NRX Pharmaceuticals Inc (NRXP) 2022 Q4 法說會逐字稿

Good afternoon and welcome to the NRx Pharmaceuticals' full-year 2022 results conference call. (Operator Instructions) Please note this event is being recorded.

下午好，歡迎來到 NRx Pharmaceuticals 的 2022 年全年業績電話會議。 （操作員說明）請注意正在記錄此事件。

I would now like to turn the conference over to Suzanne Messere, Stern Investor Relations. Please go ahead.

我現在想將會議轉交給斯特恩投資者關係部的 Suzanne Messere。請繼續。

Thank you, Danielle. Before we proceed with the call, I would like to remind everyone that certain statements made during this call are forward-looking statements under US federal securities laws. These statements are subject to risks and uncertainties that could cause actual results to differ materially from historical experience or present expectation. Additional information concerning factors that could cause actual results to differ from statements made on this call is contained in our periodic reports filed with the SEC.

謝謝你，丹妮爾。在我們繼續通話之前，我想提醒大家，根據美國聯邦證券法，本次通話中做出的某些陳述屬於前瞻性陳述。這些陳述受風險和不確定因素的影響，這些風險和不確定因素可能導致實際結果與歷史經驗或當前預期存在重大差異。我們向美國證券交易委員會提交的定期報告中包含有關可能導致實際結果與本次電話會議聲明不同的因素的更多信息。

The forward-looking statements made during this call speak only as of the date hereof, and the company undertakes no obligation to update or revise the forward-looking statements. Information presented on this call is contained in the press release issued earlier today and in the company's Form 10-K planned to be filed tomorrow, which may be accessed from the Investor Relations Section of the NRx Pharmaceuticals website.

本次電話會議期間作出的前瞻性陳述僅在本新聞稿發布之日有效，公司不承擔更新或修改前瞻性陳述的義務。本次電話會議中提供的信息包含在今天早些時候發布的新聞稿和計劃於明天提交的公司 10-K 表格中，可從 NRx Pharmaceuticals 網站的投資者關係部分訪問。

Joining me on today's call from NRx Pharmaceuticals are Stephen Willard, Chief Executive Officer; and Seth Van Voorhees, Chief Financial Officer and Treasurer. Stephen will provide a summary of the company's progress. Seth will review the company's financial results, and then Stephen will review upcoming milestones before making closing comments. Following their prepared remarks Stephen and Seth will be joined by Jonathan Javitt, the company's Chief Scientist; and Matthew Duffy, the company's Chief Business Officer, to address your question.

與我一起參加今天來自 NRx Pharmaceuticals 的電話會議的還有首席執行官 Stephen Willard；以及首席財務官兼財務主管 Seth Van Voorhees。斯蒂芬將提供公司進展的總結。 Seth 將審查公司的財務業績，然後 Stephen 將在發表結束評論之前審查即將到來的里程碑。公司首席科學家喬納森·賈維特 (Jonathan Javitt) 將在 Stephen 和 Seth 發表完準備好的講話後加入；以及公司首席商務官 Matthew Duffy 來解答您的問題。

I will now turn the call over to Stephen.

我現在將把電話轉給斯蒂芬。

Thank you, Suzanne. Good afternoon, everyone, and thank you for joining us.

謝謝你，蘇珊娜。大家下午好，感謝您加入我們。

We scheduled this conference call to coincide with World Bipolar Day. As you know, bipolar depression is a lethal condition that affects 2% of America, nearly 7 million people, and a similar percentage of the world's population. With the commitment of our investors, our team, and our researchers, we aim to literally bring hope to the millions of patients with suicidal bipolar depression and PTSD, who have been systematically excluded from the trials of previous antidepressant.

我們將本次電話會議安排在世界雙極日期間。如您所知，雙相抑鬱症是一種致命疾病，它影響著 2% 的美國人口、近 700 萬人，以及類似比例的世界人口。在我們的投資者、我們的團隊和我們的研究人員的承諾下，我們的目標是真正為數百萬患有自殺性雙相抑鬱症和創傷後應激障礙的患者帶來希望，他們被系統地排除在以前的抗抑鬱藥試驗之外。

Today, we will discuss full-year 2022 results and provide a business update. As you can see from our filings, 2022 was a pivotal year for NRx. When we filed our 2021 earnings, the COVID pandemic was just winding down, and we announced our intention to redirect our energy to NRx's core business, the development of life-saving drugs for lethal central nervous system conditions with an initial focus on suicidal bipolar depression.

今天，我們將討論 2022 年全年業績並提供業務更新。從我們的文件中可以看出，2022 年是 NRx 的關鍵一年。當我們提交 2021 年收益時，COVID 大流行剛剛結束，我們宣布打算將我們的精力轉移到 NRx 的核心業務，即開發針對致命的中樞神經系統疾病的救命藥物，最初的重點是自殺性雙相抑鬱症.

As we promised investors a year ago, we have now completed manufacture of NRX-101 and aligned with the FDA on a path to commercial stage product. We've reinstituted our clinical trials for NRX-101 for patients with suicidal treatment-resistant bipolar depression. We have continued to align with FDA on a path to approve NRX-101. And this week, we announced encouraging findings from the first evaluation of unblinded data by our independent Data Safety and Monitoring Board.

正如我們一年前向投資者承諾的那樣，我們現在已經完成了 NRX-101 的製造，並與 FDA 就商業階段產品的道路保持一致。我們重新開始了 NRX-101 的臨床試驗，以治療難治性雙相抑鬱症患者。我們在批准 NRX-101 的道路上繼續與 FDA 保持一致。本週，我們宣布了我們的獨立數據安全和監測委員會對非盲數據進行的首次評估的令人鼓舞的結果。

As you know from the online publications we have posted, this DSMB initiative is being led by a highly experienced executive team together with leading psychiatrists from around the world. Today, we are delighted to announce the appointment of two world-class psychiatrists to our advisory board. Professor Andrew Nierenberg, a Chair Professor of Psychiatry at Harvard Medical School, is the Director of the Dauten Family Center for Bipolar Research at the Massachusetts General Hospital and one of the world's most published scientists in the area of psychiatric research particularly as it relates to bipolar disease. We are honored to have him as principal investigator of our ongoing clinical trials.

正如您從我們發布的在線出版物中了解到的那樣，這項 DSMB 計劃由經驗豐富的執行團隊以及來自世界各地的領先精神病學家領導。今天，我們很高興地宣布任命兩位世界級的精神科醫生加入我們的顧問委員會。 Andrew Nierenberg 教授是哈佛醫學院精神病學講座教授，是馬薩諸塞州總醫院 Dauten 家庭雙相情感研究中心主任，也是世界上在精神病學研究領域（尤其是與雙相情感障礙相關的領域）發表論文最多的科學家之一疾病。我們很榮幸邀請他擔任我們正在進行的臨床試驗的首席研究員。

Professor Marion Leboyer is one of France's leading psychiatrists and an extensively published researcher in the field of neuropsychiatry particularly as it relates to bipolar disease and autism. In addition to our academic achievement, Professor Leboyer chairs the Fondation FondaMental and has facilitated an important collaboration with French psychiatry researchers that I will describe in a few moments. You can see their biographies on our website.

Marion Leboyer 教授是法國領先的精神病學家之一，也是神經精神病學領域的一位發表廣泛著作的研究員，尤其是與雙相情感障礙和自閉症有關的領域。除了我們的學術成就外，Leboyer 教授還是 FondaMental 基金會的主席，並促進了與法國精神病學研究人員的重要合作，我將在稍後描述。您可以在我們的網站上查看他們的傳記。

I'll begin by reviewing our lead development program NRX-101. NRX-101 is a fixed dose combination of D-cycloserine, an NMDA receptor modulator, and lurasidone, a standard-of-care medicine for treating bipolar depression. We initially introduced NRX-101 as a drug that showed benefit in conjunction with ketamine in acute care patients and, this week, announced encouraging findings from our outpatient trial of NRX-101 versus lurasidone that may offer a path to a far broader indication.

我將首先回顧我們的主要開發計劃 NRX-101。 NRX-101是 D-環絲氨酸（一種 NMDA 受體調節劑）和魯拉西酮（一種治療雙相抑鬱症的標準護理藥物）的固定劑量組合。我們最初將 NRX-101 作為一種藥物引入，該藥物與氯胺酮聯合使用對急性護理患者有益，本週，我們宣布了 NRX-101 與魯拉西酮的門診試驗令人鼓舞的結果，這可能為更廣泛的適應症提供途徑。

NRX-101 aims to target a critical area of unmet need among patients with bipolar depression, PTSD, and, as you will see in our filings, possibly chronic pain. Multiple investigators around the world have published encouraging findings on the use of D-cycloserine in these areas. However, the NRx discovery of the unique synergy between NMDA and 5HT2a targeted drug, together with the discovery of the critical dosages at which D-cycloserine may be effective in these conditions, has resulted in a portfolio of 90 patents around the world, 48 of which have now been issued, all related to the treatment of bipolar depression, major depressive disorder, PTSD, and other central nervous system conditions. It is well established that patients with bipolar depression are at far greater risk of self-harm than those with major depressive disorder.

NRX-101旨在針對雙相抑鬱症、創傷後應激障礙以及您將在我們的文件中看到的可能慢性疼痛患者中未滿足需求的關鍵領域。世界各地的多名研究人員發表了關於在這些領域使用 D-環絲氨酸的令人鼓舞的發現。然而，NRx 發現 NMDA 和 5HT2a 靶向藥物之間的獨特協同作用，以及發現 D-環絲氨酸在這些條件下可能有效的臨界劑量，已在全球產生了 90 項專利組合，48 項專利現在已經發布，所有這些都與雙相抑鬱症、重度抑鬱症、創傷後應激障礙和其他中樞神經系統疾病的治療有關。眾所周知，雙相抑鬱症患者自殘的風險遠高於重度抑鬱症患者。

Tragically, however, patients with suicidal bipolar depression have been excluded from the clinical trials of known antidepressant. To our knowledge, NRx is the first company to attempt to bring a medicine to people whose only FDA-approved treatment alternative is currently electroshock therapy. D-cycloserine has been shown to reduce suicidal ideation in our STABIL-B trial and similarly been shown to reduce suicidal ideation by independent investigators in a peer reviewed study reproduced in our 10-K filing.

然而，可悲的是，患有自殺性雙相抑鬱症的患者已被排除在已知抗抑鬱藥的臨床試驗之外。據我們所知，NRx 是第一家嘗試為那些目前唯一獲得 FDA 批准的治療方法是電擊療法的人提供藥物的公司。在我們的 STABIL-B 試驗中，D-環絲氨酸已被證明可以減少自殺意念，在我們的 10-K 文件中轉載的同行評審研究中，獨立研究人員也同樣證明可以減少自殺意念。

The tragic reality of bipolar depression is that if you know two people with this condition, the odds are that one will attempt suicide. And if you know five people with this condition, the odds are that one will die from suicide. As the first potential oral NMDA antagonist target bipolar depression with suicidality, NRX-101's proof-of-concept data from the Phase 2 STABIL-B trial has shown a highly differentiated therapeutic profile compared to the other commercial therapies and investigative drugs under development. Our Phase 2 data shows statistically significant reduction in both depression and suicidality compared to standard therapy in patients with bipolar depression, who were acutely suicidal and those who are initially stabilized with ketamine.

雙相抑鬱症的悲慘現實是，如果你認識兩個患有這種疾病的人，那麼其中一個人很可能會嘗試自殺。如果你認識五個患有這種疾病的人，那麼其中一個人死於自殺的可能性很大。作為第一個潛在的口服 NMDA 拮抗劑靶向具有自殺傾向的雙相抑鬱症，與其他商業療法和正在開發的研究藥物相比，NRX-101來自 2 期 STABIL-B 試驗的概念驗證數據顯示出高度差異化的治療概況。我們的第 2 階段數據顯示，與雙相抑鬱症患者的標準療法相比，抑鬱症和自殺傾向在統計學上顯著降低，這些患者有急性自殺傾向，並且最初使用氯胺酮穩定下來。

To our knowledge, no oral drug therapy has ever demonstrated a reduction in both depression and suicidal tendencies in this patient population. This is a potentially life-saving event because antidepressants carry black box warning labels regarding potential for increased risk of suicide in vulnerable populations. Based on NRX-101's differentiated therapeutic profile, we believe that we have the potential to address a significant unmet need for patients who are currently underserved by available treatment options.

據我們所知，沒有任何一種口服藥物治療能夠降低該患者群體的抑鬱症和自殺傾向。這是一個可能挽救生命的事件，因為抗抑鬱藥帶有黑框警告標籤，可能會增加弱勢人群的自殺風險。基於 NRX-101 的差異化治療概況，我們相信我們有可能解決目前可用治療方案服務不足的患者的重大未滿足需求。

Based on our Phase 2 results, the FDA granted Breakthrough Therapy Designation and a Special Protocol Agreement for NRX-101 in bipolar depression with acute suicidality. The breakthrough therapy designation allows for an expedited rolling submission for the new drug application for investigational drugs that have demonstrated substantial improvement over existing approved therapy. And the special protocol agreement allows for a single registrational trial of NRX-101 in this indication after stabilization with ketamine using a protocol similar to the STABIL-B trial with a patient population of fewer than 100.

根據我們的 2 期結果，FDA 授予 NRX-101突破性治療指定和特別協議協議，用於治療伴有急性自殺傾向的雙相抑鬱症。突破性療法指定允許加快滾動提交研究藥物的新藥申請，這些藥物已證明比現有批准的療法有實質性改進。特殊協議協議允許在用氯胺酮穩定後使用類似於 STABIL-B 試驗的協議對患者人數少於 100 人進行 NRX-101 的單一註冊試驗。

During 2022, we made substantial progress in advancing our development plans for NRX-101 for the treatment of bipolar depression with suicidality as well as a new area, PTSD. As you recall from our initial public filings, our psychiatry drug development program was halted by the closure of psychiatry study sites during the COVID pandemic. This time last year, we advised investors that we were reinitiating our psychiatry program. Our first order of business was to transfer our manufacturing and analytic technology to the United States, and we were fortunate to secure Alcami, headquartered in North Carolina, as our lead manufacturing partner.

在 2022 年期間，我們在推進 NRX-101治療雙相抑鬱症伴自殺以及新領域 PTSD 的開發計劃方面取得了實質性進展。正如您從我們最初的公開文件中回憶的那樣，我們的精神病學藥物開發計劃因 COVID 大流行期間精神病學研究地點的關閉而停止。去年的這個時候，我們告知投資者我們正在重新啟動我們的精神病學項目。我們的首要任務是將我們的製造和分析技術轉移到美國，我們很幸運地獲得了總部位於北卡羅來納州的 Alcami 作為我們的主要製造合作夥伴。

Over a period of six months, we transferred our manufacturing and analytic methods to Alcami and by September manufactured our first Phase 3 and potentially commercial scale batch of NRX-101. We submitted our manufacturing and stability data to the FDA in October 2022. And in January 2023, we reached alignment with FDA on our proposed manufacturing plan based on the Type C meeting to review our chemistry, manufacturing, and controls. As a result, NRx is now positioned to conduct registrational trials of NRX-101 and able to make NRX-101 available through expanded access and right to track programs for patients who have exhausted approved treatment options.

在六個月的時間裡，我們將我們的製造和分析方法轉移到 Alcami，並在 9 月份製造了我們的第一個第 3 階段和潛在商業規模的 NRX-101 批次。我們於 2022 年 10 月向 FDA 提交了製造和穩定性數據。2023 年 1 月，我們與 FDA 就基於 C 類會議的擬議製造計劃達成一致，以審查我們的化學、製造和控制。因此，NRx 現在可以進行 NRX-101的註冊試驗，並能夠通過擴大訪問權限和權利來為已經用盡批准的治療方案的患者跟踪計劃，從而使 NRX-101可用。

We're excited about this milestone in particular as we believe that adopting a commercial-ready manufacturing process at this stage of our development can lead to a more seamless NDA submission, review, and approval process under our Breakthrough Therapy Designation without the need for bridging study. In January 2023, we initiated a Phase 3 registrational clinical trial of NRX-101 for the treatment of severe bipolar depression with acute suicidal ideation and behavior and contracted the first study site. The study was designed to show that following stabilization in the acute care setting, treatment with NRX-101 is superior to lurasidone in maintaining improvement in symptoms of depression as measured by the Montgomery-Asberg Depression Rating Scale total score.

我們對這一里程碑感到特別興奮，因為我們相信，在我們開發的這個階段採用商業就緒的製造工藝可以在我們的突破性治療指定下實現更加無縫的 NDA 提交、審查和批准流程，而無需橋接學習。 2023年1月，我們啟動了NRX-101治療伴有急性自殺意念和行為的重度雙相抑鬱症的3期註冊臨床試驗，並簽約了第一個研究中心。該研究旨在表明，在急性護理環境穩定後，根據蒙哥馬利-阿斯伯格抑鬱量表總分衡量，NRX-101治療在維持抑鬱症狀改善方面優於魯拉西酮。

We met with the US FDA earlier this year to discuss the design of this Phase 3 trial of NRX-101 in patients with bipolar depression suffering from acute suicidality and are following FDA's suggestion to pursue the indication of quote-unquote treatment of recently suicidal patients with bipolar depression. We conducted our initial STABIL-B trial of NRX-101 versus lurasidone in acutely suicidal patients following acute stabilization with ketamine. However, both FDA and prospective commercial partners have suggested broadening the indication to test the use of NRX-101 as a means of maintaining remission for acute suicidality in patients stabilized by a variety of standard inpatient approaches in order that our label, should we prove safety and efficacy, not be dependent on prior use of ketamine.

今年早些時候，我們與美國 FDA 會面，討論了 NRX-101 在患有急性自殺傾向的雙相抑鬱症患者中的 3 期試驗的設計，並遵循 FDA 的建議，對最近有自殺傾向的患者進行 quote-unquote 治療。雙相抑鬱症。我們在氯胺酮急性穩定後的急性自殺患者中進行了 NRX-101 與魯拉西酮的初步 STABIL-B 試驗。然而，FDA 和潛在的商業合作夥伴都建議擴大適應症，以測試 NRX-101 的使用，作為通過各種標準住院治療方法穩定患者急性自殺傾向維持緩解的一種手段，以便我們的標籤，如果我們證明安全和療效，不依賴於之前使用的氯胺酮。

Although NRx is not actively researching the use of ketamine, a potent NMDA antagonist, we do recognize its role as a potential agent for stabilizing acutely suicidal patients and recognize FDA's desire for more data on its efficacy. Therefore, we have partnered with the leading psychiatrists in France who conducted what we believe to be the most comprehensive study of ketamine for treatment of acute suicidality among hospitalized patients, particularly patients with bipolar depression.

儘管 NRx 並未積極研究氯胺酮（一種有效的 NMDA 拮抗劑）的使用，但我們確實認識到它作為穩定急性自殺患者的潛在藥物的作用，並認識到 FDA 希望獲得更多關於其療效的數據。因此，我們與法國領先的精神病學家合作，他們進行了我們認為最全面的氯胺酮研究，用於治療住院患者（尤其是雙相抑鬱症患者）的急性自殺傾向。

Their study, which is summarized in tomorrow's 10-K filing, demonstrates that patients with bipolar depression had a sevenfold greater response to ketamine in reducing suicidality than did those with major depressive disorder. Our colleagues have provided us with the detailed clinical study report that we have now translated into English and are submitting to the FDA. To our knowledge, this is the first multicentered placebo-controlled trial that shows an enhanced benefit of NMDA targeted drugs in patients with bipolar depression compared to those with major depressive disorder. We look forward to having Professor Leboyer and her colleagues explain the importance of this study in greater detail and accompany us to the FDA to discuss the finding.

他們的研究在明天的 10-K 文件中進行了總結，表明雙相抑鬱症患者對氯胺酮在降低自殺率方面的反應比重度抑鬱症患者高七倍。我們的同事向我們提供了詳細的臨床研究報告，我們現已將其翻譯成英文並提交給 FDA。據我們所知，這是第一個多中心安慰劑對照試驗，表明與重度抑鬱症患者相比，NMDA 靶向藥物對雙相抑鬱症患者的益處更大。我們期待 Leboyer 教授和她的同事更詳細地解釋這項研究的重要性，並陪我們去 FDA 討論這一發現。

In the January 2023 Type B meeting with the FDA Psychiatry Division to align on the registration strategy for NRX-101, FDA suggested a potential expanded indication for NRX-101 in addition to reaffirming NRX-101's Special Protocol Agreement, which was originally granted in April 2019. The FDA suggested that NRx's clinical development program be enlarged to allow for the chronic treatment of patients with bipolar depression and intermittent suicidality. This update would broaden the addressable population of the indication under the SPA or otherwise for patients with chronic intermittent episodes of bipolar depression and would enable the use of NRX-101 on a long-term basis by a broader segment of the approximately 7 million individuals in the United States with bipolar disorder.

在 2023 年 1 月與 FDA 精神病學部門就 NRX-101 的註冊策略進行協調的 B 型會議上，FDA 除了重申 NRX-101 的特別協議協議外，還建議擴大 NRX-101 的適應症，該協議最初於 4 月授予2019. FDA 建議擴大 NRx 的臨床開發計劃，以允許對患有雙相抑鬱症和間歇性自殺的患者進行長期治療。此更新將擴大 SPA 或雙相抑鬱症慢性間歇性發作患者適應症的可尋址人群，並將使美國約 700 萬人中的更廣泛人群能夠長期使用 NRX-101美國患有躁鬱症。

Prior to pursuing this extremely broad indication, we have focused our outpatient clinical trial first on those greatest unmet medical need, specifically those with suicidal treatment-resistant bipolar depression. In other words, we are enrolling patients who are under the care of a physician for bipolar depression and have ongoing depressive symptoms and active risk to self-harm despite treatment with available medicine. The object of the double-blind study is to demonstrate NRX-101's ability to significantly improve symptoms of depression and suicidality over six weeks when taken twice daily on a home use basis. The population is significantly larger than the severe bipolar depression population with acute suicidal ideation and behavior seen in the hospital emergency setting and does not require initial stabilization with ketamine or other treatment.

在追求這個極其廣泛的適應症之前，我們首先將門診臨床試驗的重點放在那些最大的未滿足醫療需求上，特別是那些患有自殺治療抵抗性雙相抑鬱症的患者。換句話說，我們正在招募接受雙相抑鬱症醫生治療的患者，這些患者儘管接受了現有藥物治療，但仍有持續的抑鬱症狀和自殘風險。雙盲研究的目的是證明 NRX-101 在家庭使用的基礎上每天服用兩次，在六週內顯著改善抑鬱和自殺症狀的能力。該人群明顯大於在醫院急診環境中出現急性自殺意念和行為的嚴重雙相抑鬱症人群，並且不需要使用氯胺酮或其他治療進行初始穩定。

This study has the potential to expand the use of our medicines to nearly 1 million people who currently suffer from severe depression and suicidal ideation despite expert medical care with currently available medicines. These are the patients who were targeted by the recently funded $50 million Patient-Centered Outcomes Research initiative, which documents the extraordinary unmet medical need in this area. We announced the initiation of this clinical trial when we met with you a year ago and this week announced guidance to continue enrolling patients by our independent Data Safety Monitoring Board, what I call DSMB, who examined unblinded data from the first 50 patients.

這項研究有可能將我們的藥物的使用範圍擴大到近 100 萬人，這些人目前患有嚴重的抑鬱症和自殺意念，儘管使用目前可用的藥物進行專家醫療護理。這些患者是最近資助的 5000 萬美元以患者為中心的結果研究計劃的目標患者，該計劃記錄了該領域未滿足的非凡醫療需求。我們在一年前與您會面時宣布啟動這項臨床試驗，並於本周宣布我們的獨立數據安全監測委員會（我稱之為 DSMB）繼續招募患者的指南，該委員會檢查了前 50 名患者的非盲數據。

The DSMB found no futility signal at this stage of the trial. Similarly, no safety signals were identified in association with NRX-101, and the DSMB recommended that the enrollment of the trial continue as planned. According to the study statistical analysis plan, the failure to identify futility requires that an advantage, but not yet a statistically significant advantage, of the investigational drug relative to the comparative treatment must be observed by the DSMB. The DSMB will continue to monitor safety and efficacy in the trial.

DSMB 在審判的這個階段沒有發現無效信號。同樣，沒有發現與 NRX-101 相關的安全信號，DSMB 建議按計劃繼續進行試驗。根據研究統計分析計劃，未能確定無效性要求 DSMB 必須觀察到研究藥物相對於比較治療的優勢，但還不是統計學上顯著的優勢。 DSMB 將繼續監測試驗的安全性和有效性。

Based on the DSMB's finding, together with the recent completion of Phase 3 anticipated commercial stage manufacture of NRX-101, the company has upgraded the ongoing trial with Phase 2b/3 trial. Those results may be used in a future registrational filing should the primary endpoint commit.

根據 DSMB 的調查結果，連同最近完成的 NRX-101 的第 3 階段預期商業階段製造，該公司已將正在進行的試驗升級為第 2b/3 階段試驗。如果主要終點提交，這些結果可能會用於未來的註冊文件。

With the guidance of the DSMB enhanced, the company has now requested a comprehensive breakthrough therapy planning meeting for NRX-101 as was suggested by FDA in their recent correspondence. Based on the comments and guidance from the FDA and its recent Type B meeting regarding the registrational acute suicidality trial and a potentially broader indication as well as the guidance we received from the DSMB regarding our currently enrolling Phase 2b/3 clinical study of NRX-101, the company is evaluating changes to its registrational program for NRX-101 and will seek to consolidate the current clinical trials. This broader indication may also offer significant advantages in commercialization. Data is expected by the end of this year.

在 DSMB 的指導得到加強的情況下，該公司現在已經要求按照 FDA 在最近的信件中建議的 NRX-101的全面突破性治療計劃會議。根據 FDA 及其最近的 B 類會議關於註冊急性自殺試驗和潛在更廣泛適應症的評論和指導，以及我們從 DSMB 收到的關於我們目前正在註冊的 NRX-101 2b/3 期臨床研究的指導，該公司正在評估對其 NRX-101 註冊計劃的變更，並將尋求鞏固當前的臨床試驗。這種更廣泛的適應症也可能在商業化方面提供顯著優勢。預計數據將在今年年底公佈。

We are evaluating the potential of NRX-101 in post-traumatic stress disorder or PTSD, another area of high unmet need, which is also associated with suicidality. Approximately 9 million individuals in our country experienced PTSD and 1/3 has severe PTSD with 10% experiencing suicidality. Between 17 and 22 members of our Armed Forces and veterans are lost every day to suicide. Depression and PTSD may be driven by pathways that are similar to those that drive depression and other conditions. However, NMDA antagonist (inaudible) and D-cycloserine in particular, may have a more specific effect in the treatment of PTSD.

我們正在評估 NRX-101 在創傷後應激障礙或 PTSD 中的潛力，這是另一個高度未滿足需求的領域，也與自殺有關。我國約有 900 萬人經歷過 PTSD，其中 1/3 患有嚴重的 PTSD，其中 10% 有自殺傾向。每天有 17 至 22 名武裝部隊成員和退伍軍人死於自殺。抑鬱症和創傷後應激障礙可能是由類似於驅動抑鬱症和其他疾病的途徑驅動的。然而，NMDA 拮抗劑（聽不清），尤其是 D-環絲氨酸，可能在治療 PTSD 方面具有更具體的作用。

In a preclinical PTSD study described in today's filing -- tomorrow's filing, D-cycloserine demonstrated the ability to extinguish recurring images of traumatic event, also known as peer memory, in a validated WKY model of PTSD. This model has similarly been used by others to document a PTSD-specific effect as ketamine. Repeated IV ketamine has also been demonstrated to improve PTSD scores in a randomized controlled trial. Unlike ketamine, however, NRX-101 is not neurotoxic, is not addictive, and has not caused psychedelic side effect in clinical trial.

在今天的申請和明天的申請中描述的一項臨床前 PTSD 研究中，D-環絲氨酸展示了在經過驗證的 PTSD WKY 模型中消除創傷事件的反復出現的圖像（也稱為同伴記憶）的能力。這個模型同樣被其他人用來記錄 PTSD 特定的效果，如氯胺酮。一項隨機對照試驗也證明重複靜脈注射氯胺酮可以改善 PTSD 評分。然而，與氯胺酮不同的是，NRX-101 沒有神經毒性，不會上癮，並且在臨床試驗中沒有引起迷幻副作用。

We anticipate that our investigational drug will show antidepressant effects in PTSD compared to placebo, and we hope that it will demonstrate specific effect of fair memory component of PTSD and directly reduce symptoms of PTSD itself. Today, there is no approved medicine for these specific PTSD symptoms. We are on track to initiate a Phase 2 study of NRX-101 in PTSD in the second quarter of 2023. We are incredibly excited about the potential life-saving effect of NRX-101.

我們預計，與安慰劑相比，我們的研究藥物將在 PTSD 中表現出抗抑鬱作用，我們希望它能夠展示 PTSD 公平記憶成分的特異性作用，並直接減輕 PTSD 本身的症狀。今天，沒有針對這些特定 PTSD 症狀的批准藥物。我們有望在 2023 年第二季度啟動 NRX-101 在 PTSD 中的第二階段研究。我們對 NRX-101 的潛在挽救生命效果感到非常興奮。

And in order to continue to support the clinical development of these programs, we announced the close of the $2.9 million registered direct offering to support our pipeline efforts and, more specifically, the initiation of an expanded access protocol and safety database for NRX-101, studying treatment-resistant bipolar depression with risk of self-harm.

為了繼續支持這些項目的臨床開發，我們宣布結束 290 萬美元的註冊直接發售，以支持我們的管道工作，更具體地說，啟動 NRX-101 的擴展訪問協議和安全數據庫，研究具有自殘風險的難治性雙相抑鬱症。

This database allows us to investigate the expanded indication put forth by the FDA's Psychiatric Division in our Type B meeting for our registrational trials, and we look forward to providing you all with an update of our clinical activity in the months to come. The continued financial support from our existing shareholders based on our existing data and ongoing clinical trials demonstrate their commitment to people living with serious CNS disorders and the potential of NRX-101 to become commercially successful.

該數據庫使我們能夠調查 FDA 精神病學部門在我們的註冊試驗 B 類會議上提出的擴展適應症，我們期待在未來幾個月為您提供我們臨床活動的最新信息。根據我們現有的數據和正在進行的臨床試驗，我們現有股東的持續財政支持表明他們對患有嚴重中樞神經系統疾病的人的承諾以及 NRX-101取得商業成功的潛力。

Finally, we achieved a number of significant corporate milestones in recent months. In February, we received notice of the issuance of the US patent for NRX-101, which covers the use of NRX-101 to treat patients suffering from depression, including bipolar depression or major depression with or without to suicidality. This patent strengthens the company's intellectual property position until at least 2033.

最後，我們在最近幾個月實現了一些重要的企業里程碑。 2 月，我們收到了 NRX-101 的美國專利頒發通知，該專利涵蓋使用 NRX-101 治療抑鬱症患者，包括雙相抑鬱症或伴有或不伴有自殺傾向的重度抑鬱症。該專利至少在 2033 年之前加強了公司的知識產權地位。

We are pleased to announce that Matthew Duffy has joined as Chief Business Officer of the company. Many of you may know him from his time at leading pharmaceutical and biotechnology companies including Pfizer and Medimmune and his efforts in Investor Relations and investment banking. Matt will be responsible for a range of duties including Investor Relations. Similarly, Dr. Martin Brecher, a distinguished psychiatrist who has held leadership positions at the FDA, AstraZeneca, Johnson & Johnson, and other leading corporations, is serving as medical director for our clinical trial.

我們很高興地宣布 Matthew Duffy 已加入公司擔任首席商務官。你們中的許多人可能從他在領先的製藥和生物技術公司（包括 Pfizer 和 Medimmune）的時間以及他在投資者關係和投資銀行方面的努力而認識他。 Matt 將負責一系列職責，包括投資者關係。同樣，Martin Brecher 博士是一位傑出的精神病學家，曾在 FDA、AstraZeneca、Johnson & Johnson 和其他領先公司擔任過領導職務，他正在擔任我們臨床試驗的醫學主任。

These milestones achieved in the year since we reentered psychiatric drug development established a strong foundation for NRx that enables us to efficiently advance our clinical trial and make a difference in the lives of patients with life-threatening psychiatric disease. I would like to express my gratitude to the patients, the NRx team, clinical trial investigators, and shareholders for their continued support.

自我們重新進入精神科藥物開發以來的一年裡，這些里程碑為 NRx 奠定了堅實的基礎，使我們能夠有效地推進臨床試驗，並改變患有危及生命的精神疾病患者的生活。我要感謝患者、NRx 團隊、臨床試驗研究人員和股東的持續支持。

With that, I will turn it over to Seth for a review of our financial results. Seth?

有了這個，我將把它交給賽斯來審查我們的財務結果。賽斯？

Thank you, Stephen. And good afternoon, everyone. I will now review the highlights of our fiscal year 2022 financial results and our expectations for 2023.

謝謝你，斯蒂芬。大家下午好。我現在將回顧我們 2022 財年財務業績的亮點以及我們對 2023 年的預期。

For the year ended December 31, 2022, NRx Pharmaceuticals recorded $17.0 million in R&D expenses compared to $20.3 million for the year earlier. The decrease of $3.2 million is related primarily to the decrease of $2.5 million in clinical trial and development expenses related to our discontinued ZYESAMI clinical work. For the year ended December 31, 2022, we also recorded $27.4 million of general and administrative expenses compared to $74.9 million for the year earlier. The decrease of $47.6 million was primarily related to a decrease of $53.3 million in consulting fees, of which $41 million was related to the fair value of common stock issued.

截至 2022 年 12 月 31 日止年度，NRx Pharmaceuticals 的研發費用為 1700 萬美元，上年同期為 2030 萬美元。減少 320 萬美元主要與我們停止 ZYESAMI 臨床工作相關的臨床試驗和開發費用減少 250 萬美元有關。截至 2022 年 12 月 31 日止年度，我們還記錄了 2740 萬美元的一般和行政費用，而去年同期為 7490 萬美元。減少 4760 萬美元主要與諮詢費減少 5330 萬美元有關，其中 4100 萬美元與已發行普通股的公允價值有關。

For the 12-month period ended December 31, 2022, our resulting net loss was $39.8 million, which is $53.3 million improved compared to the net loss of $93.1 million for the 12 months ended the prior year. In fiscal year 2023, we expect our annual R&D expenses to decrease further from both fiscal year 2021 and 2022 levels as we focus solely on the development of NRX-101. Furthermore, we expect our annual G&A cost will decrease in 2023 due to a number of factors, including reduced legal costs related to the relief therapeutical settlement, which has the potential for significant royalty payments to us in the future, lower insurance costs especially related to D&O coverage, and as well as other cost initiatives that we have undertaken.

截至 2022 年 12 月 31 日止的 12 個月期間，我們由此產生的淨虧損為 3980 萬美元，與去年截止的 12 個月的淨虧損 9310 萬美元相比減少了 5330 萬美元。在 2023 財年，我們預計我們的年度研發費用將比 2021 財年和 2022 財年的水平進一步下降，因為我們只專注於 NRX-101 的開發。此外，由於多種因素，我們預計我們的年度 G&A 成本將在 2023 年減少，包括與救濟治療和解相關的法律成本降低，這有可能在未來向我們支付大量特許權使用費，降低保險成本，尤其是與D&O 覆蓋範圍，以及我們採取的其他成本舉措。

Now I'd like to comment on our cash resources. At year end, we had $20.1 million in cash. Our cash resources were enhanced several weeks ago when we entered into a securities purchase agreement with accredited investors who had previously established ownership positions in the company. The transaction involved the sale of approximately 3.9 million shares of the company's common stock combined with five-year warrants in a registered direct offering priced slightly above market at $0.75 per unit for the securities. The investors agreed not to sell these shares of common stock or exercise these warrants for six months following the issuance date.

現在我想評論一下我們的現金資源。年底時，我們有 2010 萬美元的現金。幾週前，當我們與之前在公司建立所有權的合格投資者簽訂證券購買協議時，我們的現金資源得到了增強。該交易涉及以略高於市場價的註冊直接發售方式出售約 390 萬股公司普通股和五年期認股權證，證券價格為每股 0.75 美元。投資者同意在發行日後六個月內不出售這些普通股或行使這些認股權證。

The aggregate gross proceeds to the company from the offering was approximately $2.9 million. As of the 10-K filing, we evaluated if there is doubt on our ability to fund our operations for the next 12 months. We have the right to make required payments for our current indebtedness in common stock, subject to certain ownership in trading volume limitations. If we are not able to make the required payments for this indebtedness, we will need to raise additional capital to support our currently anticipated operations for the next year and to strengthen our balance sheet as was done with the successful offering done several weeks ago. In addition, we may consider additional cost savings initiatives to further extend our cash resources.

公司從此次發行中獲得的總收益約為 290 萬美元。在提交 10-K 文件時，我們評估了我們是否有能力為未來 12 個月的運營提供資金。我們有權為我們目前的普通股債務支付所需的款項，但須遵守一定的所有權交易量限制。如果我們無法為這筆債務支付所需的款項，我們將需要籌集更多資金來支持我們目前預期的明年運營，並像幾週前成功發行的那樣加強我們的資產負債表。此外，我們可能會考慮採取額外的成本節約舉措，以進一步擴大我們的現金資源。

With that, I will turn it back to Steve for closing remarks. Steve?

有了這個，我將把它轉回給史蒂夫作結束語。史蒂夫？

Thank you, Seth.

謝謝你，賽斯。

Over the past year, we have built strong momentum as we advance our NRX-101 program in two indications while also positioning NRx for future growth with the potential for both the broader bipolar depression population as well as additional indications. Building on that momentum, 2023 promises to be an even more productive year as we continue to execute on multiple regulatory and clinical catalysts. We believe that NRX-101 is a potentially life-saving medicine that could change the treatment paradigm for individuals with bipolar depression, who are experiencing suicidality, which is the driving force behind our mission of meeting the needs of underserved patients with serious CNS disorders.

在過去的一年裡，我們在兩個適應症方面推進 NRX-101計劃時建立了強勁的勢頭，同時也將 NRX-101 計劃定位為未來增長，具有更廣泛的雙相抑鬱人群和其他適應症的潛力。在此勢頭的基礎上，隨著我們繼續執行多項監管和臨床催化劑，2023 年有望成為更有成效的一年。我們相信 NRX-101 是一種潛在的挽救生命的藥物，可以改變患有自殺傾向的雙相抑鬱症患者的治療模式，這是我們滿足服務不足的嚴重中樞神經系統疾病患者需求的使命背後的驅動力。

We look forward to updating you on our near-term milestones, which are on track for the coming year. Assuming that efficacy endpoints and safety are met in our Phase 3 trial, we plan to initiate the rolling submission of a new drug application by the end of this year with potential for drug approval by the end of 2024.

我們期待著向您更新我們即將在來年實現的近期里程碑。假設在我們的 3 期試驗中達到療效終點和安全性，我們計劃在今年年底前開始滾動提交新藥申請，並有可能在 2024 年底前獲得藥物批准。

Operator Danielle, we are ready to take questions from the audience.

接線員丹妮爾，我們準備好回答觀眾的問題。

(Operator Instructions) Jason Kolbert, Dawson James.

（操作員說明）Jason Kolbert，Dawson James。

Thank you for the very comprehensive update. I mean, that was really, really good, very detailed, it's what we need. Just want to understand a couple of comments you made. The DSMB lack of futility, which implies that the active drug is showing efficacy equivalent or even better than comparator, although not yet statistically significant. Can you just talk a little bit about that statement and kind of the math behind it? That would be helpful.

感謝您提供非常全面的更新。我的意思是，那真的非常非常好，非常詳細，這就是我們所需要的。只想了解您發表的一些評論。 DSMB 沒有無效性，這意味著活性藥物顯示出與比較藥物相當甚至更好的療效，儘管尚無統計學意義。你能談談這個陳述及其背後的數學原理嗎？那會很有幫助。

Sure. Jonathan, do you want to?

當然。喬納森，你想要嗎？

Sure. Jason, as you know, it's critical that we keep the blinding for the trial in place. The protocol for the trial and the statistical analysis plan are up on clinicaltrials.gov. And all we've been authorized to say by the DSMB is that no futility signal was identified. And their leading methodologists, Dr. Levine, said that we could offer the additional comment that in this trial, the way this is set up for that conclusion to be reached, a numerical superiority, though not a statistically significant superiority, would have to be identified.

當然。傑森，如你所知，我們在試驗中保持盲法是至關重要的。試驗方案和統計分析計劃已在 clinicaltrials.gov 上發布。 DSMB 授權我們只能說沒有發現無效信號。他們的主要方法學家 Levine 博士說，我們可以提供額外的評論，即在本試驗中，為得出該結論而設置的方式，數字優勢，雖然不是統計上顯著的優勢，但必須是確定。

There are some trial designs where as long as you're not worse than the placebo, you're still not futile. We put in place a stricter futility rule than that. But that's really all we're at liberty to say.

有一些試驗設計，只要你不比安慰劑差，你就仍然不是徒勞的。我們制定了比這更嚴格的無效規則。但這真的是我們可以自由說的全部。

Right. But actually, that's very critical. That last sentence when you talked about -- because that's what I was familiar with. But in most clinical trials are designed that if you're equivalent to the comparator or non-inferior to the comparator, that's how they're mostly designed.

正確的。但實際上，這是非常關鍵的。你談到的最後一句話——因為那是我所熟悉的。但在大多數臨床試驗中，如果你與比較者相當或不劣於比較者，那麼大多數臨床試驗都是這樣設計的。

And what I didn't understand until this moment was that if your trial design is a little bit different, and in fact, you're not futile because of the powering, and I'm assuming, because of the powering differences and the assumptions around the effect between active and comparator that, in fact, if no futility is shown, it suggests that there is a superiority because otherwise -- because the numbers are stacked against you because of the tough trial design. Is that kind of layman's interpretation about right?

直到這一刻我才明白，如果你的試驗設計有點不同，事實上，你不是徒勞的，因為動力，我假設，因為動力差異和假設圍繞積極和比較之間的影響，事實上，如果沒有顯示無用，則表明存在優勢，否則 - 因為由於艱難的試驗設計，數字對你不利。這種外行人的解釋對嗎？

Well, I don't think I want to wax overly optimistic. I think we're delighted that we didn't hit a futility signal given that we had a fairly strict rule in place. I don't think it would be necessarily fair for us to talk about most trial designs, but we did get permission from our methodologist.

好吧，我認為我不想過於樂觀。我認為我們很高興我們沒有發出無用的信號，因為我們有相當嚴格的規則。我認為我們談論大多數試驗設計不一定公平，但我們確實得到了我們的方法學家的許可。

Let me ask the second half it. Sure, I understand. I don't want to beat up this point because you're limited by what you can say. But I was also very interested from a clinical perspective when you talked about potential modifications of the Phase 3 trial and the combination of the two trials together. Can you talk a little bit about what that might mean? And particularly, I was -- yes, particularly the timeline (multiple speakers)

讓我問下半年吧。當然，我明白。我不想強調這一點，因為你能說的有限。但是，當您談到 3 期試驗的潛在修改以及兩項試驗的結合時，從臨床角度來看，我也很感興趣。你能談談這可能意味著什麼嗎？特別是，我 - 是的，特別是時間表（多位發言人）

Let's talk about how we got to where we are.

讓我們談談我們是如何到達現在的位置的。

Thank you.

謝謝。

When this began, it began because people were using ketamine to treat acutely depressed patients. And everybody saw that ketamine wears off after a couple of days to a week. And a lot of people thought that repeat use of ketamine wasn't a great idea. So people suggested perhaps we develop NRX-101 as a maintenance therapy to prolong the effect of ketamine. And that's what we did in the STABIL-B study.

當這開始時，它開始是因為人們使用氯胺酮來治療嚴重抑鬱的患者。每個人都看到氯胺酮會在幾天到一周後失效。許多人認為重複使用氯胺酮不是一個好主意。所以人們建議我們開發 NRX-101 作為維持療法，以延長氯胺酮的作用。這就是我們在 STABIL-B 研究中所做的。

We got results that were quite encouraging. As you know, lurasidone was originally approved on a 3.9-point difference between lurasidone placebo. And yet we beat lurasidone, a known good drug by 7.7 points. Pretty impressive effect. Remember, Auvelity just got approved on a 4-point difference between Auvelity and placebo. And we did go against placebo because it wouldn't be appropriate to do that in suicidal patients. We went against the best available standard of care drugs.

我們得到了非常令人鼓舞的結果。如您所知，lurasidone 最初獲批時與 lurasidone 安慰劑相比有 3.9 個百分點的差異。然而，我們以 7.7 分的優勢擊敗了一種已知的好藥魯拉西酮。相當可觀的效果。請記住，Auvelity 剛剛在 Auvelity 和安慰劑之間的 4 點差異上獲得批准。我們確實反對安慰劑，因為對有自殺傾向的患者這樣做是不合適的。我們違背了現有的最佳護理藥物標準。

So that's how we got into this. And that's why we've got the Breakthrough Therapy Designation. Along the way, we said, well, what if NRX-101 is actually good enough to be of benefit to patients without prior use of ketamine. And we asked that question just as we were getting back into psychiatry a year ago, where we had just enough of our old Phase 2 material to do a smallish study like this. We said let's test NRX-101 against lurasidone without prior ketamine and see if there's a signal, see if it's not futile. And that's where we are at this point.

所以這就是我們進入這個的方式。這就是我們獲得突破性療法稱號的原因。在此過程中，我們說，好吧，如果 NRX-101 實際上足夠好，可以使患者在沒有事先使用氯胺酮的情況下受益，那會怎麼樣。一年前，當我們回到精神病學時，我們問了這個問題，當時我們有足夠的舊第 2 階段材料來進行這樣的小型研究。我們說讓我們在沒有事先使用氯胺酮的情況下針對魯拉西酮測試 NRX-101，看看是否有信號，看看它是否無用。這就是我們目前所處的位置。

And based on having reached that point and based on having now the availability of newly manufactured Phase 3 and potentially commercial-scale drug, we're enlarging this to a registration study because we now believe that there is a real potential for this home use oral pill, actually capsule, to be effective in its own right, not just as a drug to take after ketamine. So that's how we got to where we are.

並且基於已經達到這一點並且基於現在新製造的第 3 階段藥物和潛在商業規模藥物的可用性，我們正在將其擴大到註冊研究，因為我們現在相信這種家用口服藥物具有真正的潛力藥丸，實際上是膠囊，本身就有效，而不僅僅是作為氯胺酮後服用的藥物。這就是我們到達現在位置的方式。

Makes perfect sense. And last question, and you just kind of touched on it also, was breakthrough designation. Is that something that you feel you've been encouraged to go after?

很有道理。最後一個問題，你也提到了它，是突破性的指定。這是你覺得你被鼓勵去追求的東西嗎？

Well, we've been awarded Breakthrough Therapy Designation for the original indication of NRX-101 to use after -- to use after ketamine. And that gives us the ability -- the important part of Breakthrough Therapy Designation is it gives you a dedicated resource at FDA, a program manager who is committed, if at all possible, to helping the drug get through the approval process. So we have that in place now.

好吧，我們已經獲得了突破性治療指定，因為 NRX-101 的最初適應症是在氯胺酮之後使用。這給了我們能力 - 突破性療法指定的重要部分是它為您提供了 FDA 的專門資源，項目經理承諾，如果可能的話，幫助藥物通過批准程序。所以我們現在已經準備好了。

And the other key benefit of Breakthrough Therapy Designation is it gives you the right to submit your new drug approval application on a rolling basis. So we've said by the end of the year, we're going to start submitting. We're going to submit the manufacturing data, the preclinical data so that the whole file is reviewed by the time we finally have the efficacy data to submit. So those benefits of Breakthrough Therapy Designation are already in place.

突破性療法指定的另一個主要好處是它使您有權以滾動方式提交新藥批准申請。所以我們說到今年年底，我們將開始提交。我們將提交製造數據、臨床前數據，以便在我們最終提交療效數據時審查整個文件。因此，突破性療法指定的那些好處已經到位。

I mentioned that we may have a conversation with FDA when more data are available about specifically extending the Breakthrough Designation to this use of NRX-101. But I'm not sure that that would really change our path to approval in any meaningful way.

我提到過，當有更多數據可用於將突破性指定專門擴展到 NRX-101 的這種用途時，我們可能會與 FDA 進行對話。但我不確定這是否真的會以任何有意義的方式改變我們獲得批准的途徑。

Perfect. Thank you. And that answer actually answers some of my timeline question. So really the only -- the critical hurdle for you is going to be, if I'm right, is just patient enrollment and then data analysis once you completed treating the last patient, right?

完美的。謝謝。這個答案實際上回答了我的一些時間軸問題。所以，如果我是對的，對你來說真正唯一的關鍵障礙就是患者登記，然後在你完成最後一名患者的治療後進行數據分析，對吧？

Patient enrollment, data analysis, and we announced after the Type B meeting with FDA, that they want to see a safety database of 1,500 patients. Now if you look at recent approvals, approvals actually happened at a smaller safety database than that, but 1,500 is the [E1 3D] target in the United States, and other countries all sort of agreed on the safety database size for drugs to treat non-lethal conditions. This, of course, is a lethal condition.

患者登記、數據分析，我們在與 FDA 的 B 類會議後宣布，他們希望看到一個包含 1,500 名患者的安全數據庫。現在如果你看看最近的批准，批准實際上發生在一個比這更小的安全數據庫中，但 1,500 是美國的 [E1 3D] 目標，其他國家都同意用於治療非藥物的安全數據庫大小- 致命的條件。當然，這是致命的情況。

And you've seen us talk about how we're going to start building that safety database not only through our clinical trials, which take a while to enroll and are expensive to enroll, but also through an expanded access program that would allow doctors who have patients with bipolar depression and have exhausted approved medications for the treatment of bipolar depression to gain access to NRX-101. And there's a fair amount of precedent for the use of such expanded access programs in this way.

你已經看到我們談論我們將如何開始建立安全數據庫，不僅通過我們的臨床試驗，這需要一段時間才能註冊，而且註冊費用昂貴，而且還通過一個擴展的訪問程序，允許醫生有患有雙相抑鬱症的患者，並且已經用盡了批准的治療雙相抑鬱症的藥物以獲得 NRX-101。以這種方式使用此類擴展訪問程序有相當多的先例。

So to the extent that people imagine the safety database will be horribly, horribly expensive, recognize that when we did expanded access in COVID, it was on the order of $3,000, $4,000 a patient as opposed to the kind of costs one would associate with a formal randomized controlled trial. Now we don't know what expanded access is going to cost us in NRX-101 yet. We don't know whether we're going to be able to gain reimbursement for expanded access, which I feel looking the FDA guidance can be applied for. But we do see it as an efficient way to get to the NDA while at the same time continuing our clinical trials for safety and efficacy full speed ahead.

因此，就人們認為安全數據庫將非常非常昂貴的程度而言，認識到當我們在 COVID 中擴展訪問權限時，每位患者的費用大約為 3,000 美元，4,000 美元，而不是與一個患者相關的那種成本。正式的隨機對照試驗。現在我們還不知道在 NRX-101 中擴展訪問將使我們付出什麼代價。我們不知道我們是否能夠獲得擴展訪問的報銷，我覺得可以申請 FDA 指南。但我們確實將其視為獲得 NDA 的有效方式，同時繼續全速推進我們的安全性和有效性臨床試驗。

Understood. Thank you.

明白了。謝謝。

Vernon Bernardino, H.C. Wainwright.

弗農貝納迪諾，H.C.溫賴特。

Congratulations on the progress, and thanks for taking my question. Hey Jonathan, Steve, and Seth.

祝賀您取得的進展，並感謝您提出我的問題。嗨，喬納森、史蒂夫和賽斯。

What is important for me to perhaps ask about is with the current trial being upgraded to a Phase 2b/3 study that may be used for registrational filing, with the nuances of this patient population and how they're treated, are there any specific changes that are going to occur or need to occur as that it has been upgraded to a registrational study? Or is it just nearly an upgrade because that's something that you've asked for and you've already fulfilled the requirement?

對我來說重要的是可能要問的是，當前的試驗正在升級為可用於註冊申請的 2b/3 期研究，該患者群體的細微差別以及他們的治療方式是否有任何具體變化升級為註冊研究後將會發生或需要發生的情況？或者它只是接近升級，因為這是您要求的並且您已經滿足了要求？

One of the things we did is posted the protocol on clinicaltrials.gov. And that's an important thing to do because when -- and we certainly hope the trial will show efficacy. The reviewers for the scientific journals want to see that we were transparent upfront about what are our endpoint, how are we measuring them. So that to the extent that there are changes along the way, those are known in a transparent manner.

我們所做的其中一件事是在 clinicaltrials.gov 上發布協議。這是一件很重要的事情，因為什麼時候——我們當然希望試驗能顯示出療效。科學期刊的審稿人希望看到我們對我們的終點是什麼、我們如何衡量它們一清二楚。因此，如果沿途發生變化，這些變化將以透明的方式為人所知。

So the main difference for us between simply Phase 2 and Phase 2b/3 is, as I said to Jason, when we started this, all we had in our warehouse was Phase 2 investigational medicine that was made five years ago in China during our partnership with WuXi AppTec. And that's not investigational product that can be used for registrational purposes.

所以對我們來說，2 期和 2b/3 期之間的主要區別是，正如我對 Jason 說的，當我們開始這個時，我們倉庫裡只有 5 年前在我們合作期間在中國製造的 2 期研究藥物與藥明康德。這不是可用於註冊目的的研究產品。

Registration study means that you're doing your clinical trial with medicine that is essentially identical to the medicine that you intend to put on the shelf for the pharmacy. So we're now at that point where we did the hard work to do the tech transfer to bring the analytic methods over from China to North Carolina, and validate those methods. We've upgraded our control of impurities from a Phase 2 level to a Phase 3 level. So now that we actually have medicine that we believe is substantially identical to the medicine that we would hope to put on a pharmacy shelf in a couple of years, we're able to make this a Phase 2b/3 registrational trial.

註冊研究意味著您正在使用與您打算放在藥房貨架上的藥物基本相同的藥物進行臨床試驗。所以我們現在正處於我們努力進行技術轉讓以將分析方法從中國帶到北卡羅來納州並驗證這些方法的時候。我們已將雜質控制從第 2 階段升級到第 3 階段。因此，現在我們實際上擁有我們認為與我們希望在幾年內放在藥房貨架上的藥物基本相同的藥物，我們能夠將其作為 2b/3 期註冊試驗。

So that's not really a protocol change per se. And I think often, investors don't realize how these days in biotech, failures in manufacturing and CMC are possibly more likely to bring down a promising drug than failures in an efficacy trial. And that's why we're so fortunate to have Dr. Panicucci, who is one of the world's more experienced drug manufacturing experts as our Chief Technology Officer.

所以這本身並不是真正的協議更改。而且我認為，投資者經常沒有意識到如今在生物技術領域，製造和 CMC 的失敗比功效試驗的失敗更有可能打敗有前途的藥物。這就是為什麼我們如此幸運地擁有 Panicucci 博士，他是世界上最有經驗的藥物製造專家之一，擔任我們的首席技術官。

Okay. And that's certainly important because conceivably, if it's a study that are very successful, you could also -- and I say conceivably, used the Phase 3 material for commercial supply. I guess what I was specifically getting at is, is there going to be any change to past the screening of patients such that it fine-tunes those that would enter a Phase 3 level type of a study that is registrational?

好的。這當然很重要，因為可以想像，如果這是一項非常成功的研究，你也可以——我說可以想像，將第 3 階段材料用於商業供應。我想我的具體意思是，是否會對過去的患者篩查進行任何更改，以便對那些將進入 3 期級別類型的註冊研究的患者進行微調？

Well, one of the things that we're intensely focused on is ensuring that the psychometric ratings achieved in this study are as accurate as possible. There has been a lot of talk in this psychiatry space about study site that yield surprising result and getting on top of study sites. And one of the things we've done that we think is a little different from what some have done is we've built a team of expert psychometric raters within the company, who are evaluating in real time the ratings that are being achieved at the study sites.

好吧，我們非常關注的一件事是確保本研究中獲得的心理測量評級盡可能準確。在這個精神病學領域有很多關於研究網站的討論，這些研究網站產生了令人驚訝的結果並在研究網站上名列前茅。我們所做的其中一件事我們認為與某些人所做的有點不同，那就是我們在公司內部建立了一個專家心理測量評估團隊，他們實時評估在學習網站。

So they get an audio recording of each rating session as it happens, and we're constantly looking at concordance between people who are being rated by the site rater on the MADRS score on the CGI suicidality scale and those same sessions being evaluated by our in-house master raters. And we've set up an adjudication system so that if there's more than three points of disagreement, that rating session immediately goes out to an independent adjudicator.

因此，他們會在每次評級會議發生時獲得錄音，並且我們一直在尋找網站評級員根據 CGI 自殺量表的 MADRS 評分進行評級的人與我們的 in 評估的那些相同會議之間的一致性-房屋大師評分員。我們已經建立了一個裁決系統，如果有超過三點的分歧，評級會議會立即交給獨立的裁決者。

If you look on clinicaltrials.gov, we've published some of our information about how we do that. And I think in the coming months, we're going to hope to get a scientific publication out that will give the investment community some sense of how we approach this whole process of trying to keep a clinical trial under control, where you don't win or lose based on a blood test or examining a piece of tissue, you win or lose based on what's inherently a subjective process where an expert psychologist is asking structured questions and assigning a score and keeping the drift between study site down as low as possible is the difference between having a very high standard deviation and a great deal of difficulty in proving statistical significance versus having a tighter standard deviation and easier ability to prove statistical significance. So that's where we're focusing every day as we try to do our job to bring this medicine to market.

如果您查看 clinicaltrials.gov，我們已經發布了一些關於我們如何做到這一點的信息。我認為在接下來的幾個月裡，我們將希望出版一份科學出版物，讓投資界了解我們如何處理整個過程，試圖控制臨床試驗，而你不基於血液測試或檢查一塊組織的輸贏，你的輸贏取決於本質上是一個主觀過程，在這個過程中，專家心理學家提出結構化問題並分配分數，並儘可能降低研究地點之間的偏差是具有非常高的標準偏差和證明統計顯著性的巨大困難與具有更嚴格的標準偏差和更容易證明統計顯著性的能力之間的區別。因此，這就是我們每天努力將這種藥物推向市場的工作重點。

Perfect. That's helpful information. And because of the placebo effect, as you know, and the problems with that in these kinds of studies, that's why I asked the question because, unfortunately, sometimes it's impossible to know if somebody's suicidal unless they actually attempt suicide. But in the screening process, you can fine-tune the -- like I said, the [psychometrics] was possible and increase the chances for success. So I appreciate you providing that additional information and wish you the best luck for the study. Thanks for taking my question.

完美的。這是有用的信息。正如你所知，由於安慰劑效應，以及此類研究中存在的問題，這就是我問這個問題的原因，因為不幸的是，有時除非某人真的嘗試自殺，否則無法知道他們是否有自殺傾向。但在篩選過程中，你可以微調——就像我說的，[心理測量學]是可能的，並增加成功的機會。因此，我感謝您提供額外的信息，並祝您在研究中好運。感謝您提出我的問題。

You just said something very important. And it's one of the early things that FDA guided us on when we first met with them. It's pretty well known that suicidality comes and goes. And it may not be something that patients talk about as readily as symptoms of depression.

你剛才說了很重要的話。這是 FDA 在我們第一次見到他們時指導我們的早期事情之一。眾所周知，自殺傾向來來去去。它可能不像抑鬱症症狀那樣容易被患者談論。

So the guidance we got from the FDA early on because our original thought was that our primary indication would be the suicidality score, the guidance we got from FDA was to make the primary endpoint for our studies the MADRS depression scale. And the exact words we got was, look if you're able to prove that you improve depression in this population of patients who have suicidality who have been excluded from previous trials, where there is no antidepressants indicated for use. No oral anti-depression because there has been some encouraging data with Johnson & Johnson's ketamine product.

所以我們很早就從 FDA 獲得了指導，因為我們最初的想法是我們的主要適應症是自殺評分，我們從 FDA 獲得的指導是將 MADRS 抑鬱量表作為我們研究的主要終點。我們得到的確切消息是，看看你是否能夠證明你可以改善這些有自殺傾向的患者的抑鬱症，這些患者被排除在之前的試驗之外，這些試驗沒有表明可以使用抗抑鬱藥。沒有口服抗抑鬱藥，因為強生公司的氯胺酮產品有一些令人鼓舞的數據。

But there's no oral anti-depression that's indicated for use in these patients with suicidality. That's great. That's enough to win. And if at the same time, we're able to show that the secondary endpoint of improvement on the CGI suicidality scale is also significantly better than the comparator drug. Well, that's even better. But that's why our primary endpoint is the MADRS depression scale.

但是沒有口服抗抑鬱藥適用於這些有自殺傾向的患者。那太棒了。這足以贏得比賽。如果同時，我們能夠證明 CGI 自殺量表改善的次要終點也明顯優於比較藥物。好吧，那更好。但這就是我們的主要終點是 MADRS 抑鬱量表的原因。

Thank you. I appreciate that. And I am very hopeful for you and the patients out there. Thanks again for taking the question.

謝謝。我很感激。我對你和那裡的病人充滿希望。再次感謝您提出問題。

(Operator Instructions) Ed Woo, Ascendiant Capital.

（操作員說明）Ed Woo，Ascendiant Capital。

Yes. Congratulations on the progress and also on the DSMB readout. Do we anticipate any more readouts or any interim data for either one of your studies this year?

是的。祝賀進展以及 DSMB 讀數。我們是否預計今年您的任何一項研究都會有更多的讀數或任何臨時數據？

We do expect that the DSMB is going to look at the data again at some point, I would guess before the end of Q3, but they haven't told us exactly when that readout is going to be. But they're going to be monitoring the study in an ongoing way to the extent that there are -- if safety signals emerge, they might look sooner. But they're working with us very closely because this is a population of patients who are actively at risk of self-harm, which is why they've been excluded from trials of ordinary antidepressants.

我們確實希望 DSMB 會在某個時候再次查看數據，我猜是在第三季度末之前，但他們沒有告訴我們確切的讀數時間。但他們將以持續的方式監測這項研究——如果出現安全信號，他們可能會更早地進行觀察。但他們正在與我們密切合作，因為這是一群有自殘風險的患者，這就是為什麼他們被排除在普通抗抑鬱藥試驗之外的原因。

Great. Well, thanks for answering my questions, and I wish you guys good luck. Thank you.

偉大的。嗯，謝謝你回答我的問題，祝你們好運。謝謝。

This concludes our question-and-answer session. I would like to turn the conference back over to Suzanne Messere for closing remarks.

我們的問答環節到此結束。我想將會議轉回給 Suzanne Messere 作閉幕詞。

Thank you, Danielle, and thank you, everyone, for participating. That is all the time we have for questions. Thank you again. This concludes the NRx Pharmaceuticals' full-year 2022 results conference call.

謝謝 Danielle，也謝謝大家的參與。這就是我們提問的全部時間。再次感謝你。 NRx Pharmaceuticals 2022 年全年業績電話會議到此結束。

The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連接。