也是我們進行這項研究的原因。

On the ones that did removed. I think we mentioned that on the slide as well, it's not only resolved the NDA, right? That was -- efficacy is not impacted like at all. In the long run, efficacy is actually better on those patients, but we should always be careful to talk about individual patient results on things like this.

對於那些確實被刪除的。我想我們在幻燈片上也提到過，它不僅解決了保密協議，對吧？也就是說——功效完全沒有受到影響。從長遠來看，這些患者的療效實際上更好，但我們在談論此類個別患者的結果時應始終保持謹慎。

So that's why we give us -- it is not that reducing the background made the patients worse, which is the general concern, right one would have and linking to your question about POWER3. I think that would be concerning if that was the case, but it's not the case at all.

所以這就是為什麼我們給出——並不是說減少背景會使病人的病情惡化，這是人們普遍關心的問題，正確的，這與你關於 POWER3 的問題有關。我認為如果事實確實如此的話那將會令人擔憂，但事實並非如此。

In a sense, I think what we established is that the background therapy is not doing anything but causing side effects and vormatrigine getting these patients better. So a mono therapy studies switch to monotherapy makes a lot of sense. We pulled a number of physicians on the last few days as they are under CGA with us -- and I think that is an incredible enthusiasm for POWER3 because they really believe on vormatrigine, but they didn't have an opportunity to do something like that before with any other drug.

從某種意義上說，我認為我們所確定的是，背景療法除了引起副作用和讓這些患者好轉之外沒有任何作用。因此，單一療法研究轉向單一療法是非常有意義的。過去幾天，我們召集了一些醫生，因為他們和我們一起接受 CGA 治療——我認為這對 POWER3 來說是一種令人難以置信的熱情，因為他們真的相信沃馬三嗪，但他們以前沒有機會對任何其他藥物做這樣的事情。

So not hearing a lot of concerns. Of course, there are ways to do it. There are dynamics on this study, but not really an overwhelming concerned about it.

因此沒有聽到太多擔憂。當然，還是有辦法的。這項研究有一些動態，但人們對此並沒有真正感到擔憂。

Jay Olson, Oppenheimer.

傑伊·奧爾森，奧本海默。

Congrats on these impressive results and thanks for providing the update. Since you mentioned the observation that seizures beget seizures, -- is there a way to show that for Vormatrigine could potentially have a disease-modifying benefit? .

恭喜這些令人印象深刻的成果並感謝您提供更新。既然您提到了癲癇發作會引發癲癇發作的觀察結果，那麼有沒有辦法證明沃馬三嗪可能具有改善病情的益處？。

Yes. Thanks, Jay. I would, again, -- I'll ask Steve to comment here as well that that's what we're already seeing when we have the direct benefit of seizure control and then the indirect benefit of patients just feeling generally better moods, better relationship with the site and with their own families and so on. And ultimately, I think what we are looking for here is to change the plan as we know it.

是的。謝謝，傑伊。我想再次——我也會請史蒂夫在這裡評論一下，這就是我們已經看到的，當我們直接受益於癲癇控制時，然後間接受益於患者總體上感覺情緒更好，與網站和家人的關係更好等等。最終，我認為我們在這裡尋求的是改變我們已知的計劃。

Take a look at our slides when we're looking to, people keep saying 30% of patients are refractory that's one of the biggest BS that anyone can say in Epilepsy. It's like over 60% of those patients are on several therapies, right? And that is just not acceptable, like those things are not benign as we know, so they affect the well-being of patients as well.

看看我們的幻燈片，人們一直說 30% 的患者是難治性的，這是癲癇領域人們能說的最大的謊言之一。好像超過 60% 的患者都接受過多種療法，對嗎？這是不可接受的，因為我們知道這些東西並不是良性的，所以它們也會影響病人的健康。

When you remove that, get an effective drug that not only reduce procedures but improve their overall well-being and particularly moods, as we discussed, I think we have an opportunity to really change everything here, but maybe Steve can talk about it.

當你去除它時，得到一種有效的藥物，不僅可以減少手術，還可以改善他們的整體健康狀況，特別是情緒，正如我們所討論的，我認為我們有機會真正改變這裡的一切，但也許史蒂夫可以談談它。

And I think it's back to that earlier point about seizures beget seizures is the disease but it's a new set point for the brain, where a higher level of activity, a higher threshold for triggering seats. It becomes the new normal. And this reduction over time in sizes that we saw and that we talked about earlier, is a sign that we're reversing that process.

我認為這又回到了先前關於癲癇發作的觀點，癲癇發作是一種疾病，但它是大腦的一個新的設定點，在這個點上，活動水平更高，觸發癲癇發作的閾值更高。這將成為新常態。我們看到的以及我們之前討論過的這種尺寸隨時間推移而減小的現象表明我們正在逆轉這一進程。

So -- and that can be exactly what you're talking about, disease modification. So -- and then all the attended things that happen. If you've got a brain that hyperexcitable mood disturbances and other things emerge and the fact that we saw changes in other domains. I think it's very encouraging that we are really tackling some fundamental issues what Epilepsy is. And we see this across rare, severe Epilepsies this there common Epilepsies like focal as well. But it is a disorder of seizures and excitability and resetting that set point is key to disease modification and improvement across multiple areas.

所以——這可能正是您所說的疾病改良。所以——然後所有發生的事情都發生了。如果你的大腦過度興奮，就會出現情緒失調和其他問題，事實上，我們在其他領域也看到了改變。我認為，我們確實正在解決癲癇的一些根本問題，這是非常令人鼓舞的。我們在罕見的嚴重癲癇和常見的局部癲癇中也發現了這種情況。但它是一種癲癇和興奮障礙，重新設定該設定點是改變和改善多個領域疾病的關鍵。

And maybe if I could just ask one follow-on. Do these impressive RADIANT results give you any hint that Vormatrigine potentially could have benefit in DE .

也許我可以再問一個問題。這些令人印象深刻的 RADIANT 結果是否暗示了沃馬三嗪可能對 DE 有益。

In theory, yes, right? I think we can with -- the good news is the Vormatrigine is quite strongly set for GEs and Emerald is off the ground that you might have seen on our corporate release a couple of minutes ago, enrolling patients. We do expect to have very strong enrollment and results there as well on the GE side.

理論上是的，對吧？我認為我們可以——好消息是，Vormatrigine 非常適合 GE，而 Emerald 已經開始招募患者，您可能已經在幾分鐘前我們的公司發布會上看到過這一點。我們確實期望通用電氣方面也能有非常強勁的入學人數和成績。

That are things, features that are important for GE patients that we might not be able to fulfil with like a solid form that is like Vormatrigine. But in theory, right, these drugs are dampening hyperexcitability on a hyperexcitable neuron that is seizing a lot, so yes, there is no reason to believe not, but we're really looking straight on and quite focused for Relutrigine for these and Vormatrigine for adults Epilepsy.

這些特徵對於胃食道逆流症患者來說非常重要，而我們可能無法透過像沃馬三嗪這樣的固體藥物來實現這些特徵。但從理論上講，這些藥物可以抑制經常發作的過度興奮神經元的過度興奮，所以是的，沒有理由不相信，但我們確實在直接關注並非常專注於治療這些疾病的 Relutrigine 和治療成人癲癇的 Vormatrigine。

Brian Skorney, Baird.

布萊恩·斯科尼，貝爾德。

Let me extend my congratulations as well on the nice data. I like the chart on slide 13, you have breaking out the efficacy by background meds, so I'm just wondering in that vein if kind of pushing on some of the color on the safety profile. Do you have a similar slide deck to kind of look at how safety breaks stand by background. ASMs, obviously, some of these are pretty potent sedatives. So I wonder if it's just a driving force behind some of the -- and some ones that could be discombobulated from drug.

我也對這些好的數據表示祝賀。我喜歡幻燈片 13 上的圖表，您按背景藥物細分了功效，所以我只是想知道是否可以在安全性概況上增加一些顏色。您是否有類似的幻燈片來了解安全斷裂是如何在背景下進行的。顯然，ASM 中的一些是相當有效的鎮靜劑。所以我想知道這是否只是一些人背後的驅動力——以及一些人可能因毒品而感到困惑的驅動力。

And just to confirm, are these all focal onset patients in this data set? Or are there any grand mal patients here?

只是為了確認一下，這個資料集中都是局部性發病患者嗎？或是這裡有大發作患者嗎？

Yes. So, Brian, this is all focal and stat seizures. We're going to have the primary channelized later in the year at AS here, so maybe get that out the way -- As you can see on both the demographics stable and on that slide, right, this number sums to much more than 100% in terms of the overall. So patients were in a multitude of antiseizure medications, which makes that analysis of what is actually the culprit a lot harder.

是的。所以，布萊恩，這都是局部性和靜態性癲癇發作。我們將在今年稍後在 AS 上進行初選渠道化，所以也許可以解決這個問題 - 正如您在人口統計穩定和幻燈片上所看到的，就總體而言，這個數字加起來遠遠超過 100％。因此，患者需要服用多種抗癲癇藥物，這使得分析真正的罪魁禍首變得更加困難。

But I think what you can say is we look into not only the ASM their end with the total levels in their blood, right? And when you look into that, it is very clear that a significant proportion of those patients are on toxic concentrations, meaning higher than the maximum allowed concentration in the United States.

但我想您可以說的是，我們不僅要研究 ASM，還要研究他們血液中的總含量，對嗎？如果你仔細研究一下，你會發現很明顯，這些患者中有很大一部分處於中毒濃度之下，也就是說，濃度高於美國允許的最大濃度。

And you do see some more out of an association on those cases. So people are not monitoring from therapeutic drug monitoring perspective to frequently and -- these patients. I would argue they should and obviously, they are a lot more prone to have side effects. And one of the reasons why we're being a lot more proactive on the reduction of the dose of the background.

你確實可以從這些案例中看到更多關聯。因此人們沒有從治療藥物監測的角度來頻繁地監測這些患者。我認為他們應該這樣做，而且顯然，他們更容易產生副作用。這也是我們更積極主動減少背景劑量的原因之一。

Rudy Li, Chardan.

魯迪李，查丹。

Congrats again on the strong results. Just a quick follow-up to the question regarding the background therapy. So can you provide additional color on the potential impact touching of current background therapies.

再次恭喜您取得的優異成績。只是想快速回答一下有關背景治療的問題。那麼，您能否提供有關當前背景療法的潛在影響的更多資訊。

I'm just curious how that change your enrollment criteria connecting the right patients for the pivotal trials? And what kind of additional data you think will be necessary to support its use in combination with other sodium -- in practice?

我只是好奇這會如何改變您的招募標準，從而為關鍵試驗找到合適的患者？您認為在實踐中需要哪些額外的數據來支持將其與其他鈉結合使用？

Yes. Rudy, I think what you've seen here is the only real sample of how patients are treated currently. Unfortunately, I would say, adjunctive therapy on this layering of ASMs is just a common practice. There is no reason to be worried concerns about the combination. If anything, again, I urge everyone to look into slide 23.

是的。魯迪，我認為你在這裡看到的是目前患者接受治療的唯一真實樣本。不幸的是，我想說，對這種 ASM 分層進行輔助治療只是一種常見的做法。沒有理由對這種組合感到擔憂。如果有的話，我再次敦促大家看一下投影片 23。

This is the lowest rate of side effects on the therapeutic developments or developed for content seizures despite the fact that the combination was probably the most aggressive at baseline. So no concern whatsoever. -- we need to deal with the market as the market stands and that's what we are doing here.

儘管這種組合在基線時可能是最具侵略性的，但這是治療進展或內容性癲癇發作的副作用發生率最低的。所以完全不用擔心。 ——我們需要根據市場現狀來應對，而這就是我們在這裡所做的。

I particularly with over like 30% of patients on Cenobamate, I would say that's what the market is. We are very confident that both the feds and the efficacy are incredibly strong there. So no real expected change other than the instructions, as we mentioned before, for physicians to be more cautious about the reduction on the background ASM.

我特別關注超過 30% 的患者使用 Cenobamate，我想說這是市場現狀。我們非常有信心，聯邦政府和政府的效力都非常強大。因此，除了我們之前提到的指示之外，沒有真正的預期變化，即醫生要對背景 ASM 的減少更加謹慎。

Ritu Baral, TD Cowen.

Ritu Baral，TD Cowen。

I just wanted to ask a little more detail on the side effect profile -- and specifically, the comment on the severe patients and this comment about recovered and resolved, can you give us a little more detail on the moderate to the year and serious side effects and that recovered and resolved comment? And then I've got a follow-up.

我只是想問一下副作用概況的更多細節 - 特別是關於重症患者的評論以及關於康復和解決的評論，您能否向我們提供關於中度至嚴重副作用以及康復和解決的評論的更多細節？然後我有一個後續行動。

Yes. So on the year specifically, one of the patients had a dizziness. So I would say that is was clearly like on targets and targets not only for therapy, but for the combinations that they were in. The other ones were background illness, like particularly an infection that leads to aspiration ammonia.

是的。具體來說，那一年，其中一名患者出現了頭暈症狀。所以我想說，這顯然不僅是針對治療的目標，而且是針對它們的組合的目標。其他原因是背景疾病，尤其是導致吸入氨的感染。

So not too concerned about that. The fact that they all like resolved, I think that the most important and resolved very quickly the most important part here. So not too concerned. I think we wanted to be very transparent and show the rates there and show the results, but not anything we're very concerned about.

所以不必太擔心這一點。事實上，它們都得到了解決，我認為這是最重要的，而且解決得非常快，這是這裡最重要的部分。所以不用太擔心。我認為我們希望非常透明，展示那裡的費率和結果，但不是我們非常關心的任何事情。

Was it resolved with removal of drug or adjustment of background meds?

是否透過停藥或調整背景藥物解決了這個問題？

Very good question. Sorry for misunderstanding before. No, it was actually just resolved like with the continuous dosing.

非常好的問題。抱歉之前造成誤會。不，實際上它只是透過持續給藥來解決。

I'm showing no further questions at this time. I'd like to turn the call back over to Marcio for closing remarks.

我目前沒有其他問題。我想將電話轉回給馬西奧，請他做最後發言。

Thanks, everyone, for joining. We are thrilled on these results. I think it's important for all of us, but it's particularly important for patients living with Focal Onset Seizures and with Epilepsy in general. It's not every day that we've got a field that's been going on for like 100 years since the -- a little bit over 100 years since the first treatment and you can deliver after more than 25 drugs in the market like over -- like 50% production, 60% overall response rate of patients. It's quite remarkable to put in context. I wanted to take a second to show my appreciation for all the patients participating on this study and all the other studies and for everyone at Praxis and our investigators and site staff.

謝謝大家的參與。我們對這些結果感到非常興奮。我認為這對我們所有人來說都很重要，但對於患有局部癲癇和癲癇的患者來說尤其重要。我們每天都會接觸到這個領域，自從第一次治療以來已經發展了 100 多年，在市場上推出了 25 多種藥物之後，產量可以達到 50% 以上，患者的總體反應率可以達到 60%。放在上下文中來看，這是相當了不起的。我想花一點時間向參與這項研究和所有其他研究的所有患者以及 Praxis 的每個人、我們的研究人員和現場工作人員表示感謝。

Thank you so much. Exciting days ahead of us. I appreciate the support and looking forward to interacting with all of you.

太感謝了。令人興奮的日子就在我們面前。我感謝大家的支持並期待與大家互動。

Thank you for your participation. You may now disconnect. Everyone, have a great day.

感謝您的參與。您現在可以斷開連線。祝大家有個愉快的一天。