Marinus Pharmaceuticals Inc (MRNS) 2024 Q2 法說會逐字稿

Greetings. Welcome to the Marinus Pharmaceuticals second quarter financial results and business update call. (Operator Instructions) It is now my pleasure to introduce your host, Sonya Weigle, Chief People and Investor Relations Officer. You may now begin Ms. Weigle.

問候。歡迎參加 Marinus Pharmaceuticals 第二季財務業績和業務更新電話會議。（操作員指示）現在我很高興介紹您的主持人，首席人才和投資者關係官 Sonya Weigle。韋格爾女士，您現在可以開始了。

Thank you and good morning. With me from Marinus are Dr. Scott Braunstein, Chairman and Chief Executive Officer; Lisa Lejuwaan, Senior Vice President and Business Unit Lead, Rare Genetic Epilepsy; Dr. Joe Hulihan, Chief Medical Officer; and Steve Pfanstiel, Chief Financial Officer and Chief Operating Officer.

謝謝你，早安。和我一起來自 Marinus 的還有董事長兼執行長 Scott Braunstein 博士； Lisa Lejuwaan，罕見遺傳性癲癇資深副總裁兼業務部負責人；首席醫療官 Joe Hulihan 博士；以及財務長兼營運長 Steve Pfanstiel。

Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by such forward-looking statements.

在我們開始之前，我想提醒大家，我們今天所做的一些聲明根據證券法是前瞻性的聲明。這些前瞻性陳述涉及重大風險和不確定性，可能導致我們的臨床開發計劃、未來結果、績效或成就與這些前瞻性陳述表達或暗示的存在重大差異。

These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Form 10-K, 10-Q and 8-K.

這些風險和不確定性以及與我們的業務相關的風險在公司向美國證券交易委員會提交的報告中有所描述，包括 10-K、10-Q 和 8-K 表格。

I will now turn the call over to our CEO, Dr. Scott Braunstein.

現在我將電話轉給我們的執行長史考特·布勞斯坦博士。

Thank you, Sonya, and thanks, everyone, for joining us this morning. On today's call, our team will highlight the significant commercial clinical and operational progress that we have made throughout 2024. We'll also discuss our plans for the second half of the year and beyond, including how we're preparing for the upcoming Phase 3 readout in tuberous sclerosis complex and expanding access to ZTALMY for patients on a global scale.

謝謝你，索尼婭，也謝謝大家今天早上加入我們。在今天的電話會議上，我們的團隊將重點介紹我們在 2024 年取得的重大商業臨床和營運進展。我們還將討論今年下半年及以後的計劃，包括如何為即將到來的結節性硬化症第三階段試驗做準備，以及如何在全球範圍內擴大患者獲得 ZTALMY 的機會。

Starting with ZTALMY, it is now been two years since our commercial launch in CDKL5 deficiency disorder. And I cannot be prouder of the success that we have achieved in growing the brand in the US and the regulatory accomplishments globally. Launching a new product particularly in the orphan epilepsy space is no easy task, but our commercial team has proven its ability to be highly effective, attaining profitability on a commercial investment in the first quarter of 2024, well ahead of our initial expectations.

從 ZTALMY 開始，距離我們在 CDKL5 缺乏症領域的商業化推出已經兩年了。我對我們在美國品牌發展和全球監管方面的成功感到無比自豪。推出一款新產品，特別是在孤兒癲癇領域，並非易事，但我們的商業團隊已經證明了其高效的能力，並在2024 年第一季度實現了商業投資盈利，遠遠超出了我們最初的預期。

We believe these efforts will only be bolstered by a considerable number of scientific presentations across several medical meetings by year end. I'm also proud of the progress that we have made to expand access to the ZTALMY for patients around the world.

我們相信，到今年年底，大量在多個醫學會議上發表的科學報告將會進一步加強這些努力。我也為我們在擴大世界各地患者獲得 ZTALMY 的機會方面所取得的進展感到自豪。

In July, we announced that ZTALMY was approved in China as the first treatment for seizures associated with CDD in patients, two years of age and older. Tenacia Biotechnology is responsible for commercialization of ganaxolone in China and expects to launch ZTALMY as early as the first quarter of 2025.

7 月，我們宣布 ZTALMY 在中國獲得批准，成為第一個治療兩歲及以上患者 CDD 相關癲癇的藥物。Tenacia Biotechnology 負責加奈索酮在中國的商業化，預計最早於 2025 年第一季推出 ZTALMY。

As a reminder, Marinus has established commercial collaboration agreement in Europe and China, distribution agreements in MENA and Russia and a managed access program to make an excellent available on a named patient basis where permissible under local regulations without regulatory approval.

提醒一下，Marinus 已在歐洲和中國建立了商業合作協議，在中東和北非以及俄羅斯建立了分銷協議，並製定了管理訪問計劃，以便在當地法規允許的情況下無需監管部門批准即可為指定患者提供優質服務。

We plan to work with our distribution partners in MENA and Russia to begin to supply ganaxolone immediately on a named patient basis before regulatory approvals are achieved in those markets.

我們計劃與中東和北非地區以及俄羅斯的分銷合作夥伴合作，在這些市場獲得監管部門批准之前，立即開始以指定患者為基礎供應加奈索酮。

Additionally, we have engaged the unified group, a specialty health care company to supply ganaxolone on a named patient basis in several additional countries, including Canada and Australia and expect to have our first patient approved for use within the coming weeks.

此外，我們也與專業醫療保健公司統一集團合作，在加拿大和澳洲等幾個國家以指定患者的方式供應加奈索酮，預計我們的第一位患者將在未來幾週內獲準使用。

With ZTALMY now approved in the US, European Union, UK and China for patients with CDD, we have made important investments to expand our manufacturing capacity to be able to meet the expected increased demand based on our global forecasts as well as our updated [TSC] projections.

隨著 ZTALMY 現已在美國、歐盟、英國和中國獲準用於治療 CDD 患者，我們已進行重大投資以擴大我們的生產能力，以便能夠根據我們的全球預測以及我們最新的 [TSC ] 預測。

It is critical to have a second manufacturing facility in place to help us achieve our mid and long-range forecasts. The investment of the second facility has been ongoing for several months and is proceeding as planned. With the support of our international partners, we expect to have several ex-US launches kicking off in the near term with the first currently anticipated by the end of this year or early next year.

建立第二個製造工廠對於幫助我們實現中長期預測至關重要。第二工廠的投資已持續數月，並正在按計劃進行。在我們國際合作夥伴的支持下，我們預計近期將啟動幾次美國以外的發射，目前預計第一次發射將在今年年底或明年年初進行。

In Europe, Orion Corporation continues to prepare for commercial launches of the ZTALMY in select EU countries and as noted previously, Tenacia expects to launch into the Chinese market in early 2025. We also anticipate broader access for patients in MENA, and Russia, once local regulatory approvals are secured.

在歐洲，Orion Corporation 繼續為在部分歐盟國家商業推出 ZTALMY 做準備，如前所述，Tenacia 預計將於 2025 年初進入中國市場。一旦獲得當地監管部門的批准，我們也預計中東和北非以及俄羅斯的患者將能夠更廣泛地獲得治療。

Finally, we are targeting a Japanese partner to come onboard in the first half of 2025 following our TSC Phase 3 data set. Since the incidence of CDD outside the United States similar to the US, we believe that the global opportunity will be meaningful to our ZTALMY forecast.

最後，我們的目標是在 2025 年上半年根據 TSC 第 3 階段資料集尋找一位日本合作夥伴。由於美國以外地區的 CDD 發生率與美國相似，我們認為全球機會將對我們的 ZTALMY 預測具有重要意義。

For example, in China where genetic testing was instituted only a few years ago, over 1,000 CDD patients have already been identified. Broader access to the ZTALMY will bring a new therapeutic option to patients and their families as well as provide support for the company's larger financial objectives, specifically achieving corporate profitability over the coming years.

例如，中國幾年前才開始推行基因檢測，但目前發現超過 1,000 名 CDD 患者。ZTALMY 的更廣泛使用將為患者及其家人帶來新的治療選擇，並為公司的更大財務目標提供支持，特別是實現未來幾年的企業盈利。

Lisa Lejuwaan who heads up the US ZTALMY business will provide a more in-depth overview of our commercial strategy in her remarks, including our plans to continue to grow the CDD franchise and how the team is preparing for the potential TSC launch in the second half of next year.

負責美國 ZTALMY 業務的 Lisa Lejuwaan 將在她的演講中更深入地概述我們的商業策略，包括我們繼續發展 CDD 特許經營權的計劃，以及團隊如何為下半年可能推出的 TSC 做準備明年。

Let me move to our clinical pipeline, as Joe will detail in his remarks, our next major milestone is the readout of the Global Trust TSC trial evaluating ZTALMY for the treatment of seizures associated with TSC. As a reminder, we completed enrollment in May and are on track for the last patient visit by mid-September.

讓我談談我們的臨床流程，正如喬將在他的演講中詳細介紹的那樣，我們的下一個重要里程碑是全球信託TSC 試驗的讀出，該試驗評估ZTALMY 用於治療與TSC 相關的癲癇發作。提醒一下，我們在五月完成了招生工作，最後一次患者就診預計在九月中旬進行。

We expect to report top line data in the first half of the fourth quarter and are targeting submission of a supplemental NDA no later than April 2025, with a request for priority review. We are pleased to see both a low overall discontinuation rate and a high percentage of patients rolling over from the double-blind portion of the trial to the open-label extension.

我們預計在第四季度上半段報告營收數據，並計劃不遲於 2025 年 4 月提交補充 NDA，並請求優先審查。我們很高興地看到整體中止率較低，並且有較高比例的患者從試驗的雙盲部分轉入開放標籤延長階段。

Pending a positive outcome and FDA approval, the commercial team plans to leverage the existing ZTALMY infrastructure to hit the ground running. We have learned a tremendous amount in the last two years and are well positioned to adapt our formula in CDD to achieve success in the larger TSC market.

在獲得積極成果和 FDA 批准後，商業團隊計劃利用現有的 ZTALMY 基礎設施快速開展工作。我們在過去兩年中學到了很多東西，並且已經做好準備，透過調整 CDD 公式在更大的 TSC 市場中取得成功。

As I commented earlier, we are now setting our sights on achieving company profitability, which we believe can occur 12 to 18 months following the TSC launch. We also wanted to share that on September 20, we will host an investor and analyst event focused on our oral franchise. Our leadership team will be joined by key opinion leaders to share a deep dive into the TSC patient journey, current treatment landscape, and the TSC market opportunity.

正如我之前所說，我們現在的目標是實現公司獲利，我們相信這可能在 TSC 推出後的 12 到 18 個月內實現。我們也想分享一下，9 月 20 日，我們將舉辦一場以我們的口服特許經營為重點的投資者和分析師活動。我們的領導團隊將與關鍵意見領袖一起深入探討 TSC 患者的治療歷程、當前的治療前景以及 TSC 的市場機會。

We will review some of the new findings that continue to make us feel confident that ZTALMY will be successful in its current Phase 3 study and share our thoughts on why this data readout can create a unique growth potential for the organization.

我們將回顧一些新發現，這些發現讓我們繼續相信 ZTALMY 將在其當前的第 3 階段研究中取得成功，並分享我們對為什麼該數據讀數可以為該組織創造獨特成長潛力的看法。

Finally, one added note. In March of 2023, Marinus initiated the PGR challenging Ovid 817 SC patent for IV ganaxolone on the basis that the claims of the patents were invalid and should not have been issued by the USPTO. I am pleased to share that Marinus was successful in this PGR challenge with the PTAB, including that all challenge claims were unpalatable.

最後，補充一點。2023 年 3 月，Marinus 發起 PGR，對 Ovid 817 SC 的 IV 加奈索酮專利提出質疑，理由是專利的權利要求無效，不應由 USPTO 頒發。我很高興地告訴大家，Marinus 在向 PTAB 提出的這次 PGR 挑戰中取得了成功，包括所有挑戰的主張都是令人難以接受的。

With that, I'll now turn the call over to our Senior Vice President, Lisa Lejuwaan, who will be covering the commercial update for our Chief Commercial Officer Christy Shafer.

說完這些，我現在將電話轉給我們的高級副總裁 Lisa Lejuwaan，她將為我們的首席商務官 Christy Shafer 介紹商業更新。

Thank you, Scott. Good morning, everyone. I'm Lisa Lejuwaan, Senior Vice President and Business Unit lead of rare genetic epilepsy at Marinus. Today, I'll be highlighting the significant progress we have made to grow the ZTALMY brand since its launch in CDD two years ago and will provide an update on our commercial planning activities for potential expansion into TSC.

謝謝你，斯科特。大家早安。我是 Lisa Lejuwaan，Marinus 資深副總裁兼罕見遺傳性癲癇業務部負責人。今天，我將重點介紹自兩年前在 CDD 推出 ZTALMY 品牌以來我們在發展品牌方面所取得的重大進展，並提供我們可能擴展到 TSC 的商業規劃活動的最新情況。

With approximately 200 patients active on therapy, we continue to see steady growth and adoption of ZTALMY and CDKL5 deficiency disorder after two years of launch. For the second quarter, we generated net product revenue of $8 million, representing growth of over 85% compared to the same period in 2023.

目前約有 200 名患者正在接受治療，在推出兩年後，我們持續看到 ZTALMY 和 CDKL5 缺乏症的穩定成長和採用。第二季度，我們創造了 800 萬美元的淨產品收入，與 2023 年同期相比成長了 85% 以上。

We believe we're on track to achieve our projected full year 2024 revenue guidance of between $33 million and $35 million. This growth highlights the vital role of ZTALMY in the comprehensive management of seizures associated with CDD.

我們相信，我們預計將實現預計的 2024 年全年收入目標 3,300 萬美元至 3,500 萬美元。這一增長凸顯了 ZTALMY 在綜合管理與 CDD 相關的癲癇發作中的重要作用。

We continue to hear from HCPs that ZTALMY is making a difference in patients' lives and changing the way they think about treating these patients. We see physicians increasingly prescribing to ZTALMY for younger patients, signifying, we believe, a broader adoption in a patient population where parents are often more cautious about starting new treatments and a growing comfort with ZTALMY.

我們不斷聽到 HCP 說 ZTALMY 正在改變患者的生活並改變他們對這些患者的看法。我們看到醫生越來越多地為年輕患者開出ZTALMY 處方，我們相信，這意味著患者群體中採用該藥物的情況更加廣泛，因為父母通常對開始新療法更加謹慎，並且對ZTALMY 的適應性越來越強。

We are very pleased with the patient experience, as highlighted by low discontinuation rate with greater than 70% of patients remaining on active therapy center launch. This matches our experience from the Phase 3 Marigold trial in CDD and is aligned with our expectation.

我們對患者的體驗非常滿意，中斷治療率很低，超過 70% 的患者仍在接受主動治療中心的治療。這與我們在 CDD 第三階段 Marigold 試驗的經驗相符，也符合我們的預期。

In terms of coverage, we continue to see widespread acceptance across both commercial and government programs reflecting the value that ZTALMY brings to CDD patients and families affected by refractory epilepsy.

在覆蓋範圍方面，我們繼續看到商業和政府計劃的廣泛接受，反映了 ZTALMY 為受難治性癲癇影響的 CDD 患者和家庭帶來的價值。

Notably, no CDD patients have been denied coverage to date, underscoring the favorable reimbursement dynamics. Over the past two years, we've proven that our rare disease approach is working. We've built an infrastructure that is lean and efficient, and our sales team continues to reach KOLs and HCPs, both in specialized treatment centers and community setting, resulting in continued strong new patient enrollment and growth of new prescribers driving demand.

值得注意的是，迄今為止還沒有 CDD 患者被拒絕承保，這強調了有利的報銷動態。在過去的兩年裡，我們已經證明了我們的罕見疾病治療方法是有效的。我們已經建立了精益高效的基礎設施，我們的銷售團隊繼續接觸專門治療中心和社區環境中的 KOL 和 HCP，從而持續強勁增加新患者數量並增加新處方者，從而推動需求。

We continue to grow and evolve the ZTALMY brand and maximize its impact in the CDD market, we're implementing several key initiatives. First, we now have robust data analysis with more than 1,000 CDD patients identified, by using new data sources and analytics, we have identified patient not build with the CDD ICD-10 code and third party claims and patients who may have CDD, but do not yet have a diagnosis.

我們將繼續發展和改良 ZTALMY 品牌，並最大限度地發揮其在 CDD 市場的影響力，我們正在實施多項關鍵措施。首先，我們目前擁有強大的數據分析能力，已識別出1,000 多名CDD 患者。有CDD 但尚未做出診斷。

We're educating physicians on the importance of having confirmatory genetic testing, which is supported by the American Epilepsy Societies goal of making sure every patient with unidentified seizures has access to genetic testing to understand the underlying cause of their disease.

我們正在教育醫生進行確認性基因檢測的重要性，這得到了美國癲癇協會的目標的支持，該協會的目標是確保每位患有不明原因癲癇的患者都能接受基因檢測，以了解其疾病的根本原因。

And second, by showcasing a range of voices and stories to the community, including family members of newly treated patients, we intend to engage more families to elevate ZTALMY in CDD awareness. We are launching our on-demand shining moments period, where families can hear from experienced caregivers and families on how ZTALMY has affected their lives at a time that fit into their schedule.

其次，透過向社區展示一系列的聲音和故事，包括新治療患者的家庭成員，我們打算讓更多的家庭參與進來，提高 ZTALMY 對 CDD 的認識。我們正在推出按需的閃亮時刻節目，在此期間，家庭可以在適合他們日程安排的時間裡，從經驗豐富的護理人員和家人那裡了解 ZTALMY 如何影響他們的生活。

We continue engaging with the International Foundation for CDKL5 research, most recently at their annual conference where over 100 families were in attendance. We're proud of the growing adoption of ZTALMY and are planning to replicate the success of CDD and TSC with a potential launch in the fourth quarter of 2025.

我們繼續與國際基金會合作進行CDKL5研究，最近一次是在他們的年度會議上，有超過100個家庭出席。我們為 ZTALMY 的日益普及感到自豪，並計劃在 2025 年第四季度推出，複製 CDD 和 TSC 的成功。

Looking ahead, we plan to build upon the foundation of our proven CDD infrastructure to meet the needs of TSC patients who are also suffering from refractory seizures. With approximately 5 times to 6 times the addressable patient population compared to CDD, we have the potential to unlock a significant growth opportunity.

展望未來，我們計劃在我們成熟的 CDD 基礎設施的基礎上，滿足同樣患有難治性癲癇的 TSC 患者的需求。與 CDD 相比，我們的可尋址患者數量大約是後者的 5 到 6 倍，因此我們有可能釋放出巨大的成長機會。

Our colleagues in the TSC alliance and our market research make it clear that there remains a significant unmet need in these patients and that a new therapy would be welcomed. Furthermore, when told physicians are excited about the potential for an effective and safe product that can be used concomitantly with other anti-seizure medications, is easily accessible and has the potential to meaningfully improve quality of life.

TSC 聯盟的同事和我們的市場研究表明，這些患者仍然存在大量未滿足的需求，新的治療方法將受到歡迎。此外，當醫生被告知這種產品有潛力與其他抗癲癇藥物同時使用且有效、安全時，他們會感到興奮，這種產品易於獲取，並有可能顯著改善生活品質。

When we launched in CDD, we had relatively quick uptake due to the significant unmet medical need in this patient population. However, we anticipate even quicker uptake with TSC for several reasons. First, patient finding an ultra-rare disease is often the largest hurdle. However, this patient population is much easier to identify through a well-known ICD-10 code and through physical and neurological identifiers such as tumors, cardiac rhabdomyolysis, and refractory seizures.

當我們在 CDD 領域推出時，由於該患者群體中存在大量未滿足的醫療需求，因此我們的應用速度相對較快。然而，由於多種原因，我們預計 TSC 的採用速度會更快。首先，發現極為罕見的疾病往往是患者面臨的最大障礙。然而，透過眾所周知的 ICD-10 代碼以及腫瘤、心臟橫紋肌溶解症和難治性癲癇等身體和神經系統標識符，可以更容易地識別這類患者群體。

Trust TSC will be the first Phase 3 global trial executed in TSC that includes prior and concomitant usage of mTOR inhibitors and epidiolex, giving HCPs and families confidence in combining medications and further underscoring the current needs in the TSC community.

Trust TSC 將是 TSC 中執行的首個 3 期全球試驗，其中包括 mTOR 抑制劑和 epidiolex 的先前和同時使用，讓 HCP 和家庭對聯合用藥充滿信心，並進一步強調了 TSC 社群的當前需求。

From a payer perspective, we expect a rapid and broad access across the majority of payers supported by the protected class of epilepsy and the label extension from CDD to TSC. Patient activation is expected to be straightforward.

從付款人的角度來看，我們期望在受保護的癲癇類別和從 CDD 到 TSC 的標籤擴展的支持下，大多數付款人能夠快速、廣泛地獲得該藥物。患者的活化預計會很簡單。

In refractory TSC patients, seizure control is the main priority, making adding or changing medication an easier choice. The unique GABAergic mechanism of action of the ZTALMY is differentiated from other ASMs and supports ZTALMY place in the treatment algorithm.

對於難治性 TSC 患者，控制癲癇發作是首要任務，因此添加或更換藥物是更容易的選擇。ZTALMY 獨特的 GABAergic 作用機制與其他 ASM 不同，並支持 ZTALMY 在治療演算法中的地位。

Additionally, this will be the second completed global randomized trial of ZTALMY which will have been on the market for over three years by the time of the TSC launch, giving physicians even greater confidence in the brand.

此外，這將是 ZTALMY 第二次完成的全球隨機試驗，到 TSC 推出時，該藥物已上市三年多，這讓醫生對該品牌更有信心。

The growth and continued uptake of ZTALMY and CDD reinforces our confidence that we can replicate and accelerate the success in TSC, which is a significantly larger market opportunity. Our team look forward to sharing further updates on our progress and plans at our TSC focused Investor and Analyst Day in September, where we will highlight the work that our commercial team has been doing behind the scenes to prepare for potential expansion into TSC.

ZTALMY 和 CDD 的成長和持續成長增強了我們的信心，我們可以複製並加速 TSC 的成功，這是一個更大的市場機會。我們的團隊期待在9 月以TSC 為重點的投資者和分析師日上分享我們進展和計劃的進一步更新，屆時我們將重點介紹我們的商業團隊在幕後所做的工作，為可能擴展到TSC 做準備。

This will include key insights from our demand study, value proposition, key product positioning, and patient services portfolio enhancements.

這將包括我們的需求研究、價值主張、關鍵產品定位和病患服務組合增強的關鍵見解。

I would now like to turn the call over to our Chief Medical Officer, Dr. Joe Hulihan, for an update on our clinical programs.

現在，我想將電話轉給我們的首席醫療官 Joe Hulihan 博士，以了解我們的臨床課程的最新進展。

Thank you, Lisa. Good morning. I'm pleased to share an overview of our pipeline progress, which includes the upcoming Phase 3 data readout in TSC, preparation for our other rare genetic epilepsy programs and a recap of our Phase 3 RAISE trial readout and next steps for that program.

謝謝你，麗莎。早安.我很高興與大家分享我們管道進展的概況，其中包括即將在 TSC 中進行的 3 期數據讀數、我們其他罕見遺傳性癲癇項目的準備以及 3 期 RAISE 試驗讀數的回顧和該項目的後續步驟。

I'll start with the Trust TSC trial of oral ganaxolone in tuberous sclerosis complex. TSC is one of the most common genetic epilepsies and is caused by a defect or mutation of the TSC1 or TSC2 genes. Common symptoms include seizures, cognitive impairment, behavioral difficulties, and skin, kidney or lung abnormalities among other manifestations.

我首先會介紹 Trust TSC 對結節性硬化症口服加奈索酮的試驗。TSC 是最常見的遺傳性癲癇之一，是由 TSC1 或 TSC2 基因缺陷或突變引起的。常見症狀包括癲癇、認知障礙、行為困難、皮膚、腎臟或肺部異常等表現。

Epilepsy and TSC occurs in approximately 80% to 90% of patients with seizures typically beginning in the first year of life. Seizures in TSC are often difficult to manage and remain resistant to treatment. Despite the introduction of disease-specific antiseizure medications, there's still a significant unmet need for treatments that provide effective seizure control.

大約 80% 至 90% 的患者患有癲癇和 TSC，癲癇發作通常在出生後第一年開始。結節性硬化症 (TSC) 的癲癇發作通常難以控制且難以治療。儘管已經推出了針對特定疾病的抗癲癇藥物，但對於有效控制癲癇發作的治療需求仍然存在著很大未滿足的需要。

To address this unmet need, we are evaluating oral ganaxolone in TSC patients with refractory seizures in the Trust's TSC trial. As Scott mentioned, we completed enrollment for the study in May and continue to expect to report top line results in the first half of the fourth quarter.

為了滿足這一尚未滿足的需求，我們正在信託基金的 TSC 試驗中評估口服加奈索酮對難治性癲癇的 TSC 患者的效果。正如斯科特所提到的，我們在五月完成了研究的招募，並繼續預計在第四季度上半段報告營收結果。

Trust TSC is a global Phase 3 randomized, double-blind, placebo-controlled trial of adjunctive ganaxolone, which enrolled 129 patients with TSC associated seizures. As a reminder, the trial provides 90% power to detect a 25% difference in seizure reductions between ganaxolone and placebo.

Trust TSC 是一項全球性的 3 期隨機、雙盲、安慰劑對照的輔助性加奈索酮試驗，招募了 129 名患有 TSC 相關癲癇的患者。提醒一下，該試驗提供了 90% 的功效來檢測加奈索酮和安慰劑之間癲癇發作減少量的 25% 差異。

The trial consists of a 4-week baseline period, followed by a 16-week double-blind phase with the primary endpoint being the percent change in 28 day seizure frequency.

試驗包括 4 週的基線期，隨後是 16 週的雙盲期，主要終點是 28 天癲癇發作頻率的百分比變化。

Then for patients continuing to the open-label extension, there's a four week cross titration from double-blind study medications to open label ganaxolone. Key secondary endpoints of the double-blind portion of the study or the percent change in seizure frequency during the maintenance period, the 50% responder rate and clinical global Impression scales reported by the treating clinician and the patient or their caregiver.

然後，對於繼續進行開放標籤擴展的患者，需要進行為期四週的雙盲研究藥物與開放標籤加奈索酮的交叉滴定。該研究雙盲部分的關鍵次要終點或維持期間癲癇發作頻率的百分比變化、50% 反應率以及治療醫生和患者或其護理人員報告的臨床總體印象量表。

This trial is the first double-blind study in TSC to allow enrollment of patients taking epidiolex or mTOR inhibitors, including a finitor, relatively newer additions to the range of medication used in TSC management.

該試驗是 TSC 中首次進行雙盲研究，允許招募使用 epidiolex 或 mTOR 抑制劑（包括 finitor）的患者，這些藥物是 TSC 管理中使用的藥物系列中相對較新的藥物。

As a reminder, in Marinus Phase 2 TSC trial patients taking these medications have a 25% and 36% responder rate, respectively. As reported in May, patients entering the Trust TSC study had failed an immune of 4.8 antiseizure medications with approximately 27%, having current or prior experience with epidiolex and approximately 58% having experience with inventory inhibitors.

提醒一下，在 Marinus 第 2 期 TSC 試驗中，服用這些藥物的患者的回應率分別為 25% 和 36%。根據 5 月報告，參加 Trust TSC 研究的患者對 4.8 種抗癲癇藥物免疫失敗，其中約 27% 的患者目前或之前使用過 Epidiolex，約 58% 的患者有使用庫存抑制劑的經驗。

Patients had a median baseline rate of 50 TSC associated seizures per 28 days. As discussed previously, based on information from our Phase 2 TSC study, we modified that Phase 3 titration schedule. When we reviewed the Phase 2 study results, we believed ganaxolone had been titrated to quickly leading to increased somnolence, some unexpectedly that this led to an associated decrease in efficacy with a discontinuation rate of approximately 26%.

患者基線時 TSC 相關癲癇發作的平均發生率為每 28 天 50 次。如前所述，根據我們第 2 階段 TSC 研究的信息，我們修改了第 3 階段滴定計劃。當我們回顧第二階段研究結果時，我們認為加奈索酮的劑量已快速滴定，導致嗜睡增加，出乎意料的是，這導致療效相關下降，停藥率約為 26%。

With the revised titration schedule, the discontinuation rate in the Phase 3 study is below 7%, which is consistent with what we saw in the CDD Marigold Study. Importantly, only two patients have discontinued from the Trust TSC study to date due to somnolence related adverse events.

隨著滴定計畫的修訂，第 3 階段研究的停藥率低於 7%，這與我們在 CDD Marigold 研究中看到的情況一致。重要的是，迄今為止，只有兩名患者因嗜睡相關不良事件而退出 Trust TSC 研究。

In addition, we are seeing over 90% of patients who complete the Phase 3 study transitioning into the open-label extension, suggesting that patients are not only tolerating the drug well but unlikely also benefiting from treatment overall.

此外，我們發現超過 90% 的完成第 3 階段研究的患者正在過渡到開放標籤擴展階段，這表明患者不僅對藥物耐受性良好，而且不太可能從整體治療中受益。

I look forward to sharing updated information on baseline patient demographics and characteristics at our September Investor and Analyst event, including details on seizure types, use of concomitant medications, discontinuation rates, and average patient doses.

我期待在九月份的投資者和分析師活動中分享有關基線患者人口統計和特徵的最新信息，包括癲癇發作類型、伴隨藥物的使用、停藥率和患者平均劑量的詳細信息。

We're targeting submission of a supplemental NDA in April 2025 with a request for priority review. Assuming all goes according to plan, we anticipate a PDUFA date in the fourth quarter of 2025. We plan to present the results at AES in December following the announcement of our top line data in early Q4 was the goal publication in a major journal prior to the commercial launch.

我們計劃於 2025 年 4 月提交補充 NDA，並請求優先審查。假設一切按計劃進行，我們預計 PDUFA 日期為 2025 年第四季。我們計劃在第四季度初公佈頂線數據後，於 12 月在 AES 上公佈結果，目標是在商業發布之前在主要期刊上發表。

In addition to TSC, we plan to expand our investment in ZTALMY to explore its potential and the treatment of other rare epilepsies. Planning is underway for a clinical trial that would assess oral ganaxolone for the treatment of a broad range of developmental and epileptic encephalopathies, including Lennox-Gastaut syndrome.

除了 TSC，我們還計劃擴大對 ZTALMY 的投資，以探索其潛力以及其他罕見癲癇的治療方法。目前正計劃進行一項臨床試驗，評估口服加奈索酮對包括 Lennox-Gastaut 症候群在內的多種發育性和癲癇性腦病變的治療效果。

LGS is characterized by the presence of developmental delay and refractory seizures. It affects approximately 48,000 patients in the US, which is 4 times larger than the refractory TSC population.

LGS 的特徵是發育遲緩和難治性癲癇。它影響了美國約 48,000 名患者，是難治性 TSC 患者數量的 4 倍。

Despite the availability of several antiseizure medications approved for the treatment of seizures in LGS, there remains a considerable unmet need for effective treatments. We plan to initiate a proof of concept trial with ZTALMY in the first half of 2025, pending the TSC top line data.

儘管已有數種抗癲癇藥物已被批准用於治療 LGS 癲癇，但對於有效治療的需求仍有相當大的未滿足需求。我們計劃在 2025 年上半年與 ZTALMY 啟動概念驗證試驗，等待 TSC 頂線資料。

We believe the ganaxolone could be a valuable addition to the treatment options for LGS and [DEE's] overall, given its unique mechanism of action. The planned proof-of-concept trial can help guide us in the design and conduct of a future Phase 3 study.

我們相信，鑑於其獨特的作用機制，加奈索酮可以成為 LGS 和 [DEE] 整體治療方案的寶貴補充。計劃中的概念驗證試驗可以幫助指導我們設計和進行未來的第三階段研究。

Additionally, we're continuing our efforts to develop a second-generation ganaxolone product. Our goals are to optimize PK parameters for efficacy, tolerability and dosing frequency. We've initiated IND-enabling studies for ganaxolone pro-drug which are expected to be completed by the end of 2025.

此外，我們正在繼續努力開發第二代加奈索酮產品。我們的目標是優化療效、耐受性和給藥頻率的 PK 參數。我們已經啟動加奈索酮前藥的 IND 支持研究，預計將於 2025 年底完成。

Lastly, I'll briefly recap the results of our Phase 3 RAISE trial of IV ganaxolone in refractory status epilepticus and we'll also share the next steps in our clinical and regulatory approach. We believe that the totality of the RAISE trial data showed that ganaxolone produced rapid cessation of status and evidence of durable cessation in a highly refractory patient population.

最後，我將簡要回顧我們針對難治性癲癇持續狀態的 IV 加奈索酮的 3 期 RAISE 試驗的結果，並分享我們在臨床和監管方法方面的後續步驟。我們相信，RAISE 試驗的全部數據均表明，加奈索酮可以在高度難治的患者群體中快速產生戒斷狀態，並有證據表明戒斷效果持久。

Specifically, onset of effect was rapid with 80% of patients receiving IV ganaxolone having status epilepticus cessation within 30 minutes compared to 13% from placebo. A result that was statistically significant with a P value of less than 0.0001.

具體而言，其起效迅速，接受靜脈注射加奈索酮的患者中 80% 在 30 分鐘內癲癇持續狀態停止，而接受安慰劑的患者中這一比例僅為 13%。P 值小於 0.0001 且具有統計意義的結果。

Unfortunately, the second co-primary endpoint lack of progression to IV anesthesia within 36 hours failed to achieve statistical significance. Our analysis of the RAISE data showed that the use of IV anesthesia was likely driven by clinical and treatment factors unrelated to status severity.

不幸的是，第二個共同主要終點——36 小時內未進展到靜脈麻醉——未能達到統計學意義。我們對 RAISE 數據的分析表明，靜脈麻醉的使用可能是由與病情嚴重程度無關的臨床和治療因素所驅動的。

In contrast, continuous CEG monitoring demonstrated objective and durable control of status, specifically, analysis of 36 hours of new CEG data demonstrated a median 93% reduction in EEG seizure burden in the absence of IV anesthesia for ganaxolone treated patients, compared to 36% for placebo.

相較之下，連續CEG 監測顯示出對狀態的客觀和持久控制，具體而言，對36 小時新CEG 數據的分析表明，在沒有靜脈麻醉的情況下，接受加奈索酮治療的患者腦電圖癲癇發作負擔中位數減少了93%，而接受靜脈麻醉的患者腦電圖癲癇發作負擔中位數減少了36%。

Based on our assessment of the RAISE dataset., we plan to submit a request to the FDA this month for a meeting to discuss the trial results and determine next steps for the program. This was the first placebo-controlled trial conducted in refractory status.

根據我們對 RAISE 資料集的評估，我們計劃在本月向 FDA 提交會議請求，討論試驗結果並確定該計劃的後續步驟。這是首次在難治性狀態下進行的安慰劑對照試驗。

We're proud of our team's success in enrolling and completing a complex hospital-based study in this area of tremendous unmet need. We're hopeful that the RAISE dataset can support moving forward with our program for IV ganaxolone and the treatment of status epilepticus.

我們為團隊成功招募並完成一項針對這一巨大未滿足需求領域的複雜醫院研究而感到自豪。我們希望 RAISE 資料集能夠支援我們推進靜脈注射加奈索酮和癲癇持續狀態治療計畫。

I'd also mention that we've provided IV ganaxolone for treatment of super-refractory status epilepticus for over 30 patients under emergency IND applications.

我還要提到，我們已經為 30 多名接受緊急 IND 申請的患者提供了 IV 加奈索酮，用於治療超難治性癲癇持續狀態。

Looking ahead, results from the RAISE trial have been accepted for a platform presentation at the Neurocritical Care Society meeting in October, and we plan to submit additional data for presentation at this year's American Epilepsy Society annual meeting.

展望未來，RAISE 試驗的結果已被接受於 10 月的神經重症監護協會會議的平台展示，我們計劃提交更多數據以供在今年的美國癲癇協會年會上展示。

In closing, our clinical research team has passionately committed to bringing safe, effective and innovative treatments to patients suffering the consequences of refractory seizures status epilepticus.

最後，我們的臨床研究團隊致力於為遭受難治性癲癇持續狀態患者提供安全、有效且創新的治療方法。

I'd now like to turn the call over to our CFO and COO, Steve Pfanstiel, for a financial update.

現在，我想將電話轉給我們的財務長兼營運長史蒂夫‧芬斯蒂爾 (Steve Pfanstiel)，以了解財務最新情況。

Thanks, Jeff, and good morning, everyone, I'm pleased to be able to provide a financial update as well as share our financial results for the second quarter of 2024.

謝謝，傑夫，大家早上好，我很高興能夠提供財務更新並分享我們 2024 年第二季的財務表現。

In the second quarter of 2024, we took several significant actions as a result of the Phase 3 RAISE trial to further extend our cash runway, which is now projected into the second quarter of 2025.

2024 年第二季度，我們根據第三階段 RAISE 試驗的結果採取了幾項重大行動，以進一步延長我們的現金跑道，目前預計將延長到 2025 年第二季度。

Cost reduction plans were initiated in April of this year and remain ongoing with the full impact of cost savings expected to be achieved in the third quarter. We now project our combined selling, general and administrative and R&D expenses to decrease by approximately 30% from $80.3 million in the first half of 2024 to between $55 million and $60 million in the second half of 2024.

成本削減計畫於今年四月啟動，目前仍在進行中，預計成本節約的全部效果將在第三季實現。我們現在預計，銷售、一般及行政管理以及研發費用總額將從 2024 年上半年的 8,030 萬美元減少約 30% 至 2024 年下半年的 5,500 萬至 6,000 萬美元之間。

This new reduced cost structure also aligns with our near term focus on the oral epilepsy franchise, which can be efficiently leveraged upon an indication expansion into TSC. In June of this year, we restructured our credit agreements with both Oaktree Capital and Sagard Healthcare. As a result, the $15 million minimum liquidity requirement has been removed from both agreements and amortization payments due to Oaktree in 2024 have been reduced by 50%.

這種新的降低成本的結構也符合我們近期對口服癲癇特許經營的關注，可以透過將適應症擴展到 TSC 來有效利用該特許經營權。今年 6 月，我們與 Oaktree Capital 和 Sagard Healthcare 重組了信貸協議。結果，兩項協議中取消了 1,500 萬美元的最低流動性要求，2024 年應付給 Oaktree 的攤銷付款減少了 50%。

In return, Marinus made a one-time principal payment of $15 million to Oaktree, reducing our outstanding principal with Oaktree to $60 million. As a result of these actions, we ended June 2024 with cash and cash equivalents of $64.7 million, extending our projected cash runway into the second quarter of 2025.

作為回報，Marinus 向 Oaktree 支付了 1,500 萬美元的一次性本金，將我們在 Oaktree 的未償還本金減少到 6,000 萬美元。由於這些行動，截至 2024 年 6 月，我們的現金和現金等價物為 6,470 萬美元，將我們預計的現金流量延長至 2025 年第二季。

As mentioned by Scott and Lisa, we remain committed to growing ZTALMY franchise and have made important investments to expand our manufacturing capacity to support expansion outside of the US and in preparation of a potential launch in TSC.

正如斯科特和麗莎所說，我們仍然致力於發展 ZTALMY 特許經營權，並進行了重要投資以擴大我們的製造能力，以支持在美國以外的擴張以及為在 TSC 的潛在推出做準備。

We are proud of the progress we have made to expand patient access on a global scale while also creating meaningful revenue opportunities from markets outside the US. We expect to see positive returns from our managed access program before the end of the year and remain eligible to receive several milestone payments from our commercial partners upon the achievement of certain CDD and TSC related regulatory and commercialization activities.

我們為在全球範圍內擴大患者獲得治療機會所取得的進展感到自豪，同時也在美國以外的市場創造了有意義的收入機會。我們預計在年底之前從我們的管理訪問計劃中獲得積極的回報，並且在完成某些 CDD 和 TSC 相關的監管和商業化活動後，仍然有資格從我們的商業夥伴那裡獲得幾筆里程碑付款。

Full year 2024 guidance remains unchanged with projected ZTALMY net product revenues between $33 million and $35 million and combined SG&A and R&D expense in the range of approximately $135 million to $140 million, including non-cash stock-based compensation expense of approximately $20 million.

2024 年全年指引維持不變，預計ZTALMY 淨產品收入在3,300 萬美元至3,500 萬美元之間，銷售、一般及行政開支和研發開支總計在約1.35 億美元至1.4 億美元之間，其中包括約2000 萬美元的非現金股票薪酬開支。

I'll now take a few minutes to summarize our financial results for the second quarter. We recognized the Tommy product revenues of $8 million and $15.5 million for the three and six months ended June 30, 2024 as compared to $4.2 million and $7.6 million for the same periods in the prior year. This represents robust quarterly growth of 87% over the second quarter of 2023.

現在我將花幾分鐘總結我們第二季的財務表現。我們確認，截至 2024 年 6 月 30 日的三個月和六個月內，Tommy 產品的收入分別為 800 萬美元和 1550 萬美元，而去年同期分別為 420 萬美元和 760 萬美元。這意味著與 2023 年第二季相比，季度成長率強勁，達到 87%。

Separately, we recognized barter revenues of $0.1 million and $0.2 million for the three and six months ended June 30, 2024, as compared to $1.8 million and $8.9 million for the same periods in the prior year. As a reminder, the first quarter 2023 included activity associated with startup of the API onshoring initiative and the base period funding was completed in the fourth quarter of 2023.

另外，截至2024 年6 月30 日的三個月和六個月，我們確認的以物易物收入分別為0.1 百萬美元和0.2 百萬美元，而去年同期分別為1.8 百萬美元和8.9 百萬美元。提醒一下，2023 年第一季包括與啟動 API 在岸計畫相關的活動，基期融資已於 2023 年第四季完成。

Research and development expenses were $20.9 million and $45 million for the three and six months ended June 30, 2024, as compared to $21.4 million and $49.3 million for the same periods in the prior year.

截至 2024 年 6 月 30 日的三個月和六個月的研發費用分別為 2,090 萬美元和 4,500 萬美元，而去年同期分別為 2,140 萬美元和 4,930 萬美元。

Year to date change was due to decreased costs associated with our API onshoring effort. Selling, general and administrative expenses were $16.7 million and $35.3 million for the three and six months ended June 30, 2024, as compared to $15.7 million and $30.9 million for the same periods in the prior year.

年初至今的變化是由於我們的 API 在岸工作相關的成本降低。截至 2024 年 6 月 30 日的三個月及六個月的銷售、一般及行政費用分別為 1,670 萬美元及 3,530 萬美元，而去年同期分別為 1,570 萬美元及 3,090 萬美元。

The primary drivers of the change on a year to date basis were increased commercial and personnel expense. Restructuring costs were $2 million for the three months ended June 30, 2024, these one-time expenses reflects severance costs and the termination of trial related lease assets.

從年初至今，變化的主要驅動因素是商業和人事費用的增加。截至 2024 年 6 月 30 日的三個月的重組成本為 200 萬美元，這些一次性費用反映了遣散費和試用相關租賃資產的終止。

Interest income was $1.1 million and $2.6 million for the three and six months ended June 30, 2024, as compared to $2.1 million and $4.5 million for the same periods in the prior year. The decrease in interest income was driven by the overall decrease in cash, cash equivalents and short-term investments.

截至 2024 年 6 月 30 日的三個月和六個月的利息收入分別為 110 萬美元和 260 萬美元，而去年同期的利息收入分別為 210 萬美元和 450 萬美元。利息收入的減少是由於現金、現金等價物和短期投資的整體減少。

Interest expense was $4.6 million and $9 million for the three and six months ended June 30, 2024, as compared to $4.2 million and $8.4 million for the same periods in the prior year. The increase is primarily driven by interest expense associated with the $15 million prepayment to Oaktree.

截至 2024 年 6 月 30 日的三個月和六個月的利息支出分別為 460 萬美元和 900 萬美元，而去年同期的利息支出分別為 420 萬美元和 840 萬美元。成長的主要原因是向 Oaktree 預付的 1500 萬美元相關的利息支出。

The company reported a net loss before income taxes of $35.8 million and $74.5 million for the three and six months ended June 30, 2024, as compared to a net loss before income taxes of $33.5 million and $68.2 million in the same periods in the prior year.

該公司報告稱，截至2024 年6 月30 日的三個月和六個月的稅前淨虧損分別為3,580 萬美元和7,450 萬美元，而去年同期的稅前淨虧損分別為3,350 萬美元和6,820萬美元。

These totals include non-cash stock-based compensation expense of $4.9 million and $10.1 million for the three and six months ended June 30, 2024, as compared to $3.9 million and $7.6 million for the same periods in the prior year. Cash used in operating activities increased to $68.3 million for the six months ended June 30, 2024 as compared to cash used in operating activities of $65.8 million in the prior year.

這些總額包括截至 2024 年 6 月 30 日的三個月和六個月的非現金股票薪酬費用 490 萬美元和 1,010 萬美元，而去年同期分別為 390 萬美元和 760 萬美元。截至 2024 年 6 月 30 日的六個月，經營活動所用現金增加至 6,830 萬美元，而上一年經營活動所用現金為 6,580 萬美元。

Before we move to the Q&A, I will make a few concluding remarks. We are proud of what we've been able to achieve these past two years in both delivering the first product to market, specifically for patients with CDD and driving continued development of ganaxolone through our Trust TSC and RAISE Phase 3 trials. We remain committed to the further development of ganaxolone with a strong belief in the positive impact we can make on patients suffering from refractory epilepsy.

在我們進入問答環節之前，我將做幾點總結性發言。我們為過去兩年所取得的成就感到自豪，我們不僅向市場推出了第一款專門針對 CDD 患者的產品，而且還透過我們的 Trust TSC 和 RAISE 第 3 階段試驗推動了加奈索酮的持續開發。我們始終致力於加奈索酮的進一步開發，堅信我們能夠為患有難治性癲癇的患者帶來正面的影響。

Finally, as Scott mentioned, we will be hosting an Investor and Analyst Day event that will focus on TSC and our broader oral epilepsy franchise. The event will be in-person and webcasted on the morning of Friday, September 20. More details will follow in the coming weeks. We look forward to seeing many of you in attendance. Thanks again for your continued interest in Marinus. Operator, you may now open the call to questions.

最後，正如斯科特所提到的，我們將舉辦投資者和分析師日活動，重點關注 TSC 和我們更廣泛的口腔癲癇特許經營權。該活動將於 9 月 20 日星期五上午以現場形式舉行並進行網路直播。更多詳細資訊將在未來幾週內公佈。我們期待你們的出席。再次感謝您對 Marinus 的持續關注。接線員，您現在可以開始提問了。

(Operator Instructions)

（操作員指令）

Charles Duncan, Cantor Fitzgerald.

查爾斯鄧肯、康托菲茨傑拉德。

Yeah, hi. Good morning, Scott and team. Thanks for the update and congrats on the commercial progress in the quarter. I wanted to ask you about ZTALMY specifically and I did have a pipeline question, but I'll stick with one. In terms of the new patients add additions in the quarter, could you provide a little bit more color on that.

是的，你好。早上好，斯科特和團隊。感謝您的更新，並祝賀本季的商業進展。我想具體問您有關 ZTALMY 的問題，而且我確實有一個管道問題，但我會堅持一個問題。關於本季新患者增加的情況，您能否提供更多詳細資訊。

And then if Lisa could perhaps clarify a little bit about her statement, around 70% of patients remaining active on drug since launch. Could you give us a sense of a little bit better sense of persistence on patients are that patients have on drug? Thanks.

然後，如果麗莎可以稍微澄清一下她的陳述，大約 70% 的患者自藥物推出以來一直在服用該藥物。您能否讓我們更了解患者對藥物的堅持程度？謝謝。

And then Charles, I'll kick it off and then I'll turn it over to Lisa. I think one of the things we've seen with this launch almost from the get-go is relatively steady growth in new patient adds every quarter. There's always some variation quarter to quarter. But I think we really understand that this is a patient population that has a lot on their play, very often, it's months to get started on new therapy, one that we think is going to be very different than the TSC population where seizure control is really a paramount issue in those patients' lives.

然後查爾斯，我將開始討論，然後我將把它交給麗莎。我認為我們幾乎從一開始便看到的一件事就是每個季度新增患者的數量相對穩定地增長。每個季度之間總是會存在一些變化。但我認為我們確實明白，這是一個患者群體，他們往往需要幾個月的時間才能開始新的治療，我們認為這與 TSC 患者非常不同，因為 TSC 患者的癲癇發作控制這確實是這些病人生活中最重要的問題。

And so I think we've generally been very consistent with the growth of the franchise since the time of launch. And certainly there was a small bolus of patients in clinical trials from the beginning of our launch. In terms of the discontinuation rate, if you go back to Marigold, we saw about 70% of patients on long-term therapy, a good number there.

所以我認為，自推出以來，我們總體上一直非常關注特許經營的成長。當然，從我們推出產品之初，就有一小部分患者參加臨床試驗。就停藥率而言，如果你回顧 Marigold，我們發現大約 70% 的患者接受長期治療，這是一個不錯的數字。

We lost two to three years in follow-up, but the persistence of effect has really been one of the nicer experiences we've seen with the drug and to date, our commercial experience really mirrors or incrementally better than what we saw in Marigold. So we're still north, -- Lisa's comments, north of 70% on persistent, seeing very durable effect. We're going to also show some durability data in the TSC population at the Analyst Day and then at AES.

我們在後續研究中損失了兩到三年的時間，但療效的持久性確實是我們在使用該藥物時看到的較好的體驗之一，到目前為止，我們的商業體驗確實與我們在萬壽菊中看到的情況相同或略有改善。所以我們仍然在北方 - - Lisa 的評論，在持續性方面超過 70%，看到了非常持久的效果。我們也將在分析師日和 AES 上展示一些 TSC 群體的耐久性數據。

But Lisa, I'm happy to flip it over to you for some additional comments on what you're seeing in the marketplace, both in terms of new patient starts and persistence.

但是麗莎，我很高興把它交給你，請你對市場上看到的情況提出一些額外的評論，包括新患者開始和持久性方面的資訊。

Thanks so much, Scott. I think you covered most of it there, but I'll just add that we're extremely proud of the work the team has done on to reach a significant portion of the market CDD patients with many more patients yet to find. Our team is also very proud of the durability of this drug, when you talk about a 30% -- less than 30% discontinuation rate.

非常感謝，斯科特。我想你已經講到了大部分內容，但我只想補充一點，我們對團隊所做的工作感到非常自豪，他們已經覆蓋了市場上很大一部分 CDD 患者，並且還有更多的患者有待發現。我們的團隊也對這種藥物的耐用性感到非常自豪，停藥率為 30%——不到 30%。

This speaks to the unique mechanism of action of this drug and these patients, it's a very complicated mix of multiple therapies and we're proud of the fact that these patients have remained on ZTALMY, signifying that they are getting the seizure reduction that they need with relatively few, if any side effect. And it has such a wonderful drug-drug interaction profile that the community is quite happy with this response.

這說明了這種藥物的獨特作用機制，對於這些患者來說，這是一種非常複雜的多種療法的組合，我們為這些患者繼續使用ZTALMY 而感到自豪，這意味著他們正在獲得所需的癲癇發作減少副作用相對較少，甚至沒有。而且它具有如此出色的藥物交互作用特性，社區對此反應非常滿意。

Thanks, Lisa. Trying to make one other comment. The second half of the year tend to be stronger for us, a lot of the medical meetings are really back and weighted. Certainly, AES and some other additional pediatric meetings, which are really critical to the messaging. There's really a paucity of medical meetings in the first half of the year. So

謝謝，麗莎。嘗試提出另一條評論。下半年對我們來說會更加強勁，許多醫療會議確實回來了，而且很有分量。當然，AES 和其他一些兒科會議對於傳遞訊息來說確實至關重要。上半年的醫事會議確實很少。所以

we're really looking forward to the second half of the year and the medical meetings and the interest that we see almost immediately following medical meetings for ZTALMY.

我們非常期待今年下半年的醫學會議以及在醫學會議結束後幾乎立即看到的對 ZTALMY 的興趣。

So thanks for that. That drives prescribing or does it take prescribers out of the office? What are the countervailing --

非常感謝。這會推動處方的開出還是會讓開處方者離開辦公室？什麼是反補貼--

Generally, we've seen very strong prescription trends following our medical meetings.

總體而言，我們在醫學會議之後看到了非常強勁的處方趨勢。

Okay. Got it. Thank you.

好的。知道了。謝謝。

Brian Abrahams, RBC Capital Markets.

加拿大皇家銀行資本市場 (RBC Capital Markets) 的 Brian Abrahams。

Hi, this is John for Brian. Thanks for taking our question. On CNC, can you talk about some of the subgroup analyses you've done for the Phase 2 open-label study that gives you most confidence that Phase 3 study will readout positively.

你好，我是 Brian 的約翰。感謝您回答我們的問題。在 CNC 上，您能否談談您為第 2 階段開放標籤研究所做的某些亞組分析，這些分析讓您最有信心第 3 階段研究將取得積極成果。

How consistent was the seizure reduction for dose who stayed on the therapy until the end of the maintenance phase? And I guess for the ongoing Phase 3 study. Can you tell us how many patients had their last visit and entered into the open-label extension so far? Thank you.

對於堅持治療直至維持期結束的患者，癲癇發作的減少與劑量有多一致？我想這是正在進行的第三階段研究。您能告訴我們到目前為止有多少患者進行了上次就診並進入了開放標籤擴展期嗎？謝謝。

Yeah. Well, let me start with the last question, and then I'll turn it over to Joe to talk a little bit about what we saw in the Phase 2, but we are well north of 100 patients now close to 110 patients that are into the open label. The last patient visit is in September the first or second week in September. We should have the last patient visit in the study. So the vast majority of patients have now rolled into open label.

是的。好吧，讓我從最後一個問題開始，然後我會把問題交給喬，讓他談談我們在第二階段看到的情況，但是我們已經遠遠超過了 100 名患者，現在接近 110 名患者開放標籤。最後一次患者就診是在九月的第一或第二週。我們應該進行研究中的最後一次患者訪視。因此，絕大多數患者現在都已接受開放標籤治療。

To the question, I think we continue to see consistency of those high percentages of patients rolling into open-label we're north, about 90% of patients completing the study, or who are rolling into open-label and staying on open label.

對於這個問題，我認為我們繼續看到高比例的患者轉入開放標籤，我們處於北方，大約 90% 的患者完成了研究，或者轉入開放標籤並保持開放標籤。

So we'll give the final numbers at the Analyst Day, but certainly from we haven't seen a bump in those discontinuations early on in the trial. We feel very confident that now north of 100 patients are really tolerating the drug extremely well, very different than what we saw in Phase 2 is a reminder, we had a 26% discontinuation rate in the Phase 2.

因此，我們將在分析師日公佈最終數據，但可以肯定的是，在試驗初期我們並沒有看到這些停藥事件的增加。我們非常有信心，現在已有超過100 名患者對該藥物的耐受性非常好，與我們在第2 階段看到的情況非常不同，這提醒我們，在第2 階段，我們的停藥率為26％。

And I think we're in a different place today much because of the work that Joe has done and the team has done to reconfigure the dosing paradigm. Joe, you want to talk about some of the highlights that we saw in Phase 2 and our confidence going into the Phase 3?

我認為我們今天所處的位置不同了，這很大程度上是因為喬和他的團隊為重新配置劑量模式所做的工作。喬，你想談談我們在第二階段看到的一些亮點以及我們對進入第三階段的信心嗎？

Yeah, Scott. Yeah, as you mentioned -- as Scott mentioned, there were 26% discontinuations. For side effects, so that was six patients for side effects, it was four. So really, despite the rapid titration in Phase 2, we had four patients discontinued due to adverse events.

是的，斯科特。是的，正如您所說——正如斯科特所說，停產率為 26%。對於副作用，有六名患者出現副作用，只有四名患者出現副作用。因此，儘管在第 2 階段我們進行了快速滴定，但實際上仍有 4 名患者因不良事件而停藥。

Now the one thing about the current open label study that's ongoing, patients from the Phase 2 study could roll into the open label. And so we have a combined open-label extension for the Phase 3 and the Phase 2, and we still have patients the latest number is not at the tip of my tongue, we have patient from Phase 2 who have continued to this point in the open-label extension.

目前正在進行的開放標籤研究的一件事是，來自第 2 階段研究的患者可以加入開放標籤研究。因此，我們有一個針對第 3 階段和第 2 階段的聯合開放標籤擴展，我們仍然有患者，最新的數字我還沒說出來，我們有第 2 階段的患者，他們一直持續到現在開放標籤擴展。

And so I think the titration really makes a big difference. I think you asked about them subpopulations, and we looked at patients with focal seizure types. They had a better response 25% reduction compared to the overall population. And then we looked at patients on cannabidiol and everolimus, and they also had a good response, particularly everolimus, 20% greater response in the population as a whole some. So again, encouraging signals. Did I answer your question?

所以我認為滴定確實會產生很大的影響。我覺得您問的是他們的亞群，我們研究了局部癲癇類型的患者。與整體人群相比，他們的反應更好，減少了 25%。然後，我們觀察了使用大麻二酚和依維莫司的患者，他們的反應也很好，特別是依維莫司，整個人群的反應高出 20％。這再次表明，這是一個令人鼓舞的信號。我回答你的問題了嗎？

Yes. Thank you, Scott. Thank you Joe.

是的。謝謝你，斯科特。謝謝你，喬。

Yeah. Let me add one or two comments to Joe's comments. Joe, hit the mark in terms of what we saw in the Phase 2 and as a reminder, what we said publicly about 70% of the seizure types close to 75% that we're seeing in the blinded Phase 3 are focal in nature. So that's exactly what we had hoped to see.

是的。讓我對喬的評論補充一兩則評論。喬，就我們在第2 階段看到的情況而言，您說對了，提醒一下，我們公開說過，在盲法第3 階段中，70% 的癲癇發作類型（接近75%）都是局灶性的。這正是我們希望看到的。

So to Joe's point, strong signal in Phase 2, even with the tolerability issues, which is why we expect that number to be more robust in the Phase 3 and in the Phase 3 more than half the patients are coming into the study on into our inhibitors. And again, that was our strongest 50% responder number from the Phase 2. And certainly we saw a robust responder number with the cannabidiol group, which will make up about 25% of the population.

因此，正如喬所說，即使存在耐受性問題，第二階段的訊號也很強烈，這就是為什麼我們預計第三階段的數字會更加強勁，並且在第三階段，超過一半的患者進入我們的研究抑制劑。再次，這是我們第二階段最強勁的 50% 響應者數字。當然，我們看到大麻二酚組的響應者數量非常可觀，該組約佔總人口的 25%。

So we have all the right subtypes in the in Phase 3. We have the right seizure type. And certainly that's where the efficacy signals are strongest, even in the setting of some real tolerability issues in the Phase 2. So we have a lot of confidence going into the Phase 3. Thanks for the question.

因此，我們在第 3 階段擁有所有正確的亞型。我們有正確的癲癇發作類型。當然，這是療效訊號最強的地方，即使在第二階段存在一些真正的耐受性問題的情況下也是如此。因此，我們對進入第三階段充滿信心。謝謝你的提問。

Joseph Thome, TD.

約瑟夫·托米（Joseph Thome）, TD。

Hi there. Good morning and thank you for taking my question. Maybe a little bit of a follow-on to your explanation from the last question. But the Phase 3 looks like the baseline seizure frequency is a little bit higher than what you saw on the Phase 2 and the number of prior therapies failed is also a little bit higher in the Phase 3 blinded data than versus the Phase 2.

你好呀。早上好，感謝您回答我的問題。也許可以稍微延續一下你上一個問題的解釋。但第 3 階段的基線癲癇發作頻率似乎比第 2 階段略高，且第 3 階段盲法資料中先前治療失敗的數量也比第 2 階段略高。

I guess, does that indicate that you think it's potentially going to be a little bit easier to show a benefit of ganaxolone in the Phase 3 or are these more challenging patients to treat kind of based on your experience in the CDD and the Phase 2, what's sort of your expectation there? Thank you.

我想，這是否表明您認為在第 3 階段顯示加奈索酮的益處可能會更容易一些，或者根據您在 CDD 和第 2 階段的經驗，這些患者是否更難治療？謝謝。

Yeah, thanks, Joe. Let me kick it off and then I'll turn it over to Joe. I will tell you my experience, at least from talking to some of our key investigators, what's really critical in a study like this is that we have patients, who for lack of a better are seizing through their medications at a steady state, right, that there isn't an acute acceleration or worsening of their symptoms, which would tend to set yourself up for value just in the disease is progressing, whether or not any therapy can kind of acutely address that.

是的，謝謝，喬。讓我先開始，然後再交給喬。我會告訴你我的經驗，至少從與我們的一些主要研究人員的交談中，在這樣的研究中真正重要的是，我們的患者由於缺乏更好的藥物而處於穩定的狀態，對吧，他們的症狀沒有急劇加速或惡化，這往往會使病情惡化，無論是否有任何治療方法可以急劇解決這個問題。

So I think I give Joe all the credit in the world that he really stuck to our guns and kept our enrollment criteria at more than eight seizures per month. And I think that's a critical factor for minimizing placebo rate. You can imagine that if a patient was allowed to enroll with only four seizures per month and there's natural variability that placebo response could be 25% if they went from [four] to [three].

因此，我認為我應該把所有的榮譽歸功於喬，他真正堅持我們的立場，將我們的入組標準保持在每月癲癇發作超過八次。我認為這是最大限度降低安慰劑率的關鍵因素。你可以想像，如果一個病人每個月只允許發作四次，並且存在自然變異，那麼如果他們從 [四] 到[三]。

So Joe was really instrumental in driving the team and in fact keeping us at eight seizers per month, which is higher than what you see in multiple seizure studies. But again, our view is how do we minimize placebo rate to maximize success. So I think controlling for placebo is going to be critical for us. Look my experience from talking to our investigators is that we're getting a group of patients a little bit older, many of who have gone to surgery, many have gone through multiple medications.

因此，喬在推動團隊發展方面發揮了重要作用，事實上，他讓我們每個月的癲癇發作次數保持在 8 次，這比你在多項癲癇研究中看到的次數要高。但同樣，我們的觀點是如何盡量減少安慰劑率以最大限度地提高成功率。因此我認為控制安慰劑對我們來說至關重要。從我與研究人員的交談中我得到的經驗是，我們接待了一群年齡稍大的患者，其中許多人都做過手術，許多人都服用過多種藥物。

I think it's a very classic phenotype in this population. Certainly that's at least as market research is showing and again, to this discussion, I think just the high seizure burden really will minimize placebo effect. So yeah, when you asked this, I think we feel good about the efficacy, we feel very good about placebo rates, not only because of baseline seizure type, but where we went by countries, we really enrolled in.

我認為這是該群體中非常典型的表型。當然，至少市場研究表明如此，並且對於本次討論，我認為較高的癲癇發作負擔確實會最大限度地減少安慰劑效應。是的，當您問到這個問題時，我認為我們對療效感到滿意，我們對安慰劑率感到滿意，這不僅是因為基線癲癇發作類型，還因為我們所到過的國家，我們確實招募了這些患者。

I'll remind folks that if you go back to the GW study, the placebo rate was about 25%. Poland was the second largest enroller in that study. We had a very unfortunate experience in Poland with CDKL5, that was a very high placebo rate. Certainly, the GW study suggests that a high placebo rate.

我要提醒大家，如果你回顧 GW 研究，安慰劑率約為 25%。波蘭是這項研究中第二大招募國。我們在波蘭使用CDKL5的經驗非常不幸，安慰劑率非常高。當然，喬治華盛頓大學的研究顯示安慰劑使用率很高。

So we chose to stay out of Eastern European countries to minimize the risk of high placebo. So between that and the [EUR80] per month, we feel very good about the placebo rate coming in somewhere in the high single digits, no more than low double digits, which gives us the best chance to win.

因此，我們選擇遠離東歐國家，以盡量降低高安慰劑風險。因此，在這個數字和每月 [80 歐元] 之間，我們對安慰劑率處於高個位數、不超過低兩位數感到非常滿意，這讓我們有最大的獲勝機會。

Joe, you want to comment additionally on seizure types or anything else that we've seen in the blinded data and the Phase 3 in terms of seizures that give you comfort?

喬，您想對癲癇發作類型或我們在盲法數據和第 3 階段中看到的任何其他讓您感到舒適的情況進行額外評論嗎？

Yeah. Well, a lot of things. One, I mean, you mentioned seizure types. The vast majority of the patients coming into the Phase 3 have focal onset seizures, where we expect to see good efficacy and less variability in the response in the patients with focal onset seizures, that we saw say, with [ZTALMY] seizures, still a good effect size. And I'm talking about CDD. Still a good effect size, but there was the variability is less of the patients with focal seizures.

是的。嗯，有很多事情。首先，我的意思是，您提到了癲癇發作的類型。進入第 3 階段的絕大多數患者都患有局部性癲癇，我們預期該藥物療效良好，且對局部癲癇患者的反應變化較小，例如，我們看到的 [ZTALMY] 癲癇發作仍然效果良好。我說的是 CDD。仍具有良好的效果，但局部癲癇患者的變異性較小。

And just tag on to what Scott said, Scott said about patients coming in. It's really eliminating those patients with very few seizures. It's not really linear in terms of seizure frequency, the bigger, the number of baseline, the more response you get, but it's really just those patients with very low seizure numbers, that there's that kind of mathematical problem with not being able to get much better.

繼續說史考特說的話，史考特說的是病人進來的狀況。這其實是在淘汰那些癲癇發作次數很少的患者。就癲癇發作頻率而言，它並不是線性的，基線數量越大，您獲得的反應越多，但實際上只有那些癲癇發作次數非常少的患者，才會出現無法獲得太多反應的數學問題更好的。

But once you get beyond 8 or 10 seizures a month, the response doesn't differ that much depending on baseline seizure rate higher is better, but just really eliminating the very, very low patients.

但是一旦您每月癲癇發作次數超過8 次或10 次，反應就不會有太大差異，這取決於基線癲癇發作率，越高越好，但實際上只是淘汰了那些發作率非常非常低的患者。

The other thing I'll mention, too, that gives it well, a couple of things. One is we want to make sure the patients had disease stability coming in, so that they didn't have full regression to the mean when they came into the study. So we want them to have seizures in each of the two months at a certain frequency and no more than one month -- one week seizure-free during those months to make sure the disease is stable when they come into the baseline.

我還要提到的另一件事是，它很好地說明了幾件事。一是我們要確保患者的病情穩定，這樣他們在進入研究時就不會完全回歸平均值。因此，我們希望他們在兩個月內的每個月都以一定的頻率發作癲癇，並且發作頻率不超過一個月——在這幾個月內有一周時間沒有癲癇發作，以確保他們進入基線時病情穩定。

And the other thing, too, is the somnolence. The lower titration rate and the lower discontinuations due to somnolence. We saw this odd relationship between somnolence -- higher somnolence and lower efficacy. And so by reducing the somnolence, that also gives me optimism about the efficacy we're going to see in Phase 3.

另一件事就是嗜睡。滴定率較低且因嗜睡而停藥的情況較少。我們發現了嗜睡之間存在著奇怪的關係──嗜睡程度越高，功效越低。因此，透過減少嗜睡，我也對我們將在第三階段看到的療效充滿樂觀。

Hey operator, let's go to the next questions. Thanks.

嘿，接線員，我們來討論下一個問題。謝謝。

Joon Lee, Truist.

Joon Lee，Truist。

Good morning this is (inaudible) for Joon, thanks for taking the questions. Just curious what the timing on the type c meeting with the FDA and what scenarios you think could come out of the meeting. And then I know this is mentioned on the call, but I want to be sure what the discontinuation rate due to somnolence was in the Phase 3, Trust TSC trial and what that number was in the Phase 2 trial? Thank you.

早上好，這是 Joon 的（聽不清楚），謝謝您回答問題。只是好奇 FDA 的 C 型會議的時間表以及您認為會議可能出現哪些情況。然後我知道電話中提到了這一點，但我想確定在第 3 階段 Trust TSC 試驗中因嗜睡而停藥的比例是多少，在第 2 階段試驗中這個數字是多少？謝謝。

Thanks Joon. Just to start backwards, we've only reported the total discontinuation rate of 26% in the Phase 2, vast majority of those were related to tolerability issues. We believe all of them are related to tolerability issues.

謝謝 Joon。從過去開始，我們僅報告了第 2 階段的總停藥率為 26%，其中絕大多數與耐受性問題有關。我們相信所有這些都與耐受性問題有關。

And certainly the other piece of that puzzle is more than 70% of the patients in the Phase 2 required dosing adjustments. So they were patients who were really struggling with the dosing. And that was really something we did become aware of until -- very effectively until the trial was completed.

當然，這個難題的另一個部分是，第二階段超過 70% 的患者需要調整劑量。所以，他們是真正在劑量上遇到困難的病人。直到試驗完成，我們才真正意識到了這一點。

One of the physicians who will be at our analyst day, I'm quite excited about because he was in our Phase 2 and really struggled with the patients on the Phase 2 dosing regimen. It took a lot of personal convincing from our medical team and myself to get this physician to participate in the Phase 3. And I think he'll share with you at the Analyst Day what a good response that he had at least in a blinded fashion from the Phase 3 thus far.

我對參加我們分析師日的其中一位醫生感到非常興奮，因為他參與了我們的第 2 階段研究，並且在第 2 階段的給藥方案中為患者付出了很大努力。我們的醫療團隊和我自己花了大量個人說服才讓這位醫生參加第三階段的治療。我認為，他會在分析師日上與大家分享，至少到目前為止，他對第三階段的盲目反應有多正面。

Joon, I really apologize. I forgot your first question.

俊，我真的很抱歉。我忘了你的第一個問題。

I was just curious about the timing on the type C meeting with the FDA in general if you thing could come out of that? Thanks.

我只是好奇與 FDA 舉行 C 類會議的總體時間安排，您認為會有什麼結果嗎？謝謝。

Absolutely. Yeah. So Joe, Alex, the regulatory team has been working incredibly hard, putting -- go into the IV dataset and really understanding that data. There's no question, Joe's comments, we are quite convinced that the drug was highly efficacious and had a durable effect.

絕對地。是的。因此，喬、亞歷克斯和監管團隊一直非常努力地工作，深入研究 IV 資料集並真正理解這些數據。毫無疑問，根據喬的評論，我們非常確信這種藥物非常有效並且具有持久的效果。

I think, unfortunately, the endpoint that we chose had a great deal of variability. And it did not really reflect the durability of the drug. It really reflected what we believe is more physicians practice and that's unfortunate, that's really counterintuitive to what we were told going into the study time and time again by the medical community and the experts that we talk to.

我認為，不幸的是，我們選擇的終點具有很大的變異性。而且並不能真正體現出藥物的持久性。這確實反映了我們所認為的更多醫生的實踐，這是不幸的，這與醫學界和我們交談過的專家在研究中一次又一次告訴我們的情況完全違背直覺。

So our real goal for the meeting with the FDA is really to realign on endpoints that we think are much more objective that we can define the durability of the product, that will be the critical piece and really thinking about a study design. And certainly we're going to share our data set with the FDA and have what we hope is a very robust discussion.

因此，我們與 FDA 會面的真正目標是重新調整我們認為更客觀的終點，以便我們能夠定義產品的耐用性，這將是關鍵部分，並真正考慮研究設計。當然，我們將與 FDA 分享我們的數據集，並希望進行非常深入的討論。

Our hope and goal is to get the filing in by the end of the month and a typical type C meeting is a 90-day review. So our hope is to have that meeting in the early part of the fourth quarter. And I think we really understand the data that Joe's done an amazing job, looking at the EEG dataset, looking at practice patterns.

我們的希望和目標是在月底之前提交文件，典型的 C 類會議是 90 天的審查。因此我們希望在第四季初召開該會議。我認為我們確實了解了數據，喬做了一項了不起的工作，他查看了腦電圖數據集，查看了練習模式。

And unfortunately, I think we're learning an ICU study where physicians believe after 12 hours new physicians come in, it's just -- we've just seen a lot of practice patterns, which are disheartening to me as a physician, but certainly it's helping us rethink how to best show the efficacy of this drug. I mean, there's nothing in this study that gave us pause for the efficacy of this drug.

不幸的是，我認為我們正在學習一項 ICU 研究，醫生們認為 12 小時後新醫生進來，這只是——我們剛剛看到了很多實踐模式，這讓我作為一名醫生感到沮喪，但肯定的是幫助我們重新思考如何最好地展示這種藥物的功效。我的意思是，這項研究中沒有任何內容讓我們對這種藥物的功效產生懷疑。

I think the other thing that we'll really align yet with the FDA is how we should think about, enrolling this population, we saw some variability in terms of differences in patient outcomes. And we want to align on our stratification strategy with the FDA to make sure that there are no significant imbalances and we can really show the value prop of the drug.

我認為我們與 FDA 真正達成一致的另一件事是我們應該如何考慮招募這些人群，我們看到患者結果存在一些差異。我們希望與 FDA 保持一致的分層策略，以確保不存在重大不平衡，並且我們能夠真正展現藥品的價值主張。

I'll finally -- I'll just -- last noted we'll be presenting the vast majority of this data at a medical meeting in October, the NCS meeting, and it we will be a platform presentation. So folks will really get to see all of what we've seen in terms of the efficacy and the tolerability of the drug. And certainly we're going to share all of that with the FDA as well. Thanks for the question.

我最後 — — 我只是 — — 最後指出，我們將在 10 月的醫學會議，即 NCS 會議上展示絕大部分數據，並且我們將進行平台演示。因此，人們將真正了解我們所看到的有關藥物的功效和耐受性的一切。當然，我們也會與 FDA 分享所有這些資訊。謝謝你的提問。

Andrew Tsai, Jefferies.

傑富瑞 (Jefferies) 的 Andrew Tsai。

Hey, thanks. Good morning. Thanks for taking my question. And so on top of the RSC thanks for sharing all this tidbits. If you had to run another study after the FDA meeting, how would you design it to not only succeed, but also have it done, say, within one or two years? Or is there anything you can think us to ensure? Thanks.

嘿，謝謝。早安.感謝您回答我的問題。因此，非常感謝 RSC 分享這些趣聞。如果您必須在 FDA 會議後進行另一項研究，您會如何設計它才能不僅取得成功，而且還能在一兩年內完成？或者您認為我們可以確保什麼？謝謝。

Yeah. Well, I think Andrew, first and foremost, thanks for the question. I think we're going to be very, very thoughtful about the trial design. I think once we got through our protocol amendment and our product issues, recall we had some manufacturing issues that we were able to resolve, and we now have great stability and shelf life of the product. So once we got through those issues, we were screening about 15 patients per month.

是的。好吧，我想安德魯，首先感謝你提出這個問題。我認為我們會非常非常認真地考慮試驗設計。我認為，一旦我們完成了協議修訂和產品問題，回想一下，我們曾經遇到過一些能夠解決的製造問題，現在我們的產品就具有很高的穩定性和保質期。因此，一旦我們解決了這些問題，我們每月就會篩選大約 15 名患者。

And quite honestly, all of those patients and the vast majority would be eligible for what we think is the right patient population to study in a future study. So I don't worry a tremendous amount about the enrollment because we know which sites are very powerful. I think they're eager to be involved in another study.

坦白說，我們認為所有這些患者以及絕大多數患者都符合未來研究的正確患者群體的資格。因此，我並不太擔心招生問題，因為我們知道哪些網站非常強大。我認為他們渴望參與另一項研究。

But I think to be honest, we really have to think about the financial impact of that to the company and where we want to place our resources, but fortunately, we have multiple strategics. We started engaging for the data, the vast majority of those strategics are still in our data room talking to us regularly.

但我認為說實話，我們確實必須考慮這對公司造成的財務影響以及我們希望將資源投入到哪裡，但幸運的是，我們有多種策略。我們開始參與數據研究，絕大多數策略制定者仍然在我們的數據室定期與我們交流。

Really curious I think about the FDA outcome. We're still in conversations with [Bardas], unequivocally once this product develop commercially, so that unfortunate case and let's hope there never is and there gets attacked within the United States, they would have access to ganaxolone for that.

我真的很好奇 FDA 的結果。我們仍在與[Bardas] 進行對話，明確地說，一旦該產品實現商業化開發，那麼那個不幸的案例（我們希望永遠不會發生）和它在美國境內受到攻擊，他們就能夠獲得加奈索酮。

And so we are really thinking hard about ways to finance another trial with the help of other another party and certainly, I think getting alignment with the agency thinking about the size of the trial, which I think we're thinking right now, roughly in the 150 plus or minus patient range is really quite durable within a two year window.

因此，我們正在認真思考如何在其他方的幫助下為另一項試驗提供資金，當然，我認為要與該機構協調試驗的規模，我認為我們現在正在考慮的規模大致是在兩年的時間範圍內，150 名左右的患者範圍確實相當持久。

But again, I think from a resource allocation standpoint, we're going to -- we put almost all our resources behind the oral program, we really want to see a future for the IV program, but we also have to recognize that it has to be a smart financial investment. So we'll see how the meeting goes with the FDA. I think we're very optimistic we can get to an alignment on some of these key elements.

但我認為，從資源分配的角度來看，我們將把幾乎所有的資源都投入到口服藥物項目上，我們真的希望看到靜脈注射計畫的未來，但我們也必須認識到，它已經成為一項明智的金融投資。我們將觀察與 FDA 的會議進度。我認為我們非常樂觀地認為我們可以就一些關鍵要素達成一致。

We then feel we can really run the study in a reasonable amount of time, and we'll figure out the best way to finance that study with, shareholder interest certainly in mind. So that's kind of where we stand. And I think we'll be able to walk away with this from our interaction with the FDA with a relatively clear path forward.

然後我們覺得我們可以在合理的時間內真正進行這項研究，並且我們會找出為這項研究提供資金的最佳方式，當然也會考慮到股東的利益。這就是我們的現狀。我認為，透過與 FDA 的互動，我們將能夠找到一條相對清晰的前進道路。

I think -- we think the solution is relatively simple. I think the agency has been a great thought partner. So we're looking forward to meeting them and getting this drug to market. I think it's a critically important resource for physicians to have. But we recognize the hospital environment is one that we have to be able to show the value, and that's our plan. So that's how we're going to move forward, and we will be really excited to share those plans with you in the coming months.

我認為——我們認為解決方案相對簡單。我認為該機構是一個很好的思想合作夥伴。因此，我們期待與他們會面並將這種藥物推向市場。我認為這對醫生來說是至關重要的資源。但我們認識到醫院環境是我們必須能夠展示其價值的環境，這就是我們的計劃。這就是我們前進的方向，我們將非常高興在接下來的幾個月與你們分享這些計劃。

Thanks for the question. Appreciate it.

謝謝你的提問。非常感謝。

Douglas Tsao, H.C. Wainwright.

曹國偉，H.C.溫賴特。

Hi, good morning. Thanks for taking the questions. Just insurances, the analysis of the IV program, Scott, obviously we seen there were challenges in terms of physician behavior. I'm just curious if you have a chance to look at results by sites, -- by individual site.

嗨，早安。感謝您回答這些問題。只是保險，對 IV 計劃的分析，斯科特，顯然我們看到醫生行為方面存在挑戰。我只是好奇您是否有機會查看各個站點的結果——各個站點的結果。

Were there particular sites that really sort of deviated from your expectations and what your sort of expectation and understanding of treatment patterns would be, especially in terms of advancing patients to IV anesthesia? Or was it really just a broader phenomenon that you saw in the study?

是否有特定的站點確實與您的預期有所不同，您對治療模式的期望和理解是什麼，特別是在讓患者接受靜脈麻醉方面？或者這實際上只是您在研究中看到的更廣泛的現象？

Yeah. Thanks, Doug. We did look at an analysis of how our larger sites did, and certainly there was a stronger signal for the drug in our bigger sites in our high enrolling sites. And I think quite honestly, that was driven as much by the factor that those physicians advanced care more commonly.

是的。謝謝，道格。我們確實對我們的大型試驗中心的表現進行了分析，並且確實在我們招募人數較多的大型試驗中心中，該藥物的信號更強。而且我認為，坦白說，這很大程度上是由這些醫生更普遍地提供先進護理的因素造成的。

We're not afraid or concerned about moving to IV anesthesia, to as result, there were lower placebo rates and certainly the delta was larger than the overall study. I think to be quite fair that matters a bit, but not necessarily. I think we would not feel comfortable enrolling another study where advancement to IV anesthesia is the endpoint.

我們並不害怕或擔心轉向靜脈麻醉，因此，安慰劑率較低，而且差異肯定比整體研究大。我認為公平地說這有點重要，但不一定。我認為我們不願意進行另一項以靜脈麻醉進展為終點的研究。

I think what we learned is that regardless of what physicians told us, which was, they would move to IV anesthesia at 80% of the time after failing two drug, patient with who received an excellent in the study, typically received three drugs. Typically, we're in and out of status for about a day and a half and in even in that scenario or in this case, the control group physicians were only advancing care 50% of the time.

我認為，我們所了解到的是，無論醫生告訴我們什麼，在兩種藥物治療失敗後，80% 的患者都會轉為靜脈麻醉，而研究中獲得優異成績的患者通常會接受三種藥物治療。通常情況下，我們的狀態大約持續一天半的時間，即使在這種情況下，對照組的醫生也只有 50% 的時間在進行護理。

So and that may have been, changing the EEG patterns, it may have been a changing physicians, it may have been not necessarily following the behaviors of the EEG, but I think we've just learned that this is too subjective in endpoint, regardless of what physician have told us time and time again. And remember, we did a very big survey, we specifically went to all our sites, we after their practice patterns.

因此，這可能是改變腦電圖模式，可能是改變醫生，也可能不一定遵循腦電圖的行為，但我認為我們剛剛了解到，這在終點上太主觀了，無論如何醫生一次又一次地告訴我們。請記住，我們進行了一項非常大的調查，我們專門去了我們所有的站點，追蹤他們的實踐模式。

And I think, yes, we saw a much more consistent treatment pattern in our bigger enrolling sites. And I would say a variation in those patterns and sites that enrolled one or two patients. I think by nature, when you have a study and you have sites that are enrolling one or two patients, you do run the risk of site bias that is their site behavior influencing the outcome of the study. That certainly played a factor here. But I don't think the biggest factor.

是的，我認為我們在更大的招募點看到了更一致的治療模式。我想說的是，這些模式和地點有所不同，只招募了一到兩名患者。我認為，從本質上講，當您進行一項研究並且您的研究地點只招募一兩名患者時，您確實會面臨研究地點偏見的風險，即他們的研究地點行為會影響研究結果。這確實起到了一定作用。但我不認為這是最大的因素。

Joe is anything you want to add? I mean, you've spent so much time on data.

喬，您還有什麼要補充嗎？我的意思是你在數據上花了太多時間。

Yeah. No, I don't think there were particular sites, as you mentioned, Scott, it was kind of some patients at each site are not at every site. But no, and I think we're doing a lot to minimize the variability, if we do another study, I think we understand a lot. We've learned a lot from the RAISE study, obviously, in terms of what endpoints to look at and patient selection.

是的。不，我不認為有特定的站點，正如你提到的，斯科特，有些患者並不在每個站點。但事實並非如此，我認為我們正在做很多工作來盡量減少變異性，如果我們再進行一項研究，我想我們會了解很多。顯然，我們從 RAISE 研究中學到了很多東西，包括要關注的終點和患者選擇。

And Scott mentioned stratification, we want to make sure that we get a representative population, a population that's likely to respond in another study. So I think that we've learned an incredible amount from RAISE now and that will pay off when we come sign to do another study.

斯科特提到了分層，我們希望確保獲得一個具有代表性的人群，一個可能在另一項研究中做出反應的人群。所以我認為我們現在已經從 RAISE 學到了很多東西，當我們開始進行另一項研究時，這些知識將會得到回報。

And I think Doug, the big thing that we want to really discuss with the FDA is, what is the right endpoint. We certainly saw very strong signals, as Joe has talked about with EEG's and the differences between the EEG of patients with ganaxolone and who receive placebo, certainly every SAB member, every expert, we've shared that data with feel unequivocally, powerful that we should be discussing this and pushing for approval with the FDA. It's very nice to have their support.

我認為道格，我們真正想與 FDA 討論的重點是，什麼是正確的終點。我們確實看到了非常強烈的訊號，正如Joe 談到的腦電圖以及接受加奈索酮治療的患者和接受安慰劑治療的患者腦電圖之間的差異，當然，我們分享了這些數據的每位SAB 成員、每位專家都毫無疑問地感受到了強大的力量，應該討論此事並爭取 FDA 的批准。我很高興得到他們的支持。

I recognize the reality of what we agreed upon with the FDA, but I think we have other very clear measures of durability in this study. We'll share those at the NCS meeting, but you can imagine thinking about how many drugs in escalation of care being a logical one, right.

我承認我們與 FDA 達成的協議的真實性，但我認為我們在這項研究中還有其他非常明確的耐用性衡量標準。我們將在 NCS 會議上分享這些內容，但你可以想像一下，考慮升級護理中需要多少種藥物是合乎邏輯的，對吧。

So I think we really feel there is durability in this data set that is clearly differentiated from placebo. Unfortunately, the alignment with the agency -- the agency never specifically demanded durability defined by avoidance of IV anesthesia and I think we need to have a discussion with them of what other durability measures they would agree to.

因此我認為我們確實感覺到該數據集的持久性與安慰劑有明顯區別。不幸的是，與該機構的協調——該機構從未具體要求避免靜脈麻醉來定義耐久性，我認為我們需要與他們討論他們會同意哪些其他耐久性措施。

And I think we have several that we think our objective and is really the key piece of this puzzle, I think more than slight variability. And I think we will really even talk about that per se at our FDA meeting.

我認為我們有幾個目標，這些目標實際上是這個難題的關鍵部分，我認為這不僅僅是輕微的變化。我認為我們甚至會在 FDA 會議上討論這個問題。

Okay. If I could add one quick question on TSC. In terms of the long-term extension, are you really seeing any discontinuations once patients are able to sort of tolerate the drug for some amount of time and the continuation rate in the long-term extension so far?

好的。如果我可以就 TSC 補充一個簡短的問題的話。就長期延長而言，一旦患者能夠在一定時間內耐受該藥物，您是否真的看到任何停藥情況，以及迄今為止長期延長的延續率？

Well, so we are very fortunate that one of our investigators is going to be presenting the long-term extension data set submitted for AES. It hasn't been excepted as would be outright. It's a little early, but we accept -- we expect a presentation, we'll share that top-line data with you all at our Analyst Day in September.

好吧，我們非常幸運，我們的一位研究人員將展示提交給 AES 的長期擴展資料集。它並沒有被完全接受。現在有點早，但我們接受——我們期待一個演示，我們將在九月份的分析師日與大家分享這些最重要的數據。

We are really encouraged that the durability that we see across disease state, is really quite robust. And we really believe the [pen] extra synaptic activity of ganaxolone is something very unique in time and time again, when we do our market research, it's not only about initial response rate. It's about durability and it's about safety as Lisa talked about and ability to play nicely in the sandbox with other drugs.

我們真的很高興地看到，在整個疾病狀態下，其耐久性確實相當強。我們確實相信，加奈索酮的額外突觸活動是非常獨特的，當我們進行市場調查時，不僅僅是關注初始回應率。正如麗莎所說，這與耐用性和安全性有關，也與其他藥物在沙盒中良好配合的能力有關。

So I think when we go into this TSC launch, we will have a lot of talking points, a lot of measures, a durability, and certainly see that with other drugs. But I think in particular, we've seen it in some disease states that you just wouldn't expect to see an end right of comparing a little bit of apples and oranges that we've really tackled what I think are two of the most refractory seizure disorders out there.

因此，我認為，當我們進行 TSC 上市時，我們將有很多討論要點、很多措施、耐久性，並且肯定會在其他藥物上看到這一點。但我認為，特別是，我們已經看到了一些疾病狀態，你只是不希望看到結束，就像比較蘋果和橘子一樣，我們真正解決了我認為最嚴重的兩個問題存在難治性癲癇病。

So we believe it's going to be an important message and we're looking forward to sharing all that data with you guys at the Analyst Day.

因此，我們相信這將是一個重要的訊息，我們期待在分析師日與大家分享所有這些數據。

Thanks, Doug.

謝謝，道格。

Marc Goodman, Leerink.

馬克古德曼，Leerink。

Can you talk about on any off-label use you seen with ganaxolone? And secondly, you mentioned eligibility for milestones can you elaborate a little bit for this year? Thanks.

您能談談您所見過的加奈索酮的說明書外使用情況嗎？其次，您提到了里程碑的資格，您能詳細說明一下今年的情況嗎？謝謝。

Marc, I am sorry, I missed the first question. On ganaxolone. .

馬克，很抱歉，我錯過了第一個問題。關於加奈索酮。。

About (inaudible)

關於（聽不清楚）

I'm sorry. I'm having a little in appearance.

對不起。我看起來有點不對勁。

Steve, do you want to take those questions?

史蒂夫，你想回答這些問題嗎？

Off-label use?

未列入說明書用途？

Yeah, sure. I can jump in here. I think, Marc, I'll maybe I'll answer the second first. You mentioned milestones. So the nearest term milestone that we've talked about is a EUR10 million payment from Orion that would be due upon commercialization of CDD.

是的，當然。我可以跳進這裡。馬克，我想我可能會先回答第二個問題。您提到了里程碑。因此，我們談到的最近的里程碑是 Orion 支付的 1000 萬歐元，該款項將在 CDD 商業化後到期。

So that happens when they launch in two of the major markets or no later than 18 months after their first market, there's a similar type of payment associated with TSC commercialization. And then we also have a commercialization payments with China, with our Tenacia partnership, those are a little further out and not quite to the same magnitude but a nice amount as well.

因此，當他們在兩個主要市場推出產品或在第一個市場推出後不遲於 18 個月時，就會出現與 TSC 商業化相關的類似付款。然後，我們還與中國以及我們的 Tenacia 合作夥伴簽訂了商業化付款，這些付款時間稍長，數額也不完全相同，但數額也不錯。

In terms of off label on, I know we've got Lisa and Lisa, do you want to touch on kind of off-label use with ganaxolone.

關於標籤外使用，我知道我們有 Lisa 和 Lisa，您想談談加奈索酮的標籤外使用嗎？

Absolutely. Thank you, Steve. We said about 15% of our patients on therapy did not have a CDD diagnosis, and they're affected by other DEEs. I'll just add that most payers are covering the drug for these patients. I'm acknowledging a significant unmet need here.

絕對地。謝謝你，史蒂夫。我們說，接受治療的患者中約有 15% 並沒有被診斷為 CDD，而且他們受到其他 DEE 的影響。我只想補充一點，大多數付款人都為這些患者承擔藥費。我承認這裡存在著一個尚未滿足的重要需求。

And maybe I'll just add a little here. I couldn't hear you, but the thing I'll add is I think we've heard a lot of back-and-forth about the GW launch in TSC. And I think we have several GW team members as part of the Marinus team and between their expanded access program and the overlap with LGS that they went into their TSC launch with a substantial number of patients already on drug.

或許我只需在這裡補充一點。我聽不到你的聲音，但我想補充的是，我想我們已經聽到了很多關於在 TSC 中發射 GW 的爭論。我認為我們有幾位 GW 團隊成員是 Marinus 團隊的一部分，在他們的擴展訪問計劃和與 LGS 的重疊之間，他們在 TSC 啟動時已經有大量患者在服用藥物。

I think we can confidently say there are close to no patients currently on ganaxolone today that are being reimbursed with the diagnosis of TSC or certainly that we don't -- we do not know of any in terms of those developmental on epilepsy. So we really feel like the entire TSC market is open for us from day one and there's certainly not a big part of our business today. Thanks.

我認為我們可以自信地說，目前服用加奈索酮的患者中，幾乎沒有因診斷為結節性硬化症(TSC) 而獲得報銷，或者肯定沒有——就癲癇發展而言，我們不知道有任何患者獲得報銷。因此，我們真的覺得從第一天起整個 TSC 市場就對我們開放了，而且這肯定不是我們目前業務的很大一部分。謝謝。

Thank you.

謝謝。

Jason Butler, JMP.

傑森·巴特勒，JMP。

Hey this is Ryan for Jason. Just a quick one and maybe you just answered this, but for ZTALMY, Lisa mentioned that the key initiatives over 1,000 patients IV and agency might have CDD but not a diagnosis. I guess is what proportion of the patients today do have a diagnosis I guess?

嘿，我是 Jason 的 Ryan。這只是一個簡單的問題，也許您剛剛回答了這個問題，但是對於 ZTALMY，Lisa 提到，超過 1,000 名患者 IV 和機構的關鍵舉措可能患有 CDD，但沒有診斷。我想問的是，目前有多少比例的病人已經被診斷出來了？

Let me kick it off then I'll submit it over to Lisa Jason, remember the two major advocacy groups, IFCR. and Lulu foundation in the US fought very hard for CDKL5 codes that went into effect a little bit more than a year before we launch. So roughly 3.5 years ago.

讓我先開始，然後我會將其提交給 Lisa Jason，記住兩個主要的倡導團體，IFCR。和美國的Lulu基金會為CDKL5規範進行了艱苦的鬥爭，該規範在我們推出之前一年多就生效了。大約 3.5 年前。

To kind of put that in perspective and we expected about 100 newborns a year and in the last 3, 3.5 years, they've gone from 0 to 200 to 400 to now roughly a thousand unique patient codes for CDKL5. So what we expected, as we've always talked about is roughly 2,000 patients below the age of 21 and certainly another 3,000 adult patients but many of those adult patients won't be genetically tested. Certainly some are being tested and some are being treated with ZTALMY.

從某個角度來看，我們預計每年約有 100 名新生兒，但在過去 3 到 3.5 年裡，新生兒數量從 0 增加到 200、400，現在大約有 1,000 個 CDKL5 獨特患者代碼。因此，正如我們一直所說的，我們預計大約有 2,000 名 21 歲以下的患者，另外肯定還有 3,000 名成年患者，但其中許多成年患者不會接受基因檢測。當然，有些人正在接受檢測，有些人正在接受 ZTALMY 治療。

So I think we have good line of sight of roughly 2,000 patients, a lot less on the side of the other 3,000 so I think we estimate probably more than 2,500 patients are out there with a diagnosis or with the symptoms that haven't yet been diagnosed.

因此，我認為我們大致了解了 2,000 名患者，而其他 3,000 名患者的數量則少得多，因此，我認為我們估計可能有超過 2,500 名患者已經確診或有症狀但尚未被診斷出來診斷。

And we're clearly seeing this exponential growth in the use of the ICD-10 code. And we know there's not more than 100 boards a year, right so it's just physician recognition of the code on the advocacy groups pushing for the code, reimbursement around the code, all of those pieces of the puzzle are leading physicians to use the code, but we also know even as of a year ago, we had some centers of excellence that were not using the code appropriately.

我們清楚地看到 ICD-10 代碼的使用呈指數增長。我們知道每年的委員會不超過 100 個，對吧，所以這只是醫生對代碼的認可，倡導團體推動代碼，圍繞代碼進行報銷，所有這些難題都在引導醫生使用代碼，但我們也知道，即使在一年前，我們的一些卓越中心仍未正確使用程式碼。

So it's a little bit of the education around code, but I think we feel pretty good the fact that there is already more than 1,000 patients that have a code, that we can find these patients. We don't really feel like the 200 or so patients that are currently on therapy.

因此，這有點像是關於代碼的教育，但我認為，我們很高興看到，目前已有超過 1,000 名患者擁有代碼，我們可以找到這些患者。我們確實感覺不像目前正在接受治療的 200 名左右的患者。

Now close to 300 patients who have tried therapy or have been prescribed are the only patients out there. I think we feel very good about finding additional patients to keep growing the business. And certainly, I think we're really focused on that.

現在，只有近 300 名嘗試過治療或接受過處方的患者是那裡唯一的患者。我認為我們很高興能夠找到更多的患者來繼續發展業務。當然，我認為我們確實專注於此。

And Lisa, you can talk about that more. And I think we're going to have to make this the last question, operator, we've got over about 10 minutes. Lisa, anything else you want to add?

麗莎，你可以進一步談論這個問題。我覺得我們要把這個問題當作最後一個問題了，接線員，我們還有大約 10 分鐘的時間。Lisa，您還有什麼要補充的嗎？

I think you covered it nicely. I'll just add that one thing that we've done is shift our strategy towards a more data-driven approach because we have so many more HCPs utilizing the code over the past four years, the code has only been available for four years.

我認為你已經很好地解釋了這一點。我只想補充一點，我們所做的事情之一就是將我們的策略轉向更加數據驅動的方法，因為在過去四年中，我們有更多的HCP 使用該程式碼，而該程式碼僅推出了四年。

And we've seen an increase in that data from 200 to 1,000 patients over time identified, that there's also been an increase in general and genetic testing with the support from the American Epilepsy Society who really are putting it out there that every physician should genetically test patients who are receiving and haven't identified underlying etiology for their disease.

隨著時間的推移，我們發現患者數據從 200 例增加到 1000 例，在美國癲癇協會的支持下，常規和基因檢測的數量也有所增加，該協會確實表明，每位醫生都應該進行基因對正在接受治療但尚未確定其疾病潛在病因的患者進行測試。

So that combination has really driven up the CDKL5 diagnosis in general. And we are very confident in the patients that are out there left for us to still on introduced ZTALMY to.

因此，這種組合確實總體上提高了 CDKL5 診斷的準確性。我們對於剩下的等待我們介紹 ZTALMY 的患者非常有信心。

Thanks Lisa. operator I think we're going to take one more call. We have Charles Duncan online.

謝謝麗莎。接線生：我想我們還要接一個電話。我們有查爾斯鄧肯在線。

Yeah, that's correct. Please go ahead, Mr. Duncan.

是的，正確。請繼續，鄧肯先生。

Yes. Thanks for taking the follow up. Scott, I'm going to make the simplifying assumption that Trust TSC works out well and that SNDA is filed and approved. I guess the question that I have is relative to manufacturing capacity at the end of '25, I assume that you'll be able to get there. And -- yeah, so that's the key question that I had to follow up with you.

是的。感謝您的跟進。斯科特，我將做出簡單的假設，即 Trust TSC 運行良好並且 SNDA 已提交並獲得批准。我想我的問題是關於 25 年底的製造能力，我假設你能夠達到那個水準。是的，這就是我要跟進的關鍵問題。

Sure, Charles. I think we feel very good about our current manufacturing capabilities and our partner who effectively will dedicate much of their resources to helping us with ganaxolone. And we're very fortunate. The API has a five-year shelf life. We've been only growing the shelf life of our brand in ZTALMY. We're hoping to expand that shelf life as well.

當然，查爾斯。我認為我們對我們目前的生產能力感到非常滿意，我們的合作夥伴將有效地投入大量資源來幫助我們生產加奈索酮。我們非常幸運。該 API 的有效期為五年。我們一直在延長我們品牌在 ZTALMY 的保質期。我們也希望延長保質期。

So we really have the ability to continue to manufacture ZTALMY. And once we once we kick off these global launches to really start preparing for the TSC launch, but certainly by our internal expectations are we are going to need additional supply certainly by '27 and by our internal expectations, additional supply in '29.

所以我們確實有能力繼續生產ZTALMY。一旦我們啟動這些全球發布，並真正開始為 TSC 的發布做準備，但根據我們的內部預期，我們肯定會在 27 年之前需要額外的供應，按照我們的內部預期，在 29 年需要額外的供應。

I think we feel very good about the opportunity in TSC in the US and we really believe that a market that's at least 5 times and potentially as large as 10 times. The CDD market is very realistic, and Lisa will share some of those numbers with everyone during the Analyst Day.

我認為我們對美國 TSC 的機會非常看好，我們確實相信這個市場至少是我們的 5 倍，甚至可能達到我們的 10 倍。CDD市場非常現實，Lisa 將在分析師日與大家分享其中一些數據。

And I think equally important, we're expecting strong volumes across Europe, very strong volumes in China, expanding volumes throughout the world. And so we're getting prepared and doing in a very stepwise in staged fashion. And certainly, we think it's critical to have a second unique manufacturing site to minimize risk. And that process, we've made the investment for the equipment.

我認為同樣重要的是，我們預期歐洲的銷售量將會很強勁，中國的銷售量也會非常強勁，全球的銷售量也會不斷擴大。因此，我們正在做好準備，並分階段、有步驟地開展工作。當然，我們認為擁有第二個獨特的生產基地對於降低風險至關重要。在這個過程中，我們對設備進行了投資。

The room build-out will start shortly, and we want to make sure that in 2027, we have more than enough product. So those plans are in place and we feel really good about the way we're preparing for that and fortunate lucky was very hard decision for us to let some people go in June, restructure the organization. But as we've said all along, we've always had high confidence in the TSC launch. We think it can drive profitability and we have not shortcut or shortchange the oral franchise at all.

房間建設即將開始，我們希望確保到 2027 年，我們有足夠的產品。所以這些計劃已經到位，我們對我們的準備方式感到非常滿意，幸運的是，我們在六月解僱一些人並重組組織是一個非常艱難的決定。但正如我們一直所說的，我們始終對 TSC 的發布充滿信心。我們認為這可以提高獲利能力，而且我們並沒有走捷徑或虧待口服特許經營權。

And obviously, Christine she's been a great -- she is a great Chief Commercial Officer. You can hear from this call that Lisa is incredibly qualified as well. We've got great leadership in place. We're thinking about the manufacturing. We're thinking about the global regulatory strategy. We are going to be quite ready to execute post this data. So thanks so much for the call, Charles. Really appreciate it.

顯然，克里斯汀是一位出色的首席商務官。從這通電話中您可以聽出，Lisa 也非常有資格。我們已擁有出色的領導力。我們正在考慮製造問題。我們正在考慮全球監管策略。我們將做好充分準備來執行這些數據。非常感謝您的來電，查爾斯。真的很感激。

Thanks, everyone. I really appreciate you joining the call. We're about 15 minutes over, but that's great share in some of our thoughts, and we look forward to seeing you at the Analyst Event in September. And thanks again, for dialing in.

謝謝大家。非常感謝您參加此通話。我們大約超時了 15 分鐘，但這很好地分享了我們的一些想法，我們期待在 9 月的分析師活動中見到您。再次感謝您撥通電話。

This will conclude today's conference. You may disconnect your lines at this time. Thank you for your participation, and have a wonderful day.

今天的會議到此結束。現在您可以斷開您的線路。感謝您的參與，祝您有美好的一天。