Marinus Pharmaceuticals Inc (MRNS) 2022 Q4 法說會逐字稿

Greetings, everyone, and welcome to the Marinus Pharmaceuticals Fourth Quarter and Full Year 2022 Financial Results and Business Update Call. (Operator Instructions) It is now my pleasure to introduce your host, Sasha Damouni Ellis, Senior Vice President of Corporate Affairs and Investor Relations. Please go ahead.

大家好，歡迎參加 Marinus Pharmaceuticals 第四季度和 2022 年全年財務業績和業務更新電話會議。 （操作員說明）現在我很高興向您介紹主持人，公司事務和投資者關係高級副總裁 Sasha Damouni Ellis。請繼續。

Good afternoon. With me from Marinus are Dr. Scott Braunstein, Chairman and Chief Executive Officer; Christy Shafer, Chief Commercial Officer; Dr. Joe Hulihan, Chief Medical Officer; and Steve Pfanstiel, Chief Financial Officer and Chief Operating Officer.

下午好。和我一起來自 Marinus 的還有董事長兼首席執行官 Scott Braunstein 博士； Christy Shafer，首席商務官； Joe Hulihan 博士，首席醫療官； Steve Pfanstiel，首席財務官兼首席運營官。

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. 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.

在我們開始之前，我想提醒大家，我們今天所做的一些聲明是證券法規定的前瞻性聲明。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、業績或成就與此類前瞻性陳述所表達或暗示的顯著不同。這些風險和不確定性以及與我們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 Chief Executive Officer, Scott Braunstein.

我現在將把電話轉給我們的首席執行官斯科特布勞恩斯坦。

Thank you, Sasha, and welcome to our call. In 2022, we continue to make important progress advancing our oral and IV ganaxolone programs driven by the cross-functional commitment of the Marinus team.

謝謝你，Sasha，歡迎來電。到 2022 年，在 Marinus 團隊的跨職能承諾的推動下，我們將繼續取得重要進展，推進我們的口服和 IV 加奈索酮計劃。

At the forefront of our achievements was the landmark U.S. approval of ZTALMY in March and the subsequent commercial launch in late July. ZTALMY represents the cornerstone of our rare epilepsy franchise and its U.S. approval validates our belief in the potential of ganaxolone's differentiated mechanism of action and our ability to grow the commercial franchise.

我們取得成就的最前沿是 ZTALMY 在美國的里程碑式批准在 3 月和隨後在 7 月下旬的商業發布。 ZTALMY 代表了我們罕見的癲癇特許經營權的基石，它在美國的批准證實了我們對加奈索酮差異化作用機制的潛力以及我們發展商業特許經營權的能力的信念。

Importantly, we are pleased to report our first full quarter of sales, which are reflecting robust demand and give us confidence we are meeting the needs of this underserved patient population. Christy will provide further details on our commercial progress, including key launch metrics and an update on payer coverage.

重要的是，我們很高興地報告我們第一個完整季度的銷售額，這反映了強勁的需求，並讓我們相信我們正在滿足這一服務不足的患者群體的需求。 Christy 將提供有關我們商業進展的更多詳細信息，包括關鍵發布指標和付款人覆蓋範圍的更新。

In parallel with our first product launch, we made significant progress advancing our broader clinical pipeline, including our second generation formulation program and our 2 critically important pivotal trials for both the IV and oral franchise.

在我們推出第一個產品的同時，我們在推進更廣泛的臨床管道方面取得了重大進展，包括我們的第二代配方計劃和我們針對 IV 和口服特許經營權的 2 個至關重要的關鍵試驗。

We remain focused on expanding the value proposition of ganaxolone for rare epilepsies and believe that a second-generation formulation is an important piece of that puzzle.

我們仍然專注於擴大加奈索酮治療罕見癲癇的價值主張，並相信第二代製劑是這一難題的重要組成部分。

We are pleased with the early data we have seen in our Phase I dosing studies, which Joe will discuss shortly, and look forward to seeing this program advance through the clinic.

我們對我們在第一階段劑量研究中看到的早期數據感到滿意，Joe 將很快討論這些數據，並期待看到該計劃在臨床上取得進展。

In a very short period of time and with a focused investment, we now see a new and expanded pathway for the oral ganaxolone franchise. Although it is early, we are also on track to replicate this developmental success with a second-generation IV formulation.

在很短的時間內，通過集中投資，我們現在看到了口服加奈索酮專營權的新途徑和擴展途徑。雖然現在還早，但我們也有望通過第二代 IV 配方復制這一研發成功。

Furthermore, we believe that the adjustments made to support recruitment and enrollment in the Phase III RAISE trial in refractory status epilepticus are trending positively, and we've been met with enthusiasm by a growing number of participating sites.

此外，我們認為，為支持難治性癲癇持續狀態 III 期 RAISE 試驗的招募和入組而進行的調整呈積極趨勢，越來越多的參與機構對我們表示了熱情。

Just this month, I have met live with key investigators from Tampa, Baltimore and Boston, and they are highly motivated to participate given the unmet medical need in this life-threatening condition. The protocol amendment has been fully implemented and topline results continue to be expected in the second half of 2023.

就在這個月，我與來自坦帕、巴爾的摩和波士頓的主要調查人員進行了現場會面，鑑於在這種危及生命的情況下未滿足的醫療需求，他們非常積極地參與。協議修正案已全面實施，預計 2023 年下半年將繼續取得頂線結果。

I would like to also acknowledge that the other IV programs, RAISE II in RSE for European registration and reset and established status continue to press forward. While all 3 trials progress, we will continue to focus our primary efforts on RAISE, the U.S. pivotal program and have begun the commercial investments that we believe can help drive a successful U.S. launch.

我還要感謝其他 IV 計劃，即 RSE 中的 RAISE II 歐洲註冊和重置以及已建立狀態繼續推進。在所有 3 項試驗都取得進展的同時，我們將繼續將主要精力集中在美國的關鍵項目 RAISE 上，並已開始我們認為有助於推動美國成功推出的商業投資。

Let's move on to the current oral franchise. We are working closely with the TSC community and will continue to raise awareness around the Phase III TrustTSC clinical trial, which is now recruiting in the U.S. and Europe with additional site activations expected over the coming weeks and months in Canada, Israel, Italy, Belgium, Australia and China.

讓我們繼續討論當前的口頭專營權。我們正在與 TSC 社區密切合作，並將繼續提高人們對 III 期 TrustTSC 臨床試驗的認識，該試驗目前正在美國和歐洲招募，預計未來幾周和幾個月內將在加拿大、以色列、意大利、比利時開展更多站點活動、澳大利亞和中國。

Last week, Marinus participated in a panel discussion hosted by the TSC alliance and we will use these types of forums to continue to educate the community about this clinical trial, one that we believe is first of its kind in a highly refractory TSC population.

上週，Marinus 參加了由 TSC 聯盟主辦的小組討論，我們將利用這些類型的論壇繼續向社區宣傳這項臨床試驗，我們認為這是首次在高度難治性 TSC 人群中進行此類試驗。

As we have learned with CDD, efficacy and tolerability are key attributes to success in the refractory epilepsy population. And we are confident that changes to the titration schedule give us the maximum opportunity for a successful Phase III outcome. We remain on track to disclose topline data in the first quarter of 2024.

正如我們從 CDD 中了解到的那樣，療效和耐受性是難治性癲癇人群成功的關鍵屬性。我們相信滴定時間表的改變為我們提供了成功獲得 III 期結果的最大機會。我們仍有望在 2024 年第一季度披露頂線數據。

I would like to provide an update on the status of the ZTALMY Marketing Authorization Application in Europe. We submitted our day 120 responses to the EMA in November. We received the Day 180 report, including a list of outstanding issues in January. The list contained a number of major objections, including our choice of regulatory starting material, which is expected to be the biggest hurdle in bringing this medicine to patients in Europe.

我想提供有關歐洲 ZTALMY 營銷授權申請狀態的最新信息。我們在 11 月向 EMA 提交了第 120 天的回复。我們收到了第 180 天的報告，其中包括 1 月份的未決問題清單。該清單包含許多主要反對意見，包括我們選擇的監管起始材料，預計這將是將這種藥物帶給歐洲患者的最大障礙。

The formulation of ZTALMY recently approved in the U.S. contains the same starting material. The CHMP is expected to present its opinion on the MAA in the second quarter of 2023. We remain committed to working closely with the EMA, the advocacy community and our partners at Orion Corporation to advance this important medicine.

最近在美國批准的 ZTALMY 的配方包含相同的起始材料。 CHMP 預計將在 2023 年第二季度就 MAA 發表意見。我們將繼續致力於與 EMA、倡導團體和我們在 Orion Corporation 的合作夥伴密切合作，以推進這一重要藥物的發展。

There remains a broad global opportunity for ganaxolone. We announced a collaboration with Tenacia Biotechnology in November 2022 for the development and commercialization of ganaxolone in China. Tenacia has moved quickly on the regulatory front, and as a result of our combined efforts, we plan to include Chinese sites within the TrustTSC trial.

加奈索酮在全球範圍內仍有廣闊的商機。我們於 2022 年 11 月宣布與 Tenacia Biotechnology 合作，在中國開發和商業化加奈索酮。 Tenacia 在監管方面行動迅速，作為我們共同努力的結果，我們計劃將中國站點納入 TrustTSC 試驗。

Development plans are also underway to maximize the RSE opportunity. We continue to explore additional ex U.S. commercial alliances, including the MENA region and Japan and expect to expand the commercial footprint of ZTALMY in 2023.

開發計劃也在進行中，以最大限度地利用 RSE 機會。我們繼續探索其他美國以外的商業聯盟，包括 MENA 地區和日本，並預計在 2023 年擴大 ZTALMY 的商業足跡。

Before I hand it over to Christy, I want to share some exciting news. We received the notice of allowance from the U.S. Patent and Trademark Office on March 1 for additional claims related to our clinical therapeutic regimen for the treatment of status epilepticus using IV ganaxolone. This would be our second newly issued patent for the IV franchise. We believe the allowed claims will strengthen our IV portfolio in our status epilepticus program.

在我把它交給克里斯蒂之前，我想分享一些令人振奮的消息。我們於 3 月 1 日收到美國專利商標局的許可通知，要求我們使用靜脈注射加奈索酮治療癲癇持續狀態的臨床治療方案的額外索賠。這將是我們為 IV 特許經營權授予的第二個新專利。我們相信，允許的索賠將加強我們在癲癇持續狀態計劃中的 IV 產品組合。

Additionally, as many of you know, Steve Pfanstiel since joining the organization nearly 2 years ago has played an integral role in the launch of ZTALMY, helped strengthen our balance sheet and has been an important contributor to our strategic planning. He established himself as a leader within the organization and has driven a number of important agreements since taking over as Chief Financial Officer. I am pleased to share that Steve will now be taking on the expanded role as Chief Operating Officer in addition to his responsibilities as CFO.

此外，正如你們中的許多人所知，Steve Pfanstiel 自從近 2 年前加入該組織以來，在 ZTALMY 的推出中發揮了不可或缺的作用，幫助加強了我們的資產負債表，並且一直是我們戰略規劃的重要貢獻者。他確立了自己在組織內的領導地位，自接任首席財務官以來推動了多項重要協議的達成。我很高興地與大家分享，史蒂夫現在除了擔任首席財務官的職責外，還將擔任首席運營官一職。

Finally, we are pleased to announce the appointment of Christine Silverstein to our Board of Directors and Audit Committee in January. Christine brings a deep capital markets background and extensive expertise in corporate strategic planning, business development, compliance and risk management. Her financial and strategic acumen combined with her experience in neurology and rare diseases make her an outstanding addition to the Board.

最後，我們很高興地宣布 Christine Silverstein 將於 1 月份被任命為我們的董事會和審計委員會成員。克里斯汀在企業戰略規劃、業務發展、合規和風險管理方面擁有深厚的資本市場背景和廣泛的專業知識。她的財務和戰略敏銳度，加上她在神經病學和罕見疾病方面的經驗，使她成為董事會的傑出成員。

Now I would like to turn the call over to our Chief Commercial Officer, Christy Shafer, for updates on the commercial launch of ZTALMY.

現在我想把電話轉給我們的首席商務官 Christy Shafer，了解 ZTALMY 商業發布的最新情況。

Thank you, Scott. I'm pleased to provide you with an update on our continued progress as we execute on the U.S. commercial launch of ZTALMY.

謝謝你，斯科特。我很高興向您提供我們在 ZTALMY 的美國商業發布中執行的持續進展的最新情況。

As a reminder, we launched ZTALMY on July 28, 2022, and generated $560,000 in initial net product revenue in the third quarter. In the fourth quarter, the first full quarter following launch, ZTALMY had net revenues of $2.3 million, bringing the total for the fiscal year ended December 31, 2022, to $2.9 million.

提醒一下，我們於 2022 年 7 月 28 日推出了 ZTALMY，並在第三季度產生了 560,000 美元的初始產品淨收入。第四季度，即推出後的第一個完整季度，ZTALMY 的淨收入為 230 萬美元，使截至 2022 年 12 月 31 日的財政年度總收入達到 290 萬美元。

We received over 40 completed CDKL5 deficiency disorder prescription enrollment forms in the fourth quarter of 2022 and over 90 total completed CDD prescription enrollment forms for the fiscal year ended December 31, 2022, inclusive of clinical trial patient transitions and naive commercial patients.

我們在 2022 年第四季度收到了 40 多份完整的 CDKL5缺陷症處方登記表，截至 2022 年 12 月 31 日的財政年度共收到了 90 多份完整的 CDD 處方登記表，其中包括臨床試驗患者過渡期和未接受治療的商業患者。

We continue to see a steady build of treatment-naive commercial patients and a healthy distribution of prescriptions from centers of excellence, large epilepsy centers and local community physicians with prescriptions coming from a growing and diverse prescriber base of more than 60 unique accounts.

我們繼續看到未接受過治療的商業患者穩步增長，並且來自卓越中心、大型癲癇中心和當地社區醫生的處方健康分佈，處方來自 60 多個獨特賬戶的不斷增長和多樣化的處方者基礎。

Since launching ZTALMY, we have been particularly encouraged by the progress the team has made with market access. More than 75% of CDD patients with completed enrollment forms were able to receive reimbursed therapy by the end of 2022. And most of these prescriptions were filled within 30 days or less.

自推出 ZTALMY 以來，我們對團隊在市場准入方面取得的進展感到特別鼓舞。到 2022 年底，超過 75% 的已填寫登記表的 CDD 患者能夠接受報銷治療。而且這些處方中的大多數在 30 天或更短時間內完成。

We are pleased to announce that as of February 28, 2023, total payer coverage for ZTALMY increased to approximately 220 million lives, including both commercial and government programs.

我們很高興地宣布，截至 2023 年 2 月 28 日，ZTALMY 的總付款人覆蓋範圍增加到約 2.2 億人，包括商業和政府計劃。

ZTALMY has received favorable coverage determinations from 35 payers, representing close to 125 million commercial lives, which represents 79% of commercial plans. We expect most of the remaining coverage statements in the first half of 2023.

ZTALMY 已獲得 35 家付款人的有利承保範圍決定，代表近 1.25 億商業生活，佔商業計劃的 79%。我們預計大部分剩餘的覆蓋範圍報表將在 2023 年上半年發布。

Medicaid access has been confirmed in all U.S. states as well as Washington, D.C. and Puerto Rico, representing approximately 95 million lives. We believe this early success speaks to the strength of our market access and patient services capabilities, as well as an appreciation for the unmet medical need and an impact of the disease on CDD patients and their families.\

美國所有州以及華盛頓特區和波多黎各都已確認可享受醫療補助，代表著大約 9500 萬人的生命。我們相信這一早期的成功說明了我們的市場准入和患者服務能力的優勢，以及對未滿足的醫療需求和疾病對 CDD 患者及其家人的影響的認識。\

We continue to see a steady build of treatment-naive commercial patients and a healthy distribution of prescriptions from both COEs, large epilepsy centers and local community physicians. We are delighted with the response and feedback we have received from the patient community regarding Orsini specialty pharmacies, white glove approach and dedication to supporting patients and families throughout their treatment journey.

我們繼續看到未接受過治療的商業患者穩步增長，並且 COE、大型癲癇中心和當地社區醫生的處方分佈健康。我們很高興我們從患者社區收到了關於 Orsini 專業藥房、白手套方法以及在整個治療過程中為患者和家庭提供支持的奉獻精神的回應和反饋。

Thus far, the average patient maintenance dose is approximately 50% above the initial titration dose, which is in line with our label and expectation. Based upon our experience to date, we have not seen anything in the marketplace that warrants us to change our forecasting structure.

到目前為止，平均患者維持劑量比初始滴定劑量高出約 50%，這符合我們的標籤和預期。根據我們迄今為止的經驗，我們在市場上沒有看到任何值得我們改變預測結構的東西。

We have seen a handful of adult and young adult patients being treated, consistent with the broad uptake in patients 2 and above. Our momentum has benefited from the strength of our digital marketing tools, publication strategy and robust education and awareness efforts ahead of and following launch.

我們已經看到少數成年和年輕成年患者正在接受治療，這與 2 號及以上患者的廣泛接受情況一致。我們的發展勢頭得益於我們強大的數字營銷工具、出版策略以及發布前後強有力的教育和宣傳工作。

We see continued steady engagement rates on our ZTALMY patient and health care provider websites, which confirms the effectiveness of our authentic patient-centric marketing approach.

我們在 ZTALMY 患者和醫療保健提供者網站上看到持續穩定的參與率，這證實了我們真正以患者為中心的營銷方法的有效性。

The field interactions are being supported by the launch of our Speakers Bureau and the execution of a significant number of programs that have been well received with great attendance. We plan to expand the ZTALMY Speakers Bureau to add more clinical voices to the CDD treater community, filling a need for peer-to-peer education of the ZTALMY clinical data, CDD diagnostic indicators and the importance of early diagnosis.

現場互動得到了我們演講局的啟動和大量項目的執行，這些項目受到了廣泛的歡迎。我們計劃擴大 ZTALMY 演講局，為 CDD 治療者社區增加更多臨床聲音，滿足對 ZTALMY 臨床數據、CDD 診斷指標和早期診斷重要性的同行教育的需求。

With the solid foundation we have established, we are well positioned and extremely excited to grow our promotional strategies in several ways in 2023.

憑藉我們已經建立的堅實基礎，我們處於有利地位，並且非常高興能夠在 2023 年以多種方式發展我們的促銷策略。

The CDD diagnostic journey is one area where we think we can offer meaningful support for health care providers and families, and we continue to further our understanding of the current CDD genetic testing and diagnostic paradigm in the U.S. These insights will help inform our next steps to support unencumbering the CDD diagnostic journey and determining our expanded offering of education, tools, resources and solutions.

CDD 診斷之旅是我們認為可以為醫療保健提供者和家庭提供有意義支持的一個領域，我們將繼續加深對美國當前 CDD 基因檢測和診斷範例的理解。這些見解將有助於為我們的下一步提供信息支持解除 CDD 診斷之旅並確定我們擴展的教育、工具、資源和解決方案。

Planning has also commenced to activate a Caregiver Ambassador Program to share experiences of families who have initiated treatment with ZTALMY and what that experience has meant for their loved one and their families.

計劃還開始啟動護理人員大使計劃，以分享開始接受 ZTALMY 治療的家庭的經驗，以及這種經驗對他們所愛的人及其家人的意義。

These stories are planned to be incorporated into our branded promotion along with the webinar series for the CDD community that also features health care providers who can educate on the clinical profile of ZTALMY.

這些故事計劃與 CDD 社區的網絡研討會系列一起納入我們的品牌推廣中，該系列還包括可以就 ZTALMY 的臨床概況進行教育的醫療保健提供者。

We feel there are many opportunities to continue to grow our brand, and we are committed to supporting CDD families in meaningful ways throughout the year.

我們覺得有很多機會可以繼續發展我們的品牌，我們致力於全年以有意義的方式支持 CDD 家庭。

We are very pleased with our early launch progress and are grateful for the impact we believe we are making on CDD patients and families.

我們對我們的早期啟動進展感到非常高興，並感謝我們相信我們正在對 CDD 患者和家庭產生的影響。

I'll now hand the call over to our Chief Medical Officer, Joe Hulihan, to discuss our ongoing development programs.

我現在將電話轉給我們的首席醫療官 Joe Hulihan，討論我們正在進行的開發計劃。

Thank you, Christy, and hello, everyone. In addition to the strong commercial progress we've made in 2022, we continue to generate consistent and compelling data that highlighted the potential of ganaxolone's differentiated mechanism of action and its safety and efficacy profile to benefit patients, including 2-year open-label extension data in CDKL5 deficiency disorder.

謝謝你，克里斯蒂，大家好。除了我們在 2022 年取得的強勁商業進展外，我們繼續生成一致且令人信服的數據，這些數據強調了加奈索酮差異化作用機制的潛力及其使患者受益的安全性和有效性概況，包括 2 年開放標籤延期CDKL5 缺乏症的數據。

Over the course of the year, data from our clinical portfolio are presented at major medical meetings, including the annual meetings of the American Epilepsy Society, Neurocritical Care Society and Child Neurology Society. Also, results of our studies were published in top-tier medical journals, including Lancet Neurology and Epilepsia.

在這一年中，我們臨床產品組合的數據在主要醫學會議上發表，包括美國癲癇協會、神經重症監護協會和兒童神經病學協會的年會。此外，我們的研究結果發表在頂級醫學期刊上，包括《柳葉刀神經學》和《癲癇》。

Most recently, the results of the Phase II placebo-controlled study of oral ganaxolone in PCDH19 related epilepsy were published in epilepsy research. Ganaxolone led to a greater median reduction in seizure frequency compared to placebo and was generally well tolerated.

最近，口服加奈索酮治療 PCDH19 相關癲癇的 II 期安慰劑對照研究結果發表在癲癇研究中。與安慰劑相比，加奈索酮導致癲癇發作頻率的中位數降低幅度更大，並且通常耐受性良好。

If you recall, we reduced the scope of the study to a proof of concept for several reasons. Though the study results did not achieve statistical significance, we believe it's important to continue to keep the patient and advocacy community informed about the data generated in clinical trials with ganaxolone.

如果您還記得的話，出於多種原因，我們將研究範圍縮小為概念驗證。儘管研究結果沒有達到統計學意義，但我們認為繼續讓患者和宣傳社區了解加奈索酮臨床試驗中產生的數據非常重要。

Now I'd like to share some exciting updates on our clinical development programs, starting with our efforts in developing a second-generation ganaxolone. I'm pleased to announce encouraging results from our Phase I second-generation ganaxolone formulation studies, where we recently completed the third and final cohort in a single ascending dose trial, utilizing doses up to 1,200 milligrams in healthy volunteers.

現在我想分享一些關於我們臨床開發計劃的激動人心的更新，首先是我們開發第二代加奈索酮的努力。我很高興地宣布我們第一階段第二代加奈索酮製劑研究的令人鼓舞的結果，我們最近完成了單次遞增劑量試驗的第三個也是最後一個隊列，在健康志願者中使用高達 1,200 毫克的劑量。

We saw a linear dose exposure relationship up to this higher end of the dose range and a profile that has the potential for BID dosing with a longer percentage of time at a blood level above a minimum effective concentration.

我們看到了直到劑量範圍上限的線性劑量暴露關係，以及 BID 給藥可能在高於最低有效濃度的血藥濃度下時間百分比更長的情況。

The next step is a multiple ascending dose study looking at repeat BID dosing, which will be initiated in the second quarter. Along with some additional PK modeling, the MAD study will be important for defining dosing in our pivotal clinical trials. Ideally, we'd be able to move straight to Phase III rather than having to do dose ranging in Phase II.

下一步是一項多劑量遞增研究，著眼於重複 BID 給藥，該研究將於第二季度啟動。除了一些額外的 PK 建模外，MAD 研究對於確定我們關鍵臨床試驗中的劑量也很重要。理想情況下，我們將能夠直接進入 III 期，而不必在 II 期進行劑量範圍調整。

The initial clinical indication we will pursue is Lennox-Gastaut Syndrome, a severe form of epilepsy that begins in childhood with neurodevelopmental impairment and intractable atonic, tonic and generalized seizures.

我們將追求的最初臨床適應症是 Lennox-Gastaut 綜合徵，這是一種嚴重的癲癇症，始於兒童時期，伴有神經發育障礙和頑固性失張力、強直和全身性癲癇發作。

Given the overlap in seizure types and etiologies with other disorders where ganaxolone has therapeutic potential, such as CDD and TSC, we believe that LGS represents a promising opportunity to address the continuing unmet need in this patient population.

鑑於癲癇發作類型和病因與加奈索酮具有治療潛力的其他疾病（例如 CDD 和 TSC）的重疊，我們認為 LGS 代表了一個有希望的機會來解決該患者群體中持續未滿足的需求。

We're targeting finalization of the plans for clinical development in the second half of this year. We are also advancing the development of ganaxolone prodrugs for both oral and IV administration. An oral prodrug candidate has been selected and preclinical development is ongoing, and we expect to select a lead IV candidate shortly.

我們的目標是在今年下半年完成臨床開發計劃。我們還在推進用於口服和靜脈給藥的加奈索酮前藥的開發。已經選擇了一種口服前藥候選藥物，並且正在進行臨床前開發，我們預計很快就會選擇一種先導 IV 候選藥物。

Moving to our Phase III TrustTSC trial in tuberous sclerosis complex, we're pleased to share that we are actively screening and enrolling patients, targeting 90 clinical sites, predominantly in the U.S. and Europe with additional site activations expected in Canada, Australia and China.

轉到我們在結節性硬化症中的 III 期 TrustTSC 試驗，我們很高興地與大家分享，我們正在積極篩选和招募患者，目標是 90 個臨床地點，主要在美國和歐洲，預計在加拿大、澳大利亞和中國還會有更多的地點激活。

We're encouraged with the high level of enthusiasm in the medical community for this trial and anticipate topline data in the first quarter of 2024.

我們對醫學界對這項試驗的高度熱情感到鼓舞，並預計 2024 年第一季度的頂線數據。

Now I'll move on to our IV programs. As Scott mentioned, the protocol amendment for the Phase III RAISE trial in refractory status epilepticus has been broadly adopted at our clinical trial sites. We're expanding the number of participating RAISE study centers in the U.S. as well as Canada and Australia.

現在我將繼續我們的 IV 程序。正如 Scott 提到的，難治性癲癇持續狀態的 III 期 RAISE 試驗方案修正案已在我們的臨床試驗地點廣泛採用。我們正在擴大美國、加拿大和澳大利亞參與 RAISE 研究中心的數量。

In November, we held an investigator meeting in the U.S. to emphasize the importance of this study for patients and to educate our sites on the updated protocol. Investigators have expressed considerable optimism about the potential of the amended protocol to allow recruitment of a greater number of eligible patients, particularly patients transferred from other centers to study sites or from the emergency room to the ICU.

11 月，我們在美國召開了一次研究人員會議，以強調這項研究對患者的重要性，並就更新後的方案對我們的網站進行教育。研究人員對修訂後的方案允許招募更多符合條件的患者的潛力表示相當樂觀，特別是從其他中心轉移到研究地點或從急診室轉移到 ICU 的患者。

We are working closely with sites to support timely study enrollment, actively monitoring what's working well at a site level and identifying where we can provide additional support for trial recruitment and execution.

我們正在與站點密切合作以支持及時的研究註冊，積極監控站點級別的有效方法並確定我們可以在哪些地方為試驗招募和執行提供額外支持。

These protocol changes and site engagements are critical to enrolling appropriate patients for the Phase III study and replicating the success of the Phase II trial.

這些方案變更和現場參與對於為 III 期研究招募合適的患者和復制 II 期試驗的成功至關重要。

In addition, members of our scientific affairs and clinical development teams have been on the road, maintaining intensive site engagement and responding to questions about the protocol and study procedures.

此外，我們的科學事務和臨床開發團隊的成員一直在路上，保持密集的現場參與並回答有關協議和研究程序的問題。

Marinus Scientific Affairs has a group fully dedicated to supporting study enrollment and engaging with RAISE principal investigators and other site personnel. With these enrollment initiatives, more sites being activated on a global scale and a reduction in the impact of COVID on health care systems, we're seeing an uptick in enrollment and remain on track for data in the second half of 2023.

Marinus Scientific Affairs 有一個小組完全致力於支持研究註冊並與 RAISE 主要研究人員和其他現場人員接觸。通過這些註冊計劃、更多站點在全球範圍內被激活以及 COVID 對醫療保健系統的影響減少，我們看到註冊人數有所增加，並在 2023 年下半年繼續跟踪數據。

As a reminder, based on previous conversations with the FDA, we expect that a positive RAISE study will be sufficient for filing in the U.S. There is also the potential for expansion of the age range of eligible patients. The trial is currently designed to enroll patients 12 years of age and older. However, we recognize that there's a high incidence of status epilepticus in children.

提醒一下，根據之前與 FDA 的對話，我們預計積極的 RAISE 研究將足以在美國提交申請。還有可能擴大符合條件的患者的年齡範圍。該試驗目前旨在招募 12 歲及以上的患者。然而，我們認識到兒童癲癇持續狀態的發生率很高。

We're currently working with the FDA to determine what information would be required to support the inclusion of patients below the age of 12 in our studies, which could expand the pool of eligible patients and further support enrollment.

我們目前正在與 FDA 合作，以確定需要哪些信息來支持將 12 歲以下的患者納入我們的研究，這可以擴大符合條件的患者群體並進一步支持入組。

As we've previously mentioned, there is the option for an independent data monitoring committee to conduct an interim analysis when 2/3 of the participants, approximately 82 patients have completed the study. We will make a determination in the second quarter, whether we will move forward with an interim analysis later this year.

正如我們之前提到的，當 2/3 的參與者（大約 82 名患者）完成研究時，獨立的數據監測委員會可以選擇進行中期分析。我們將在第二季度做出決定，是否會在今年晚些時候進行中期分析。

While conduct of an interim analysis often affects the statistical power of the study should it continue to full enrollment, the interim analysis for the RAISE study is designed to have a minimal effect on the efficacy outcome of a fully enrolled trial.

雖然中期分析的進行通常會影響研究的統計功效，如果它繼續完全註冊，RAISE 研究的中期分析旨在對完全註冊試驗的療效結果產生最小影響。

We're also happy to share that we have successfully manufactured a modified IV formulation of ganaxolone with a new buffer and expect to incorporate it into the RAISE trial in the second quarter of this year. We believe this formulation change will lead to increased product stability and are targeting a shelf life of at least 24 months. Registration batches of the modified formulation are expected to be placed on stability shortly.

我們也很高興地與大家分享，我們已經成功地製造出一種改良的加奈索酮 IV 製劑，其中含有一種新的緩衝液，並預計將在今年第二季度將其納入 RAISE 試驗。我們相信這種配方變化將提高產品穩定性，並且目標保質期至少為 24 個月。修改後的配方的註冊批次預計很快就會穩定下來。

Planning continues for the RAISE II study in refractory status for European registration, which is expected to begin enrolling patients in the second half of 2023.

歐洲註冊難治性狀態的 RAISE II 研究計劃繼續進行，預計將於 2023 年下半年開始招募患者。

Moving on to the Phase II RESET study in established status epilepticus, we remain on track to begin U.S. enrollment this year. The first phase of the study is designed to determine the optimal regimen of ganaxolone for established status and will include up to 8 sequential cohorts of 5 patients each, with the results from each cohort used to determine dosing in the next. We expect to complete the first cohort by the end of this year.

繼續進行已建立的癲癇持續狀態的 II 期 RESET 研究，我們仍有望在今年開始在美國註冊。該研究的第一階段旨在確定最佳的加奈索酮治療方案以達到既定狀態，並將包括多達 8 個連續隊列，每個隊列 5 名患者，每個隊列的結果用於確定下一階段的劑量。我們預計在今年年底完成第一批。

We're excited with the momentum of our programs going into 2023, focusing on our late-stage clinical trials, second-generation formulations of ganaxolone, as well as our continued support for ZTALMY and CDD. I appreciate the cross-functional efforts from our R&D, regulatory and scientific affairs teams in executing our studies and engaging with the clinical, scientific and advocacy communities.

我們對進入 2023 年的項目勢頭感到興奮，重點是我們的後期臨床試驗、第二代加奈索酮製劑，以及我們對 ZTALMY 和 CDD 的持續支持。我感謝我們的研發、監管和科學事務團隊在執行我們的研究以及與臨床、科學和宣傳社區合作方面的跨職能努力。

Now I'll turn the call over to Steve Pfanstiel, who will provide you with a financial update.

現在，我會將電話轉給 Steve Pfanstiel，他將為您提供最新的財務信息。

Thanks, Joe, and good afternoon to everyone. I am pleased to be able to share our financial results for the fourth quarter and full year 2022, as well as initial guidance for 2023.

謝謝，喬，大家下午好。我很高興能夠分享我們 2022 年第四季度和全年的財務業績，以及 2023 年的初步指導。

Before going into our results, I'd like to touch briefly on what was a very active fourth quarter on the financing front. In the quarter, we successfully completed a follow-on equity offering, which raised $64.5 million of net funding. We are very pleased to bring in several new investors to the Marinus story as a part of the offering.

在進入我們的結果之前，我想簡要介紹一下融資方面非常活躍的第四季度。本季度，我們成功完成了後續股權發行，籌集了 6450 萬美元的淨資金。作為此次發行的一部分，我們很高興為 Marinus 的故事引入幾位新投資者。

Additionally, we completed a revenue interest financing agreement with Sagard Healthcare Partners, which brought in $32.5 million upfront in return for future payments on U.S. net sales of ganaxolone, including ZTALMY.

此外，我們還完成了與 Sagard Healthcare Partners 的收入利息融資協議，該協議帶來了 3250 萬美元的預付款，以換取未來支付加奈索酮（包括 ZTALMY）在美國的淨銷售額。

Additionally, we received a gross upfront payment of $10 million from Tenacia as a part of our development and commercialization collaboration with them for the Chinese market. These 3 deals added over $100 million in cash to our balance sheet, which, when combined with our existing cash results in a year-end 2022 cash balance of $240.6 million.

此外，作為我們與 Tenacia 在中國市場的開發和商業化合作的一部分，我們從 Tenacia 獲得了 1000 萬美元的預付款總額。這 3 筆交易為我們的資產負債表增加了超過 1 億美元的現金，加上我們現有的現金，2022 年底的現金餘額為 2.406 億美元。

Our cash is projected to be sufficient to fund our operations into the second half of 2024, inclusive of maintaining the required minimum cash balance of $15 million required under our credit agreement.

我們的現金預計足以為 2024 年下半年的運營提供資金，包括維持我們的信貸協議規定的 1500 萬美元的最低現金餘額。

I'll now move into our financial results. In 2022, we recognized product revenues of $2.3 million and $2.9 million for the 3 and 12 months ended December 31, 2022. As a note, this revenue consists of ZTALMY product sales in the U.S.

我現在將進入我們的財務結果。 2022 年，我們確認了截至 2022 年 12 月 31 日止的三個月和十二個月的產品收入分別為 230 萬美元和 290 萬美元。請注意，該收入包括 ZTALMY 產品在美國的銷售額。

Separately, we recognized BARDA revenues of $1.8 million and $6.9 million for the 3 and 12 months ended December 31, 2022, respectively, as compared to $1.5 million and $6.4 million in each of the same periods in the prior year. Our actual 2022 BARDA revenue of $6.9 million was at the bottom of our guidance range of between $7 million and $10 million.

另外，我們確認 BARDA 在截至 2022 年 12 月 31 日的三個月和十二個月的收入分別為 180 萬美元和 690 萬美元，而去年同期分別為 150 萬美元和 640 萬美元。我們 2022 年 BARDA 的實際收入為 690 萬美元，處於我們 700 萬至 1000 萬美元指導範圍的底部。

We also recognized collaboration revenue of $3 million in the fourth quarter of 2022 related to the upfront payment associated with our agreement with Tenacia.

我們還確認了 2022 年第四季度 300 萬美元的合作收入，這與我們與 Tenacia 達成的協議相關的預付款有關。

Research and development expenses increased to $21.4 million and $79.9 million for the 3 and 12 months ended December 31, 2022, respectively, as compared to $18 million and $73.5 million for the same period in the prior year. The change was due primarily to costs associated with increased R&D headcount and clinical trial activity.

截至 2022 年 12 月 31 日止的三個月和十二個月，研發費用分別增加至 2,140 萬美元和 7,990 萬美元，而去年同期為 1,800 萬美元和 7,350 萬美元。這一變化主要是由於與研發人員和臨床試驗活動增加相關的成本。

Selling, general and administrative expenses increased to $14.7 million and $56.8 million for the 3 and 12 months ended December 31, 2022, respectively, as compared to $10.6 million and $37.3 million for the same period in the prior year. The primary drivers of the change were increased headcount and commercial support for the U.S. launch of ZTALMY.

截至 2022 年 12 月 31 日止的三個月和十二個月，銷售、一般和行政費用分別增加至 1,470 萬美元和 5,680 萬美元，而去年同期為 1,060 萬美元和 3,730 萬美元。這一變化的主要驅動因素是增加了員工人數和對美國推出 ZTALMY 的商業支持。

For the full year 2022, total operating expenses, inclusive of R&D and SG&A, were $136.8 million, which was below our guidance of $150 million to $155 million and was driven by the timing of certain activities, including our API onshoring initiative and general spend management.

2022 年全年，包括研發和 SG&A 在內的總運營費用為 1.368 億美元，低於我們 1.5 億至 1.55 億美元的指導，這是由某些活動的時間驅動的，包括我們的 API 外包計劃和一般支出管理.

The company reported net losses of $34.3 million and $19.8 million for the 3 and 12 months ended December 31, 2022, respectively, as compared to net losses of $28.3 million and $98.8 million for the same periods in the prior year.

該公司報告截至 2022 年 12 月 31 日的三個月和十二個月分別淨虧損 3430 萬美元和 1980 萬美元，而去年同期淨虧損 2830 萬美元和 9880 萬美元。

As a note, the 2022 net loss includes the onetime gain of $107.4 million from the sale of our priority review voucher in Q3 2022. These totals also include noncash stock-based compensation expense of $3.8 million and $14.9 million for the 3 and 12 months ended December 31, 2022, respectively, as compared to $3 million and $13.9 million for the same periods in the prior year.

請注意，2022 年的淨虧損包括 2022 年第三季度出售我們優先審查憑證的一次性收益 1.074 億美元。這些總額還包括截至 3 個月和 12 個月的非現金股票補償費用 380 萬美元和 1490 萬美元分別為 2022 年 12 月 31 日，而去年同期為 300 萬美元和 1390 萬美元。

Cash used in operating activities was $112.9 million for the 12 months ended December 31, 2022, as compared to cash used in operating activities of $55.5 million for the same period in the prior year.

截至 2022 年 12 月 31 日止的 12 個月，經營活動使用的現金為 1.129 億美元，而去年同期經營活動使用的現金為 5550 萬美元。

For the fiscal year 2023, we are projecting U.S. ZTALMY revenues to be in the range of $15 million to $17 million and BARDA revenues to be in the range of $8 million to $11 million.

對於 2023 財年，我們預計美國 ZTALMY 的收入將在 1500 萬至 1700 萬美元之間，BARDA 的收入將在 800 萬至 1100 萬美元之間。

We project our GAAP operating expenses, inclusive of SG&A and R&D expenses to be in the range of $165 million to $175 million, of which we expect approximately $16 million to be noncash stock-based compensation.

我們預計我們的 GAAP 運營費用（包括 SG&A 和研發費用）在 1.65 億美元至 1.75 億美元之間，我們預計其中約 1600 萬美元為非現金股票補償。

The increase in operating expenses is driven by several critical incremental activities, including the initiation of our API onshoring program, which, as a reminder, is 70% funded by BARDA, CMC IV investments related to commercial readiness, our second RAISE trial for the EU market and full year annualization of ZTALMY launch and support costs.

運營費用的增加是由幾項關鍵的增量活動推動的，包括啟動我們的 API 外包計劃，作為提醒，該計劃的 70% 由 BARDA 資助，與商業準備相關的 CMC IV 投資，我們在歐盟的第二次 RAISE 試驗ZTALMY 發布和支持成本的市場和全年年化。

Now I'll turn the call back to Scott, who will provide concluding remarks.

現在我將把電話轉回給 Scott，他將發表總結性意見。

2022 was a transformational year for the Marinus team, and we are thrilled to enter 2023 with a strong balance sheet, positive momentum advancing our 2 late-stage clinical programs and encouraging data surrounding our second-generation product development.

2022 年對 Marinus 團隊來說是轉型的一年，我們很高興進入 2023 年，擁有強勁的資產負債表、推進我們 2 個後期臨床項目的積極勢頭以及圍繞我們第二代產品開發的令人鼓舞的數據。

As always, we remain committed to delivering shareholder value, and we'll continue to expand opportunities to serve patients that may benefit from ZTALMY.

一如既往，我們仍然致力於為股東創造價值，我們將繼續擴大機會，為可能受益於 ZTALMY 的患者提供服務。

With that, I would like to thank our employees for their hard work and dedication to advancing our mission. Operator, can you now open the call to questions.

藉此，我要感謝我們的員工為推進我們的使命所做的辛勤工作和奉獻。接線員，您現在可以打開問題電話嗎？

Certainly. (Operator Instructions) We'll hear first today from Brian Abrahams with RBC Capital Markets.

當然。 （操作員說明）今天我們將首先從 RBC 資本市場的 Brian Abrahams 那裡聽到。

Hey guys, good afternoon. Congrats on all the progress. Congrats to Steve on the expanded role. Maybe just starting on [SE] on the RAISE study. I was wondering if you could elaborate a little bit more on what you're seeing with regards to some of the -- to the protocol modifications, I guess with regards to the types of patients going on to therapy, seizure burden.

嘿伙計們，下午好。祝賀所有的進步。祝賀史蒂夫的角色得到擴展。也許只是從 RAISE 研究的 [SE] 開始。我想知道你是否可以更詳細地說明你所看到的一些 - 協議修改，我想關於接受治療的患者類型，癲癇發作負擔。

And then, I guess, your sense of how the pace of enrollment is proceeding now and your latest thoughts on whether or not you would potentially take an interim? And then I had a follow-up.

然後，我想，您對現在招生速度的感覺以及您對是否有可能採取臨時措施的最新想法？然後我進行了跟進。

This is Scott. And have Joe with me, this is the first time the Marinus team is all in a conference room together in a long time. So it's kind of fun.

這是斯科特。讓喬和我一起，這是很長一段時間以來 Marinus 團隊第一次一起在會議室裡。所以這很有趣。

Maybe I'll just -- I'll make 1 or 2 comments, and I'll pass it over to Joe. It was the -- really the fall of last year when we kind of gave a comparison between the early enrollment trends in RAISE and our Phase II data, and we'll plan to do that again around the time that we'll send the data to the DSMB.

也許我會-- 我會發表一兩條評論，然後我會把它傳遞給喬。那是——真的是去年秋天，當時我們比較了 RAISE 的早期入學趨勢和我們的第二階段數據，我們計劃在發送數據時再次這樣做給 DSMB。

And so I don't think we can specifically comment on any updates in the most recent weeks. And certainly, as we see enrollment continue to expand, this is a very active process. And I think you're going to have to be patient with us that realistically, we -- this is not something we're going to be updating on a regular basis.

因此，我認為我們不能對最近幾週的任何更新發表具體評論。當然，正如我們看到入學人數繼續擴大一樣，這是一個非常活躍的過程。而且我認為你必須對我們耐心等待，實際上，我們 - 這不是我們要定期更新的內容。

I think from a site perspective, as Joe and I both said on the call, we're really enthusiastic about where we are today. The team is working hard. We're seeing that in the enrollment numbers. And I think generally, we feel like we've got the right investigators, the right sites that are going to drive high-quality patients, the appropriate patients for the study.

我認為從網站的角度來看，正如喬和我都在電話中所說的那樣，我們對我們今天所處的位置非常熱情。團隊正在努力工作。我們在註冊人數中看到了這一點。而且我認為總的來說，我們覺得我們有合適的研究人員，合適的地點將推動高質量的患者，適合研究的患者。

And certainly, we're really still focused on patients more than anything whose next treatment would move to general anesthesia and guaranteeing or expecting that will drive a low placebo rate in the study.

當然，我們確實仍然更關注患者，而不是下一次治療將轉向全身麻醉的患者，並保證或期望這將在研究中降低安慰劑率。

And I think most importantly, we are still very confident about those type of patients being enrolled. Joe, any other comments you want to make specifically?

而且我認為最重要的是，我們對招募的這類患者仍然非常有信心。喬，你還有什麼要特別說的嗎？

No, I'll just add. You asked about seizure burden. And so far, the seizure burden in the Phase III closely replicates the Phase II. And this protocol amendment should even more closely – bring in patients and even more closely replicate the population in Phase II patients.

不，我只是補充一下。你問的是癲癇發作負擔。到目前為止，第三階段的扣押負擔與第二階段非常相似。並且該協議修正案應該更緊密地——引入患者，甚至更緊密地複制 II 期患者的人群。

There was actually a misunderstanding the patients who were intubated couldn't come into the trial, but there were about half the patients in the Phase II study were intubated on trial entry.

其實有一個誤區是插管的患者不能進入試驗，但是II期研究中大約有一半的患者是在進入試驗時插管的。

And so that's one thing that's going to facilitate enrollment of more patients that the amendment will allow more patients coming in on intubation for transfer to the hospital from the ER.

因此，修正案將允許更多患者插管，以便從急診室轉移到醫院，這將促進更多患者的入組。

Got it. And then maybe if I could a follow up on the oral. You recently had the publication of the PCDH19 data that you mentioned. Can you give us any sense of the potential for reimbursement in that indication and sort of the interest amongst physicians to use ZTALMY there? I guess how much expectations for off-label use are baked into your guidance? Or would that be all upside? And I'll hop back in the queue.

知道了。然後也許我可以跟進口語。您最近發布了您提到的 PCDH19 數據。您能否告訴我們該適應症的報銷潛力以及醫生在那裡使用 ZTALMY 的興趣？我想您的指南中包含了多少對標籤外使用的期望？還是這一切都是好的？我會跳回到隊列中。

Brian, we've been pretty open about just reporting our CDD numbers overall. And although the epidemiology for PCDH19 is very similar from a number standpoint compared to CDD. We've spoken to quite a few physicians in the community and the unmet need is dramatically different. There's really only a small subgroup of patients who suffer from PCDH19 who have intractable seizures.

布賴恩，我們一直非常開放地報告我們的總體 CDD 數字。儘管從數量的角度來看，PCDH19 的流行病學與 CDD 非常相似。我們已經與社區中的許多醫生交談過，未滿足的需求截然不同。實際上只有一小部分患有 PCDH19 的患者有頑固性癲癇發作。

So I think we think about it as a much smaller market opportunity. We certainly think the Phase II data in the publication is something that the payers and Compendia can look at and review and see that data in the public domain. We think that's important.

所以我認為我們將其視為一個小得多的市場機會。我們當然認為出版物中的 II 期數據是付款人和 Compendia 可以查看和審查並在公共領域看到該數據的東西。我們認為這很重要。

We have seen a few spontaneous prescriptions, but we don't see it as a meaningful part of the prescription story in the near future. But certainly, it's nice to know that payers understand that these patients who have retractable PCDH19 could potentially benefit from ZTALMY. And I think that it's really important that in those rail cases, there is access potentially available to them. So it's really nice to see.

我們已經看到了一些自發的處方，但我們認為在不久的將來它不會成為處方故事中有意義的一部分。但當然，很高興知道付款人了解這些擁有可伸縮 PCDH19 的患者可能會從 ZTALMY 中受益。而且我認為，在那些鐵路案例中，他們有可能獲得訪問權限，這一點非常重要。所以很高興看到。

That’s really helpful.

這真的很有幫助。

You got it, Brian.

你明白了，布賴恩。

(Operator Instructions) We'll hear now from Joon Lee with Truist Securities.

（操作員說明）我們現在將收到來自 Truist Securities 的 Joon Lee 的消息。

Hi, thanks for the updates and for taking our questions. It's impressive that you're able to provide guidance at such an early stage of the launch, what has the reimbursement rate been like in fourth quarter and overall gross to net? And what can we expect in terms of reimbursement rate and gross net for the first quarter of 23? And I have a follow-up.

您好，感謝您的更新和回答我們的問題。令人印象深刻的是，您能夠在發布的如此早期階段提供指導，第四季度的報銷率和整體毛淨額情況如何？我們對 23 年第一季度的報銷率和淨毛額有何期待？我有一個後續行動。

Yes. Hi, Joon, it's Steve Pfanstiel here. I'll touch on the gross to net piece. So we have kind of consistently said we expect gross to net discount to be in the low 20% right around there. We still think that's the right expectation. We're still seeing approximately 60% or more patients with Medicaid coverage. We know that's a 23% discount. Separately, we have co-pay programs for commercial payments.

是的。嗨，Joon，我是 Steve Pfanstiel。我會談一談從毛到淨的部分。因此，我們一直表示，我們預計毛淨折扣將在 20% 左右。我們仍然認為這是正確的期望。我們仍然看到大約 60% 或更多的患者有醫療補助計劃。我們知道這是 23% 的折扣。另外，我們有商業支付的共同支付計劃。

We did see upside in the back half of last year. I think our gross to net deductions were around 15% in Q4. And that's really driven by a few dynamics of having a second half of the year launch.

我們確實在去年下半年看到了上漲空間。我認為我們在第四季度的總扣除額與淨扣除額之間的比例約為 15%。這實際上是由今年下半年推出的一些動態推動的。

One is simply, a lot of patients are through the co-pay, so they don't need as much support for that. The other piece is we simply didn't have access to all state Medicaid programs, which we now do. So now that we expect to have kind of more Medicaid patients coming in, we see it stabilizing this year around that 20% gross to net deduction.

一個很簡單，很多病人都是通過共同支付的，所以他們不需要那麼多的支持。另一點是我們根本無法使用我們現在可以使用的所有州醫療補助計劃。所以現在我們預計會有更多的醫療補助患者進來，我們看到它今年穩定在 20% 的總扣除額與淨扣除額之間。

Great. And the follow-up question is, if and when you do an interim look, will you have an opportunity to expand the trial or stop the trial either [due to] efficacy or futility? Basically trying to understand the goal of the interim look for rates?

偉大的。後續問題是，如果以及當您進行臨時審查時，您是否有機會擴大試驗或因 [由於] 有效性或無效而停止試驗？主要是想了解臨時尋找利率的目標？

Yes. The interim is being done for the potential to stop for efficacy. Stopping for futility is really hard to demonstrate. So the primary goal is whether or not we can stop for efficacy at that point.

是的。正在為可能停止療效而進行過渡。徒勞地停下來真的很難證明。所以主要目標是我們是否可以在那個時候停下來獲得療效。

I'm sorry, operator. Let me just add a little color Joon, to your question. I think when we initially powered the study, we had very conservative assumptions about a 30% efficacy delta on both primary endpoints. We had really very limited data on our key secondary endpoint. I think we continue to be confident that the delta between placebo will be significantly greater than 30%. That's our hope and expectation.

對不起，接線員。讓我為你的問題添加一點顏色 Joon。我認為當我們最初為這項研究提供動力時，我們對兩個主要終點的療效增量有 30% 的假設非常保守。我們在關鍵次要終點上的數據真的非常有限。我認為我們繼續相信安慰劑之間的差異將顯著大於 30%。這是我們的希望和期待。

And certainly now, one of the key elements that goes into an interim is our belief that when we look at a key secondaries, specifically looking at days in the ICU, we have an 80% power of that interim to show a 2-day or more benefit.

當然現在，進入過渡階段的關鍵要素之一是我們相信，當我們查看關鍵的次要數據時，特別是查看 ICU 中的天數時，我們有 80% 的能力顯示 2 天或更多的好處。

And so you add those pieces up, and I think to Joe's point, it gives us a lot of confidence that not only can we hit efficacy at the interim analysis, but really show a meaningful health economic benefit, which is going to be critical for the launch of the drug. Sorry, operator, I'll turn it back to you.

所以你把這些加起來，我認為喬的觀點，它給了我們很大的信心，我們不僅可以在中期分析中達到療效，而且真正顯示出有意義的健康經濟效益，這對藥物的推出。抱歉，接線員，我會把它轉回給你。

No problem. We'll move next to SVB Securities, Marc Goodman.

沒問題。接下來我們將介紹 SVB Securities 的 Marc Goodman。

This is Rudy on the call for Marc. Maybe can you talk about the trend of new patient [starts] moving into 2023? And for now, how long it takes to fulfill the prescription? Maybe just walk us through the process.

我是 Rudy，正在為 Marc 打電話。也許你能談談進入 2023 年新患者[開始]的趨勢嗎？而現在，完成處方需要多長時間？也許只是引導我們完成整個過程。

Thanks for the question. Considering the fact that we've seen about 30 new prescription enrollment forms in Q3 and then another 40 in Q4, we seem to be very pleased with the progress and continued momentum that we see moving into Q4 -- or excuse me, into Q1.

謝謝你的問題。考慮到我們在第三季度看到了大約 30 個新的處方註冊表格，然後在第四季度又看到了 40 個，我們似乎對我們看到進入第四季度的進展和持續勢頭感到非常滿意——或者對不起，進入第一季度。

With that progress, we're tracking at about a 40% increase in total prescriptions over Q4 at this time.

隨著這一進展，我們目前追踪到第四季度總處方量增加了約 40%。

And can you provide more color like how long it takes to fill the prescription [amount]

你能提供更多的顏色嗎，比如需要多長時間才能完成處方[數量]

Yes. I'm sorry. I forgot that note, I apologize for that. Right now, we planned for around 90 days to get through that prescription fulfillment process, and we're very pleased with the fact that right now, we are tracking at around 30 days. 75% of our patients right now have received reimbursed therapy through Q4, and we continue to see those enrollment curves going and moving forward into Q1.

是的。對不起。我忘記了那張紙條，對此我深表歉意。現在，我們計劃用大約 90 天的時間來完成處方履行過程，我們很高興現在我們正在跟踪大約 30 天的時間。我們現在有 75% 的患者在第 4 季度接受了報銷治療，我們繼續看到這些入組曲線在進入第 1 季度。

Its very helpful.

它非常有幫助。

We'll hear next from Andrew Tsai with Jefferies.

接下來我們將聽到 Andrew Tsai 與 Jefferies 的對話。

Congrats on the progress. Thanks for sharing all these updates. I did have one clarification question on the interim analysis. Pardon my summary, but hopefully, we captured it correctly is that if you did hit on the interim, it is possible the study completely stops due to overwhelming efficacy. The other scenario would be study continues as is for the final analysis, but it may be unknown whether there was a trend as opposed to perhaps the drug not showing anything. Is that the kind of the right scenario we should be thinking about?

祝賀進步。感謝您分享所有這些更新。我確實有一個關於中期分析的澄清問題。請原諒我的總結，但希望我們正確地抓住了這一點，即如果您確實遇到了過渡期，則該研究可能會由於壓倒性的功效而完全停止。另一種情況是研究繼續進行最終分析，但可能不知道是否存在趨勢，而不是藥物可能沒有顯示任何結果。這是我們應該考慮的正確場景嗎？

Yes. So if there's efficacy at the interim the trial takes about 2 months to clean the data and do the analysis. That would be conducted by a blinded statistician, in conjunction with the data monitoring committee. If they see efficacy at that point, then they'll notify us, the decision is made whether or not to stop the trial.

是的。因此，如果在此期間有效，則試驗需要大約 2 個月的時間來清理數據並進行分析。這將由盲法統計學家與數據監測委員會一起進行。如果他們在那個時候看到了療效，那麼他們會通知我們，決定是否停止試驗。

If they do not show efficacy, we won't know anything. They'll just say continue the trial without modification. And then we'll complete to 124 patients, but we won't know anything about the direction of the study, the direction of the results would just be continue without modification.

如果它們不顯示功效，我們將一無所知。他們只是說繼續試驗而不做任何修改。然後我們將完成 124 名患者，但我們對研究的方向一無所知，結果的方向將繼續不加修改。

And I'd point out, too, and I think I said this in the prepared remarks that we pay -- we don't pay a substantial penalty for doing the interim. It's really a minimal effect on the statistical power, if it goes to completion.

我也要指出，我想我在我們支付的準備好的評論中說過這一點——我們不會因為臨時執行而支付大量罰款。如果完成的話，這對統計能力的影響真的很小。

And just for one additional clarifier, why should we choose to do an interim analysis in that period while the data is being cleaned or reviewed by the DSMB, we will continue to enroll patients during that period of time. We would view those patients important for the overall safety within the label for the FDA requirements. And ultimately, we would collect that data set as well.

還有一個額外的澄清，為什麼我們要選擇在 DSMB 清理或審查數據的那個時期進行中期分析，我們將在那個時期繼續招募患者。我們會根據 FDA 的要求將這些患者視為對整體安全性很重要的標籤。最終，我們也會收集該數據集。

Let's assume we -- on day 1, we choose to do an interim analysis at day 60 when the DSMB comes back to the company, we might have enrolled 5, 10, 15 or 20 more patients, and that would be critical to evaluate that double-blind portion of the study with the final FDA filing.

假設我們 - 在第 1 天，我們選擇在 DSMB 返回公司時的第 60 天進行中期分析，我們可能已經招募了 5、10、15 或 20 名患者，這對於評估至關重要研究的雙盲部分與最終的 FDA 備案。

Very clear. And secondly, as a follow-up, in terms of the ZTALMY guidance, $15 million to $17 million for 2023. Just curious, to the extent you guys can share is, what kind of assumptions are being baked in on the lower and upper end?

非常清楚。其次，作為後續行動，根據 ZTALMY 指導，2023 年為 1500 萬至 1700 萬美元。只是好奇，你們可以分享的是，在低端和高端有什麼樣的假設？

I guess the root of the question is, is this a realistic type of guidance? Or is it a conservative one such that you can beat and raise throughout the year?

我想問題的根源是，這是一種現實的指導嗎？或者它是一個保守的，你可以全年擊敗和提高？

Hi, Andrew. This is Steve. I'll address that question. Look, we've tried to be really reasonable with our assumptions. And I think we've talked about some of those in the past. I think we feel pretty tight about the gross to net deductions being in that 20% range.

嗨，安德魯。這是史蒂夫。我會解決這個問題。看，我們已經嘗試讓我們的假設變得非常合理。我想我們過去已經討論過其中的一些。我認為我們對總扣除額與淨扣除額之間的 20% 範圍感到非常緊張。

It is still early. We just have that one full quarter of launch so far. But we feel pretty confident when we look at bottles per script, and we're seeing it just over 5 in the naive patient population, that's a reasonable number as we look forward. We do think that will increase slowly over time as patients age.

現在還早。到目前為止，我們只有整整四分之一的發佈時間。但是，當我們查看每個腳本的瓶子時，我們感到非常有信心，而且我們在天真的患者群體中看到它剛剛超過 5，這是我們期待的合理數字。我們確實認為，隨著患者年齡的增長，這一數字會隨著時間的推移而緩慢增加。

We're seeing a steady build of patients. This isn't a bolus situation. We know that these patients have a lot going on. It's a complicated decision, a lot factors in. So we expect to see kind of the steady build of patients over time.

我們看到患者數量穩定增長。這不是推注情況。我們知道這些患者有很多事情要做。這是一個複雜的決定，有很多因素。所以我們希望隨著時間的推移看到患者的穩定增長。

And then from an attrition standpoint, again, still very early. But using the Marigold Phase III open-label data, we know that over 60% of the patients are still on drug at 2 years. There will be some that will [atrip] where they just won't reach the right level ganaxolone or for other reasons.

然後從減員的角度來看，還是很早。但是使用 Marigold III 期開放標籤數據，我們知道超過 60% 的患者在 2 年時仍在服藥。會有一些人會 [atrip] 他們只是達不到正確的水平 ganaxolone 或其他原因。

But we think for the vast majority of the patients, call it, 70% or so are going to stay on the therapy for a long period of time with annual attrition more in the single digits after that initial 3 to 6 month period. So that should give you kind of the broad outlines of how we came to the $15 million to $17 million range.

但我們認為，對於絕大多數患者來說，70% 左右的人會長期接受治療，在最初的 3 到 6 個月之後，每年的流失率會以個位數增長。因此，這應該讓您大致了解我們如何達到 1500 萬至 1700 萬美元的範圍。

Very clear. Congrats.

非常清楚。恭喜。

And Charles Duncan with Cantor Fitzgerald has our next question.

Charles Duncan 和 Cantor Fitzgerald 有我們的下一個問題。

Okay. Super. Congratulations on all the progress. i had a question on RAISE. And then really my main questions are on the second-generation ganaxolone. And so just quickly on RAISE, I guess, there's been a debate among some investors, whether or not the broadly adopted changes in the protocol result in more or less heterogeneous patient population. And how do you feel about that relative to the trade-off for timing?

好的。極好的。祝賀所有的進步。我有一個關於 RAISE 的問題。然後我真正的主要問題是關於第二代加奈索酮。所以很快就在 RAISE 上，我猜，一些投資者之間一直在爭論，協議中廣泛採用的變化是否會導致或多或少的異質性患者群體。相對於時間的權衡，你怎麼看？

Yes. This is Joe Hulihan. So I don't think it's going to introduce more heterogeneity into the population. It's -- the range of etiologies we are seeing so far in Phase III mirror very closely Phase II. And the treatment is really more of a final common pathway of status than dependent on etiology, although ultimate patient outcome obviously depends on etiology.

是的。這是喬·胡里漢。所以我不認為它會給人口帶來更多的異質性。到目前為止，我們在第三階段看到的病因範圍非常接近第二階段。治療實際上更像是一種最終的共同狀態途徑，而不是依賴於病因，儘管最終患者的結果顯然取決於病因。

So we don't see that the amendment is contributing more heterogeneity. And on the flip side, I think the thing that's much more powerful as Scott mentioned, is the change to the protocol that the next treatment, the next likely treatment would be IV anesthesia. And that is going to, I think, increase the sensitivity to detect a treatment difference on that second endpoint and get us patients again that are consistent in terms of their severity, but also, as I mentioned, mirror the patients in the Phase II study.

所以我們看不到修正案導致了更多的異質性。另一方面，我認為正如 Scott 提到的那樣，更強大的是對協議的改變，下一次治療，下一次可能的治療將是 IV 麻醉。我認為，這將提高檢測第二個終點治療差異的敏感性，並讓我們的患者再次獲得嚴重程度一致的患者，而且正如我提到的，反映了 II 期研究中的患者.

Yes. And Charles, I'll add status epilepticus by definition is a heterogeneity -- a disease of heterogeneity. And as Joe mentioned, the Phase II, there was no evidence that the disease state underlying status was it all affected by treatment.

是的。 Charles，我將根據定義添加癲癇持續狀態是一種異質性——一種異質性疾病。正如 Joe 提到的，在第二階段，沒有證據表明疾病狀態的潛在狀態完全受治療影響。

Ganaxolone was an independent predictor of success. And what I loved about the Phase II was that we saw every etiology. I was a little worried in the Phase II, particularly sites like Duke and [Brigham] that see a of glioblastoma is that we would get a disproportionate number of glioblastoma’s in the Phase II, and we did it because in real-world status is quite interestingly has 5 or 6 major etiologies. And as Joe said, that's what we're seeing in the Phase III.

加奈索酮是成功的獨立預測指標。我喜歡第二階段的原因是我們看到了每一種病因。我在第二階段有點擔心，特別是像 Duke 和 [Brigham] 這樣看到膠質母細胞瘤的網站是我們會在第二階段得到不成比例的膠質母細胞瘤，我們這樣做是因為在現實世界中有趣的是，這種情況有 5 或 6 種主要病因。正如喬所說，這就是我們在第三階段看到的。

I think the critical piece that we're spending our energy on is really making sure that the protocol amendments still lead to patients whose next step would be general anesthesia. I think we're very fortunate when patients are screened. They are in constant contact with our medical team. Our medical team is talking to those physicians.

我認為我們正在花費精力的關鍵部分是真正確保協議修正案仍然導致患者的下一步是全身麻醉。我認為我們對患者進行篩查是非常幸運的。他們一直與我們的醫療團隊保持聯繫。我們的醫療團隊正在與那些醫生交談。

[Henry Vaitkevicius], who is our lead investigator from the Phase II who many of you know are in many of those calls. Dr. Gasior, [Maciej] Gasior who wrote the Phase II protocol is on many of those calls. So every one of these patients who are enrolled in the trial, we've not only are aware of, but we are in constant communication with those investigators, and we continue to believe the quality of the patients are far and away what we need them to be to really show the value proposition of the drug. Joe is going to add one comment.

[Henry Vaitkevicius]，他是我們第二階段的首席調查員，你們中的許多人都知道他參與了許多這樣的電話會議。編寫第二階段協議的 Gasior 博士 [Maciej] Gasior 參與了其中的許多電話會議。因此，每一位參加試驗的患者，我們不僅知道，而且與這些研究人員保持著不斷的溝通，我們仍然相信患者的質量遠非我們所需要的真正展示藥物的價值主張。 Joe 將要添加一條評論。

Yes. One other thing that occurs to me, and that is that at the baseline before they're treated, we do a score called the status - status epilepticus severity score. And that also seems to be mirroring what we saw in Phase II.

是的。我想到的另一件事是，在他們接受治療之前的基線，我們做了一個稱為狀態的評分 - 癲癇持續狀態嚴重程度評分。這似乎也反映了我們在第二階段看到的情況。

So that is probably a good measure of heterogeneity, more so than diagnosis, the severity of the status. It's based on a number of clinical factors. So that score is so far looking similar to Phase II.

因此，這可能是衡量異質性的一個很好的衡量標準，比診斷更能衡量狀態的嚴重程度。它基於許多臨床因素。所以到目前為止，這個分數看起來與第二階段相似。

Very helpful added color, looking forward to that data. If I may, just one follow-up with regard to the second-generation ganaxolone really intrigued with that. I'm wondering if you could provide any additional color on why you think that could be a BID dosing.

非常有用的補充顏色，期待該數據。如果可以的話，關於第二代加奈索酮的一項後續行動真的很感興趣。我想知道您是否可以提供任何其他顏色來說明為什麼您認為這可能是 BID 劑量。

And then any sense in terms of the size of the trial for the Phase III in Lennox-Gastaut?

然後，就 Lennox-Gastaut 的 III 期試驗規模而言，有什麼意義嗎？

So the first part of your question, Charles, that we are seeing kinetics with the single-dose studies that really support the ID dosing. I mean the goal is to see increased exposure, increased AUC and relative to Cmax. And so we're seeing a good bump in the AUC with a slower decay of the plasma concentration.

所以你的問題的第一部分，查爾斯，我們看到了真正支持 ID 劑量的單劑量研究的動力學。我的意思是目標是增加暴露量，增加 AUC 和相對於 Cmax。因此，我們看到 AUC 有了很好的提升，血漿濃度的衰減較慢。

And then we've modeled the BID dosing, done some pharmacokinetic modeling from the single-dose results and that looks very favorable. We're seeing a good minimum plasma concentration at what we think may be the target dose. And so -- and that was a limitation, especially in the early focal epilepsy studies when they gave it twice a day. The [semen] would drop below the minimum effective concentration.

然後我們對 BID 劑量進行了建模，根據單劑量結果進行了一些藥代動力學建模，這看起來非常有利。在我們認為可能是目標劑量的情況下，我們看到了良好的最低血漿濃度。所以——這是一個局限性，特別是在早期的局灶性癲癇研究中，他們每天給它兩次。 [精液]會降到最低有效濃度以下。

In fact, the modeling, we did modeling for both the suspension, the current formulation and the reformulation and giving the suspension BID, we actually saw similar actual results in one of the focal epilepsy studies that it was reproduced by the modeling. So we're very comfortable with the modeling results.

事實上，建模，我們對懸架、當前配方和重新配方進行了建模，並給出了懸架 BID，我們實際上在模型複制的一項局灶性癲癇研究中看到了類似的實際結果。所以我們對建模結果非常滿意。

Yes. And I'd only add, Charles, I think do we actually think we need an MAD study? Probably not just from what we've seen. But I think for us to think about leapfrogging the Phase III, having a comprehensive MAD study, understanding how the product does with different foods, which is so important in a pediatric population and seeing those curves so that when we should we choose to go to Phase III, we will really be able to -- my hope would be to target 2 different blood concentrations as a critical part of that study.

是的。我只想補充一點，查爾斯，我認為我們真的認為我們需要進行 MAD 研究嗎？可能不僅僅是我們所看到的。但我認為我們應該考慮跨越 III 期，進行全面的 MAD 研究，了解該產品對不同食物的作用，這對兒科人群非常重要，並看到這些曲線，以便我們應該選擇何時去在第三階段，我們將真正能夠——我希望將兩種不同的血液濃度作為該研究的關鍵部分。

So again, early days, but I would think about a Phase III that has 3 arms, 2 active arms and a placebo very similar to what you've seen with Epidiolex in, for example, their TSC study, their Phase III study.

所以，再一次，早期，但我會考慮一個 III 期，它有 3 個手臂，2 個活躍的手臂和一個安慰劑，非常類似於你在 Epidiolex 中看到的，例如，他們的 TSC 研究，他們的 III 期研究。

I do think we have the ability to have some interesting regulatory discussions, whether it be a single or -- single study or 2 studies, I think we are thinking very hard about safety and what would be required from a safety database perspective.

我確實認為我們有能力進行一些有趣的監管討論，無論是單項研究還是 - 單項研究或兩項研究，我認為我們正在認真考慮安全性以及從安全數據庫的角度來看需要什麼。

So more to come on that. And we certainly haven't made a final decision. I think what we wanted to communicate with you this call is that the kinetics are incrementally better than we had hoped for. And given that it makes it a bit of a more potential to move quickly into Phase III if we see a consistent signal from that MAD study.

所以還有更多的事情要做。我們當然還沒有做出最終決定。我想我們想在這次電話會議上與您交流的是，動力學比我們希望的要好得多。如果我們從 MAD 研究中看到一致的信號，那麼考慮到它更有可能快速進入 III 期。

So it is really exciting. We're seeing things that this franchise has never seen with its oral program before. And we really are believers that higher blood levels on a chronic basis can increase the efficacy of an already very favorable product. So thanks for the question. Appreciate it. I hope we got it all?

所以這真的很令人興奮。我們看到了這個專營權以前從未在其口頭計劃中看到的東西。我們確實相信，長期較高的血液濃度可以提高本已非常受歡迎的產品的功效。所以謝謝你的問題。欣賞它。我希望我們得到了一切？

Yes. Very good.

是的。非常好。

We'll hear next from Douglas Tsao with H.C. Wainwright.

接下來我們將聽到 Douglas Tsao 和 H.C.溫賴特。

Hi, good afternoon. Just to clarify, I think you said in terms of the interim analysis on the secondary endpoint in terms of -- improvement in terms of days in the ICU. So was this something that you have subsequently felt more comfortable in terms of the powering, just given some additional work that you've done on the health economics front or just understanding how long patients are in the ICU that you feel more comfortable that you will be able to hit that given the power numbers for the interim analysis?

嗨，下午好。澄清一下，我想你是在對次要終點的中期分析中說的——在 ICU 天數方面的改善。那麼，這是否是您隨後在動力方面感到更自在的東西，只是考慮到您在衛生經濟學方面所做的一些額外工作，或者只是了解患者在 ICU 中待了多長時間，您會感覺更自在考慮到中期分析的功率數字，能否達到這個目標？

Yes. This is Joe. So yes, the short answer is, yes, we're confident we'll hit on that key secondary. We have a number of health care utilization end points built in. One is days in the ICU.

是的。這是喬。所以是的，簡短的回答是，是的，我們有信心我們會擊中那個關鍵的中學。我們有許多內置的醫療保健利用端點。一個是在 ICU 的天數。

One of them is actually built into the hierarchy of analysis. It's a stepwise analysis. You get the first primary and the second primary hit 2 key clinical primaries and then that health utilization endpoint is actually in that hierarchy of analyses.

其中之一實際上內置於分析層次結構中。這是逐步分析。您獲得第一個主要和第二個主要命中 2 個關鍵臨床主要，然後該健康利用端點實際上位於該分析層次結構中。

So if they all hit, and that health care utilization endpoint is statistically significant, that will be considered a substantial level of evidence and would be appropriate for promotion and it'll be a high level of evidence.

因此，如果它們都達到了，並且醫療保健利用終點具有統計顯著性，那麼這將被視為大量證據並且適合推廣，這將是高水平證據。

And so we looked at the powering assumptions, not just for the primary but for the secondary and that key health care utilization endpoint is time on ventilator due to status epilepticus. And that's less confounded. Days in the ICU may be confounded by whether there's pressure on beds and so on.

因此，我們研究了供電假設，不僅針對初級，還針對次級，關鍵的醫療保健利用終點是由於癲癇持續狀態而使用呼吸機的時間。這不那麼令人困惑。在 ICU 的日子可能會因床位是否有壓力等而感到困惑。

And so -- but the time on ventilator, and we've gotten advice about this from someone who's very versed in health economics, Adam Strzelczyk is a neurologist in Germany, who's done a lot of work with this. And that is a much -- will be a much more sensitive endpoint to look at, but we're also looking at days in the ICU. And we'll see what happens on that one. I also think we have adequate power to show a difference on that as well.

所以——但是呼吸機上的時間，我們從一位非常精通健康經濟學的人那裡得到了這方面的建議，Adam Strzelczyk 是德國的一名神經學家，他在這方面做了很多工作。這是一個非常——將是一個更敏感的終點，但我們也在關注重症監護病房的天數。我們將看看那個會發生什麼。我還認為我們也有足夠的能力在這方面表現出差異。

Yes. And the only thing I'll add, Doug, is this was something when we first met with the FDA and we thought about powering the study did not really play -- we included it into key primary endpoints, but we really didn't have the scientific team, and I give Alex Aimetti and his team a lot of credit, who spent a lot of time helping us really look at the literature, think about where these patients would come out and what we would need to see in terms of an improvement to win on these key outcomes.

是的。道格，我唯一要補充的是，這是我們第一次與 FDA 會面時的事情，我們考慮為這項研究提供動力並沒有真正發揮作用——我們將其納入關鍵的主要終點，但我們確實沒有科學團隊，我非常感謝 Alex Aimetti 和他的團隊，他們花了很多時間幫助我們真正審視文獻，思考這些患者會從哪裡出來，以及我們需要根據改進以贏得這些關鍵成果。

So to this discussion, before we went to the FDA and asked to perform an interim, our team vetted what we thought we could win on and that drove the end of [NF82] specifically. And certainly, when we looked at an NF60 for example, we still felt very confident about the primary, but our ability to hit secondaries were significantly lower, power to about 50%. So that NF82 was the sweet spot from primary and those key secondary analysis.

因此，對於這次討論，在我們去 FDA 並要求進行過渡之前，我們的團隊審查了我們認為我們可以贏得的東西，這特別推動了 [NF82] 的結束。當然，當我們以 NF60 為例，我們仍然對初級非常有信心，但我們擊中次級的能力明顯較低，功率約為 50%。因此，NF82 是初級分析和那些關鍵的二級分析的最佳結合點。

Even at the interim, we have 90% power on that -- on the time on ventilator endpoint.

即使在過渡期間，我們也有 90% 的權力——在呼吸機終點時間。

Okay. Great. And then just as a quick follow-up. Scott, just to clarify. So if you do the interim look, you would still enroll patients and would ultimately the NDA filing be based on the interim? Or would it be based on the full data set?

好的。偉大的。然後作為快速跟進。斯科特，只是為了澄清一下。因此，如果您進行臨時審查，您仍會招募患者，最終 NDA 申請是否會基於臨時審查？或者它會基於完整的數據集嗎？

Yes, our basic assumption today is that it would be based on the interim as the primary label, we would collect all of the blinded data, we would submit it all. So there is a potential and there have been 1 or 2 cases where you've seen that blinded data included in the label.

是的，我們今天的基本假設是，它將以臨時作為主要標籤，我們將收集所有的盲數據，我們將提交所有數據。所以有可能並且有 1 或 2 個案例，您已經看到標籤中包含盲化數據。

Normally, those things are pre-negotiated. We wouldn't expect it today. But the only piece I will mention is that the agency has said if you choose to do an interim remember, there is a safety burden and of safety that we would like from the company.

通常，這些事情是預先協商好的。我們今天不會期望它。但我要提到的唯一一點是，該機構已經說過，如果你選擇做一個臨時記住，我們希望公司有安全負擔和安全。

So we are continuing to not only enroll double blinded to have an additional number of patients that we can evaluate, but should the trial be stopped for efficacy on an interim, which would be our expectation. Should we take that look, we would continue in all probability to keep an open-label arm for data, safety collection or use RAISE II as another venue to collect additional safety as part of our requirements for registration.

因此，我們不僅繼續採用雙盲法招募更多可以評估的患者，而且還應該停止試驗以獲得臨時療效，這也是我們的預期。如果我們考慮一下，我們很可能會繼續保留開放標籤的數據、安全收集或使用 RAISE II 作為另一個場所來收集額外的安全作為我們註冊要求的一部分。

But we've had these discussions about what we expect the label will look like. I think base case is that it would look -- it will be primarily based on the patients in the interim analysis. But that being said, we will have double-blind placebo-controlled data on another set of patients that we certainly would submit to the agency as part of the package.

但是我們已經就我們期望標籤的外觀進行了這些討論。我認為基本情況是它看起來——它將主要基於中期分析中的患者。但話雖這麼說，我們將有另一組患者的雙盲安慰劑對照數據，我們當然會作為一攬子計劃的一部分提交給該機構。

Great.

偉大的。

Yes, sure.

是的，當然。

And from Oppenheimer we move next to Jay Olson.

我們從奧本海默搬到傑伊奧爾森旁邊。

Congrats on all the progress. Have you seen any increase in the CDD diagnosis rate since the launch of ZTALMY? What are the current factors that limit the diagnosis rate? And how do you plan to increase diagnosis?

祝賀所有的進步。自從 ZTALMY 推出以來，您是否看到 CDD 診斷率有所提高？目前限制確診率的因素有哪些？你打算如何增加診斷？

And what are the largest drivers of volume growth for ZTALMY in 2023?

2023 年 ZTALMY 銷量增長的最大驅動力是什麼？

Hi, there. This is Christy. I'll take the first part of this question. So from a CDD diagnosis point, we do a lot of analysis on the usage of the ICD-10 code across the United States. And what we've realized is that our promotional efforts have utilized the code much more at the end of 2022 into 2023, which is supportive of not only identifying these patients, coding them correctly and then getting them properly on therapy.

你好呀。這是克里斯蒂。我將回答這個問題的第一部分。所以從CDD診斷的角度，我們對ICD-10代碼在美國的使用情況做了很多分析。我們已經意識到，我們的促銷工作在 2022 年底到 2023 年期間更多地使用了代碼，這不僅有助於識別這些患者，正確編碼他們，然後讓他們正確接受治療。

So from a diagnosis standpoint, that currently is how we're triangulating and finding these patients. Currently, we have found -- we made some assumptions on where these patients are being treated. I'll remind you that there are 8 CDD centers of excellence across the United States. However, we do know that these patients go to these centers of excellence on a more limited basis, sometimes on every 6, every 12 months, and then they're seeing more routinely at their home physician.

因此，從診斷的角度來看，這就是我們目前進行三角測量和尋找這些患者的方式。目前，我們發現——我們對這些患者在哪裡接受治療做出了一些假設。我會提醒您，美國有 8 個 CDD 卓越中心。然而，我們確實知道，這些患者去這些卓越中心的次數更為有限，有時每 6 個月，每 12 個月一次，然後他們會更經常地去看他們的家庭醫生。

So the increase in these diagnostic rates may be limited, if you will, at the home physician and then these increased rates at the centers of excellence.

因此，如果您願意，這些診斷率的增加可能會受到限制，在家庭醫生中，然後在卓越中心的這些增加的比率。

The other thing that we know is that in more rural areas, these patients don't have the capabilities to get to a center of excellence. So are they utilizing the code at the best of their capabilities? Probably not right now. So in 2023, we have some efforts to not only be able to educate more distinctly. We're increasing our speakers' programs. We have a very distinct effort to increase awareness through our patient advocacy partners through partners that have patients on therapy to speak to families who have new diagnosed patients.

我們知道的另一件事是，在更多的農村地區，這些患者沒有能力前往卓越中心。那麼他們是否在盡其所能地利用代碼？可能不是現在。所以在 2023 年，我們有一些努力，不僅能夠更清晰地進行教育。我們正在增加演講者的節目。我們有一個非常獨特的努力，通過我們的患者宣傳合作夥伴提高意識，通過有患者接受治療的合作夥伴與有新診斷患者的家庭交談。

So there's a lot planned for 2023 to increase awareness, increase education and ultimately get the code used more specifically in this patient population.

因此，2023 年有很多計劃來提高意識、加強教育並最終讓代碼更具體地用於這一患者群體。

That’s helpful.

這很有幫助。

We'll hear next from Brian Skorney with Baird.

接下來我們將聽到 Brian Skorney 和 Baird 的談話。

Congrats s Steve on the promotion, well deserve. Just also wanted to get some additional guidance on your thoughts around the interim. Just it sounds like you're giving a lot of comfort that you shouldn't be powered based on what you've seen for ganaxolone to hit the interim.

恭喜史蒂夫升職，當之無愧。只是還想就您對過渡期的想法獲得一些額外的指導。聽起來你給了很多安慰，你不應該根據你所看到的加奈索酮進入過渡時期來提供動力。

So I really wanted to get a handle on what sort of delta assumptions you have, the differences between the primary endpoint for a full analysis without the [alpha hit] to the P-value versus the alpha hit, if you do take the interim. I mean it just seems well in my calculation, it's like a 30% delta versus a 33% delta. And I guess I'm under some -- I'm having trouble understanding why it's just not an obvious decision to take the interim in that case. So really my question is, what are the factors to consider as to why you wouldn't take the interim?

所以我真的很想了解你有什麼樣的 delta 假設，沒有 [alpha hit] 的完整分析的主要終點與 P 值與 alpha hit 之間的差異，如果你採取臨時。我的意思是在我的計算中它看起來很好，就像 30% 的增量與 33% 的增量。而且我想我有一些問題——我無法理解為什麼在這種情況下採取臨時措施並不是一個顯而易見的決定。所以我的問題真的是，要考慮哪些因素，為什麼你不接受臨時？

Well, this is Joe. Thanks, Brian, for the question. So the study is well powered. We were looking -- I think we have more data now on the secondary endpoints and wanted to be comfortable, as Scott mentioned, that it was powered to hit on the key health care utilization endpoints. The assumption about the delta is the same.

嗯，這是喬。謝謝布賴恩提出這個問題。所以這項研究是有力的。我們一直在尋找——我認為我們現在在次要端點上有更多數據，並且希望像 Scott 提到的那樣感到舒服，因為它有能力擊中關鍵的醫療保健利用端點。關於 delta 的假設是相同的。

The reason we would decide not to do the interim would be if the enrollment is just gangbusters. And by the time we got done with performing the interim analysis, the study would be fully enrolled. So there'd be no reason to do the interim. And that -- that would be the consideration. Otherwise, we're going to do it.

我們決定不進行過渡的原因是，如果註冊只是一鳴驚人。當我們完成中期分析時，該研究將全部納入。所以沒有理由做臨時。這將是考慮因素。否則，我們將這樣做。

Now it gets a little bit into the weeds, but there is -- there's a lot of assumptions you can use to build an interim analysis, how much well, as you know, how much alpha you spent at the interim versus the end?

現在它有點雜草了，但是有很多假設可以用來建立中期分析，如你所知，你在中期和結束時花費了多少 alpha？

There is an alpha spend at the interim analysis. However, if you look at the actual outcomes on the endpoints, the difference between 4.05 of a fully enrolled study and the alpha we would have at the end, having performed an interim is a difference in one patient outcome.

中期分析中有阿爾法支出。但是，如果您查看端點的實際結果，完全納入研究的 4.05 與我們最終將擁有的 alpha 之間的差異，執行了中期是一個患者結果的差異。

And so even though there's -- you have to hit a lower p-value at the end, if it proceeds to the end after an interim, the actual clinical penalty you pay is very low. But the assumptions for the interim are the same, 30% delta and it still remains well powered.

因此，即使有 - 你必須在最後達到較低的 p 值，如果它在中間之後繼續到最後，你支付的實際臨床懲罰非常低。但過渡時期的假設是相同的，30% delta 並且它仍然保持良好的動力。

Let me jump in, Joe. Look, Brian, I'm totally with you. I don't think we have any expectation that the delta in the study is going to be 30%. We think it's going to be potentially 40%, 50%, potentially 60%.

讓我跳進去，喬。聽著，布賴恩，我完全支持你。我認為我們對研究中的增量不會達到 30% 有任何期望。我們認為它可能是 40%、50%，可能是 60%。

That being said, I think in a small study, 1 or 2 patients couldn't potentially do wonky things to your ICU days or other health economic outcomes. So in general, my bias would be to have more patients in the study to reduce that risk of an outlier. Joe has reminded me the outlier could come on patient #95 or 105 the same way it could come on patient #5.

話雖如此，我認為在一項小型研究中，1 或 2 名患者不可能對您的 ICU 天數或其他健康經濟結果做出不穩定的事情。所以總的來說，我的偏見是讓更多的患者參與研究以降低異常值的風險。 Joe 提醒我異常值可能會出現在 95 號或 105 號患者身上，就像它可能出現在 5 號患者身上一樣。

So we keep that into consideration as well. But to this point, I think the bigger end certainly gives us a little bit of comfort on outliers more than anything else and really has minimal impact in our view of the primary endpoint.

所以我們也會考慮到這一點。但就這一點而言，我認為更大的終點肯定比其他任何事情都更能讓我們對異常值感到些許安慰，並且對我們對主要終點的看法的影響確實很小。

That said, I think every time a site now initiates and treats a patient and gets comfortable with the protocol, they're going to be a little bit better on patient #2 and #3. That's normal. And I think as we saw in the Phase II, that comfort only led to equally, if not greater success in terms of the utilization of the drug.

就是說，我認為每次一個站點現在啟動和治療患者並且對協議感到滿意時，他們都會對患者 #2 和 #3 好一點。這很正常。而且我認為，正如我們在第二階段所看到的那樣，這種安慰只會在藥物的利用方面帶來同樣的成功，如果不是更大的成功的話。

So there is a comfort level as our clinicians get into a sweet spot. There is an element of sites that are activating now and starting to get busy that we give them several months to participate in the study.

因此，當我們的臨床醫生進入最佳狀態時，會有一個舒適度。有一些網站現在正在激活並開始變得忙碌，我們給他們幾個月的時間來參與研究。

But I don't think any of us are really losing a lot of sleep on the key powering assumptions. It's just a small end always creates some unknown risk, particularly on the placebo side. So nothing more than that. I think it's more theoretical than practical. But it is nice to have a lot of data points while the study is ongoing to what we've shared with you in terms of understanding baseline characteristics and not being surprised by the types of patients being enrolled, et cetera.

但我不認為我們中的任何人真的在關鍵的動力假設上失眠了。這只是一個小的結束總是會產生一些未知的風險，特別是在安慰劑方面。所以僅此而已。我認為這是理論多於實踐。但是，在研究正在進行的同時，我們在了解基線特徵方面與您分享的內容以及對登記的患者類型等不感到驚訝的情況下，有很多數據點是很好的。

So it is -- that's what we're balancing and we feel that we're fortunate that we have the luxury of the FDA support if we choose to take an interim.

所以它是 - 這就是我們正在平衡的東西，我們感到很幸運，如果我們選擇採取臨時措施，我們可以獲得 FDA 的支持。

We'll hear now from Jason Butler with JMP Securities.

我們現在將聽到 Jason Butler 與 JMP Securities 的對話。

Hi. Just a couple more on the novel formulations. First one, from the MAD data, do you expect to have? Well, there'll be enough data there to make a meaningful interpretation of the somnolence -- sorry incidents?

你好。關於新配方的更多信息。第一個，從MAD數據來看，你預計會有嗎？好吧，那裡會有足夠的數據來對嗜睡做出有意義的解釋——抱歉的事件？

And then secondly, if you move forward quickly with the first reformulation -- formulation into a Phase III trial in LGS, how should we think about the utility of the prodrug and how you could use that strategically moving forward?

其次，如果你快速推進第一個重新制定——制定 LGS 的 III 期試驗，我們應該如何考慮前藥的效用以及你如何戰略性地使用它向前推進？

Yes. I could comment on the first part about the somnolence, Jason. Thanks for the question. Okay. And so I think we do see increases in Cmax with increasing dose. I think the major factor that's going to affect the rate of somnolence is going to be titration rate.

是的。我可以評論關於嗜睡的第一部分，Jason。謝謝你的問題。好的。所以我認為我們確實看到 Cmax 隨著劑量的增加而增加。我認為影響嗜睡率的主要因素是滴定率。

We've adjusted the titration rate in the current ongoing TSC study, kind of the low and slow approach, start the escalations at a low level and then ramp them up toward the end of the titration. And I think that's going to be the major factor affecting somnolence.

我們已經在當前正在進行的 TSC 研究中調整了滴定速率，這是一種低速和緩慢的方法，從低水平開始升級，然後在滴定結束時逐漸升高。我認為這將是影響嗜睡的主要因素。

I wouldn't expect a detailed read on somnolence. We'll get some idea from the MAD study, but these are healthy volunteers, and they aren't on the concomitant medications, they don't have the cognitive impairments and so on, neurodevelopmental problems. So it really takes the clinical trial to get a good idea about that.

我不希望有關於嗜睡的詳細閱讀。我們將從 MAD 研究中得到一些想法，但這些都是健康的志願者，他們沒有服用伴隨藥物，他們沒有認知障礙等神經發育問題。所以真的需要臨床試驗才能對此有一個很好的了解。

And in terms of the prodrug, I'll let -- Scott, can you comment on the prodrug piece of it?

就前藥而言，我會讓——斯科特，你能對它的前藥部分發表評論嗎？

Sure. And let me just back up, I think, on the MAD and the somnolence, Jason. I'll use this opportunity to share as we have, that we continue to feel as though in the blinded Phase II TSC study, we are seeing improved rates of tolerability, lower rates of discontinuations.

當然。我想，讓我回顧一下 MAD 和嗜睡，Jason。我將利用這個機會分享我們所擁有的，我們繼續感覺好像在盲法 II 期 TSC 研究中，我們看到耐受率提高，停藥率降低。

And I really think the work that Joe has done to create that new titration schedule, we're seeing what we believe is going to be a meaningful impact in the TSC study. And at the lower doses of our novel formulation, it behaves very similarly to ganaxolone. So we would expect to use the same type of titration, almost the identical titration for the new formulation.

我真的認為 Joe 為創建新的滴定計劃所做的工作，我們正在看到我們相信將對 TSC 研究產生有意義的影響。在我們的新配方的較低劑量下，它的行為與加奈索酮非常相似。所以我們希望使用相同類型的滴定，新配方幾乎相同的滴定。

Certainly, when you are absorbing much more drug, you are going to get some bigger Cmax’s. But again, we believe in a very reasonable fashion via titration, we don't see it as an issue today, and we certainly will get some additional insight on that from the MAD study, but we're only doing some mild titrations in the MAD study at the 1,200-milligram dose.

當然，當您吸收更多的藥物時，您會獲得更大的 Cmax。但同樣，我們相信滴定是一種非常合理的方式，我們今天不認為這是一個問題，我們肯定會從 MAD 研究中獲得一些額外的見解，但我們只是在做一些溫和的滴定1,200 毫克劑量的 MAD 研究。

So it's not truly a titration schedule. It's an MA -- or a titration study. It's an MAD study. And so just to be clear, there are some of those frank differences.

所以這不是真正的滴定時間表。這是一個 MA - 或滴定研究。這是一項 MAD 研究。因此，需要明確的是，其中存在一些坦率的差異。

The prodrug has a few different value propositions. I'll start on the IV side. It would really eliminate our need to use Captisol. And although our partners at Ligand have been very helpful. It's a lot of work to work with Captisol. It's limited the drug in -- it's certainly going to have some limitations in very young patients. It's going to have limitations today in super refractory status. And it's an important opportunity for us to expand the amount of ganaxolone we can give in a day without tying it specifically to Captisol. So it is really an important piece of our future that we are investing in today.

前藥有幾個不同的價值主張。我將從 IV 側開始。這將真正消除我們使用 Captisol 的需要。儘管我們在 Ligand 的合作夥伴提供了很大幫助。使用 Captisol 需要做很多工作。它限制了藥物的使用——它肯定會對非常年輕的患者產生一些限制。今天在超級難治性狀態下會有局限性。這對我們來說是一個重要的機會，可以擴大我們每天可以給予的加奈索酮的量，而無需將其專門與 Captisol 捆綁在一起。因此，這確實是我們今天投資的未來的重要組成部分。

On the oral side, right now, the PK profile of our lead candidate on the prodrug side has the potential for once-a-day dosing, certainly has the potential for a unique IP profile, has the potential for a significantly lower cost of goods. And I think we're very fortunate right now that we have 2 programs that look incredibly exciting. And I think what we have to weigh is a prodrug is still a year plus away from IND. And in the interim, certainly, given the -- what we're seeing with the current new formulation, I think we feel compelled to move that program along rapidly, and we have the potential benefit of moving to the prodrug down the road for all of the reasons mentioned earlier.

在口服方面，目前，我們前藥方面的主要候選藥物的 PK 特性有可能每天給藥一次，當然有可能形成獨特的 IP 特性，有可能顯著降低商品成本.我認為我們現在非常幸運，因為我們有兩個看起來非常令人興奮的項目。而且我認為我們必須權衡的是，前藥距離 IND 還需要一年多的時間。在此期間，當然，考慮到——我們在當前新配方中看到的情況，我認為我們感到有必要迅速推進該計劃，並且我們有可能為所有人轉向前藥帶來的好處前面提到的原因。

So this is really a fantastic problem that we have to solve for. It should be our biggest problem in life choosing 2 great future compounds that can deliver higher blood levels and easier dosing for patients, which we ultimately think will drive greater efficacy.

所以這確實是一個我們必須解決的奇妙問題。選擇 2 種未來偉大的化合物應該是我們生活中最大的問題，它們可以提供更高的血液水平和更容易為患者給藥，我們最終認為這將帶來更大的療效。

But to your point, right now, that new formulation program has actually behaved better than we thought via the preclinical models. But again, that's the real reason we're moving it rapidly forward. And we'll see how prodrug fits in. Time will tell. So thanks for the question. I think it was a really good one. With that, operator, we're going to call it a night. Thank you, everyone, for all your questions. Appreciate the support. Again, we are really excited going into an incredibly important year for the organization. Our commercial team continues to do great things. Our clinical operations team and our clinical team is doing their best to move our clinical trials along. And we really feel we're at a major inflection point, and we appreciate all of you making the time tonight. Thanks so much. Operator, we'll end the call.

但就你的觀點而言，現在，新的配方計劃實際上比我們通過臨床前模型想像的要好。但同樣，這也是我們快速推進它的真正原因。我們將看看藥物前體如何適應。時間會證明一切。所以謝謝你的問題。我認為這是一個非常好的。有了這個，接線員，我們就到此為止吧。謝謝大家提出的所有問題。感謝支持。再一次，我們真的很高興進入對組織來說非常重要的一年。我們的商業團隊繼續做偉大的事情。我們的臨床運營團隊和臨床團隊正在盡最大努力推進我們的臨床試驗。我們真的覺得我們正處於一個重要的轉折點，我們感謝你們今晚抽出時間來。非常感謝。接線員，我們將結束通話。

Thank you. And again, that concludes today's conference. You may now disconnect.

謝謝。再一次，今天的會議到此結束。您現在可以斷開連接。