DURECT Corp (DRRX) 2023 Q2 法說會逐字稿

Greetings, and welcome to the DURECT Corporation Second Quarter Earnings Call.

您好，歡迎參加 DURECT 公司第二季財報電話會議。

(Operator Instructions)

（操作員說明）

As a reminder, this conference is being recorded.

提醒一下，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, Sir. You may begin.

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

Good afternoon, and welcome to DURECT Corporation's Second Quarter 2023 Earnings Conference Call. This is Tim Papp, Chief Financial Officer of DURECT.

下午好，歡迎參加 DURECT Corporation 2023 年第二季財報電話會議。我是 Tim Papp，DURECT 財務長。

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 the development of larsucosterol, expected product benefits, market potential, clinical trial results, regulatory approval and the company's financial projections. These forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements, including the risk that larsucosterol does not meet the endpoints in the AHFIRM trial. 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.

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 larsucosterol 的開發、預期產品效益、市場潛力、臨床試驗結果、監管部門批准和公司財務預測做出前瞻性陳述。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有重大差異，包括 larsucosterol 未達到 AHFIRM 試驗終點的風險。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 second quarter 2023 financial results. Our total revenue in the second quarter were $2.1 million, similar to the prior year. R&D expenses were $7.9 million compared with $8.8 million for the prior year. The decrease was primarily due to lower employee-related costs and contract research expenses, partially offset by higher costs associated with the AHFIRM trial and higher contract manufacturing costs. SG&A expenses were $3.8 million compared with $4 million for the prior year. This decrease was primarily due to lower patent expenses and recruiting costs.

首先，我想回顧一下我們 2023 年第二季的財務表現。我們第二季的總營收為 210 萬美元，與去年持平。研發費用為 790 萬美元，前一年為 880 萬美元。減少的主要原因是與員工相關的成本和合約研究費用減少，但部分被 AHFIRM 試驗相關成本增加和合約製造成本增加所抵消。 SG&A 費用為 380 萬美元，而前一年為 400 萬美元。這一下降主要是由於專利費用和招聘成本降低。

As of June 30, 2023, we had cash and investments of $34.9 million as opposed to $43.6 million at December 31, 2022. Subsequent to the end of the quarter, in July 2023, we completed a registered direct offering, raising $13.8 million in net proceeds. Our cash burn in the second quarter was approximately $10.1 million, excluding proceeds from sales under our ATM program, and we believe our cash on hand is sufficient to fund operations through mid-2024.

截至2023 年6 月30 日，我們擁有現金和投資3,490 萬美元，而截至2022 年12 月31 日為4,360 萬美元。本季末後，即2023 年7 月，我們完成了註冊直接發行，淨籌集1,380萬美元收益。我們第二季的現金消耗約為 1,010 萬美元，不包括 ATM 計畫下的銷售收益，我們相信我們手頭上的現金足以為 2024 年中期的營運提供資金。

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

現在，我想將電話轉給我們的執行長吉姆布朗，以了解我們計劃的最新情況。

Thank you, Tim. Hello, everyone. Thank you for joining us today for our second quarter 2023 update.

謝謝你，提姆。大家好。感謝您今天加入我們的 2023 年第二季更新。

We had a productive second quarter, during which we achieved a significant milestone on our journey toward completing the AHFIRM Phase IIb clinical trial for larsucosterol and alcohol-associated hepatitis. In June, we announced that we had completed enrollment for AHFIRM, and we continue to be on track to report top line data in the fourth quarter of this year. We are eagerly anticipating this event, which we believe has the potential to be transformative for DURECT and our shareholders.

我們度過了富有成效的第二季度，在完成 larsucosterol 和酒精相關性肝炎的 AHFIRM IIb 期臨床試驗的過程中，我們實現了一個重要的里程碑。 6 月，我們宣布已完成 AHFIRM 的註冊，並且我們將繼續按計劃在今年第四季度報告營收數據。我們熱切期待這一事件，我們相信這有可能為 DURECT 和我們的股東帶來變革。

Our primary focus as a company remains gaining approval for larsucosterol and AH, and bringing this potentially life-saving therapeutics to patients with no effective treatment options today. Assuming a positive outcome from AHFIRM, we plan to review the results with the FDA in the first quarter of 2024. If approved, larsucosterol would be the first FDA-approved treatment for AH, and we look forward to the possibility of bringing this potentially life-saving therapeutics to patients with no effective therapies available today.

作為一家公司，我們的主要關注點仍然是獲得 larsucosterol 和 AH 的批准，並將這種可能挽救生命的療法帶給當今沒有有效治療選擇的患者。假設 AHFIRM 取得積極成果，我們計劃在 2024 年第一季與 FDA 審查結果。如果獲得批准，larsucosterol 將成為 FDA 批准的第一個 AH 治療方法，我們期待有可能為這種潛在的生命帶來希望-為目前沒有有效治療方法的患者節省治療方法。

Furthermore, during the second quarter, the American Journal of Gastroenterology published clinical data from our Phase IIa trial in AH, and we held an AH-focused KOL event. Lastly, we're excited to announce the expansion of our epigenetic modulator platform into the field of oncology. By leveraging our expertise in epigenetic modulation, we have internally developed multiple new chemical entities that we think have attractive properties for the potential treatment of both solid and liquid tumor types.

此外，第二季度，《美國胃腸病學雜誌》發表了我們在 AH 的 IIa 期試驗的臨床數據，我們還舉辦了一場以 AH 為重點的 KOL 活動。最後，我們很高興地宣布我們的表觀遺傳調節劑平台擴展到腫瘤學領域。透過利用我們在表觀遺傳調節方面的專業知識，我們在內部開發了多種新的化學實體，我們認為這些化學實體對於實體和液體腫瘤類型的潛在治療具有有吸引力的特性。

I'll come back to our new oncology program in a few minutes. But first, I'd like to provide a quick refresher on our AH program as we get closer to the upcoming data readout.

幾分鐘後我將回到我們的新腫瘤學課程。但首先，隨著即將到來的數據讀出，我想快速回顧一下我們的 AH 程式。

As I mentioned, we completed enrollment in our AHFIRM trial in June of this year. We follow these patients for 90 days, so our last patient's last visit will be in early September, which puts us on track to report top line data in the fourth quarter. As a reminder, AHFIRM is a placebo-controlled, double-blind, multinational study with 2 active dosing arms and a placebo arm of approximately 100 patients each. In total, we randomized and dosed 301 patients with severe AH, which are patients with MELD scores ranging from 21 to 30 and Maddrey Discriminate Function scores greater than or equal to 32.

正如我所提到的，我們在今年 6 月完成了 AHFIRM 試驗的註冊。我們對這些患者進行了 90 天的跟踪，因此最後一位患者的最後一次就診將在 9 月初，這使我們有望在第四季度報告頂線數據。需要提醒的是，AHFIRM 是一項安慰劑對照、雙盲、跨國研究，有 2 個主動給藥組和一個安慰劑組，每組約有 100 名患者。總共，我們對 301 名嚴重 AH 患者進行了隨機分組和給藥，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。

The primary endpoint for AHFIRM is the difference in mortality or liver transplant at 90 days between larsucosterol treatment and placebo. We enrolled patients in AHFIRM through a global network of clinical sites, including leading hospitals in the United States, Australia, the EU and the U.K. Our sites include renowned liver centers, and we are working with some of the world's preeminent thought leaders in AH.

AHFIRM 的主要終點是 larsucosterol 治療和安慰劑之間 90 天死亡率或肝臟移植的差異。我們透過全球臨床中心網絡將患者納入 AHFIRM，其中包括美國、澳大利亞、歐盟和英國的領先醫院。我們的中心包括著名的肝臟中心，我們正在與 AH 領域的一些世界傑出思想領袖合作。

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 patients. Our confidence that the AHFIRM trial will be successful is supported by our compelling Phase IIa 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 studies where we observed a profound survival benefit in multiple relevant acute organ injury models.

FDA 已授予我們的 larsucosterol AH 計畫快速通道資格，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，因為患者的需求尚未得到滿足。我們對AHFIRM 試驗將成功的信心得到了令人信服的IIa 期研究數據的支持，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，以及我們觀察到的多項臨床前動物研究在多種相關的急性器官損傷模型​​中具有深遠的生存益處。

We designed AHFIRM to be a potentially pivotal trial based on our Phase IIa data. In our open-label Phase IIa trial, all 19 patients survived at 28 days, an encouraging result given that based on historical data, approximately 26% of hospitalized AH patients are expected to die within 28 days. We also observed a consistent improvement in key biochemical markers, including bilirubin level, MELD score and Lille scores across patients and doses.

我們根據 IIa 期數據將 AHFIRM 設計為潛在的關鍵試驗。在我們的開放標籤 IIa 期試驗中，所有 19 名患者在 28 天時存活，這是一個令人鼓舞的結果，因為根據歷史數據，大約 26% 的住院 AH 患者預計將在 28 天內死亡。我們還觀察到關鍵生化標記的持續改善，包括不同患者和劑量的膽紅素水平、MELD 評分和 Lille 評分。

In the second quarter, the data from our Phase IIa trial were published in the American Journal of Gastroenterology. This peer-reviewed article includes cross-study comparisons with well-matched severe AH patients from a contemporaneous trial conducted by the Defeat Alcoholic Steatohepatitis or DASH Consortium. While the sample sizes were small and these 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 significant lower Lille scores compared to patients treated with the standard of care, including steroids.

第二季度，我們的 IIa 期試驗數據發表在《美國胃腸病學雜誌》。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 聯盟同期進行的一項試驗中匹配的嚴重 AH 患者的交叉研究比較。雖然樣本量較小且不是對照研究的一部分，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 larsucosterol 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。

Lille scores, as a reminder, are a predictor of mortality in liver disease. In addition, liver enzymes levels decreased rapidly in the larsucosterol-treated patients, including a statistically significant reduction in the liver enzyme, ALT. We believe these results provide further evidence of the potential for larsucosterol as a treatment for AH.

提醒一下，裡爾評分是肝病死亡率的預測指標。此外，接受 larsucosterol 治療的患者的肝臟酵素水平迅速下降，其中肝臟酵素 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。

In May, we hosted a KOL event for our investors to provide physician perspectives on this devastating disease. We were pleased to be joined by Dr. Paul Gaglio from Columbia Presbyterian and Dr. Brett Fortune from Montefiore Einstein. They were able to draw from their wealth of experience treating AH patients and share their views on the unmet need in AH and the potential role larsucosterol could play to transform the treatment of this highly lethal disease. The slides and audio from this presentation are available on our website.

五月，我們為投資者舉辦了一場 KOL 活動，以提供醫生對這種毀滅性疾病的看法。我們很高興哥倫比亞長老教會的 Paul Gaglio 博士和 Montefiore Einstein 的 Brett Fortune 博士加入。他們能夠借鑒治療 AH 患者的豐富經驗，並分享他們對 AH 未滿足需求的看法，以及 larsucosterol 在改變這種高度致命疾病的治療方面可能發揮的潛在作用。本簡報的幻燈片和音訊可在我們的網站上取得。

During our KOL event, we shared additional information on the commercial opportunity for larsucosterol, and if we attain approval, our approach to building for a successful launch.

在我們的 KOL 活動中，我們分享了有關 larsucosterol 商業機會的更多信息，以及如果我們獲得批准，我們為成功推出而構建的方法。

In addition to its high mortality rate, AH represents a significant cost to the U.S. healthcare system, with over 150,000 hospitalizations attributed to AH at a cost of between $50,000 to $150,000 each. As a result, in addition to the potential saving of patients' lives, larsucosterol represents a potential multibillion-dollar opportunity in the United States alone that could simultaneously provide overall cost savings to the healthcare system.

除了高死亡率之外，AH 還為美國醫療保健系統帶來了巨大的成本，超過 150,000 例因 AH 住院，每次住院費用在 50,000 至 150,000 美元之間。因此，除了可以挽救患者的生命之外，larsucosterol 僅在美國就代表了潛在的數十億美元的機會，同時為醫療保健系統節省總體成本。

We've begun to lay the groundwork for potentially commercializing larsucosterol in the United States and believe we can launch the product effectively through a moderately-sized hospital-focused sales force. We also continue to build awareness around the role of epigenetic regulation in acute diseases like AH.

我們已經開始為在美國潛在的 larsucosterol 商業化奠定基礎，並相信我們可以透過中等規模的以醫院為中心的銷售團隊有效地推出該產品。我們也持續提高人們對表觀遺傳調控在 AH 等急性疾病中作用的認識。

As one of these initiatives, we launched a new disease education website that you can find at www. exploreahepigenetics.com to elucidate the role of the epigenome in AH.

作為這些舉措之一，我們推出了一個新的疾病教育網站，您可以在 www. exploreahepigenics.com 闡明表觀基因組在 AH 中的作用。

AH is also a global concern, allowing larsucosterol the potential to serve ex-U.S. AH patients and their healthcare system. These ex-U.S. markets represent additional attractive commercial 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. We are also pleased to announce the expansion of our epigenetic modulation platform into the field of oncology. Our mission at DURECT is to be a global leader in the emerging field of epigenetic medicine, and this latest development is a significant step towards achieving that goal. Aberrant DNA methylation has been shown to play an important role in the development of tumors. As a result, we believe DNMT inhibitors have significant potential as a drug class for the treatment of cancer.

AH 也是一個全球性的問題，這使得 larsucosterol 有可能在美國以外的地區服務。 AH 患者及其醫療保健系統。這些前美國市場代表著額外有吸引力的商業機會。由於我們從全球站點網路招募患者，因此我們相信 AHFIRM 的正面結果可能會支持 EMA 和其他地區的監管備案。我們也很高興地宣布將我們的表觀遺傳調節平台擴展到腫瘤學領域。我們 DURECT 的使命是成為表觀遺傳醫學新興領域的全球領導者，這項最新進展是實現這一目標的重要一步。異常的 DNA 甲基化已被證明在腫瘤的發展中發揮重要作用。因此，我們相信 DNMT 抑制劑作為一類治療癌症的藥物具有巨大潛力。

Building on our knowledge of epigenetic regulation and our unique understanding of DNMTs, we have focused on a novel approach to DNMT inhibition. The inhibition of DNMT is a well-established and highly desired target in oncology. Working with teams of experienced chemists and biologists, we have created a large complement of internally developed novel small molecule DNMT inhibitors that exhibit broad spectrum activity against multiple liquid and solid tumor types. We currently have multiple new chemical entities that are in preclinical development for a variety of oncology applications. These compounds display unique and desirable physiochemical properties and pharmacokinetic profile as well as favorable tolerability. By the end of 2023, we intend to select a product candidate to advance into clinical trials in cancer patients. Our goal for this program is to be prepared to initiate clinical trials by the end of 2024.

基於我們對錶觀遺傳調控的知識和對 DNMT 的獨特理解，我們專注於抑制 DNMT 的新方法。 DNMT 的抑制是腫瘤學中公認的且非常理想的標靶。我們與經驗豐富的化學家和生物學家團隊合作，創建了大量內部開發的新型小分子 DNMT 抑制劑，這些抑制劑對多種液體和實體瘤類型表現出廣譜活性。我們目前擁有多種新的化學實體，正處於臨床前開發階段，用於各種腫瘤學應用。這些化合物表現出獨特且理想的理化性質和藥物動力學特徵以及良好的耐受性。到 2023 年底，我們打算選擇一種候選產品進入癌症患者的臨床試驗。我們該計劃的目標是在 2024 年底前準備好啟動臨床試驗。

In summary, we completed AHFIRM enrollment in the second quarter and are on track to report top line results in the fourth quarter of 2023. If AHFIRM is successful, we intend to review the results with the FDA in the first quarter of 2024. We are leveraging our knowledge of epigenetic regulation to the field of oncology and look forward to selecting a lead product candidate from our NCE development program and advancing into the clinic.

總而言之，我們在第二季度完成了 AHFIRM 註冊，並預計在 2023 年第四季度報告頂線結果。如果 AHFIRM 成功，我們打算在 2024 年第一季與 FDA 審查結果。我們正在將我們在表觀遺傳調控方面的知識運用到腫瘤學領域，並期待從我們的NCE 開發計劃中選擇領先的候選產品並進入臨床。

We would now like to take any questions you may have.

我們現在願意回答您可能提出的任何問題。

(Operator Instructions)

（操作員說明）

Our first question is from Kristen Kluska with Cantor Fitzgerald.

我們的第一個問題是克里斯汀·克魯斯卡和坎托·菲茨杰拉德提出的。

This is Rick on for Kristen. Maybe first on the oncology program you talked about today. Is there any color you can give us into the screening process that you've gone through with these library of molecules in terms of how large the library was? And maybe kind of where you're adding your screening process in terms of the magnitude of different molecules here?

這是克里斯汀的瑞克。也許首先是你今天談到的腫瘤學計畫。您能否向我們介紹一下您對這些分子庫進行的篩選過程，即庫有多大？也許您在這裡根據不同分子的大小添加篩選過程？

We probably won't give that kind of detail, but just sufficient to say we screened a large number of cancers against a large number of molecules and we have actually, from there, pared it down into the group that the initial class is graduating that we're taking forward. So we have -- we're very close in between now and end of the year. We'll select the first cancer and first drug that we're taking forward.

我們可能不會提供此類細節，但足以說明我們針對大量分子篩選了大量癌症，並且實際上，從那裡開始，我們將其縮減為第一批即將畢業的群體我們正在前進。所以，從現在到年底，我們已經非常接近了。我們將選擇我們正在推進的第一種癌症和第一種藥物。

Excellent. You also mentioned ex-U.S. opportunities for larsucosterol. So just as you're thinking about kind of ex-U.S. opportunities, is there any development kind of in thinking about whether you'd be looking at ex-U.S. commercial partners? Or how are you thinking about that process?

出色的。您也提到了美國以外的地區larsucousterol 的機會。所以就像你正在考慮某種前美國一樣機會，在考慮您是否會考慮美國以外的地區時，是否有任何發展？商業夥伴？或者你是如何看待這個過程的？

Yes, we certainly wouldn't be looking to commercialize it ourselves ex-U.S. We think the opportunity is, from a patient number standpoint, I think Western Europe is probably equivalent to or a bit larger than the U.S. patient population size. And so we think it's an exciting opportunity, and these patients are in as desperate need as they are here in the United States. So the opportunity is absolutely there, and we're looking to put a partnership in place actually.

是的，我們當然不會尋求在美國以外的地區將其商業化。我們認為，從患者數量的角度來看，西歐的患者人數可能相當於或略大於美國的患者人數。因此，我們認為這是一個令人興奮的機會，這些患者和美國的患者一樣迫切需要幫助。因此，機會絕對存在，我們正在尋求實際建立合作夥伴關係。

And I'll let Keith, who's on the line as well, maybe speak a little bit more to that.

我會讓同樣在線的基思對此多說一點。

Yes. I would just add that given the diversity of the reimbursement pricing and various other regulatory factors in Europe and other ex-U.S. markets. it's likely that we would look for a formidable partnership there. So I agree with Jim's comments there, and there's certainly an equal, if not potentially larger marketplace outside of just the U.S. where we think larsucosterol could achieve prominence there. AH is not regional to just the U.S., so it certainly is a global issue.

是的。我想補充一點，考慮到歐洲和美國以外其他地區的報銷定價和各種其他監管因素的多樣性。市場。我們很可能會在那裡尋找強大的合作關係。因此，我同意吉姆的評論，除了美國之外，肯定存在一個平等的、甚至可能更大的市場，我們認為 larsucosterol 可以在那裡取得突出的地位。 AH 不僅僅是美國的地區性問題，因此它肯定是一個全球性問題。

Okay. And maybe 1 more. Maybe we'll swing back to the oncology program, just to ask, given the different indications with potential for DNMT inhibitors, can you talk a little bit about the decision-making process that led to undertaking in oncology specifically? And maybe also touch on whether there could be different indications for larsucosterol down the road, as you've talked about in the past?

好的。也許還有 1 個。也許我們會回到腫瘤學項目，只是想問一下，考慮到 DNMT 抑制劑潛在的不同適應症，您能具體談談導致腫瘤學項目的決策過程嗎？也許還可以談談，正如您過去談到的那樣，larsucotosterol 是否可能有不同的適應症？

Yes. First, I just stay with larsucosterol, because that is the main theme here at DURECT. And so, yes, we, obviously, looking at AH, but as we've talked about in the past, we've done about a dozen different animal models where we've shown it can protect against multi-organ damage from things as broad ranging as acute pancreatitis, sepsis, stroke, acute kidney injury, things like that, so there's a lot of opportunity there as well. As you know, we did the 1-month study in NASH, where we showed tremendous potential as well for larsucosterol.

是的。首先，我只選擇 larsucosterol，因為這是 DURECT 的主題。所以，是的，我們顯然正在研究 AH，但正如我們過去談到的，我們已經做了大約十幾種不同的動物模型，我們已經證明它可以防止多器官損傷，例如範圍廣泛，如急性胰臟炎、敗血症、中風、急性腎損傷等，所以那裡也有很多機會。如您所知，我們對 NASH 進行了為期 1 個月的研究，其中我們顯示了 larsucosterol 的巨大潛力。

As far as the oncology program, what we're doing here is we often get a question from shareholders, kind of what is next outside of larsucosterol. And so it's a program that WeiQi has been guiding for a number of years now and has finally gotten to the point where we're ready to bring things into development, and that's why we're talking about it at this point in time.

就腫瘤學計畫而言，我們在這裡所做的是我們經常收到股東的提問，類似於除了 larsucosterol 之外的下一步是什麼。因此，這是 WeiQi 多年來一直在指導的一個項目，並最終達到了我們準備將其投入開發的階段，這就是我們此時此刻談論它的原因。

Certainly, DNMTs are important targets for various cancers in the hematology space. Currently, we think we have potential advantages over the azacitidines and decitabines in the world because of tolerability, because of dosing, because of a whole number of advantages that we see, at least to date. And we think we can expand the use of DNMTs into beyond liquid tumors but into the solid tumor space as well.

當然，DNMT 是血液學領域各種癌症的重要標靶。目前，我們認為我們比世界上的阿扎胞苷和地西他濱具有潛在優勢，因為耐受性、劑量、至少迄今為止我們看到的一系列優勢。我們認為我們可以將 DNMT 的使用擴展到液體腫瘤以外的領域，也可以擴展到實體腫瘤領域。

Our next question comes from François Brisebois with Oppenheimer.

我們的下一個問題來自弗朗索瓦·布里斯布瓦和奧本海默。

Can you maybe remind us the differences in trial design between the Phase IIa and the Phase IIb?

您能否提醒我們 IIa 期和 IIb 期試驗設計的差異？

That's a great question. Good to hear from you, by the way. Yes, there really aren't many. The -- first, if you look at dosing, it's the same. We dose the patients on day 1 and then they get another dose on day 3. In the first trial, we allowed steroids to be used. In this trial, we didn't want the confusion -- potential confusion of steroid side effects to be laid upon the shoulders of larsucosterol. So we've set up this double-blind, double-dummy arrangement so that if I get placebo, then I get a capsule that would have active steroids. If I get 1 of the 2 doses of larsucosterol, then I would receive a placebo capsule instead. So that is 1 difference.

這是一個很好的問題。順便說一句，很高興收到你的來信。是的，確實沒有很多。首先，如果你看一下劑量，你會發現是一樣的。我們在第一天給患者服用藥物，然後他們在第三天再服用一劑。在第一個試驗中，我們允許使用類固醇。在這次試驗中，我們不希望將類固醇副作用的潛在混淆歸咎於拉糖甾醇。所以我們建立了這個雙盲、雙模擬的安排，這樣如果我得到安慰劑，那麼我就會得到一個含有活性類固醇的膠囊。如果我服用 2 劑 larsucosterol 中的 1 劑，那麼我會收到安慰劑膠囊。所以這是 1 的差異。

The other difference is the severity of the illness of the patients. In the first study, we had 2 components. We had the moderate patients, which were MELDs up to 21, and then we had the severe, which were 21 to 30. In this trial, all 301 patients that were dosed received -- excuse me, had MELD scores that started at MELD of 21 and could go as high as MELD of 30. And we followed for 90 days versus 28 days. So 90 days versus 28 days, all severe, and absolutely no steroids in larsucosterol group. And if the physician wanted, they could give steroids to their placebo patients in a blinded fashion.

另一個差異是患者病情的嚴重程度。在第一項研究中，我們有兩個組成部分。我們有中度患者，MELD 高達 21，然後我們有重度患者，MELD 為 21 至 30。在這項試驗中，所有 301 名接受給藥的患者 - 對不起，MELD 評分從 MELD 開始21，MELD 可能高達30 .我們追蹤了90 天，而不是28 天。所以 90 天與 28 天，都是嚴重的，在 larsucosterol 組中絕對沒有類固醇。如果醫生願意，他們可以以盲目的方式給安慰劑患者服用類固醇。

Can you just remind us the mortality rate at 28 days, what's historically known versus 90 days? And has that changed in the past?

您能否提醒我們 28 天的死亡率（歷史上已知的死亡率與 90 天的死亡率相比）是多少？過去情況有改變嗎？

No, it really hasn't changed really in the last 40 years, and it's been confirmed with this -- what was that 8,000 -- 7,000, 8,000 patients publication?

不，在過去的 40 年裡，它確實沒有真正改變，並且已經被證實了——那篇關於 8,000、7,000、8,000 名患者的出版物是什麼？

Yes. 1 in 2,000, 2,800.

是的。 2,000 分之一、2,800 分之一。

Yes, yes. So that's right. Yes. Yes. 2,800, okay. And so there was a 2,800-patient large publication that kind of spoke to it. But the mortality rate at 28 days has been historically 26%, and at 90 days, 30%. So you can see you're only adding another 4% over the last 2 months. So it's -- the majority of the damage is done, and the majority of the deaths occur early on.

是的是的。所以說是這樣的。是的。是的。 2,800，好吧。因此，有一份包含 2,800 名患者的大型出版物對此進行了闡述。但 28 天的死亡率歷史記錄為 26%，90 天的死亡率為 30%。因此，您可以看到在過去 2 個月中您只增加了 4%。所以，大部分傷害已經造成，而​​且大部分死亡發生在早期。

Our next question comes from Ed Arce with H.C. Wainwright.

我們的下一個問題來自 Ed Arce 和 H.C.溫賴特。

Can you hear me okay?

你聽得到我說話嗎？

We can.

我們可以。

Great. Okay. So first, I wanted to ask about your commercialization plans. The focus rightly has been for several years now on the development. And now that we're on the cusp of a readout, potentially enabling a filing, I wanted to ask if you could provide a little more details on your preparations at this stage? In particular, you mentioned moderately-sized, hospital-focused sales force. Are there any investments? I know you also mentioned the website. Any investments now into awareness for physicians or other things to sort of prime the market? And then I have 1 more.

偉大的。好的。首先，我想問一下你們的商業化計畫。多年來，人們一直將重點放在開發上。現在我們正處於宣讀的風口浪尖，可能會進行備案，我想問您是否可以提供有關現階段準備工作的更多細節？您特別提到了規模適中、以醫院為中心的銷售團隊。有投資嗎？我知道您也提到過該網站。現在是否有對醫生意識或其他方面的投資來推動市場？然後我還有 1 個。

Yes, we certainly are, and I'll let Keith speak to that.

是的，我們當然是，我會讓基斯談談這一點。

Yes. Thanks, Jim. Thanks for the question, Ed. On the commercialization front, surely, we've been doing -- we've had a number of efforts there. We have personnel that have launch experience, both on the medical affairs side and the marketing side, even though we are a small but mighty team. Jim mentioned in his remarks, the Explore AH Epigenetics, the disease awareness site that we launched late last year actually. And then we certainly, in the past couple of years, have had a live presence at the major international liver conferences.

是的。謝謝，吉姆。謝謝你的提問，艾德。當然，在商業化方面，我們一直在做——我們在那裡做了很多努力。儘管我們是一個小而強大的團隊，但我們在醫療事務方面和行銷方面都有具有啟動經驗的人員。 Jim 在演講中提到了 Explore AH Epi Genetics，這是我們去年年底推出的疾病意識網站。當然，在過去的幾年裡，我們也現場出席了主要的國際肝臟會議。

We're just coming off of presenting a poster actually at EASL in Austria just last month. We've been at both EASL and AASLD with booths. And last year, really, the focus was on AHFIRM awareness recruitment. Now that that's closed, we really have shifted gears into disease education. But we've certainly invested in various market research and market landscaping, understanding the unmet medical needs where a drug with larsucosterol's product profile could sit. And we explained some of those top line results when I presented at the KOL event in New York back in May. But we continue those launch readiness efforts.

上個月我們剛在奧地利的 EASL 上展示了一張海報。我們在 EASL 和 AASLD 上都設有展位。事實上，去年的重點是 AHFIRM 意識招募。現在一切都結束了，我們確實已經轉向疾病教育了。但我們確實投資了各種市場研究和市場景觀，了解具有 larsucosterol 產品特徵的藥物可能滿足的未滿足的醫療需求。當我五月在紐約舉行的 KOL 活動上發表演講時，我們解釋了其中一些重要結果。但我們會繼續這些發射準備。

Really, it's about putting plans in place internally to ensure all of our cross-functional groups are singing off the same hymn sheets on timelines, on budget, on expectations. And we certainly have a fully-integrated launch readiness plan that we work with both internal and external consultants on to ensure that everybody is moving at the same pace with the same expectations because every launch is different, every launch has its own challenges and obstacles. And really, it's going to take a village, both the folks at DURECT as well as our outside consultants.

實際上，這是在內部製定計劃，以確保我們所有的跨職能團隊都按照時間表、預算和期望唱出同樣的讚美詩。我們當然有一個完全整合的發布準備計劃，我們與內部和外部顧問合作，以確保每個人都以相同的速度和相同的期望前進，因為每次發布都是不同的，每次發布都有自己的挑戰和障礙。事實上，這需要整個團隊的努力，包括 DURECT 的人員以及我們的外部顧問。

But right now, between now and top line results, it's really about preparation and not overpreparing, if you will, but preparing at the right pace and having plans in place after top line results and after our interactions with FDA to execute what could be a very short time launch, if everything, [heads].

但現在，從現在到頂線結果，這實際上是關於準備，而不是過度準備，如果你願意的話，而是以正確的速度準備，並在頂線結果之後以及在我們與FDA 互動之後製定計劃來執行可能的計劃發射時間非常短，如果一切順利的話，[正面]。

Great. That's helpful, Keith. And maybe just a little bit further, wondering if you can discuss how you view the initial ramp of the launch? In particular, I know this is a very specific call point really dealing with hospital ICUs, and there's a lot of inertia with physicians changing therapies in general, but in particular, in high-stress situations like this. But on the other hand, you potentially have a therapy that is life-changing, could save lives. So I'm just wondering in the mix of that, how you think about the speed of ramp in regards to not only physicians but also payers?

偉大的。這很有幫助，基思。也許更進一步，想知道您是否可以討論一下您如何看待發布的初始階段？特別是，我知道這是一個非常具體的呼叫點，真正涉及醫院重症監護室，而且醫生通常會改變治療方法，但特別是在像這樣的高壓力情況下，存在著很大的惰性。但另一方面，您可能有一種可以改變生活、可以挽救生命的療法。所以我只是想知道，您如何看待醫生和付款人的成長速度？

Yes. I'll start and then I'll certainly have Keith continue. First of all, you're right and that these are hospitalized patients, oftentimes in the ICU. But these aren't patients who are typically going to die in the very, very near term or their outcome is going to be determined in the next 12 hours kind of thing, as you would get with stroke and sepsis and things like that. That was the reason we selected AH as the first acute indication for larsucosterol because one could take the time.

是的。我會開始，然後我一定會讓基斯繼續。首先，你是對的，這些都是住院患者，通常在加護病房。但這些患者通常不會在短期內死亡，或者他們的結果將在接下來的 12 小時內確定，就像中風和敗血症等類似疾病一樣。這就是我們選擇 AH 作為 larsucosterol 的第一個急性適應症的原因，因為需要時間。

And when you look at these other diseases that -- for which we've done a lot of preclinical work, there have been a history of more challenging clinical trials because of the variability one gets with patients. And here, we have the time to talk to these patients because -- and their families, because they're on a very slow, unrelenting train ride that leads to death in 30% of them.

當你觀察這些其他疾病時，我們已經針對這些疾病做了很多臨床前工作，因為患者的變異性，歷史上一直存在更具挑戰性的臨床試驗。在這裡，我們有時間與這些患者交談，因為——以及他們的家人，因為他們正在乘坐非常緩慢、無情的火車，這會導致 30% 的人死亡。

And just to witness on our first -- in our Phase IIa trial that was a man in his 30s at the San Diego site who was at another hospital for a month and was sent home on hospice to die, enrolled in our trial. The study coordinator commented how good he looked just a week or so after dosing. And last time I talked to Dr. Hassanein, he was just a gentleman who's alive 2 years -- more than 2 years later. So certainly, one has the time in the circumstance to be able to evaluate the patients.

我們的第一個 IIa 期試驗見證了聖地牙哥現場一名 30 多歲的男子參加了我們的試驗，他在另一家醫院住了一個月，被送回家接受臨終關懷直至死亡。研究協調員評論說，服藥後僅一周左右，他看起來就很好。上次我與哈薩因博士交談時，他只是一位還活著兩年的紳士──兩年多後。因此，當然，人們有時間在這種情況下能夠評估患者。

As far as the ramp and the like, we -- obviously, if you want more information on some of this information that Keith presented during our KOL event, we have what he discussed from ClearView, which is off of our website. But I'll let Keith kind of give a description of thoughts with regard to that.

至於坡道等，顯然，如果您想了解 Keith 在 KOL 活動期間提供的一些信息的更多信息，我們可以從 ClearView 中討論他的內容，該內容不在我們的網站上。但我會讓基斯描述一下對此的想法。

Yes. Ed, good question. As it relates to physicians, one of the outputs that we had from our commercial assessment earlier this year when we were looking at blinded target product profiles with data that we would assume would hit statistical significance for AHFIRM, we had very high willingness in that qualitative study from physicians to that product profile with a statistically significant overall survival or transplant primary end point, especially given a disease area like AH, where there are no drug approved and the SATO's standard of care being steroids that are only applicable in about 50% of patients that, that is suboptimal, never shown any kind of survival benefit past 28 days.

是的。艾德，好問題。由於它與醫生有關，這是我們今年早些時候商業評估的結果之一，當時我們正在研究盲法目標產品概況，其中的數據我們認為會對AHFIRM 產生統計顯著性，我們在定性方面有非常高的意願。醫生對具有統計顯著性總體生存或移植主要終點的產品概況進行研究，特別是考慮到像AH 這樣的疾病領域，該領域沒有批准藥物，並且SATO 的護理標準是類固醇，僅適用約50% 的患者在過去 28 天從未表現出任何存活獲益的次優患者。

So the willingness to prescribe from the physician standpoint, particularly in the AHFIRM patient population, the severe AH, MELD 20 to 30 range was very high. And so we think that the willingness to prescribe there and the ramp there could be significant. But we also cross-check that with the reality of the reimbursement environment and the DRG-driven reimbursement of hospital inpatient delivered drugs.

因此，從醫生的角度來看，特別是在 AHFIRM 患者群體、嚴重 AH、MELD 20 至 30 範圍內開藥的意願非常高。因此，我們認為在那裡開處方的意願和增長可能會很大。但我們也會根據報銷環境的實際情況以及按 DRG 驅動的醫院住院藥物報銷進行交叉檢查。

So we've done quite a lot of work as it relates, again, to the commercialization plan, particularly on the market access, understanding the landscape, looking at other, like, acute care in-hospital delivered products, and learning from what's worked and where the challenges have been understanding those obstacles and internally, working on developing strategies to positively influence those factors, understanding what we're -- what we have up against us for launch, and what we can do now to better understand that environment and what strategies we can deploy early. And certainly, after top line results, market access will be the initial focus for our commercialization strategic efforts.

因此，我們做了很多與商業化計劃相關的工作，特別是在市場准入、了解情況、研究其他醫院內提供的急症護理產品以及從行之有效的方法中學習挑戰在於了解這些障礙，並在內部製定策略以積極影響這些因素，了解我們是什麼——我們在推出時面臨什麼，以及我們現在可以做些什麼來更好地了解環境和我們可以儘早部署哪些策略。當然，在取得最高業績之後，市場准入將成為我們商業化策略努力的首要重點。

We can get out now, given some of the changes in the commercialization regulatory environment, that allows us to interact with hospitals and certain payers prior to the launch. And building those value propositions, those health economics and outcomes research models, that will be on top of mind for our commercial team to develop those and start those efforts even prior to our launch.

鑑於商業化監管環境的一些變化，我們現在可以退出，這使我們能夠在推出之前與醫院和某些付款人互動。建立這些價值主張、那些健康經濟學和結果研究模型，這將是我們商業團隊開發這些價值主張的首要考慮因素，甚至在我們推出之前就開始這些努力。

That's great. If I can, I'd like to squeeze 1 more in, and that is regarding your new expansion into oncology. I'm just wondering, given this platform, there's -- you already produced several NCEs and you've mentioned that they could apply to both solid and liquid tumors.

那太棒了。如果可以的話，我想再補充一點，那就是關於你們在腫瘤學方面的新拓展。我只是想知道，鑑於這個平台，您已經製作了幾個 NCE，並且您提到它們可以適用於實體腫瘤和液體腫瘤。

So I guess a couple of questions here is what would be your preference? And how would you decide that, sort of what criteria are you looking at to help best decide sort of which would be your first candidate that you nominate to go into the clinic by the end of next year?

所以我想這裡有幾個問題是您的偏好是什麼？您將如何決定，您正在考慮什麼標準來幫助最好地決定哪一個將是您提名的明年年底進入診所的第一個候選人？

Sure. I think we're going to let the science really drive it, but I will let WeiQi give a brief.

當然。我認為我們將讓科學真正推動它，但我會讓 WeiQi 做一個簡短的介紹。

Well, I think the criteria is really would be determined by many multiple aspects of lead compounds that have generated. And then the indications, including also the trial designs, including the populations, including the -- so it's really not a 1 single factor what is driving in the process. And it's quite -- we also need to talk to various experts -- people with expertise in oncology and then get their input. So it's really driven by multiple, multiple factors.

嗯，我認為標準實際上是由已生成的先導化合物的許多方面決定的。然後是適應症，包括試驗設計，包括人群，包括 - 所以這實際上不是推動這一過程的單一因素。我們還需要與各種專家——具有腫瘤學專業知識的人交談，然後聽取他們的意見。所以它確實是由多種因素所驅動的。

So I think we will be happy to talk about that more information in the future time.

因此，我認為我們將很樂意在未來討論更多資訊。

Yes, I think so. I think we'll be taking the same filter that we use when we selected an indication for larsucosterol. So we'll be looking at unmet need, time to market, time to proof of concept, in this case. Obviously, with oncology, it's different. So that kind of thing.

是的，我想是這樣。我認為我們將採用與選擇 larsucosterol 適應症時使用的相同過濾器。因此，在這種情況下，我們將專注於未滿足的需求、上市時間、概念驗證時間。顯然，對於腫瘤學來說，情況有所不同。諸如此類的事情。

Our next question comes from Sean Kim with JonesTrading.

我們的下一個問題來自 JonesTrading 的 Sean Kim。

My first question is, could you please remind us whether the statistical plan for the AHFIRM trial has been submitted? And if you have provided any detail on the statistical powering for the trial?

我的第一個問題是，您能否提醒我們AHFIRM試驗的統計計劃是否已提交？您是否提供了有關試驗統計功效的任何詳細資訊？

Yes. It certainly has been submitted, but we haven't really provided a great bit of color to that. Suffice to say, we've designed it such that 300 patients -- should the trial proceed as we hope, and the placebo group perform as history has dictated and we're in the range of events that would allow for that, then we'll have a statistically significant trial. But it all remains to be seen, as always. Data will dictate at the end.

是的。它確實已經提交了，但我們還沒有真正為此提供太多的色彩。可以說，我們設計了 300 名患者——如果試驗按照我們希望的方式進行，安慰劑組的表現符合歷史規定，並且我們處於允許這一點的事件範圍內，那麼我們'將進行具有統計意義的試驗。但這一切還有待觀察，一如既往。數據將在最後決定。

Okay. And about the physician survey that you did recently, could you share some more color on the excitement expressed by the doctors from the survey, maybe specifically around their willingness and intent to prescribe...

好的。關於您最近進行的醫生調查，您能否分享更多有關調查中醫生所表達的興奮的色彩，也許特別是圍繞他們開處方的意願和意圖...

I'd love to, but I'll let Keith do that. Yes, that was certainly quite nice.

我很願意，但我會讓基斯這麼做。是的，那確實很好。

Yes. This is Keith. So on the market assessment that we did earlier this year, we worked with a group called ClearView who's well known in the space, and with the physicians that we recruited for the study. Again, they had very high willingness to prescribe. This is based off of a blinded target product profile, just a 1-page profile of what our drug may look like and what those statistical parameters would look like for safety efficacy based on a presumed positive AHFIRM trial. Again, it was blinded to the company and to what the product name is, so physicians had no idea of that. .

是的。這是基斯。因此，在我們今年稍早進行的市場評估中，我們與該領域知名的 ClearView 團隊以及我們為這項研究招募的醫生合作。同樣，他們開藥的意願非常高。這是基於盲法目標產品概況，僅一頁紙的概況，介紹我們的藥物可能是什麼樣子，以及基於假定的積極 AHFIRM 試驗的安全功效的統計參數是什麼樣子。再次，它對公司和產品名稱一無所知，因此醫生對此一無所知。 。

But again, their affinity for the product and pleasure with something that would have a statistical significant difference versus standard of care and especially how we designed the trial, where it really is physician discretion on whether or not steroids are used in that placebo arm really mimicked their current standard of care. And with that kind of an improvement with what they considered as the highest order endpoint of survival or transplant, particularly in 90 days for an acute disease like this, would be very significant for them.

但同樣，他們對產品的親和力以及對與標準護理相比具有統計顯著差異的東西的愉悅感，特別是我們如何設計試驗，實際上是醫生自行決定是否在安慰劑組中使用類固醇，這確實模仿了他們目前的護理標準。隨著他們認為生存或移植的最高終點終點的改善，特別是在像這樣的急性疾病的 90 天內，對他們來說將非常重要。

And so we did see that -- it was nice to see that their preference share that they have signed to this product mix was quite high, particularly in that severe patient population that we are testing for -- that we're testing in AHFIRM with MELDs between 20 and 30.

因此，我們確實看到，很高興看到他們簽署的該產品組合的偏好份額相當高，特別是在我們正在測試的重症患者群體中，我們正在 AHFIRM 中進行測試MELD 在 20 到 30 之間。

Yes. I think it's -- it is exactly what one would have hoped if you have a disease where 30% of the patients are dying and there's no therapy that's able to change that. Yes, so it was well-received.

是的。我認為，如果你患有一種疾病，30% 的患者正在死亡，並且沒有任何療法可以改變這一點，那麼這正是人們所希望的。是的，所以很受歡迎。

And maybe just 1 more point. I mentioned that there was high affinity for prescribing product X or larsucosterol in that study with the AHFIRM patient population. But given that we're not sure what the final label would be, but there also was a willingness to prescribe this product for MELDs greater than 30. There are no products approved at all, and there's certainly high unmet medical need for those who are extremely severe with MELDs rate greater than 30. So again, reassuring to hear that unbiased take from our key hepatologists. That would be our target from a commercial standpoint.

也許還多了 1 分。我提到過，在針對 AHFIRM 患者群體的研究中，開出產品 X 或 larsucosterol 的處方具有很高的親和力。但考慮到我們不確定最終的標籤是什麼，但也有人願意為MELD 大於30 的患者開出該產品。根本沒有任何產品獲得批准，而且對於那些患有這種疾病的人來說，肯定存在很高的未滿足的醫療需求。 MELD 率大於 30 的情況極其嚴重。因此，聽到我們的主要肝病專家的公正看法再次令人放心。從商業角度來看，這將是我們的目標。

Sean, just 1 other additional piece. If you have a MELD of 30, you've got -- the mortality expected 90 days is 50%. So it gets -- goes up very quickly.

肖恩，還有另外一件。如果 MELD 為 30，則 90 天的預期死亡率為 50%。所以它的上升速度非常快。

Okay. Got you. And my last question for today is, as you look to move cancer programs in the clinic by end of next year, just curious to hear your thoughts on strategic prioritization and resource allocation between these upcoming cancer programs and potential expansion into other hepatological indications for larsucosterol?

好的。明白你了。我今天的最後一個問題是，當您希望在明年年底前將癌症項目轉移到臨床時，我只是想听聽您對這些即將到來的癌症項目之間的戰略優先順序和資源分配的想法，以及可能擴展到其他肝病適應症的larsucosterol ？

Yes, it's a great question. The first and the primary focus is AH. That's where our efforts are certainly, and we already discussed because 1 of the questions earlier to find a partnership. So if the data comes out as we hope and we have a successful trial with AHFIRM, we'll be looking to partner it for ex-U.S. to advance to submission as quickly as possible. We here at DURECT will be all hands on deck to move that forward. And then as well, we'll be looking at the next indications for larsucosterol.

是的，這是一個很好的問題。第一個也是主要的焦點是 AH。這當然是我們努力的方向，我們已經討論了之前的問題之一來尋找合作夥伴。因此，如果數據如我們所願，並且我們與 AHFIRM 的試驗取得成功，我們將尋求在美國以外地區與其合作。盡快進入提交階段。我們 DURECT 將全力以赴推動這項進程。然後，我們也將研究 larsucosterol 的下一個適應症。

And then -- but that -- the oncology effort that WeiQi is running is not a very large budget item. As most of you who've been involved with research know, it just takes time, but it doesn't take a lot of money. It doesn't cut costing any reasonable amount of money at all to get into the clinic. And so as the year unfolds, we'll be obviously preparing for that, and that will take its own course.

然後，但是，WeiQi 正在進行的腫瘤學工作並不是一個非常大的預算項目。大多數參與研究的人都知道，這只是需要時間，但不需要很多錢。它根本不會減少進入診所的任何合理費用。因此，隨著這一年的展開，我們顯然會為此做好準備，而這將順其自然。

But the primary focus will be AHFIRM and meeting with the FDA, deciding if 1 trial will be sufficient for submission of an NDA and commercialization partnerships, and all the rest of those kind of things.

但主要焦點將是 AHFIRM 和與 FDA 的會議，決定一項試驗是否足以提交 NDA 和商業化合作夥伴關係，以及所有其他此類事情。

There are no further questions at this time. I would now like to turn the floor back over to Jim Brown for closing comments.

目前沒有其他問題。我現在想請吉姆·布朗發表結束評論。

Just want to thank you all for your time. And as always, we are here. So if you have a follow-up question, just reach out. We look forward to talking to you. Thanks a lot, and take care.

只是想感謝大家抽出寶貴的時間。一如既往，我們在這裡。因此，如果您有後續問題，請直接與我們聯繫。我們期待與您交談。非常感謝，保重。

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。