Vistagen Therapeutics Inc (VTGN) 2024 Q1 法說會逐字稿

Greetings, and welcome to the Vistagen Therapeutics Fiscal Year 2024 First Quarter Corporate Update Conference Call. (Operator Instructions) And as a reminder, this conference is being recorded, Thursday, August 10, 2023.

您好，歡迎參加 Vistagen Therapeutics 2024 財年第一季度公司最新情況電話會議。 （操作員說明）謹此提醒，本次會議將於 2023 年 8 月 10 日星期四進行錄製。

I would now like to turn the conference over to Mark Flather, Vice President of Capital Markets. Please go ahead.

現在我想將會議交給資本市場副總裁馬克·弗拉瑟 (Mark Flather)。請繼續。

Thank you, Jennifer. Good afternoon, everyone, and welcome to Vistagen's First Quarter Fiscal Year 2024 Corporate Update Conference Call and Webcast. This afternoon, we issued a press release providing an overview of our progress this last quarter. We encourage you to review this, which can be found on the Investors section of the Vistagen website.

謝謝你，詹妮弗。大家下午好，歡迎參加 Vistagen 2024 財年第一季度公司更新電話會議和網絡廣播。今天下午，我們發布了一份新聞稿，概述了我們上季度的進展。我們鼓勵您查看此內容，您可以在 Vistagen 網站的投資者部分找到該內容。

Before starting today, we want to remind you that we may make forward-looking statements regarding our business based on our current expectations and information. The forward-looking statements speak only as of today, and except as required by law, we do not assume any duty to update the future -- in the future any forward-looking statement made today. Of course, forward-looking statements involve risks and uncertainties, and our actual results could differ materially from those anticipated by any forward-looking statements we may make today. Additional information concerning risks and factors that could affect our business and financial results is included in our fiscal year 2024 first quarter Form 10-Q for the period ending June 30, 2023, and in future filings that we'll make with the SEC from time to time, all of which will be -- which are and will be available on our website and the SEC's website.

在今天開始之前，我們想提醒您，我們可能會根據我們當前的預期和信息對我們的業務做出前瞻性陳述。前瞻性陳述僅代表今天的情況，除非法律要求，否則我們不承擔任何更新未來的義務——未來今天所做的任何前瞻性陳述。當然，前瞻性陳述涉及風險和不確定性，我們的實際結果可能與我們今天可能做出的任何前瞻性陳述的預期存在重大差異。有關可能影響我們業務和財務業績的風險和因素的更多信息包含在我們截至 2023 年 6 月 30 日期間的 2024 財年第一季度表格 10-Q 中，以及我們將來向 SEC 提交的文件中到時候，所有這些都將在我們的網站和SEC 的網站上提供。

With that taken care of, we'd like to thank and welcome all the stockholders, analysts and everyone taking an interest in Vistagen. I'm joined on the call today by Shawn Singh, our Chief Executive Officer; and Josh Prince, our Senior Vice President of Business Operations.

考慮到這一點，我們要感謝並歡迎所有股東、分析師和所有對 Vistagen 感興趣的人。我們的首席執行官肖恩·辛格 (Shawn Singh) 也加入了我今天的電話會議。喬希·普林斯 (Josh Prince)，我們的業務運營高級副總裁。

Shawn will provide an overview of our progress, focusing specifically on the results from our positive Phase III PALISADE-2 trial evaluating the efficacy, safety and tolerability of fasedienol, PH94B nasal spray in adults with social anxiety disorder, or SAD, followed by a brief opportunity for questions from sell-side analysts.

Shawn 將概述我們的進展，特別關注我們積極的III 期PALISADE-2 試驗的結果，該試驗評估了fasedienol、PH94B 鼻噴霧劑對患有社交焦慮症(SAD) 的成人的有效性、安全性和耐受性，然後簡要介紹了我們的進展賣方分析師提問的機會。

We want to remind you that this call is being webcast and will be available for replay after the call is completed. The replay link can be found in the Investors Events section on our website.

我們想提醒您，本次通話正在進行網絡直播，通話結束後可重播。重播鏈接可以在我們網站的投資者活動部分找到。

I'd now like to turn the call over to our Chief Executive Officer, Shawn Singh, to update you on a recent inspiring news regarding the PALISADE-2 Phase III study results.

現在我想將電話轉給我們的首席執行官 Shawn Singh，向您通報有關 PALISADE-2 第三階段研究結果的最新鼓舞人心的消息。

Thank you, Mark, and good afternoon, everyone, and thanks for joining our call. As I've said before, many times, our team has remained steadfast in our core mission, which is to radically improve the mental health and well-being of millions of individuals around the world who are suffering from a wide variety of anxiety, depression and other CNS disorders that severely disrupt their daily lives. And as we've recently announced, we've solidified a major cornerstone in that mission focused on improving the lives of the over 25 million individuals in America who are affected by social anxiety disorder or SAD.

謝謝馬克，大家下午好，感謝您加入我們的電話會議。正如我之前多次說過的，我們的團隊始終堅定不移地執行我們的核心使命，即從根本上改善世界各地數百萬患有各種焦慮、抑鬱症的人的心理健康和福祉。以及其他嚴重擾亂他們日常生活的中樞神經系統疾病。正如我們最近宣布的那樣，我們已經鞏固了這一使命的一個重要基石，重點是改善美國超過 2500 萬受社交焦慮症或 SAD 影響的人的生活。

There's indeed an active and growing need for a new faster-acting option for treatment of SAD without abuse potential or the side effects and safety concerns that often are associated with the currently approved medicines. We remain focused on addressing this significant unmet health -- mental health need for individuals across a broad range of demographics and in a diverse range of communities across the globe. We're committed to innovation of multiple differentiated treatments in alignment with our mission to shift the treatment paradigm for anxiety, depression and multiple other CNS disorders.

確實，人們迫切需要一種新的、起效更快的治療 SAD 的選擇，而不會出現與目前批准的藥物相關的濫用可能性或副作用和安全問題。我們仍然致力於解決全球範圍廣泛的人口統計數據和不同社區的個人這一重大未滿足的健康需求——心理健康需求。我們致力於創新多種差異化治療方法，以實現我們改變焦慮、抑鬱和多種其他中樞神經系統疾病治療模式的使命。

So a lot's changed since our last conference call, and let's get right to the biggest news in our company's history. It's been a long time since a positive Phase III study has brought in new optimism for treatment of social anxiety disorder, and we are thrilled to be in a leadership position with the compelling top line results from our Phase III PALISADE-2 trial that were announced on Monday. These Phase III results highlight the potential for fasedienol with its innovative proposed mechanism of action to transform what's possible for millions of individuals living with SAD in the U.S. and millions more who are affected worldwide.

自上次電話會議以來發生了很多變化，讓我們直接了解我們公司歷史上最大的新聞。很長一段時間以來，一項積極的III 期研究為社交焦慮症的治療帶來了新的樂觀情緒，我們很高興能夠憑藉我們已宣布的III 期PALISADE-2 試驗令人信服的頂線結果處於領先地位週一。這些 III 期結果凸顯了 fasedienol 的潛力及其創新的擬​​議作用機制，可以改變美國數百萬 SAD 患者以及全球數百萬受影響的患者的可能性。

In the PALISADE-2 study, fasedienol demonstrated a rapid and clinically meaningful reduction in the subjective units of distressed score or SUDS, SUDS score, indicating that a single administration of fasedienol has the potential to reduce rapidly anxiety symptoms during an anxiety-provoking situation similar to perhaps how a rescue inhaler used on-demand helps a person with asthma.

在 PALISADE-2 研究中，fasedienol 表現出快速且具有臨床意義的痛苦評分或 SUDS、SUDS 評分主觀單位的降低，表明單次給予 fasedienol 有可能在類似的焦慮引發情況下快速減少焦慮症狀。也許是按需使用的救援吸入器如何幫助哮喘患者。

To recap, this was a U.S. multicenter, randomized, double-blind, placebo-controlled Phase III trial consisting of 4 visits by subjects to a clinic that were spaced out a week apart, a screening visit, a baseline setting public speaking challenge after administration of a placebo nasal spray, a second public speaking challenge where patients were randomized to either fasedienol or placebo, then a follow-up safety visit. SUDS scores were captured at 1 minute intervals throughout each public speaking challenge, and physician and patient assessment of improvement were captured after the second speaking challenge was completed at visit 3.

回顧一下，這是一項美國多中心、隨機、雙盲、安慰劑對照的III 期試驗，包括受試者4 次到診所就診（間隔一周）、篩選訪視、給藥後設定公開演講挑戰的基線安慰劑鼻噴霧劑，第二次公開演講挑戰，患者被隨機分配到 Fasedienol 或安慰劑，然後進行後續安全訪問。在每次公開演講挑戰中，每隔 1 分鐘記錄 SUDS 分數，並在第 3 次訪問完成第二次演講挑戰後記錄醫生和患者對改善的評估。

In order to progress the randomization of the second public speaking challenge or visit 3, subjects had to exhibit high levels of anxiety during the first public speaking challenge, the baseline challenge. Patients in the study were confirmed SAD patients with a score of 70 or above on the Liebowitz Social Anxiety Scale, which is commonly referred to as the LSAS, without other primary psychiatric disorders and not currently receiving active CNS medications.

為了推進第二次公開演講挑戰或訪問 3 的隨機化，受試者必須在第一次公開演講挑戰（基線挑戰）期間表現出高度焦慮。研究中的患者是確診的 SAD 患者，利博維茨社交焦慮量表（通常稱為 LSAS）得分為 70 分或以上，沒有其他原發性精神疾病，且目前未接受主動 CNS 藥物治療。

In total, 141 subjects were randomized in the trial, 70 on fasedienol and 71 on placebo. The total enrollment reflects the pause in enrollment after we receive top line results from PALISADE-1 to allow for independent biostatisticians to conduct an interim analysis of the 141 patients who were randomized and had completed the trial up to the date of the pause.

總共 141 名受試者被隨機分配參加該試驗，其中 70 名受試者服用 fasedienol，71 名受試者服用安慰劑。總入組人數反映了我們收到 PALISADE-1 的頂線結果後入組的暫停，以便獨立生物統計學家對截至暫停之日已完成試驗的 141 名患者進行中期分析。

Although the results of the independent interim analysis indicated the continuation of PALISADE-2 would not be futile, for business reasons, we elected to extend our pause of PALISADE-2, pending our assessment of the then impending top line results of our PALISADE open-label safety study, the results of 2 SAD public speaking challenge studies conducted by peer companies, further discussions with the FDA regarding the continuing acceptability of the LSAS as the primary efficacy end point in Phase III studies for the treatment of SAD as well as a comprehensive assessment or important assessment of the expense, time, statistical and regulatory implications and logistical challenges associated with resuming PALISADE-2.

儘管獨立中期分析的結果表明，繼續 PALISADE-2 不會是徒勞的，但出於商業原因，我們選擇延長 PALISADE-2 的暫停時間，等待我們對 PALISADE 開放的當時即將公佈的頂線結果進行評估。標籤安全性研究、同行公司進行的2 項SAD 公開演講挑戰研究的結果、與FDA 關於LSAS 作為治療SAD 的III 期研究的主要療效終點的持續可接受性的進一步討論以及全面的研究對與恢復PALISADE -2 相關的費用、時間、統計和監管影響以及後勤挑戰的評估或重要評估。

Following positive results from our PALISADE open label study, the results of the 2 SAD public speaking challenge studies conducted by peer companies, each of which did not meet their primary efficacy end point as measured by the SUDS and our positive discussions with the FDA in early 2023 about the continuing validity and reliability of the LSAS as a primary efficacy end point, for strategic reasons, we chose to close PALISADE-2 with 141 completed subjects rather than resume the study and randomize an additional 67 subjects for a total of 208 subjects as originally planned.

繼我們的 PALISADE 開放標籤研究取得積極結果之後，同行公司進行的 2 項 SAD 公開演講挑戰研究的結果，每項研究均未達到 SUDS 測量的主要療效終點，以及我們早期與 FDA 的積極討論2023 年，關於LSAS 作為主要療效終點的持續有效性和可靠性，出於戰略原因，我們選擇以141 名已完成的受試者結束PALISADE-2，而不是恢復研究，並隨機隨機分配另外67 名受試者，總共208 名受試者：原本計劃的。

It's very important to note that through this process, PALISADE-2 was not altered in any way. It was simply stopped early with an intention to treat population of 141 subjects instead of the originally planned 208. The statistical analysis plan was followed as originally planned. It was similar to PALISADE-1 and did not require a type 1 error correction because the study was not altered and the blind was never compromised as a result of the interim analysis.

值得注意的是，在這個過程中，PALISADE-2 沒有以任何方式改變。它只是提前停止，目的是治療 141 名受試者，而不是原計劃的 208 名受試者。統計分析計劃按照原計劃進行。它與 PALISADE-1 類似，不需要 1 類錯誤校正，因為研究沒有改變，並且中期分析的結果從未影響盲法。

The primary end point in PALISADE-2 was a difference in mean SUDS score during the public speaking challenge at visit 2 baseline and visit 3 treatment for patients who receive fasedienol compared to placebo. Fasedienol-treated patients demonstrated a statistically significant greater change in least-squares mean SUDS score with a reduction of 13.8 points compared to a reduction of 8 points for a difference between groups of 5.8 with a p-value of 0.015.

PALISADE-2 的主要終點是接受 fasedienol 治療的患者與安慰劑相比，在第 2 次訪視基線和第 3 次訪視治療期間公開演講挑戰期間平均 SUDS 評分的差異。 Fasedienol 治療的患者表現出統計學上顯著的更大變化，最小二乘平均 SUDS 評分降低了 13.8 分，而組間差異為 5.8，p 值為 0.015，降低了 8 分。

We believe these results to be clinically significant, especially considering they're based on a single dose of fasedienol in a highly provocative public speaking challenge and is supported by high responder rates captured in the secondary and exploratory end points.

我們相信這些結果具有臨床意義，特別是考慮到它們是基於在高度挑釁性的公開演講挑戰中使用單劑量的 fasedienol，並且得到了次要和探索性終點中捕獲的高應答者率的支持。

The study had a secondary end point, the Clinical Global Impressions Improvement scale or CGI-I. Fasedienol demonstrated a statistically significant difference in the proportion of clinician-assessed responders versus placebo as measured by the CGI-I. Responders were identified as those who were rated as very much less anxious or much less anxious after visit 3 with 37.7% of fasedienol-treated patients rated as responders as compared to 21.4% of those treated with placebo, with a p-value of 0.033.

該研究有一個次要終點，即臨床總體印象改善量表或 CGI-I。根據 CGI-I 測量，Fasedienol 與安慰劑相比，經臨床醫生評估的反應者比例存在統計學顯著差異。應答者被確定為在第3 次就診後焦慮程度大大減輕或焦慮程度大大減輕的患者，其中37.7% 的fasedienol 治療患者被評為應答者，而接受安慰劑治療的患者中這一比例為21.4% ，p 值為0.033。

Plus, these results clearly demonstrate that physicians were able to recognize the improvement in patients on fasedienol even with the full week between 2 public speaking challenges. The PALISADE-2 study also had an exploratory end point. Patient's Global Impression of Change scale or PGI-I (sic) [PGI-C]. Very excited about the patient's ability to have recognized their improvement on fasedienol because responders were identified on that scale as those who self-rated very much less anxious or much less anxious after visit 3, an impressive 40.6% of fasedienol-treated patients rated themselves as responders as compared to only 18.6% of those treated with placebo with a p-value of 0.003. This responder rate of more than double the rate of placebo clearly illustrates to us that patients could appreciate the improvement in their ability to deliver their speech and is highly relevant clinically when you think about the potential for patients to engage with less fear and reduced avoidance of their anxiety provoking events and situations, especially as they continued to use fasedienol over time, as we saw from LSAS data in our placebo-controlled Phase II crossover study and our open label -- PALISADE open label study.

此外，這些結果清楚地表明，即使在兩次公開演講挑戰之間整整一周的時間裡，醫生也能夠認識到服用 fasedienol 的患者的改善情況。 PALISADE-2 研究還有一個探索性終點。患者總體變化印象量表或 PGI-I（原文如此）[PGI-C]。對於患者能夠認識到他們在接受fasedienol 治療後取得的改善感到非常興奮，因為根據該量表確定有反應者為那些在第3 次就診後自我評價焦慮程度大大減輕或焦慮程度減輕的人，令人印象深刻的是，接受fasedienol 治療的患者中有40.6% 將自己評價為相比之下，安慰劑治療組中只有 18.6% 有反應，p 值為 0.003。這種應答率是安慰劑組的兩倍以上，清楚地向我們表明，患者可以欣賞自己演講能力的提高，並且當您考慮患者減少恐懼和減少迴避的潛力時，這在臨床上是高度相關的。他們的焦慮引發事件和情況，特別是當他們隨著時間的推移繼續使用fasedienol 時，正如我們從安慰劑對照II 期交叉研究和開放標籤- PALISADE 開放標籤研究中的LSAS 數據中看到的那樣。

In addition, other than -- the other important exploratory end point, the percentage of fasedienol patients who improved by 20 or more SUDS points at visit 3 was almost double the rate of placebo with 35.7% of fasedienol patients dropping by 20 or more points compared to 18.6% on placebo. A 20-point drop is very clinically relevant and likely makes a difference in improving patient's ability to engage in an anxiety-provoking event.

此外，除了另一個重要的探索性終點外，第3 次訪視時SUDS 改善20 分或以上的fasedienol 患者百分比幾乎是安慰劑組的兩倍，其中35.7% 的fasedienol 患者與安慰劑組相比下降20 分或更多安慰劑組為 18.6%。下降 20 分具有非常重要的臨床意義，並且可能對提高患者參與引發焦慮的事件的能力產生影響。

From a safety standpoint, similar to all of the prior studies of fasedienol completed to date, including our large PALISADE open label study that included 481 subjects and over 30,000 doses of fasedienol that were administered in that study, fasedienol in PALISADE-2 was well tolerated with no serious or severe adverse events, and there was no treatment-emergent adverse event occurring at a rate above 1.5%.

從安全角度來看，與迄今為止完成的所有fasedienol 先前研究類似，包括我們的大型PALISADE 開放標籤研究，該研究包括481 名受試者和超過30,000 劑fasedienol，PALISADE-2 中的fasedienol 具有良好的耐受性沒有嚴重或重度不良事件，並且沒有發生率超過 1.5% 的治療引起的不良事件。

So now let's compare the primary end point in PALISADE-2 to the primary efficacy end point result in PALISADE-1. As many of you know, it's not uncommon in mental health studies to have both positive and negative studies in separate studies of similar design, particularly true of the subject scales that -- given the subject scales that have to be used in such studies and the potential for high and unexpected variability and placebo effects as we saw in PALISADE-1. This becomes even more likely when you add the task of consistently administering a complex public speaking challenge across numerous sites during an unprecedented pandemic, public health crisis and mental health epidemic.

現在讓我們將 PALISADE-2 中的主要終點與 PALISADE-1 中的主要療效終點結果進行比較。正如你們許多人所知，在心理健康研究中，在類似設計的單獨研究中同時進行正面和負面研究並不罕見，特別是對於主題量表而言，考慮到此類研究中必須使用的主題量表以及正如我們在 PALISADE-1 中看到的，潛在的高且意想不到的變異性和安慰劑效應。當您在史無前例的大流行、公共衛生危機和心理健康流行病期間增加在多個地點持續管理複雜的公開演講挑戰的任務時，這種情況變得更加可能。

The key difference in the outcome of PALISADE-1 compared to PALISADE-2 was a much higher placebo effect in PALISADE-1. The drug effect in both studies was similar. This was generally true across the primary, the secondary and the exploratory end points. The end results of the primary end point in PALISADE-1 was a least-squares mean change in SUDS from visit 2 to visit 3 of 15.6 points for fasedienol and 17.3 points for placebo with a p-value of 0.506.

PALISADE-1 與 PALISADE-2 相比，結果的主要區別在於 PALISADE-1 的安慰劑效應要高得多。兩項研究中的藥物作用相似。主要終點、次要終點和探索性終點通常都是如此。 PALISADE-1 中主要終點的最終結果是 SUDS 從訪視 2 到訪視 3 的最小二乘平均變化，其中法塞烯醇為 15.6 分，安慰劑為 17.3 分，p 值為 0.506。

We firmly believe that the systemic variability introduced by the pandemic contributed to these very unexpected and very different results between these 2 studies. A large portion of PALISADE-1 was fielded in 2021 through the height of the second wave of the pandemic. While the vast majority of PALISADE-2 was fielded in 2022 as the acute phase of the pandemic has subsided. This dynamic likely impacted PALISADE-2 disproportionately in terms of patient mindset, study protocol execution and study oversight.

我們堅信，大流行帶來的系統性變異導致了這兩項研究之間出現這些非常出乎意料且截然不同的結果。 PALISADE-1 的很大一部分是在 2021 年第二波疫情最嚴重的時候部署的。隨著大流行的急性期已經消退，絕大多數 PALISADE-2 是在 2022 年部署的。這種動態可能在患者心態、研究方案執行和研究監督方面對 PALISADE-2 產生不成比例的影響。

Subjects randomized in 2021 likely were given -- were different given the overall level of anxiety and uncertainty and general unrest, restrictions, mask wearing and the like during the acute phase of the pandemic. The high placebo rate in PALISADE-1 also may have attributed to logistical issues caused by COVID-19 in '21 such as high site and CRO employee turnover, absenteeism, changes in raters, time lapses between visit 2 and visit 3 due to unpredictable and intermittent clinical site closures and patients postponing travel, delayed monitoring visits and the like.

考慮到大流行急性期的總體焦慮和不確定性以及普遍的騷亂、限制、戴口罩等情況，2021 年隨機分配的受試者可能有所不同。 PALISADE-1 中的高安慰劑率也可能歸因於21 年COVID-19 引起的後勤問題，例如站點和CRO 員工流動率高、缺勤、評估者的變化、由於不可預測和不確定性而導致的訪問2 和訪問3 之間的時間間隔。間歇性臨床站點關閉以及患者推遲旅行、延遲監測就診等。

As these dynamics became apparent as the acute phase of the pandemic subsided in early 2022, we also initiated retraining and renewed monitoring of sites as is customary with staggered start replicate studies. And that, too, may have had a much larger impact on PALISADE-2 as it was completed before the majority of patients went through that study.

隨著 2022 年初大流行急性期的消退，這些動態變得明顯，我們還按照交錯啟動重複研究的慣例啟動了再培訓和重新監測地點。這也可能對 PALISADE-2 產生了更大的影響，因為它是在大多數患者進行該研究之前完成的。

We view the results of PALISADE-1 as an outlier, driven by the aforementioned reasons, and we are highly confident in the potential of fasedienol in future studies given multiple positive Phase II studies, efficacy seen on the exploratory end point and the PALISADE open label study, and now the strong results in our placebo-controlled Phase III PALISADE-2 trial. This is especially meaningful after the recent multiple failures in SAD studies by peers that may have been subject to similar systemic variability from the pandemic.

由於上述原因，我們認為 PALISADE-1 的結果是異常值，鑑於多項積極的 II 期研究、探索性終點的療效以及 PALISADE 開放標籤，我們對 fasedienol 在未來研究中的潛力充滿信心研究，現在是我們的安慰劑對照III 期PALISADE-2 試驗的強勁結果。在最近同行的 SAD 研究多次失敗之後，這一點尤其有意義，這些研究可能受到了大流行造成的類似系統變異的影響。

With the statistically significant and clinically meaningful results of PALISADE-2, we're now positioned to move our Phase III development plan forward with the additional studies needed for a potential NDA submission, including a PALISADE-3 trial and a FEARLESS trial, allowing us to not only confirm the acute benefit of fasedienol but to confirm what we've also long believed, that the acute use of fasedienol for SAD events continued over time will lead to a reduction in disease severity. Coupled with the safety and tolerability profile we have already demonstrated, we believe fasedienol will be the ideal approach to SAD treatment in the future. Preparations are now underway to initiate these next studies.

憑藉 PALISADE-2 具有統計意義和臨床意義的結果，我們現在準備推進我們的 III 期開發計劃，並進行潛在 NDA 提交所需的額外研究，包括 PALISADE-3 試驗和 FEARLESS 試驗，使我們能夠不僅證實了fasedienol 的急性益處，而且證實了我們長期以來所相信的，即隨著時間的推移，持續快速使用fasedienol 治療SAD 事件將導致疾病嚴重程度的減輕。結合我們已經證明的安全性和耐受性，我們相信 fasedienol 將成為未來 SAD 治療的理想方法。目前正在準備啟動這些後續研究。

Protocol for PALISADE-3 will be substantially similar to PALISADE-2 with SUDS again as the primary efficacy end point in clinic-based public speaking challenges. And the study design of FEARLESS will be substantially similar to the multi-week real-world registration trials for the only 3 drugs approved for the treatment of SAD decades ago using the LSAS as the primary end point.

PALISADE-3 的方案將與 PALISADE-2 基本相似，其中 SUDS 再次作為基於臨床的公開演講挑戰的主要療效終點。 FEARLESS 的研究設計將與數十年前批准用於治療 SAD 的僅有 3 種藥物進行的為期數週的真實世界註冊試驗基本相似，使用 LSAS 作為主要終點。

As a new class of medicines, our 5-candidate pherine nasal spray pipeline holds the potential to transform the treatment landscape across numerous therapeutic areas. At the head of the class, stands fasedienol's potential, as demonstrated in the Phase III PALISADE-2 trial. That set the stage for the first fundamentally new class of medicine for individuals living with SAD in more than 20 years. Positive PALISADE-2 data bolster our growing collection of evidence, supporting future clinical studies of fasedienol across several disorders and gives us further confidence in the promise of our pherine pipeline's untapped potential overall.

作為一類新的藥物，我們的 5 種候選菲林鼻噴霧劑管道具有改變眾多治療領域的治療格局的潛力。正如 III 期 PALISADE-2 試驗所證明的那樣，fasedienol 的潛力處於同類領先地位。這為 20 多年來首個針對 SAD 患者的全新藥物奠定了基礎。 PALISADE-2 的陽性數據支持了我們不斷收集的證據，支持未來對多種疾病進行 fasedienol 的臨床研究，並使我們對我們的 pherine 管道整體未開發潛力的前景更加充滿信心。

We've had some recent advancements in our other pherine programs. Let's take a brief look at those. Results from our successful U.S. Phase I trial of itruvone, previously referred to as PH10, build on successful Phase I studies in a positive randomized double-blind, placebo-controlled Phase IIa study of itruvone in major depressive disorder, or MDD, that was previously conducted in Mexico, and stage itruvone now for Phase IIb development in the United States as a stand-alone rapid-onset pherine product candidate for the treatment of MDD.

我們的其他 pherine 項目最近取得了一些進展。讓我們簡單地看一下這些。我們在美國成功進行的伊曲酮（之前稱為PH10）I 期試驗的結果建立在一項積極隨機雙盲、安慰劑對照的伊曲酮治療重度抑鬱症（MDD）IIa 期研究的成功I 期研究的基礎上，該研究之前被稱為PH10。試驗在墨西哥進行，itruvone 現已在美國進行 IIb 期開發，作為治療 MDD 的獨立快速起效候選產品。

U.S. Phase I trial was randomized, double blind, placebo controlled, and investigated the safety and the tolerability of a single dose and multiple doses of itruvone nasal spray in healthy adult subjects. There were no reported serious adverse events or discontinuations that were due to adverse events in the study. Overall, itruvone nasal spray was well tolerated and demonstrated a favorable safety profile consistent with all prior clinical studies of itruvone.

美國 I 期試驗是隨機、雙盲、安慰劑對照的，研究了單劑量和多劑量伊曲酮鼻噴霧劑在健康成年受試者中的安全性和耐受性。研究中沒有報告嚴重不良事件或因不良事件而終止。總體而言，伊曲酮鼻噴霧劑耐受性良好，並表現出良好的安全性，與之前所有伊曲酮臨床研究一致。

For Itruvone, we also reported important preclinical data of radiolabeled intranasal itruvone in laboratory rats, which further validate its potential to treat MDD without systemic absorption. These new data additionally support the proposed mechanism of action of itruvone nasal spray as binding to receptors of peripheral chemosensory neurons in the nasal cavity but not to neuronal receptors in the brain, thereby limiting transporter molecules to the circulatory system and minimizing potential systemic exposure.

對於 Itruvone，我們還報告了實驗室大鼠中放射性標記鼻內 Itruvone 的重要臨床前數據，這進一步驗證了其在不全身吸收的情況下治療 MDD 的潛力。這些新數據還支持伊曲酮鼻噴霧劑的擬議作用機制，即與鼻腔外周化學感應神經元的受體結合，但不與大腦中的神經元受體結合，從而限制轉運分子進入循環系統並最大限度地減少潛在的全身暴露。

As was the case when we completed a similar study with fasedienol, these preclinical data further the substantial body of evidence supporting itruvone's favorable safety profile. We're continuing our preparations for advancing into Phase IIb development of itruvone for MDD in 2024.

正如我們完成對 fasedienol 的類似研究時的情況一樣，這些臨床前數據進一步提供了大量證據支持 itruvone 良好的安全性。我們正在繼續準備在 2024 年進入用於 MDD 的 itruvone IIb 期開發。

We're also very excited about our PH80 pherine nasal spray, which has been highly studied in multiple indications. We recently reported a positive exploratory Phase IIa trial of PH80 nasal spray, which provides new optimism for the acute treatment of moderate to severe vasomotor symptoms or hot flashes in women due to menopause. In a randomized double-blind, placebo-controlled exploratory Phase IIa clinical study of PH80 that was designed to explore the efficacy, safety and tolerability of PH80 for the acute treatment of menopausal hot flashes in women, PH80 induced a significant reduction in the daily number of hot flashes compared to placebo at the end of the first week of treatment, and the improvement was maintained through each treatment week until the end of the treatment period. Baseline subjects reported a mean daily number of hot flashes of 7.7 in the PH80 group of 18 subjects and 8.0 in the placebo group of 18 subjects as well. After 1 week of treatment, the number of hot flashes dropped to 2.8 in the PH80 group and 6.4 in the placebo group for a p-value of less than 0.001. And after 4 weeks of treatment, the number of hot flashes dropped to 1.5 in the PH80 group and 5.1 in the placebo group for a p-value of less than 0.001.

我們對 PH80 菲林鼻噴霧劑也感到非常興奮，它已在多種適應症中進行了深入研究。我們最近報導了 PH80 鼻噴霧劑的一項積極的探索性 IIa 期試驗，該試驗為急性治療更年期女性中度至重度血管舒縮症狀或潮熱提供了新的樂觀前景。在一項PH80 的隨機雙盲、安慰劑對照探索性IIa 期臨床研究中，該研究旨在探索PH80 對於急性治療女性更年期潮熱的有效性、安全性和耐受性，PH80 導致每日潮熱次數顯著減少與安慰劑相比，治療第一周結束時潮熱的改善得到改善，並且每個治療週都保持這種改善，直到治療期結束。基線受試者報告，PH80 組（18 名受試者）的平均每日潮熱次數為 7.7 次，安慰劑組（18 名受試者）的平均每日潮熱次數為 8.0 次。治療 1 週後，PH80 組的潮熱次數降至 2.8 次，安慰劑組則降至 6.4 次，p 值小於 0.001。治療 4 週後，PH80 組的潮熱次數降至 1.5 次，安慰劑組則降至 5.1 次，p 值小於 0.001。

PH80 treatment also significantly reduced the severity and the disruption in function and sweating related to hot flashes during the treatment period as compared to placebo. PH80, as our other pherines, was well tolerated with no serious adverse events and the adverse event profile comparable between PH80 and placebo. All 36 subjects completed 4 weeks of treatment, and no subject discontinued participation in the study as a result of adverse events.

與安慰劑相比，PH80 治療還顯著降低了治療期間與熱潮紅相關的功能和出汗的嚴重程度和破壞。 PH80 與我們的其他麻黃素一樣，耐受性良好，沒有嚴重的不良事件，並且 PH80 和安慰劑的不良事件情況相當。所有 36 名受試者均完成了 4 週的治療，沒有受試者因不良事件而停止參與研究。

One of the favorable aspects of running additional trials in this particular indication that there will be objective measures for these studies. That is to say it's easier to measure how many hot flashes are experienced and their frequency of those symptoms versus more subjective end points that we have seen in some of the other studies in different indications.

在這一特殊情況下進行額外試驗的有利方面之一是這些研究將會有客觀的衡量標準。也就是說，與我們在不同適應症的其他一些研究中看到的更主觀的終點相比，更容易測量經歷了多少次潮熱以及這些症狀的頻率。

Given the depth of our entire CNS pipeline and a robust body of successful safety and efficacy studies to date, we are also pursuing multiple potential strategic development and commercialization partnerships both global and regional to efficiently unlock the full value of our product candidate portfolio. We believe global and regional partnerships, especially for commercialization to amplify our internal expertise and development activities and potentially accelerate key development time lines and enhance overall our efforts to deliver differentiated treatment options.

鑑於我們整個中樞神經系統管道的深度以及迄今為止大量成功的安全性和有效性研究，我們還在全球和區域尋求多個潛在的戰略開發和商業化合作夥伴關係，以有效釋放我們候選產品組合的全部價值。我們相信全球和區域合作夥伴關係，特別是商業化方面的合作夥伴關係，可以擴大我們的內部專業知識和開發活動，並有可能加快關鍵開發時間線，並加強我們提供差異化​​治療方案的整體努力。

We'll now offer some brief comments about our financials. We've been able to reduce our cash burn rate as you will see in our to-be-filed 10-Q shortly. And we've been implementing corporate initiatives to streamline operations in order to conserve our resources. We do not anticipate any significant near-term cash burn increases.

我們現在將提供一些有關我們財務狀況的簡短評論。正如您將在我們即將提交的 10-Q 中看到的那樣，我們已經能夠降低現金消耗率。我們一直在實施企業計劃來簡化運營，以節省我們的資源。我們預計短期內現金消耗不會顯著增加。

As for our cash position, we've recently taken advantage of the unusually high trading volume in our stock to strengthen the cash position on our balance sheet by over an expected $30 million in gross proceeds. To put this in high trading -- to put this trading volume into perspective, more than $1 billion worth of our stock has traded since the announcement of the PALISADE-2 results on Monday, 4 trading days ago.

至於我們的現金頭寸，我們最近利用股票異常高的交易量來加強資產負債表上的現金頭寸，預計總收益超過 3000 萬美元。從高交易量來看，從這個交易量來看，自 4 個交易日前週一宣布 PALISADE-2 結果以來，我們的股票交易量已超過 10 億美元。

As is industry standard, we established an at-the-market agreement with Jefferies over 2 years ago back in May of 2021. Until just recently, we'd only use this very sparingly back in calendar Q3 of '21. Will be continue -- we will continue to be very judicious in how we use this vehicle going forward, and we have plenty of capacity remaining under our ATM to further strengthen our balance sheet should we wish to do so as well as other strategic financing options and potential non-dilutive grants and partnering arrangements.

按照行業標準，我們在 2 年前（即 2021 年 5 月）與傑富瑞 (Jefferies) 建立了一項市場協議。直到最近，我們才在 21 年第三季度非常謹慎地使用此協議。將繼續——我們將繼續非常明智地使用這種工具，如果我們願意的話，我們的 ATM 下還有足夠的剩餘容量來進一步加強我們的資產負債表以及其他戰略融資選擇以及潛在的非稀釋性贈款和合作安排。

So in closing, we remain steadfast in our core mission to improve mental health and well-being worldwide. As we continue advancing the next stages of our corporate development plan, we move forward with a solid team, a strong pipeline and an unwavering drive to innovate better solutions for CNS disorders in large primary care markets with significant unmet needs.

最後，我們仍然堅定不移地履行我們的核心使命，即改善全世界的心理健康和福祉。隨著我們繼續推進企業發展計劃的下一階段，我們將憑藉堅實的團隊、強大的產品線和堅定不移的動力，為存在大量未滿足需求的大型初級保健市場中的中樞神經系統疾病創新更好的解決方案。

So on behalf of the Vistagen team, I'd like to thank you again for the privilege, for the opportunity to make a difference.

因此，我謹代表 Vistagen 團隊再次感謝你們給予我的榮幸，感謝你們給我帶來改變的機會。

Thank you, Sean. Jennifer, we'd now like to open up the call for questions from the sell-side analysts participating on the call today.

謝謝你，肖恩。詹妮弗，我們現在想開始向參加今天電話會議的賣方分析師提問。

(Operator Instructions) And our first question is from the line of Andrew Tsai from Jefferies.

（操作員說明）我們的第一個問題來自 Jefferies 的 Andrew Tsai。

I wanted to offer a big congratulations on the recent data. So now that you have PALISADE-2 on hand, how confident are you this study could be 1 of 2 traditionally supportive placebo-controlled pivotal Phase III studies for a filing?

我想對最近的數據表示熱烈祝賀。那麼，現在您手頭有 PALISADE-2，您對這項研究成為 2 項傳統支持性安慰劑對照關鍵 III 期研究中的一項進行備案有多大信心？

And then second to that is do you think you'll meet with the FDA? And if so, when could we get a resolution on the next steps in the NDA package?

其次是您認為您會與 FDA 會面嗎？如果是這樣，我們什麼時候可以就 NDA 方案中的後續步驟做出決定？

Well, thanks, Andrew. I appreciate the question, and thanks for the congratulations. It's certainly enabling. Whether the FDA accepts the trial is pivotal. That's always to be determined downstream by the FDA, but there's no doubt in our mind, we didn't change anything. It's -- the only difference, as I noted, was the number of subjects, so there's no type 1 error. There's no protocol amendment. There was no deviation at all from the original plan other than the number of subjects.

嗯，謝謝，安德魯。我很欣賞這個問題，也感謝你的祝賀。這當然是有幫助的。 FDA 是否接受該試驗至關重要。這始終由 FDA 下游決定，但毫無疑問，我們沒有改變任何東西。正如我所指出的，唯一的區別是受試者的數量，因此不存在 1 類錯誤。沒有協議修正案。除了科目數量之外，與原定計劃沒有任何偏差。

So having a highly stat sig result with the profound safety profile that we've seen now in hundreds and hundreds of patients that have been exposed to fasedienol, you already -- remember, we had FDA feedback regarding abuse liability and a favorable amount of feedback from the FDA. And that was even before our open label study delivered the results we reported.

因此，我們已經在數百名接觸過 fasedienol 的患者中看到了高度統計結果和深刻的安全性，您已經 - 請記住，我們收到了 FDA 關於濫用傾向的反饋和大量的反饋來自FDA。甚至在我們的開放標籤研究得出我們報告的結果之前。

So I mean I like where we stand. Having something in this disorder with a validated end point with highly stat sig data and clean safety data, I really like our chances. So it's certainly going to be a key pillar in our NDA submission downstream should we get to that point with additional studies, at least one additional study.

所以我的意思是我喜歡我們的立場。在這種疾病中擁有經過驗證的終點、高統計信號數據和乾淨的安全數據，我真的很喜歡我們的機會。因此，如果我們通過額外的研究（至少一項額外的研究）達到這一點，它肯定會成為我們下游 NDA 提交的關鍵支柱。

And then now that you're going to do a PALISADE-3, as we think about the potential outcomes, do you think PALISADE-3 would look similar to what you saw in PALISADE-2 or something even better because, I don't know, PALISADE-2, there's maybe some COVID going on. But the counter argument would be maybe there's some expectation bias due to the positive results. So how are you thinking about the outcome of PALISADE-3 and why?

現在你要做 PALISADE-3，當我們考慮潛在的結果時，你認為 PALISADE-3 會看起來與你在 PALISADE-2 中看到的相似還是更好，因為，我不認為知道，PALISADE-2，可能有一些新冠病毒正在發生。但反駁的論點是，由於積極的結果，可能存在一些預期偏差。那麼您如何看待 PALISADE-3 的結果？為什麼？

Well, I think there's a lot of reasons, of course, to be confident about our next couple of steps in the PALISADE-3 direction. First, certainly, the world isn't really controlled anywhere near to the degree it was in the pandemic, and that obviously impacts the entire ecosystem associated with executing successful clinical studies.

嗯，我認為當然有很多理由讓我們對 PALISADE-3 方向接下來的幾個步驟充滿信心。首先，當然，世界並沒有像大流行時那樣受到真正的控制，這顯然會影響與執行成功的臨床研究相關的整個生態系統。

There's a lot of lessons learned that we have been able to gather from deconstruction of PALISADE-1 for sure, and I suspect we will from PALISADE-2, things like subjects will have an olfactory smell test. They'll have -- will have restrictions on use of nasal swabs upfront of the event. So there are several things that are associated with just modest amendments to the protocol, but they're positive lessons that you typically learn when you stagger start the studies.

我們確實能夠從 PALISADE-1 的解構中汲取很多經驗教訓，我懷疑我們也會從 PALISADE-2 中汲取教訓，比如受試者將進行嗅覺測試。他們將在活動開始前限制使用鼻拭子。因此，有幾件事與對方案的適度修改有關，但它們是您在錯開開始研究時通常會學到的積極教訓。

So that, plus the training that we've done, the proprietary training models that we have all up and down every aspect of conducting that type of study, I don't think there's anybody better to conduct and more expertised to conduct a public speaking challenge in a Phase III setting than we are. I have no reservations about that.

因此，加上我們已經完成的培訓，以及我們在開展此類研究的各個方面所擁有的專有培訓模式，我認為沒有人能夠更好地開展公開演講，並且更加專業。在第三階段的環境中所面臨的挑戰比我們更大。我對此沒有保留。

So I really -- I like our chances going into the study. I like the expertise we have internally. I like the force extenders that we've got in our network outside the company. Certainly, Dr. Liebowitz plays a key role in our ability to be successful with this clinical program with this drug. So yes, we're excited.

所以我真的——我很喜歡我們進入這項研究的機會。我喜歡我們內部擁有的專業知識。我喜歡我們公司外部網絡中的強制擴展器。當然，利博維茨博士在我們使用這種藥物的臨床項目取得成功方面發揮了關鍵作用。所以，是的，我們很興奮。

Got it. Okay. And speaking PALISADE-2, going back to the data, when could we expect you to share detailed results at a medical meeting or a publication? I mean it would be great to see the curves of SUDS and so forth.

知道了。好的。說到 PALISADE-2，回到數據，我們什麼時候可以期望您在醫學會議或出版物上分享詳細的結果？我的意思是如果能看到 SUDS 的曲線等等就太好了。

And secondly, you've compared PALISADE-2 to PALISADE-1, explained the differences. But can you also compare to the prior Phase II study and maybe compare and contrast any efficacy differences that you saw? Were there different baseline SUDS scores, for instance, between these 2 studies? Help us reconcile any differences.

其次，您比較了 PALISADE-2 和 PALISADE-1，解釋了差異。但是您是否也可以與之前的 II 期研究進行比較，並比較和對比您看到的任何功效差異？例如，這兩項研究之間的基線 SUDS 分數是否不同？幫助我們協調任何分歧。

Well, first to your question about the data, this obviously falls into industry standard breaking news, so we're trying to find a nice place to present the Phase II data in a breaking news context. Hopefully, sometime this fall, I think would probably be the earliest. So we'll have more information on that as we go forward. Certainly, abstracts and the like are already in circulation.

好吧，首先是關於數據的問題，這顯然屬於行業標準突發新聞，因此我們正在嘗試找到一個在突發新聞背景下呈現第二階段數據的好地方。希望今年秋天的某個時候，我認為這可能是最早的。因此，隨著我們的進展，我們將獲得更多相關信息。當然，摘要之類的東西已經在流通了。

So -- and then as to your questions about has the PALISADE-2 -- or the Phase II studies, I mean, obviously, it's a different environment. That's the 3 study -- or 3-site study. But Josh Prince, I want you to actually just address this just briefly, some of the things that we see.

那麼，關於你關於 PALISADE-2 或 II 期研究的問題，我的意思是，顯然，這是一個不同的環境。這就是 3 研究——或 3 地點研究。但是喬什·普林斯（Josh Prince），我希望你實際上只是簡單地談談我們所看到的一些事情。

Yes. Thanks, Shawn. Just to fill in the space there, I think the key is the time difference. So when we think about how long it's been since those earlier Phase II studies were done and you think about just the environment that we live in today versus then and through the pandemic, we think that has effect. But overall, the efficacy seen for both PH94B and placebo in that Phase II study was everything was kind of shifted up compared to what we've seen with PALISADE-2 and PALISADE-1. I mean we really do think it has to do with kind of the -- again, the times and the types of patients and conducting a study through the pandemic.

是的。謝謝，肖恩。只是為了填補那裡的空白，我認為關鍵是時差。因此，當我們想到自早期的第二階段研究完成以來已經過去了多長時間，並且想到我們今天生活的環境與當時以及整個大流行期間的環境時，我們認為這已經產生了影響。但總體而言，與我們在 PALISADE-2 和 PALISADE-1 中看到的效果相比，II 期研究中 PH94B 和安慰劑的療效都有所提高。我的意思是，我們確實認為這與時代和患者類型以及通過大流行進行研究有關。

And our next question is from the line of Joanne Lee from Maxim Group.

我們的下一個問題來自 Maxim Group 的 Joanne Lee。

Congratulations on the successful outcomes of the recent Phase III. The results were truly remarkable. Just given fasedienol achieved positive results in now both PAL-2 and the open label study, could you provide some insight on the rationale behind choosing to pursue both SUDS and LSAS as primary measures in the PAL-3 and FEARLESS studies? Was this decision influenced by any guidance from the FDA? Just curious on that.

祝賀最近第三階段取得的成功成果。結果確實非常顯著。鑑於 fasedienol 現在在 PAL-2 和開放標籤研究中都取得了積極的結果，您能否提供一些關於選擇將 SUDS 和 LSAS 作為 PAL-3 和 FEARLESS 研究中主要措施的理由的見解？這一決定是否受到 FDA 任何指導的影響？只是對此感到好奇。

No, no. Well, Thanks, Joanne, first of all, for the question. It's a great question. Look, we long held the way that we think fasedienol can help people. It's 2 distinct ways. It can certainly help people, as we've shown in PALISADE-2, in an acute setting. And as they take it out of their pocket or their purse or their backpack and they use it on demand in a patient-tailored way, has the ability to knock down very rapidly those symptoms. That's what PALISADE-2 showed.

不，不。嗯，首先謝謝喬安妮提出的問題。這是一個很好的問題。看，我們長期以來一直認為 fasedienol 可以幫助人們。這是兩種不同的方式。正如我們在 PALISADE-2 中所展示的那樣，它肯定可以在緊急情況下幫助人們。當他們從口袋、錢包或背包中取出它並以適合患者的方式按需使用時，有能力非常迅速地消除這些症狀。這就是 PALISADE-2 所展示的。

We also have placebo-controlled Phase II data and some exploratory data from the open label. Lots of subjects that also when it's used acutely but used over time, it increases the confidence of a person and increases their resilience, and it reduces their tendency to avoid situations that could benefit their lives. It reduces the opportunity costs in their life. And that avoidance -- a reduction in avoidance of engaging in social and performance situations is important. The Liebowitz scale captures both of those.

我們還有安慰劑對照的 II 期數據和一些來自開放標籤的探索性數據。許多科目，當它被頻繁使用但隨著時間的推移使用時，它會增加一個人的信心並增強他們的適應力，並減少他們避免可能有益於他們生活的情況的傾向。它減少了他們生活中的機會成本。這種迴避——減少迴避參與社交和表演場合是很重要的。利博維茨量表涵蓋了這兩點。

So we're at a perfect spot right now because we've got 1 successful study in Phase III, and you only need 2 adequate and well-controlled studies to get an approval of a drug. And so it could either be from a PALISADE-3 or it could be from a FEARLESS. Either way, what we're trying to do is look to the most efficient path to get this drug to patients as soon as possible. And it's 1 of those 2 tracks. It could be both, but you only need one other besides the one we've got. At least that's our opinion at this point.

因此，我們現在處於完美的位置，因為我們已經在 III 期研究中取得了 1 項成功，而您只需要 2 項充分且控制良好的研究即可獲得藥物批准。因此它可能來自 PALISADE-3，也可能來自 FEARLESS。不管怎樣，我們正在努力尋找最有效的途徑，盡快將這種藥物送到患者手中。這是這兩首曲目中的一首。兩者都可以，但除了我們現有的之外，您只需要其中之一。至少這是我們目前的看法。

So doing the LSAS-based study, again, it's consistent with the only 3 drugs ever approved for treatment of social anxiety disorder. That was the primary efficacy end point. We needed to make sure, and we did find this out in the first quarter that the FDA still believed that to be a valid and reliable end point and they do. So that provides optionality there.

因此，基於 LSAS 的研究再次證明，它與僅有的 3 種被批准用於治療社交焦慮症的藥物是一致的。這是主要療效終點。我們需要確保，我們確實在第一季度發現 FDA 仍然相信這是一個有效且可靠的終點，他們也確實如此。這樣就提供了選擇性。

The other side is, well, we already know what they think about the SUDS end point and the PALISADE program. Importantly, too, we have a keen interest given that social anxiety disorders, normally the onset is typically in adolescence between, say, ages 8 and 17. There's a huge number, as we know, of minors who are affected with mental health disorders, especially social anxiety disorder. The Liebowitz Scale, there's an LSAS-CA, which is for children and adolescents, so much easier down the road when we want to extend our treatment opportunity to pediatrics to run a Liebowitz scale-based study using a modified version of that scale similar to the way that the adult study was run.

另一方是，我們已經知道他們對 SUDS 終點和 PALISADE 計劃的看法。同樣重要的是，我們對此非常感興趣，因為社交焦慮症通常在 8 歲到 17 歲之間的青春期發病。據我們所知，有大量未成年人患有精神健康障礙，尤其是社交焦慮症。 Liebowitz 量表，有一個 LSAS-CA，適用於兒童和青少年，當我們想要將治療機會擴展到兒科以使用該量表的修改版本（類似於成人研究的進行方式。

Difficult to envision a 10-year-old giving a public speech to a group of strangers, just much easier to execute down the road in a pediatric setting as well. So it's really a nice combined set, either 1 of the 2. Ideally, we see both. And then you have a very robust commercial opportunity that extends into the pediatric arena.

很難想像一個 10 歲的孩子向一群陌生人發表公開演講，但在兒科環境中執行起來也容易得多。所以這確實是一個很好的組合，兩者之一。理想情況下，我們兩者都可以看到。然後你就有了一個非常強大的商業機會，可以延伸到兒科領域。

Got it. That was really helpful. And clearly, lots of excitement around the SAD program, but we're also really enthusiastic about the broader pherine platform as well. Could you shed some color on the current statuses and progress of those programs, PH10, 15 and 80, particularly on the latter, PH80, with the positive preclinical data? We see the hot flashing, other symptoms in menopause receiving a lot of -- a lot more attention in the area of women's health. So curious if you could walk us through some of the time lines around those programs.

知道了。這真的很有幫助。顯然，SAD 計劃令人興奮，但我們也對更廣泛的 pherine 平台充滿熱情。您能否介紹一下 PH10、15 和 80 這些項目的當前狀態和進展，特別是後者 PH80，以及積極的臨床前數據？我們看到潮熱以及更年期的其他症狀在女性健康領域受到了更多的關注。很好奇您能否向我們介紹一下這些項目的一些時間線。

Sure. Well, first, with respect to itruvone, or PH10, that's now, after a bit of a long run, it's staged to go into Phase IIb development in the U.S. Those -- the efficacy study was run outside the U.S. And so we really had to start back to the point of the U.S. IND-enabling program. For that one, because there had been no prior U.S. activity or no prior U.S. IND, we did the whole standard battery of nonclinical studies followed by a small Phase I to then now be able to leap back over, we believe, the Phase IIa that was done and move into Phase IIb, so tremendously exciting program given what we just also learned that, like 94B or fasedienol, there's no meaningful systemic exposure.

當然。嗯，首先，關於 itruvone 或 PH10，經過一段長時間的運行，現在它已準備在美國進入 IIb 期開發。那些功效研究是在美國境外進行的，所以我們確實有回到美國 IND 啟動計劃的話題。對於這一點，因為之前沒有在美國進行過活動，也沒有在美國進行過IND，我們進行了全套標準的非臨床研究，然後進行了一個小型的第一階段，我們相信，現在能夠跳回第二階段已經完成並進入 IIb 期，這是一個非常令人興奮的計劃，因為我們剛剛還了解到，像 94B 或 fasedienol 一樣，沒有有意義的系統暴露。

And the kinds of safety profile benefits that we see from fasedienol are also in the itruvone zone, meaning that we didn't -- we don't anticipate sexual side effects. We don't anticipate weight gain. We don't anticipate many of the types of side effects and safety concerns that are associated with the currently approved systemic therapy. So very excited about that as the stand-alone treatment for major depressive disorder.

我們從 fasedienol 中看到的各種安全性益處也在 itruvone 範圍內，這意味著我們沒有 - 我們預計不會產生性副作用。我們預計體重不會增加。我們預計不會出現與目前批准的全身治療相關的許多類型的副作用和安全問題。對於將其作為重度抑鬱症的獨立治療方法感到非常興奮。

As to PH80, again, you hit it. Hot flashes is hot right now. With the new NK3 antagonist that was approved, there's been a lot more interest of late in that space. There's an enormous population course that's affected by hot flashes for many years with very limited options that don't cause some concern, whether it's hormonal therapy or the new class. PH80 is majorly distinguished from both of those current treatment options and the antidepressants that are used for hot flashes because, again, like fasedienol and itruvone, we don't believe it's systemically absorbed. We think, again, that it also has the ability with neurocircuitry that's associated with temperature to be able to reduce the daily number of hot flashes that -- just as we saw in the Phase IIa study but also the severity of those hot flashes and the types of things that disrupt lives, so sweating and function and the like.

至於PH80，你又中招了。潮熱現在很熱。隨著新的 NK3 拮抗劑獲得批准，最近人們對該領域產生了更多的興趣。有大量人群多年來一直受到潮熱的影響，但無論是激素療法還是新療法，選擇都非常有限，不會引起一些擔憂。 PH80 與當前的治療方案和用於治療潮熱的抗抑鬱藥有很大區別，因為與 fasedienol 和 itruvone 一樣，我們不相信它會被全身吸收。我們再次認為，它還具有與溫度相關的神經迴路的能力，能夠減少每日潮熱次數——正如我們在IIa 期研究中看到的那樣，而且還可以減少潮熱的嚴重程度以及潮熱的嚴重程度。破壞生活的事物類型，例如出汗和功能等等。

So it's exciting that the challenge with that one is, like PH10, we've got to go through what probably will be about a 12 to 15 months IND-enabling program, where we do the CMC work and the preclinical work that's needed to get back into a Phase IIb setting. The difference with this one is that there is a -- there were -- there was a prior U.S. IND. So we don't think we need to do a Phase I study in order to get into Phase IIb for this indication.

因此，令人興奮的是，該項目面臨的挑戰是，就像PH10 一樣，我們必須完成一個可能需要12 到15 個月的IND 啟用計劃，在該計劃中我們進行CMC 工作和獲得所需的臨床前工作。回到 IIb 階段設置。與此不同的是，之前有一個美國 IND。因此，我們認為我們不需要進行 I 期研究才能進入該適應症的 IIb 期研究。

So will be -- it's not a long -- it's not a lot of money, less than $2 million for these IND-enabling programs. We have to do similar work with PH15 and PH284, the other 2 pherine assets in the pipeline. So that's the status of both.

所以，這不會很長，也不是很多錢，這些 IND 項目的資金不到 200 萬美元。我們必須對 PH15 和 PH284（管道中的另外 2 個 pherine 資產）進行類似的工作。所以這就是兩人的狀態。

Got it. Thank you for all the additional details. Once again, congratulations and looking forward to more updates this year.

知道了。感謝您提供所有其他詳細信息。再次祝賀並期待今年有更多更新。

Thanks, Joanne.

謝謝，喬安妮。

And our next question is a follow-up from the line of Andrew Tsai with Jefferies.

我們的下一個問題是安德魯·蔡 (Andrew Tsai) 與杰弗里斯 (Jefferies) 的後續問題。

Just a couple of more questions. I mean going back to PALISADE-2, there does seem to be a consistent efficacy signal across [various] end points. So I just wanted to make sure, were there other prespecified efficacy measures part of the study? And if so, how did those look? Just wanted to make sure all pre-specified measures are separated from placebo in a stat sig manner.

還有幾個問題。我的意思是回到 PALISADE-2，[各種]終點似乎確實存在一致的功效信號。所以我只是想確定一下，該研究中是否還有其他預先指定的療效指標？如果是這樣，那些看起來怎麼樣？只是想確保所有預先指定的措施都以統計信號的方式與安慰劑分開。

Sorry, Andrew. Were -- you asked if there is a separation against placebo across all the end points. Yes, there was 1 secondary -- the primary, 1 secondary and 2 exploratories, and we reported on all those, so 4 total.

對不起，安德魯。您詢問了所有終點是否與安慰劑存在差異。是的，有 1 個次要的——主要的、1 個次要的和 2 個探索性的，我們報告了所有這些，所以總共 4 個。

Okay. Great. And going to the label -- the eventual label, if both PALISADE and FEARLESS succeeded, what would your eventual label look like for SAD? And would there be precedents around that label claim?

好的。偉大的。說到廠牌——最終的廠牌，如果 PALISADE 和 FEARLESS 都成功了，你的 SAD 最終廠牌會是什麼樣子？該標籤聲明是否有先例？

No, there is no precedent for the acute treatment for social anxiety disorder. We would be the first to blaze that trail with fasedienol. Drugs are used. Benzodiazepines, for example, try to achieve that but with considerable risk of abuse and misuse and addiction. But they're never -- they're not approved for the treatment of social anxiety disorder. So only the 3 antidepressants: 2 SSRIs and 1 (inaudible), and they are approved for the chronic condition.

不，社交焦慮症的急性治療還沒有先例。我們將是第一個用 fasedienol 開闢這條道路的人。使用藥物。例如，苯二氮卓類藥物試圖實現這一目標，但存在相當大的濫用、誤用和成癮風險。但它們從未被批准用於治療社交焦慮症。因此，只有 3 種抗抑鬱藥：2 種 SSRI 和 1 種（聽不清），它們被批准用於治療慢性疾病。

The -- there likely would be no limit, in our opinion, on how frequently somebody could use the drug acutely if it's PALISADE-2 plus PALISADE-3 that supports the label initially. If it's later, eventually, FEARLESS came along and the staggered starts, which we -- is what we anticipate with PALISADE-3 first and FEARLESS second sometime in '24. It would be a case where the drug would be used acutely as needed but over time. And what you'd try to achieve for someone ultimately at the end of the day is they wouldn't have to take the drug. That's often and hopefully still also combined with talk therapy.

我們認為，如果 PALISADE-2 加上 PALISADE-3 最初支持該標籤，那麼某人急性使用該藥物的頻率可能不會受到限制。如果是後來的話，最終，FEARLESS 出現了，並且交錯開始，這就是我們所期望的，在 24 年的某個時候，PALISADE-3 首先是 PALISADE-3，第二個是 FEARLESS。在這種情況下，藥物將根據需要迅速使用，但隨著時間的推移。最終你會努力為某人實現的目標是他們不必服用藥物。這通常也希望仍然與談話療法相結合。

So yes, the PALISADE-2 hits the acute side of that match set. FEARLESS would hit the over time, although certainly, people wouldn't be precluded from using fasedienol over time if what's achieved is only the acute label.

所以，是的，PALISADE-2 擊中了該比賽的尖銳部分。隨著時間的推移，FEARLESS 將會受到關注，不過，如果所取得的只是急性標籤的話，隨著時間的推移，人們不會被排除使用 fasedienol。

Got it. And really quickly, as we think about the NDA package in the future, any peripheral studies that you would need to do such as, I guess, repeat -- just multiple dosing per day kind of studies, for instance?

知道了。很快，當我們考慮未來的新藥申請一攬子計劃時，您需要做的任何外圍研究，例如，我想，重複一下——例如，每天多次給藥之類的研究？

Sure. So we'll do open-label extensions on each of the 2, the PALISADE-3 and the FEARLESS study, so that there still has to be a safety database that gets established. And then the readout study that you mentioned, so I think that's something we've reported before. FDA wants to see what happens if someone uses the drug twice instead of just once in that acute setting.

當然。因此，我們將對 PALISADE-3 和 FEARLESS 研究這 2 項研究中的每一項進行開放標籤擴展，因此仍然需要建立一個安全數據庫。然後是你提到的讀數研究，所以我認為這是我們之前報導過的。 FDA 希望了解如果有人在這種緊急情況下使用該藥物兩次而不是一次，會發生什麼。

So that's something we will -- before NDA, that's a small study that we'd likely be completing and most likely they'd be using a public speaking challenge as well. So not too many subjects, not too expensive, but again, trying to -- not so much for safety, and we don't really worry about multiple uses in a short period of time, but I think there is some interest at the agency and wondering whether more is better.

所以這就是我們要做的——在 NDA 之前，我們可能會完成一項小型研究，而且很可能他們也會使用公開演講挑戰。因此，主題不是太多，也不是太貴，但再次嘗試——不是為了安全，我們並不真正擔心短時間內的多次使用，但我認為該機構有一些興趣並想知道是否越多越好。

We've certainly established the 3.2 micrograms used PRN is good in PALISADE-2. So if better is available, great, but it won't be an essential component for going forward in PALISADE-3 or the FEARLESS study.

我們確實已經確定，在 PALISADE-2 中使用 3.2 微克的 PRN 效果很好。因此，如果有更好的技術可用，那就太好了，但它不會成為 PALISADE-3 或 FEARLESS 研究前進的重要組成部分。

Got it. Actually, very last one, because you don't have much opportunity on conference calls. So in the study results, did PH94B work equally as well between male and females? And that's the last question.

知道了。事實上，這是最後一次，因為你沒有太多機會參加電話會議。那麼在研究結果中，PH94B對於男性和女性的效果是否相同呢？這是最後一個問題。

I think that's something we'll be able to unpack. We don't have the full data set fully unpacked. We have the top line results. So that takes a little bit of time. But I don't think we see -- and we've long held since -- that was, I think, long, long time ago that, that was a question. But we think -- we don't think there's any reason to believe the drug doesn't work as well in women as in men or men as an women, whichever way you want to put it. But FEARLESS will give us -- okay.

我認為這是我們能夠解開的東西。我們沒有完全解壓的完整數據集。我們有最重要的結果。所以這需要一點時間。但我認為我們沒有看到——而且從那以後我們一直堅持——我認為，很久很久以前，這是一個問題。但我們認為，我們認為沒有任何理由相信這種藥物對女性的效果不如對男性的效果，或者對男性的效果不如對女性的效果，無論你怎麼說。但《FEARLESS》會給我們——好吧。

Congrats.

恭喜。

Thank you.

謝謝。

And there are no other sell-side analysts in queue. You may proceed to closing comments.

並且沒有其他賣方分析師在排隊。您可以繼續結束評論。

Excellent. Thank you, Jennifer for your help today. And thank you, Andrew, and Joanne. We appreciate your questions.

出色的。謝謝你，詹妮弗今天的幫助。謝謝安德魯和喬安妮。我們感謝您的提問。

If there are any additional questions, please do not hesitate to contact us by e-mailing ir@vistagen.com or contacting the individuals listed in our press release issued today or on our website. We are -- we also encourage you to sign up on our website to stay connected with the latest news from Vistagen.

如果還有任何其他問題，請隨時通過電子郵件 ir@visagen.com 或聯繫我們今天發布的新聞稿或我們網站上列出的個人與我們聯繫。我們還鼓勵您在我們的網站上註冊，以隨時了解 Vistagen 的最新消息。

Thank you for participating in our call today. We appreciate everybody's attention and support. We look forward to keeping you current on our continuing progress. This concludes our call. Have a fantastic day. You may all disconnect now.

感謝您今天參加我們的電話會議。我們感謝大家的關注和支持。我們期待讓您了解我們的持續進展。我們的通話到此結束。擁有美好的一天。你們現在可以斷開連接了。