DURECT Corp (DRRX) 2023 Q1 法說會逐字稿

Greetings and welcome to the DURECT Corporation first-quarter 2023 earnings call. (Operator Instructions) As a reminder, this conference is being recorded.

您好，歡迎參加 DURECT Corporation 2023 年第一季度財報電話會議。 （操作員指示）謹此提醒，本次會議正在錄製中。

It is now my pleasure to introduce your host, Tim Papp, Chief Financial Officer. Thank you, Tim. You may begin.

現在我很高興向您介紹主持人蒂姆·帕普 (Tim Papp)，他是首席財務官。謝謝你，蒂姆。你可以開始了。

Good afternoon and welcome to DURECT Corporation's first-quarter 2023 earnings conference call. This is Tim Papp, Chief Financial Officer of DURECT.

下午好，歡迎參加 DURECT Corporation 2023 年第一季度收益電話會議。我是 Tim Papp，DURECT 首席財務官。

Before we begin, I would like to remind you of our Safe Harbor statement. During the course of this call, we may make forward-looking statements regarding DURECT's products and development, expected product benefits, our development plans, future clinical trials, or projected financial results.

在我們開始之前，我想提醒您我們的安全港聲明。在本次電話會議期間，我們可能會就 DURECT 的產品和開發、預期產品優勢、我們的開發計劃、未來的臨床試驗或預計的財務結果做出前瞻性陳述。

These forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Further information regarding these and other risks can be found in our SEC filings including our 10-K and 10-Qs under the heading Risk Factors.

這些前瞻性陳述涉及風險和不確定性，可能導致實際結果與此類前瞻性陳述中的結果存在重大差異。有關這些風險和其他風險的更多信息，請參閱我們向 SEC 提交的文件，包括風險因素標題下的 10-K 和 10-Q。

To begin, I would like to review our first-quarter 2023 financial results. Our total revenues in the first quarter were $2.1 million compared to $1.9 million for the prior year. This increase was due primarily to an increase in collaborative R&D revenue. R&D expense was $8.6 million for the first quarter compared with $8.2 million for the prior year. The increases were primarily due to higher clinical trial expenses for our ongoing AHFIRM trial and contract manufacturing expenses for larsucosterol.

首先，我想回顧一下我們 2023 年第一季度的財務業績。我們第一季度的總收入為 210 萬美元，而去年同期為 190 萬美元。這一增長主要是由於協作研發收入的增加。第一季度研發費用為 860 萬美元，上年同期為 820 萬美元。增加的主要原因是我們正在進行的 AHFIRM 試驗的臨床試驗費用以及 larsucosterol 的合同製造費用增加。

For the first quarter, SG&A expenses were $4.1 million compared with $3.7 million for the prior year. This increase was primarily due to higher market research expenses, higher audit-related expenses, as well as higher employee expenses. As of March 31, 2023, we had cash and investments of $44.4 million as compared to $43.6 million at December 31, 2022.

第一季度的銷售、管理及行政費用為 410 萬美元，而去年同期為 370 萬美元。這一增長主要是由於市場研究費用增加、審計相關費用增加以及員工費用增加。截至 2023 年 3 月 31 日，我們的現金和投資為 4,440 萬美元，而截至 2022 年 12 月 31 日為 4,360 萬美元。

We completed a registered direct offering in February 2023, raising $8.8 million in net proceeds. Excluding the proceeds from the financing, our cash burn in the first quarter was approximately $8 million. We believe our cash on hand is sufficient to fund operations into the first quarter of 2024. Lastly, I would like to highlight that we will be hosting a KOL event in New York City on May 16. We are pleased to be hosting Dr. Paul Gaglio from the Columbia University, Department of Medicine and Dr. Brett Fortune from the Albert Einstein College of Medicine, Department of Medicine in Division of Hepatology.

我們於 2023 年 2 月完成了註冊直接發行，籌集了 880 萬美元的淨收益。不包括融資收益，我們第一季度的現金消耗約為 800 萬美元。我們相信我們手頭的現金足以為 2024 年第一季度的運營提供資金。最後，我想強調的是，我們將於 5 月 16 日在紐約市舉辦一場 KOL 活動。我們很高興接待 Paul 博士來自哥倫比亞大學醫學系的 Gaglio 和來自阿爾伯特·愛因斯坦醫學院肝病科醫學系的 Brett Fortune 博士。

Dr. Gaglio and Dr. Fortune are both renowned hepatologists with a wealth of experience treating alcohol-associated hepatitis or AH. We look forward to hearing their insights about the current treatment paradigm for AH and the unmet medical need in this highly lethal disease.

Gaglio 博士和 Fortune 博士都是著名的肝病專家，在治療酒精相關性肝炎或 AH 方面擁有豐富的經驗。我們期待聽到他們對當前 AH 治療模式以及這種高度致命疾病未得到滿足的醫療需求的見解。

Several members of our leadership team will join Dr. Gaglio and Fortune to discuss the ongoing development and commercial landscape for larsucosterol in AH in advance of the topline readout from AHFIRM. You can find the details for the webcast of the event in our press release from April 27 on our website.

在 AHFIRM 公佈頂線數據之前，我們領導團隊的幾位成員將與 Gaglio 博士和《財富》雜誌一起討論 AH 中 larsucosterol 的持續開發和商業前景。您可以在我們網站上 4 月 27 日發布的新聞稿中找到該活動網絡直播的詳細信息。

Now, I would like to turn the call over to our CEO, Jim Brown, for an update on certain of our programs.

現在，我想將電話轉給我們的首席執行官吉姆·布朗，了解我們某些計劃的最新情況。

Thank you, Tim. Hello, everyone. Thank you for joining us today for our first-quarter 2023 update. We're excited about the continued progress for our lead clinical program, larsucosterol, for the treatment of alcohol-associated hepatitis. 2023 is poised to be a significant year for DURECT as we look forward to completing our AHFIRM trial and reporting topline data by the end of the year. If successful, we believe AHFIRM has the potential to support an NDA filing.

謝謝你，蒂姆。大家好。感謝您今天加入我們，了解 2023 年第一季度的最新情況。我們對治療酒精相關性肝炎的主要臨床項目 larsucosterol 的持續進展感到興奮。 2023 年對於 DURECT 來說將是重要的一年，因為我們期待在年底前完成 AHFIRM 試驗並報告主要數據。如果成功，我們相信 AHFIRM 有潛力支持 NDA 備案。

Our primary focus in the company remained gaining approval for larsucosterol in AH and bringing this potentially lifesaving therapeutic to patients with no effective treatment options today. We are nearing our enrollment target of 300 patients in our Phase 2b AHFIRM trial with more than 285 patients dosed to date. We continue to expect completion of enrollment by the end of this quarter.

我們公司的主要重點仍然是獲得 larsucosterol 在 AH 中的批准，並將這種可能挽救生命的治療方法帶給當今沒有有效治療選擇的患者。我們正在接近 2b 期 AHFIRM 試驗中 300 名患者的入組目標，迄今為止已有超過 285 名患者接受了給藥。我們仍然預計在本季度末完成註冊。

As a reminder, AHFIRM is a 300-patient, placebo-controlled, double-blind, multinational study with two active dosing arms and a placebo arm of 100 patients each. We're enrolling patients with severe AH, which are patients with MELD scores ranging from 21 to 30 and Maddrey Discriminant Function scores greater than or equal to 32. The primary endpoint for AHFIRM is reduction in mortality or liver transplant at 90 days.

提醒一下，AHFIRM 是一項 300 名患者、安慰劑對照、雙盲、跨國研究，有兩個主動給藥組和一個安慰劑組，每個組各 100 名患者。我們正在招募患有嚴重 AH 的患者，這些患者的 MELD 評分在 21 至 30 之間，Maddrey 判別功能評分大於或等於 32。AHFIRM 的主要終點是 90 天時死亡率或肝移植的減少。

We've enrolled patients in AHFIRM through a global network of clinical sites including leading hospitals in the US, Australia, EU, and UK. Our sites include renowned liver centers, and we are working with some of the world's preeminent thought leaders in AH. The FDA has granted our larsucosterol AH program Fast Track designation, and we are hopeful that a positive result in AHFIRM could support an NDA filing. With this in mind, larsucosterol has the potential to be the first FDA-approved treatment for AH, where there is a substantial unmet need for these patients.

我們通過全球臨床中心網絡（包括美國、澳大利亞、歐盟和英國的領先醫院）將患者納入 AHFIRM。我們的網站包括著名的肝臟中心，並且我們正在與 AH 領域的一些世界傑出思想領袖合作。 FDA 已授予我們的 larsucosterol AH 項目快速通道資格，我們希望 AHFIRM 的積極結果能夠支持新藥申請 (NDA) 申請。考慮到這一點，larsucosterol 有可能成為 FDA 批准的第一個治療 AH 的藥物，因為這些患者的需求尚未得到滿足。

We designed AHFIRM to be a potentially pivotal trial based on our Phase 2a data. In our open-label Phase 2a trial, all 19 patients survived the 28 days. An encouraging result given that approximately 26% of hospitalized AH patients die within 28 days based on historical data. In April, we announced that our Phase 2a data had been published online by the American Journal of Gastroenterology.

我們根據 2a 期數據將 AHFIRM 設計為一項潛在的關鍵試驗。在我們的開放標籤 2a 期試驗中，所有 19 名患者都存活了 28 天。根據歷史數據，大約 26% 的住院 AH 患者在 28 天內死亡，這是一個令人鼓舞的結果。今年 4 月，我們宣布我們的 2a 期數據已在《美國胃腸病學雜誌》在線發表。

This peer-reviewed article includes cross-study comparisons with well-matched, severe AH patients from the contemporaneous trial conducted by the Defeat Alcoholic Steatohepatitis or DASH consortium. While the sample sizes were small, and these patients were not part of a controlled study, these comparisons indicate that severe AH patients treated with either 30 milligrams or 90 milligrams of larsucosterol has statistically significantly lower Lille scores compared to the patients treated with standard of care including steroids.

這篇經過同行評審的文章包括與戰勝酒精性脂肪性肝炎或 DASH 聯盟同期進行的試驗中匹配良好的嚴重 AH 患者的交叉研究比較。雖然樣本量較小，並且這些患者不屬於對照研究，但這些比較表明，與接受標準護理的患者相比，接受 30 毫克或 90 毫克 larsucotosterol 治療的嚴重 AH 患者的 Lille 評分在統計學上顯著降低包括類固醇。

In addition, liver enzyme levels decreased rapidly in the larsucosterol-treated patients including statistically significant reductions in ALT. We believe these results provide further evidence of the potential for larsucosterol as a treatment for AH. Our confidence that the AHFIRM trial will be successful is driven by our compelling Phase 2a study data, including the recently published comparisons, the mechanism of action of larsucosterol which ties directly into the biology of AH, and our multiple preclinical animal study, where we observed the profound survival benefit and multiple relevant acute organ injury model.

此外，接受 larsucosterol 治療的患者的肝酶水平迅速下降，其中 ALT 顯著降低，具有統計學意義。我們相信這些結果進一步證明了 larsucosterol 作為治療 AH 的潛力。我們對 AHFIRM 試驗將取得成功的信心是由我們令人信服的 2a 期研究數據驅動的，包括最近發表的比較、與 AH 生物學直接相關的 larsucosterol 的作用機制，以及我們的多項臨床前動物研究，其中我們觀察到深遠的生存獲益和多種相關的急性器官損傷模型​​。

I'd like to briefly turn to the market opportunity for AH. In addition to this high mortality rate, AH represents a significant cost to the US healthcare system, with over 150,000 hospitalizations attributed to AH at a cost of between $50,000 to $150,000 each. As a result, larsucosterol represents a potential multibillion dollar opportunity in the United States alone and could simultaneously provide substantial overall cost savings to the healthcare system. We will discuss the economic opportunity for larsucosterol further during our upcoming KOL event.

我想簡單談談 AH 的市場機會。除瞭如此高的死亡率之外，AH 還給美國醫療保健系統帶來了巨大的成本，超過 150,000 人因 AH 住院，每次住院費用在 50,000 至 150,000 美元之間。因此，僅在美國，larsucosterol 就代表了潛在的數十億美元的機會，同時可以為醫療保健系統提供大量的總體成本節省。我們將在即將舉行的 KOL 活動中進一步討論 larsucosterol 的經濟機會。

We've begun to lay the groundwork for potentially commercializing larsucosterol in the US and believe we can effectively launch the product to a modestly sized, hospital-focused sales force. We are also continuing to build awareness around the role of epigenetic regulators in acute diseases like AH.

我們已經開始為在美國實現 larsucotosterol 的潛在商業化奠定基礎，並相信我們可以有效地向規模適中、以醫院為中心的銷售隊伍推出該產品。我們還在繼續提高人們對錶觀遺傳調節因子在急性肝炎等急性疾病中的作用的認識。

AH is also a global concern, allowing larsucosterol the potential to serve ex-US AH patients and their healthcare system. These ex-US markets represent additional attractive market opportunities. Because we enroll patients from a global site network, we believe a positive result from AHFIRM may support regulatory filings in the EMA and other regions.

AH 也是一個全球性的問題，這使得 larsucosterol 有可能為美國前 AH 患者及其醫療保健系統提供服務。這些美國以外的市場代表了額外有吸引力的市場機會。由於我們從全球站點網絡招募患者，因此我們相信 AHFIRM 的積極結果可能會支持 EMA 和其他地區的監管備案。

In summary, we continue to make great strides with AHFIRM and have enrolled more than 285 patients to-date. We are on track to complete dosing the last patient in the AHFIRM trial this quarter, which would enable reporting of topline results in the second half of this year. If successful, we believe AHFIRM has the potential to support an NDA filing.

總之，我們在 AHFIRM 方面繼續取得巨大進步，迄今為止已招募了超過 285 名患者。我們有望在本季度完成 AHFIRM 試驗中最後一名患者的給藥，這將使我們能夠在今年下半年報告主要結果。如果成功，我們相信 AHFIRM 有潛力支持 NDA 備案。

With that, we'd now like to take any questions you may have.

至此，我們現在願意回答您可能提出的任何問題。

(Operator Instructions) Kristen Kluska, Cantor Fitzgerald.

（操作員說明）Kristen Kluska、Cantor Fitzgerald。

Thanks so much for taking my questions. The first one I had is, if you could break down for us this $50,000 to $100,000 cost that you cited in your prepared remarks. I guess, how much of this is just driven by the fact that patients are often in the hospital for a couple of days. And obviously, I respect and understand the 90-day endpoint related to the FDA. But time to hospital especially because in the 2a, a number of your patients didn't even need that second dose. I guess like how important are those statistics going to be for payer conversation should this drug be successful?

非常感謝您回答我的問題。我的第一個疑問是，您能否為我們細分一下您在準備好的發言中提到的 50,000 至 100,000 美元的成本。我想，這在很大程度上是由於患者經常在醫院住幾天這一事實造成的。顯然，我尊重並理解與 FDA 相關的 90 天終點。但去醫院的時間尤其重要，因為在 2a 中，許多患者甚至不需要第二劑。我想如果這種藥物成功的話，這些統計數據對於付款人對話有多重要？

I'll start it and then I'd like Keith to maybe speak a little further on this issue as well. I think we've seen from most literature that I've seen is, the typical patient stay in the hospital is around six days for those that live and longer for those that don't. And for those that live, it's about a $50,000 cost. For those that die in the hospital, it's a $150,000. And the majority of patients that are going pass away, actually, they move them out of the hospital to hospice care.

我將開始，然後我希望基思也能就這個問題進一步談談。我認為我們從我見過的大多數文獻中看到的是，對於那些存活的患者來說，典型的患者住院時間約為六天，對於那些沒有存活的患者來說，住院時間更長。對於那些活著的人來說，這大約需要 50,000 美元。對於那些在醫院去世的人來說，這是15萬美元。事實上，大多數即將去世的病人，他們都將他們從醫院轉移到臨終關懷中心。

But Keith, do you want to maybe speak some to the pharmacoeconomic drivers vis-a-vis hospitalization cost?

但是基思，您是否想談談藥物經濟驅動因素與住院費用的關係？

Sure. Thanks for the question, Kristen. I think it's a good observation. I mean the folks that are driving the higher end of that $150,000 cost, of course, are the ones that unfortunately expire and die while in hospital. This is taken from the HCUP NIS data set. And our belief, and we're doing a continued research in this, is that those are the patients that unfortunately take up the most amount of healthcare utilization as far as diagnostics, more intensive care unit time, and hospital length of stay.

當然。謝謝你的提問，克里斯汀。我認為這是一個很好的觀察。我的意思是，那些花費 150,000 美元的高端費用的人當然是那些在醫院不幸過期並死亡的人。這取自 HCUP NIS 數據集。我們相信，並且我們正在對此進行持續的研究，不幸的是，這些患者在診斷、重症監護病房時間和住院時間方面佔用了最多的醫療保健利用率。

And you had cited our Phase 2a study that showed that two-thirds of the severe patients only required one dose. However, that may be different in the AHFIRM trial. So we'll be interpreting all of those results: length of stay, time in ICU, time to step down unit, overall length of stay. And all that will be important as we put together our value prop and budget impact models for the market access and payer environment.

您引用了我們的 2a 期研究，該研究表明三分之二的重症患者只需要一劑。然而，在 AHFIRM 試驗中情況可能有所不同。因此，我們將解釋所有這些結果：住院時間、在 ICU 的時間、退出病房的時間、總住院時間。當我們將市場准入和付款人環境的價值支撐和預算影響模型整合在一起時，所有這些都非常重要。

Thank you. Appreciate your thoughts there. And a question we've been getting is just, why do you believe that other mechanisms have failed in this space? And what is it about larsucosterol's mechanisms that might be more appropriate in the setting especially with this recent paper and some of the deeper diligence you've conducted?

謝謝。欣賞你的想法。我們一直收到的一個問題是，為什麼您認為其他機制在這個領域失敗了？ larsucosterol 的機制是什麼，可能更適合這種情況，尤其是最近這篇論文以及您進行的一些更深入的研究？

That's a great question as well. And I'll address it, and then we'll see if we have some more because we have both WeiQi and Norman on the line as well. I think, first off, it's a complex disease. AH unfortunately leads to the breakdown of a number of systems. These patients are eventually dying of multi-organ failure. So it's not just the liver. Eventually, most of them die actually from kidney disease.

這也是一個很好的問題。我會解決這個問題，然後我們會看看是否還有更多，因為我們也有 WeiQi 和 Norman 在線。我認為，首先，這是一種複雜的疾病。不幸的是，AH 導致了許多系統的崩潰。這些患者最終死於多器官衰竭。所以這不僅僅是肝臟。最終，他們中的大多數人實際上死於腎臟疾病。

And we've shown with larsucosterol that we protect against multi-organ failure, protect the kidneys, the liver, the lungs, and numerous models. And we've shown -- showing up as it were in protection of these organ systems in humans who have chronic kidney disease or chronic liver disease when we dosed and seen reductions in the cytokeratin-18, these markers of cell death.

我們已經證明，larsucosterol 可以預防多器官衰竭，保護腎臟、肝臟、肺和許多模型。我們已經證明，當我們給藥並觀察到細胞角蛋白-18（這些細胞死亡的標誌物）減少時，它可以保護患有慢性腎病或慢性肝病的人類的這些器官系統。

If we look at drugs that have been tested against AH in the past, there two main areas of focus. One was in trying to reduce apoptosis and a couple of drugs have been tested there and unfortunately didn't work. And then there has also been drugs looking to block certain cascade of the inflammatory system with monoclonal antibodies. And those also were more one note and really couldn't address the breadth of the disease.

如果我們看看過去針對 AH 進行過測試的藥物，就會發現有兩個主要關注領域。其中之一是試圖減少細胞凋亡，已經在那裡測試了幾種藥物，但不幸的是沒有作用。還有一些藥物試圖用單克隆抗體來阻斷炎症系統的某些級聯反應。這些也只是一個註釋，確實無法解決這種疾病的廣度。

With larsucosterol, we have a molecule that changes what we know has gone wrong. We know that there are elevations in DNMT or DNA methyltransferase levels in these patients. And so we know from patient data that there is hypermethylation ongoing, and we know a host of different systems within the cells are damaged. We know larsucosterol protects against mitochondrial membrane damage, and so we've got that component of it.

有了larsucosterol，我們就有了一種可以改變我們所知道的錯誤的分子。我們知道這些患者的 DNMT 或 DNA 甲基轉移酶水平升高。因此，我們從患者數據中得知，超甲基化正在發生，並且我們知道細胞內的許多不同系統都受到了損害。我們知道 larsucosterol 可以防止線粒體膜損傷，所以我們已經得到了它的成分。

We know it reduces lipotoxicity, reduces inflammation, enhances cell survival and regeneration of the cells, increases autophagy. There's just a host of different components that have gone wrong that are addressed.

我們知道它可以降低脂毒性，減少炎症，增強細胞存活和細胞再生，增加自噬。只有許多不同的組件出現了問題並得到了解決。

But maybe I give it to -- maybe WeiQi, you can start and then, Norman, maybe finish on this as well. Any additional thoughts?

但也許我會把它交給——也許 WeiQi，你可以開始，然後，諾曼，也許也可以完成這個。還有其他想法嗎？

No, I think, Jim, you have covered it quite well. I would also just add one more thing, because alcohol, particularly alcohol-associated hepatitis subjects, they do have impaired liver regeneration. So liver regeneration is very important in overcoming the acute liver injury, and then resulting acute liver failure. So larsucosterol certainly promoting liver regeneration that's also important. Jim did mention that a little bit as well.

不，我認為吉姆，你已經講得很好了。我還想補充一件事，因為酒精，特別是酒精相關性肝炎患者，他們的肝臟再生確實受到損害。因此，肝再生對於克服急性肝損傷，進而導致急性肝功能衰竭非常重要。因此，拉糖甾醇肯定會促進肝臟再生，這也很重要。吉姆也提到了一點。

Thank you. And Norman?

謝謝。諾曼呢？

Yeah, I -- I don't have, pardon me, too much to add to that. I was very impressed with the mitochondrial stabilization because mitochondrial dysfunction is a big part of the apoptosis pathway. So that was important. And the -- steroids affect inflammation, but they also probably interfere with liver regeneration, as WeiQi pointed out.

是的，我——對不起，我沒有太多可補充的。線粒體的穩定性給我留下了深刻的印象，因為線粒體功能障礙是細胞凋亡途徑的重要組成部分。所以這很重要。正如 WeiQi 指出的那樣，類固醇會影響炎症，但它們也可能會干擾肝臟再生。

You need sort of this broad improvement without inhibiting liver regeneration in order to recover from this. So I feel as if prior treatments have addressed one thing at a time, and what you need is something much broader than that. And the mechanism of action is really impressive. But even more impressive is the empiric data that we saw in the Phase 2a trial.

您需要在不抑制肝臟再生的情況下進行這種廣泛的改善才能從中恢復。所以我覺得以前的治療方法一次只能解決一件事，而你需要的是比這更廣泛的東西。而且其作用機制確實令人印象深刻。但更令人印象深刻的是我們在 2a 期試驗中看到的經驗數據。

Great. Well, thank you, both. Yeah, I think it is interesting when you see the histology of these patients. They aren't often biopsied, but sometimes you do see megamitochondria. So you know that there's a stress in that organ now anyway.

偉大的。嗯，謝謝你們兩位。是的，當你看到這些患者的組織學時，我認為這很有趣。它們不經常被活檢，但有時你確實會看到巨線粒體。所以你知道那個器官現在無論如何都存在壓力。

Okay, thanks. And then for the second half of the year readout just because we're getting really close now. Do you anticipate that you would share certain endpoints first through a press release? And then maybe save more detailed data for medical presentation? What are your kind of preliminary thoughts on this assuming that the plan goes to place with timing?

好的謝謝。然後是下半年的讀數，因為我們現在已經非常接近了。您是否預計會首先通過新聞稿分享某些端點？然後也許可以保存更詳細的數據用於醫療演示？假設該計劃按時實施，您對此有何初步想法？

Yeah, it will depend on the timing, but this is too important to wait, and we wouldn't. So when we have the last patient enrolled, which we're getting close, obviously, we know, we're now over 285. So we just have a few patients to go, a dozen or so left. And so when we enrolled that last patient, we will announce that, and then people can start the countdown.

是的，這取決於時間，但這太重要了，不能等待，我們不會。因此，當我們登記最後一名患者時，我們已經很接近了，顯然我們知道，我們現在已經超過 285 名患者了。所以我們只剩下幾個患者了，還剩下十幾個左右。因此，當我們招募最後一位患者時，我們將宣布這一點，然後人們就可以開始倒計時。

So they'll know it would be three months from then until last patient last visit. And Norman and the team have done a great job of keeping up with the patients. As we've gone through, we've been closing out centers as we can and closing out patients as we can. And so our hope is that we'll just have those last 10 or so patients to clean up as we get to the last few months.

這樣他們就會知道從那時到最後一位患者最後一次就診需要三個月的時間。諾曼和他的團隊在跟進患者方面做得非常出色。正如我們所經歷的那樣，我們一直在盡可能地關閉中心，並儘可能地關閉患者。因此，我們希望在最後幾個月內只清理最後 10 名左右的患者。

So the team is hoping to have data within two months or so after last patient last visit. That would be wonderful and happy when whenever it comes. But when that day comes when we unblind the trial, we hope to report out with just a few days. And so that would be our objective. I'm sure we'll have a press release, and I'm sure conference call.

因此，該團隊希望在最後一位患者上次就診後兩個月左右的時間內獲得數據。當它到來時，那將是美好而幸福的。但當我們揭開審判的那一天到來時，我們希望能在幾天之內得出報告。這就是我們的目標。我確信我們會發布新聞稿，也肯定會召開電話會議。

I don't know about the timing of that versus meetings. We certainly wouldn't hold anything back at that point. I think we'll talk about it. And then eventually, we'll present the data in more -- in a broader fashion through publications, through meetings.

我不知道會議的時間安排。那時我們當然不會保留任何東西。我想我們會討論一下。最終，我們將通過出版物、會議以更廣泛的方式展示數據。

But, Norman, do you want to add anything to that?

但是，諾曼，你想補充什麼嗎？

No, I think that's correct, Jim. Clearly, we're as excited as anyone to unblind and see what the topline data on the most important things and then decide on a publication and presentation strategy.

不，我認為這是正確的，吉姆。顯然，我們和任何人一樣興奮地揭開盲面，看看最重要的事情的主要數據是什麼，然後決定出版和演示策略。

Great, thanks. Look forward to seeing you in New York next week.

十分感謝。期待下週在紐約見到您。

Yes, absolutely. Thank you for reminding me. Yeah, we do have our KOL event next Tuesday in New York. So happy to have you guys over and if not, then online would be great.

是的，一點沒錯。謝謝你提醒我。是的，我們下週二在紐約舉辦 KOL 活動。很高興有你們過來，如果沒有的話，那麼在線就太好了。

Ed Arce, H.C. Wainwright.

埃德·阿爾塞，H.C.溫賴特。

Thanks for taking my questions. It was great to see you last week, and I also look forward to seeing you next week at your event. Beyond the timing of the trial, I just got a couple more questions. I think this would be important as investors start sharpening their pencils on this readout, is, to just go over and explain why there were actually two -- there are two dose arms in the study. And ultimately, if both are positive and both are powered for statistical significance, you would seek to get both of them on the label.

感謝您回答我的問題。上週很高興見到您，我也期待下週在您的活動中見到您。除了審判時間之外，我還有幾個問題。我認為這很重要，因為投資者開始在這個讀數上削尖鉛筆，只是回顧並解釋為什麼研究中實際上有兩個劑量臂。最終，如果兩者都是積極的並且兩者都具有統計顯著性，那麼您將尋求將它們都放在標籤上。

And then separately, the other question I had was just around commercialization given that this is potentially a pivotal study, and you could be looking at an approval in the not too distant future. We just wanted to get your thoughts on the hospitalization sales force, the MSL sales force, how you expect that to unroll given that there is a fairly concentrated targeted set of call points? Thanks so much.

另外，我的另一個問題是關於商業化，因為這可能是一項關鍵研究，並且您可能會在不久的將來獲得批准。我們只是想了解您對住院銷售人員、MSL 銷售人員的看法，考慮到有一組相當集中的目標呼叫點，您希望如何展開？非常感謝。

Okay, sure, Ed. And I'll start off and then I'll let WeiQi speak a little more to the doses, and then we'll certainly have Keith speak to the commercialization post that.

好吧，當然，艾德。我會開始，然後我會讓 WeiQi 多談談劑量，然後我們肯定會讓 Keith 談談商業化帖子。

So with regard to the doses, we are looking at two different doses which allows us to gain a bit more insight. And it's a -- basically we've seen pretty exciting results already in the Phase 2a with both of these doses. And we've seen in various other human experiences a variety of doses tested, and oftentimes, the low dose looks every bit good, if not better than the higher. And that has also been the case in some of the non-clinical. So it's a -- but we certainly are excited to see what will come from this.

因此，關於劑量，我們正在研究兩種不同的劑量，這使我們能夠獲得更多的了解。基本上我們已經在 2a 階段看到了這兩種劑量的非常令人興奮的結果。我們在各種其他人類經歷中看到了各種劑量的測試，而且通常情況下，低劑量看起來很好，即使不是比高劑量更好。一些非臨床研究也是如此。所以這是——但我們當然很高興看到這會帶來什麼。

But as far as dosing, WeiQi, any additional thoughts there?

但就劑量而言，WeiQi 還有什麼其他想法嗎？

Yeah, those two doses were selected based on our understanding of the dose response relationship in various mechanistic studies and also based on the ADME data involving animals and in humans. And on top of that, that was based on PK data we obtained through the Phase 2a study. So that's how we determined these two doses should be in the optimum dose range of the drug exposure to the liver because AH is specifically a liver-centric disease.

是的，這兩種劑量是根據我們對各種機制研究中劑量反應關係的理解以及涉及動物和人類的 ADME 數據選擇的。最重要的是，這是基於我們通過 2a 期研究獲得的 PK 數據。這就是我們如何確定這兩個劑量應處於藥物暴露於肝臟的最佳劑量範圍內，因為 AH 是一種專門以肝臟為中心的疾病。

So that's how we selected these two doses. Although we know that 150 milligram dose, that's the one we also use in the Phase 2a study, that the highest result is also safe in these subjects. Nevertheless, 30 milligram and the 90 milligram we selected moving to Phase 2b, we believe, are the optimal dose range.

這就是我們選擇這兩個劑量的方式。儘管我們知道 150 毫克劑量（這也是我們在 2a 期研究中使用的劑量），但最高結果對於這些受試者也是安全的。儘管如此，我們相信，我們選擇進入 2b 階段的 30 毫克和 90 毫克是最佳劑量範圍。

Yeah, I think that's a good point from a safety standpoint. We've -- in the NASH patients, we dosed for a month as high as 600 milligrams a day. So we certainly have given a huge amount more than these doses and for a much more extended period of time.

是的，我認為從安全角度來看這是一個很好的觀點。我們對 NASH 患者進行了為期一個月、每天 600 毫克的劑量治療。因此，我們提供的劑量肯定比這些劑量多得多，而且持續的時間也更長。

So maybe then, I'll hand over the commercialization question to Keith, who, for those of you who don't know, has a tremendous commercial experience in particular of late before coming to DURECT at both Genentech and Pharmacyclics, has sold a number of oncology products, and he's dealt with lethal diseases before. So we're excited for Keith and his team to take this on.

那麼，也許我會將商業化問題交給 Keith，對於那些不知道的人來說，他擁有豐富的商業經驗，特別是在來到 Genentech 和 Pharmacyclos 的 DURECT 之前，他已經售出了許多產品。腫瘤產品，他以前處理過致命疾病。因此，我們很高興 Keith 和他的團隊能夠承擔起這項工作。

Yeah, thanks, Jim. On your question of potential hospitalization sales force. We have been doing some preliminary work on just understanding the hepatology and gastroenterology marketplace and the various hospitals and their discharge volumes in AH, working with big data houses that are well known like IQVIA and Syneos, and others.

是的，謝謝，吉姆。關於潛在住院銷售人員的問題。我們一直在與 IQVIA 和 Syneos 等知名大數據公司合作，開展一些初步工作，了解肝病學和胃腸病學市場以及各醫院及其在 AH 的出院量。

But we know that there's a rough population of heps and gastros and advanced practice providers in the US about 5,000 to 6,000. We know there's around 4,000 hospital accounts, but only about half of those have had AH discharges of over 10 per year. So we're starting to get down through the funnel on what that concentrated target list may look like. But we're still pretty early in the analysis.

但我們知道，美國大約有 5,000 到 6,000 名肝病患者、胃病患者和高級實踐提供者。我們知道大約有 4,000 個醫院賬戶，但其中只有大約一半的 AH 每年出院人數超過 10 人。因此，我們開始深入了解集中目標列表的情況。但我們的分析還處於早期階段。

I think we've talked about on previous calls, a sales force roughly somewhere between 50 and 100, I think. would be ample to cover the United States for a rare disease, hospital-based disease like AH. And we continue to work through on pace of what our commercial planning looks like. We'll talk a little bit more about that at next Tuesday's KOL event as well.

我想我們在之前的電話會議中已經討論過，銷售人員大約在 50 到 100 人之間。足以覆蓋美國罕見病、醫院疾病（如 AH）的費用。我們將繼續按照商業規劃的節奏進行工作。我們也會在下週二的 KOL 活動中詳細討論這一點。

But we do have a pretty good understanding of where the targets may be and where those high volume tertiary liver transplant sites may be and start to think about [tiering] structures and how that might influence the construction of a field sales force and commercial organization would look like.

但我們確實對目標可能在哪里以及那些大容量三級肝移植地點可能在哪裡有很好的了解，並開始考慮[分層]結構以及這可能如何影響現場銷售隊伍和商業組織的建設看起來像。

Great, Keith. Thanks for that. I appreciate it. And I look forward to more details on Tuesday.

太棒了，基思。感謝那。我很感激。我期待週二獲得更多細節。

One additional question, if I may, is just around the primary endpoint. Obviously, 90-day mortality and reduction in transplant. But we know, as you mentioned, Jim, that AH natural history is about 26% mortality rate at 28 days. Do you have any measures for the rate of transplants for AH patients?

如果可以的話，還有一個問題是關於主要終點的。顯然，90 天死亡率和移植次數減少。但我們知道，正如您所提到的，Jim，AH 自然史是 28 天死亡率約為 26%。你們對於AH患者的移植率有什麼措施嗎？

Great question, and I'll let Norman speak to it a little bit after I'm done. Unfortunately, they're just -- the bottom line is there aren't enough livers to go around. There about 9,000 livers available for transplant in the United States across the entire country. We know there are 150,000 hospitalizations in 2024 for AH, and then we estimate that about 120,000 patients represent those 150,000 hospitalizations, with some coming back again.

這是一個很好的問題，我回答完之後我會讓諾曼談談這個問題。不幸的是，他們只是——底線是沒有足夠的肝臟可供使用。美國全國約有 9,000 個肝臟可供移植。我們知道 2024 年將有 150,000 例 AH 住院患者，然後我們估計這 150,000 例住院患者中約有 120,000 名患者，其中一些患者會再次回來。

So 120,000 patients, 9,000 transplants, well, they aren't -- they don't all go to AH. In fact, it's estimated that about half of those 9,000 transplanted livers go to people with alcohol-associated liver disease. The other half go to people who -- remaining viral patients and inherited diseases like Wilson's and PSC and some obviously to NASH patients as well.

所以 120,000 名患者，9,000 例移植手術，嗯，他們沒有——他們並沒有全部都去 AH。事實上，據估計，這 9,000 個移植肝臟中約有一半捐給了患有酒精相關肝病的人。另一半則分配給那些仍然患有病毒性疾病和遺傳性疾病（例如威爾遜氏病和 PSC）的人，還有一些顯然也分配給 NASH 患者。

So you've got about half of those, about 4,500, going to patients with alcohol-associated liver disease. And somewhere between a half and a third of that remaining that 4,500 go to AH patients, which means you're talking about somewhere around 2,000 patients being -- having livers available to them out of 120,000. So it's just that the numbers aren't there.

因此，其中大約一半（大約 4,500 名）將用於治療與酒精相關的肝病患者。剩下的 4,500 名患者中，有一半到三分之一流向了 AH 患者，這意味著大約 2,000 名患者在 120,000 名患者中擁有可用的肝臟。所以只是數字不存在。

And I know Norman can speak much more eloquently than I can with regard to this.

我知道諾曼在這方面比我能說得更雄辯。

I don't know about eloquently. But that is -- as you know, it's a moving target because transplanting people for AH is a fairly recent development and is sort of gaining popularity. And previously, people didn't want to admit they were transplanting them because there was sort of this general feeling that you needed six months of sobriety.

我不知道口才。但正如你所知，這是一個不斷變化的目標，因為為 AH 移植人員是一個相當新的發展，並且正在變得越來越受歡迎。以前，人們不想承認他們正在移植它們，因為人們普遍感覺你需要六個月的清醒。

And so, there was tremendous underreporting and that was shown in a very nice paper by Brian Lee. Since then, there has been general acceptance. There's growing -- actually, UNOS has now created a special category for alcohol-associated hepatitis. So we'll get more accurate numbers going forward, but right now, we don't know the exact number.

因此，存在嚴重的漏報情況，布萊恩·李（Brian Lee）在一篇非常好的論文中展示了這一點。從那時起，就得到了普遍的接受。事實上，UNOS 現在已經為酒精相關性肝炎創建了一個特殊類別。因此，我們將獲得更準確的數字，但現在我們不知道確切的數字。

And as Jim said, we think -- I think speaking to my colleagues that it's approximately a third to a half of the people attributed to alcohol. And alcohol makes up about half of the transplant volume of that 9,000 patients that are transplanted. And then getting to the endpoint, it does obscure to the 26% and 30% you mentioned is sort of an all comers.

正如吉姆所說，我們認為——我認為與我的同事交談時，大約有三分之一到一半的人歸因於酒精。在這 9,000 名接受移植的患者中，酒精約佔移植量的一半。然後到達終點，它確實對你提到的 26% 和 30% 來說是模糊的。

So if you just take a general population of AH, you should expect 30%, and that has been shown in multiple studies. But when you deal with a transplant center, they tend to see people in the higher ranges. And so the mortality of patients with a MELD of say 25 is more like 40%. And so you see higher mortality as you go up -- as your admission MELD score goes up.

因此，如果您只考慮 AH 的一般人群，您應該預期 30%，這已在多項研究中得到證實。但當你與移植中心打交道時，他們往往會看到級別較高的人。因此，MELD 為 25 的患者的死亡率更像是 40%。因此，隨著您的入學 MELD 分數的上升，您會看到更高的死亡率。

Yeah, I would add also from a pharmacoeconomic standpoint. So if we take a rough guesstimate of the number Norman just gave us, say it's close to 2,000. We know transplants can cost close to $1 million each. So you're talking about somewhere in the range of about a $2 billion check that has been written for that piece. And then the other component, the hospitalization, we think, represents probably $7 billion to maybe $8 billion as well. So it's a substantial cost to the healthcare system, for sure.

是的，我還想從藥物經濟學的角度補充一下。因此，如果我們粗略地估計諾曼剛剛給我們的數字，那就是接近 2,000。我們知道每次移植的費用接近 100 萬美元。所以你說的是為那件作品開出的大約 20 億美元的支票。我們認為，另一個組成部分，即住院治療，也可能代表 70 億至 80 億美元。因此，這對醫療保健系統來說無疑是一筆巨大的成本。

That's very helpful. Thank you so much.

這非常有幫助。太感謝了。

Sure.

當然。

Francois Brisebois, Oppenheimer.

弗朗索瓦·布里斯布瓦，奧本海默。

All right, thanks for taking the question. Just a couple here. Just in terms of the inclusion criteria, just to touch on the MELD score and the severity, can you remind us the difference between the Phase 2a and the Phase 2b in terms of severity of patients? And also from the cross comparisons either with Louisville or DASH, can you also touch on the severity of those patients and I guess the implications of the changes in severity in the Phase 2b? Thank you.

好的，感謝您提出問題。這裡只有一對夫婦。就納入標準而言，就MELD評分和嚴重程度而言，您能否提醒我們2a期和2b期在患者嚴重程度方面的區別？另外，從與 Louisville 或 DASH 的交叉比較中，您能否談談這些患者的嚴重程度以及我猜 2b 期嚴重程度變化的影響？謝謝。

Yeah, sure. And just straight up, we're taking severe patients. So these are patients -- in the AHFIRM trial, they range in MELD from 21 to 30, which match exactly with the severe patients we had in our Phase 2a trial.

好，當然。直接說，我們正在收治重症患者。這些患者在 AHFIRM 試驗中，MELD 範圍為 21 至 30 名，這與我們在 2a 期試驗中的重症患者完全匹配。

And to put that into some perspective, if you got a MELD of 21, you've got about a 20 -- say, 25%, 26%, maybe to 30% chance of dying in the next 90 days. And if you go to a MELD of 30, it's 60%. And as Norman says, in the mid-range in the 24 to 25, it's 40%. And so it's obviously a huge problem.

從某種角度來看，如果您的 MELD 為 21，那麼您在未來 90 天內死亡的可能性約為 20%、26%，甚至 30%。如果 MELD 為 30，則為 60%。正如 Norman 所說，在 24 到 25 歲的中間範圍內，這一比例為 40%。所以這顯然是一個大問題。

And as far as the consortium goes, what we tried to do is pick patients who would have matched for our study. That was the objective there to get like and like. And then we had to have patients who -- we're doing a 28-day comparison, so they had to be alive at 28 days. So we had to not count the DASH patients that died.

就該聯盟而言，我們試圖做的是挑選與我們的研究相匹配的患者。這就是獲得喜歡和喜歡的目標。然後我們必須對患者進行 28 天的比較，因此他們必須在 28 天時還活著。因此，我們必須不計算死亡的 DASH 患者。

And there were a number that unfortunately died before 28 days that aren't counted in there because they don't have 28-day [enzyme] data or score data at all. And what we saw was their survivors versus ours and all of ours survived. We still saw, to my eye, improvements in liver function and the like that looked like we had patients who were in a better space.

還有一些不幸在 28 天之前死亡的人數沒有被計算在內，因為他們根本沒有 28 天的[酶]數據或分數數據。我們看到的是他們的倖存者與我們的倖存者，而我們所有人都倖存下來。在我看來，我們仍然看到肝功能的改善等，看起來我們的病人的情況更好了。

I don't know, Norman or WeiQi, you got anything to add?

不知道 Norman 或 WeiQi，你們有什麼要補充的嗎？

I think that accurately stages the -- when you look at the paper, remember that the patients in the DASH trial, the subjects in the DASH consortium, had to survive 28 days. So any patients who died prior to that were censored out of it. And even with that, you see better survival. And what was really impressive is how much their biochemistry was better, including their markers of liver injury, bilirubin and MELD scores. Well, MELD scores, it's a bit more complicated. But survival and bilirubin were significantly better.

我認為這準確地描述了——當你看這篇論文時，請記住 DASH 試驗中的患者，即 DASH 聯盟中的受試者，必須存活 28 天。因此，任何在此之前死亡的患者都被排除在外。即使這樣，你也會看到更好的生存。真正令人印象深刻的是他們的生化指標有了明顯改善，包括肝損傷標誌物、膽紅素和 MELD 評分。嗯，MELD 分數，有點複雜。但存活率和膽紅素明顯更好。

Great, thank you. And if I could just ask one last one. And so in terms of -- as the comment to the previous answer about the doses used, is it fair to assume you don't necessarily expect a dose response here? Correct?

太好了謝謝。如果我能問最後一個問題就好了。因此，正如對之前有關所用劑量的答案的評論一樣，假設您不一定期望此處出現劑量反應是否公平？正確的？

We might -- I mean, we're doing the study in order to determine that. We couldn't get enough information out of the small number of patients in the Phase 2a, so we're doing this trial to understand those. And I certainly hope we can distinguish between the two doses, but I think it remains to be seen.

我們可能——我的意思是，我們正在進行研究以確定這一點。我們無法從 2a 期的少數患者那裡獲得足夠的信息，因此我們正在進行這項試驗來了解這些信息。我當然希望我們能夠區分這兩種劑量，但我認為這還有待觀察。

I don't know, WeiQi, what would you say to that?

不知道，偉奇，你對此有何看法？

Well, absolutely, I think that's what, Jim, you answered probably. So right, we'll have to see that -- these two doses.

嗯，當然，我想吉姆，你可能會這麼回答。是的，我們必須看看這兩個劑量。

Yeah, we just don't know.

是的，我們只是不知道。

Yeah.

是的。

Understood.

明白了。

I'll be happy -- if either one wins, I'm really happy. So I'll take either one or both.

我會很高興——如果任何一個贏了，我真的很高興。所以我會選擇其中之一或兩者。

Yeah.

是的。

Fair, thank you.

公平，謝謝。

Sean Kim, JonesTrading.

肖恩·金，瓊斯交易公司。

Thank you for taking my questions. I just have a few questions, one on the science and couple on commercial. So I guess my first question is that based on your further analysis of the Phase 2a study, just curious to hear your thoughts around some patients requiring second dose of larsucosterol to see if there was any differences in terms of demographic characteristics of these patients or their ultimate clinical outcomes versus those who received only one dose.

感謝您回答我的問題。我只有幾個問題，一個是關於科學的，還有幾個是關於商業的。所以我想我的第一個問題是，根據您對 2a 期研究的進一步分析，我只是想听聽您對一些需要第二劑 larsucosterol 的患者的想法，看看這些患者的人口特徵或其特徵是否有任何差異。最終的臨床結果與僅接受一劑的患者相比。

And kind of tying that into the commercial, if you think about potentially commercializing the product, your thoughts around potential pricing whether it'll be per dose basis or per treatment? Thank you.

如果您考慮將產品商業化，您對潛在定價的想法是按劑量還是按治療？謝謝。

Sure. Well, I'll take it first and certainly ask WeiQi to comment as well and then obviously Keith on the second.

當然。好吧，我會先接受，當然也會請 WeiQi 發表評論，然後顯然是 Keith 發表評論。

I think the first thing is important to note that, we didn't have very many second doses even in the severe patients, just a small number. And because it was the first testing of this drug in AH patients, I think early on, we had some physicians who were keeping their patients in the hospitals to enable a second dose just thinking they wouldn't give the drug its best chance, not really kind of considering the way it works.

我認為首先要注意的是，即使是重症患者，我們也沒有進行太多第二劑接種，只是少數。因為這是這種藥物在 AH 患者中的首次測試，我想在早期，我們有一些醫生將患者留在醫院，以便進行第二劑治療，只是認為他們不會給這種藥物最好的機會，而不是確實考慮了它的工作方式。

Outside of oncology, it's the first epigenetic modulator being developed in medicine. And so the whole concept that only a single dose might reset my epigenome and allow my organs to improve is a very different way of approaching and thinking about medicine. The way I think about it, for what it's worth, I think about it like a heart attack for the liver.

在腫瘤學之外，它是醫學領域開發的第一個表觀遺傳調節劑。因此，僅單次劑量就可以重置我的表觀基因組並讓我的器官得到改善的整個概念是一種非常不同的對待和思考醫學的方式。在我看來，無論它的價值如何，我認為它就像是肝臟的心髒病發作。

You've got a liver under stress. But if one can get over that acute stress circumstance, the liver does have great regenerative capacity, and this drug aids in that regard. But I think it's all about shoring it up, shoring the other organs up, so the body can begin to repair itself.

你的肝臟處於壓力之下。但如果一個人能夠克服這種急性應激環境，肝臟確實具有強大的再生能力，而這種藥物在這方面可以提供幫助。但我認為這一切都是為了支撐它，支撐其他器官，這樣身體就可以開始自我修復。

But, WeiQi, what are your thoughts around the second dose?

但是，WeiQi，你對第二劑有什麼想法？

Yeah, just like Jim mentioned that the epigenetic modulation typically, as we know, that the effect is relatively long lasting especially for DNMT1 inhibition. The effects theoretically would be even longer lasting than the DNMT3a and 3b inhibition. So larsucosterol inhibits all three, so the effect, we expect, will be relatively longer lasting than anti-inflammatory aging or anti-cell death aging, or just simply promoting the liver regeneration.

是的，就像 Jim 提到的，正如我們所知，表觀遺傳調節通常效果相對較長，尤其是對於 DNMT1 抑製而言。理論上，這種作用比 DNMT3a 和 3b 抑制更持久。因此，larsucosterol 會抑制這三種物質，因此我們預計，其效果將比抗炎衰老或抗細胞死亡衰老或僅僅促進肝臟再生更持久。

Now, talking about the liver regeneration, another factor with one or two doses is the liver is a very unique organ. It can regenerate. So it would otherwise, once you have the liver to overcome the acute episode, it would regenerate and then hopefully would recover the acute episode. These are the reasons why we only selected one or two doses for this particular indication.

現在，談論肝臟再生，一兩次劑量的另一個因素是肝臟是一個非常獨特的器官。它可以再生。所以否則的話，一旦你的肝臟克服了急性發作，它就會再生，然後有望恢復急性發作。這就是為什麼我們只針對這一特定適應症選擇一劑或兩劑的原因。

Thank you, WeiQi. And now, Keith maybe some thoughts around the one or two doses and commercialization? I know, at this point, we're a ways away from pricing. But maybe just give some general thoughts.

謝謝你，偉奇。現在，基思也許對一兩次劑量和商業化有一些想法？我知道，目前我們距離定價還有很長的路要走。但也許只是給出一些一般性的想法。

Yeah, sure. It's a good question. I would say, at this point, I would corroborate what Jim was saying. It's probably too early to say, although in our market access strategy meetings, this is certainly a topic of discussion. Obviously, the final decision is going to be influenced heavily by the AHFIRM results and looking at the cohort of patients and their outcomes that had one or two doses. But haven't run a similar analysis on previous drugs, pre-launch drugs that I've worked on.

好，當然。這是一個好問題。我想說，在這一點上，我會證實吉姆所說的話。儘管在我們的市場准入戰略會議上，這肯定是一個討論的話題，但現在說還為時過早。顯然，最終的決定將在很大程度上受到 AHFIRM 結果的影響，並觀察接受一劑或兩劑疫苗的患者群體及其結果。但還沒有對我之前研究過的藥物、上市前藥物進行類似的分析。

I will say it is challenging for pricing on a per treatment course basis as opposed on a per dose basis. You run into various issues like ASP, best pricing, and what have you, government discounts and the like. So while we have not made any kind of determined decisions on that, it is something that will take into effect the AHFIRM results and that will strongly have a heavy influence, like I said, on how we think about overall pricing and on a per treatment course versus per dose pricing arrangement.

我想說的是，按每個療程定價而不是按劑量定價是具有挑戰性的。您會遇到各種問題，例如平均售價、最佳定價以及政府折扣等。因此，雖然我們尚未就此做出任何決定，但這將影響 AHFIRM 結果，並且正如我所說，它將對我們如何考慮整體定價和每次治療產生重大影響。療程與每劑定價安排。

Okay, that's helpful. Thank you. And just one more question on the commercial side. So I guess you mentioned about 5,000 to 6000 hepatologists and gastros. Just wondering how many of those doctors are currently aware of larsucosterol and epigenetic regulator program in general? And how much effort you needed to bring these patients up-to-date on larsucosterol?

好的，這很有幫助。謝謝。還有一個關於商業方面的問題。所以我猜你提到了大約 5,000 到 6000 名肝病專家和胃腸病專家。只是想知道目前有多少醫生了解 larsucosterol 和表觀遺傳調節程序？您需要付出多少努力才能讓這些患者了解最新的 larsucosterol？

That's a great question. And I think I'd let Norman start and then I'll let Keith finish because I think that might [sullied] in perspective. So I'd love to hear this one. So, Norman?

這是一個很好的問題。我想我會讓諾曼開始，然後讓基思結束，因為我認為這可能會[玷污]觀點。所以我很想听聽這個。那麼，諾曼？

Right. Keith actually has data. So I'm just going to say that among my colleagues, I sort of have lived in the academic hepatology world which is a lose term for saying transplant centers. And among those colleagues, there is practically uniform knowledge of this trial.

正確的。基思實際上有數據。所以我只想說，在我的同事中，我有點生活在肝病學學術界，對於移植中心來說，這是一個失敗的術語。在這些同事中，對這次試驗的了解幾乎是一致的。

Keith has done a much more thorough job of looking at people sort of in what I would -- not meaning to sound pejorative but in sort of the next tier. And so, Keith, I would like you to take it from there.

基思（Keith）做了更徹底的工作，以我所希望的方式來看待人們——並不是說聽起來有貶義，而是下一層。所以，基思，我希望你從那裡開始。

Yeah, we've conducted some market research in the US, looking at unaided recall of various products in AH, and obviously there aren't too many that are under development. And certainly, the larsucosterol program is furthest along in 2b development. But I would corroborate what Norman was saying, in those hospitals that are typically transplant centers or academic referral centers with multiple hep and gastro specialists that have a particular interest in alcohol, I think the recall or the knowledge of our trial in larsucosterol is high.

是的，我們在美國進行了一些市場調查，研究了 AH 中各種產品的獨立召回情況，顯然正在開發的產品並不多。當然，larsucosterol 項目在 2b 開發中走得最遠。但我想證實諾曼所說的，在那些通常是移植中心或學術轉診中心、擁有多名對酒精特別感興趣的肝病和胃腸病專家的醫院中，我認為我們對 larsucosterol 試驗的回憶或了解很高。

However, when you look at the entire population of about 5,000 to 6,000 that I quoted earlier, that's inclusive of anybody because this is not a disease that is typically referred to only a handful of sites or only a handful of sites have AH specialists, if any hepatologists or gastroenterologists, they would have the training to treat AH. And so it is fairly spread out to our knowledge right now.

然而，當你看看我之前引用的大約 5,000 到 6,000 人的整個人口時，這包括了任何人，因為這不是一種通常只涉及少數站點或只有少數站點有 AH 專家的疾病，如果任何肝病學家或胃腸病學家，他們都會接受過治療 AH 的培訓。因此，它現在已經相當廣泛地傳播到我們的知識中。

And when you get out of those tertiary care centers and specialty sites that are still seeing AH patients, the recall is going to be a little bit lower. But therein lies the commercial opportunity, and why we're trying to understand what the baseline of that now particularly that's not too surprising given that there's nothing approved for AH and having worked in disease areas that have had little or no standard of care in other fatal diseases like in oncology, hematology, there's a lot -- there may be a number of things under development.

當你離開那些仍在收治 AH 患者的三級護理中心和專科場所時，召回率會稍微低一些。但這其中存在商業機會，以及為什麼我們試圖了解現在的基線是什麼，特別是考慮到沒有任何藥物被批准用於 AH，並且我們在其他疾病領域很少或沒有標準護理的疾病領域工作過，這並不奇怪。致命的疾病，比如腫瘤學、血液學，有很多——可能有很多東西正在開發中。

But until you hit a randomized controlled, clinical trial study endpoint, that doesn't really raise a flag for most people to start paying attention. I think if AHFIRM hits later this year, as we've talked about, we certainly will have a big flag to raise with that whole population of heps and gastros and advanced practice providers, and bring a lot of value to patients and to the AH community.

但在達到隨機對照臨床試驗研究終點之前，大多數人都不會真正開始關注。我認為，如果 AHFIRM 在今年晚些時候到來，正如我們所討論的那樣，我們肯定會向所有肝病患者、胃病患者和高級實踐提供者舉起一面大旗，並為患者和 AH 帶來很多價值社區。

Thank you very much.

非常感謝。

Thank you. There are no further questions at this time. I'd like to hand the floor back over to Jim Brown for any closing comments.

謝謝。目前沒有其他問題。我想將發言權交還給吉姆·布朗，讓其發表最後評論。

Okay. I just want to thank you all for participating today. And as always, if you have any further questions, please follow up. And we look forward to seeing hopefully a number of you in New York next Tuesday. Take care. See you soon. Bye.

好的。我只想感謝大家今天的參與。與往常一樣，如果您還有任何其他問題，請跟進。我們期待下週二在紐約見到你們中的一些人。小心。再見。再見。

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.

今天的會議到此結束。此時您可以斷開線路。感謝您的參與。