DURECT Corp (DRRX) 2023 Q3 法說會逐字稿

Good afternoon, everyone, and welcome to the DURECT Corporation third-quarter earnings conference call. All participants will be in a listen-only mode. (Operator Instructions) After today's presentation, there will be an opportunity to ask questions. (Operator Instructions) Please also note today's event is being recorded. And at this time, I'd like to turn the floor over to Tim Papp, Chief Financial Officer. Please go ahead.

大家下午好，歡迎參加 DURECT 公司第三季財報電話會議。所有參與者將處於僅聽模式。 （操作員說明）今天的演示結束後，將有機會提問。 （操作員說明）也請注意今天的活動正在錄製中。現在，我想請財務長 Tim Papp 發言。請繼續。

Thank you. Good afternoon and welcome to DURECT Corporation's third-quarter 2023 earnings conference call. Before we begin, I would like to remind everyone of our forward-looking statements. During the course of this call, we will make forward-looking statements regarding the results and clinical data from the AHFIRM trial, development plans for larsucosterol, expected product benefits, market potential, regulatory plans, potential regulatory approval, and the company's financial projections.

謝謝。下午好，歡迎參加 DURECT Corporation 的 2023 年第三季財報電話會議。在開始之前，我想提醒大家注意我們的前瞻性陳述。在本次電話會議期間，我們將就 AHFIRM 試驗的結果和臨床數據、larsucosterol 的開發計劃、預期產品效益、市場潛力、監管計劃、潛在的監管批准以及公司的財務預測做出前瞻性陳述。

These forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements, including the risk that future trials of larsucosterol, do not confirm the results from 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. To begin, I would like to review our third-quarter 2023 financial results.

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，包括未來的 larsucosterol 試驗無法證實 AHFIRM 試驗結果的風險。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。首先，我想回顧一下我們 2023 年第三季的財務表現。

Our total revenues in the -- third quarter were $1.7 million compared with $12 million for the third quarter of 2022. This difference was largely due to the recognition of $10 million of milestone revenue related to our licensing deal with Innocoll that we recognized in 2022. R&D expenses were $7.2 million compared with $9.9 million for the prior year. The decrease was primarily due to lower clinical trial and contract manufacturing expenses for larsucosterol and the elimination of feasibility programs, offset partially by an increase in spending on other R&D projects.

我們第三季的總收入為170 萬美元，而2022 年第三季的總收入為1,200 萬美元。這一差異主要是由於我們在2022 年確認了與Innocoll 的許可協議相關的1,000 萬美元的里程碑收入。研發費用為 720 萬美元，上一年為 990 萬美元。減少的主要原因是larsucosterol的臨床試驗和合約製造費用減少以及可行性計劃的取消，但部分被其他研發項目支出的增加所抵消。

SG&A expenses were $3.8 million compared with $3.9 million for the prior year, so essentially unchanged year-over-year. As of September 30, 2023, we had cash and investments of $39.1 million compared with cash and investments of $43.6 million at December 31, 2022. During the third quarter, we completed a registered direct offering, raising $13.9 million in net proceeds. Our cash burn in the third quarter was approximately $9.7 million, excluding proceeds from the offering.

SG&A 費用為 380 萬美元，而前一年為 390 萬美元，因此同比基本上沒有變化。截至2023 年9 月30 日，我們擁有現金和投資3,910 萬美元，而截至2022 年12 月31 日，現金和投資為4,360 萬美元。第三季度，我們完成了註冊直接發行，籌集了1,390 萬美元的淨收益。我們第三季的現金消耗約為 970 萬美元，不包括發行收益。

We believe our cash on hand is sufficient to fund the operations through at least the middle of 2024. Now, I would like to turn the call over to our CEO, Dr. Jim Brown, for an update on our programs.

我們相信，我們手頭上的現金至少足以為 2024 年中期的營運提供資金。現在，我想將電話轉給我們的執行長 Jim Brown 博士，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 third-quarter 2023 update. Last week, we announced the unprecedented top-line results from our AHFIRM Phase 2b clinical trial, which evaluated the larsucosterol and alcohol-associated hepatitis. The AHFIRM results showed a clinically meaningful reduction in the key secondary endpoint of 90-day mortality from larsucosterol, compared with standard of care. To my knowledge, no previously controlled trial has demonstrated an improvement in mortality of this magnitude in this devastating disease.

謝謝你，提姆。大家好，感謝您今天加入我們的 2023 年第三季更新。上週，我們宣布了 AHFIRM 2b 期臨床試驗的前所未有的頂線結果，該試驗評估了 larsucosterol 和酒精相關性肝炎。 AHFIRM 結果顯示，與標準護理相比，larsucosterol 90 天死亡率的關鍵次要終點具有臨床意義的降低。據我所知，先前的對照試驗還沒有證明這種毀滅性疾病的死亡率有如此大的改善。

We also saw an encouraging safety profile for larsucosterol with a low number of adverse events for the active arms, as compared with the standard of care. We have reviewed the AHFIRM data with many renowned hepatologists and AH thought leaders. These physicians are excited by the compelling reduction in mortality at 90 days in the larsucosterol arms. They were especially impressed with the data from the US patients and the safety data from the trial.

我們也發現，與照護標準相比，larsucousterol 的安全性令人鼓舞，主動臂的不良事件數量較少。我們與許多著名肝病學家和 AH 思想領袖一起審查了 AHFIRM 數據。這些醫生對 larsucosterol 組 90 天死亡率的顯著降低感到興奮。來自美國患者的數據和試驗的安全性數據給他們留下了特別深刻的印象。

Our Phase 2b AHFIRM trial was a placebo-controlled, double-blind multinational study with two active arms dosing 30 milligrams and 90 milligrams of our larsucosterol and the standard of care arm of approximately 100 patients each. By comparing against the standard of care, we allow the physicians to utilize their standard practice for treating AH patients, which allowed for the use of corticosteroids in addition to supportive care such as fluids, nutritional support, and antibiotics for infections. In total, we randomized 307 patients with severe alcohol associated hepatitis. These were patients with MELD scores ranging from 21 to 30 and Maddrey's Discriminant Function scores greater than or equal to 32.

我們的 2b 期 AHFIRM 試驗是一項安慰劑對照、雙盲多國研究，有兩個主動組，每組分別服用 30 毫克和 90 毫克的 larsucosterol，標準護理組各有大約 100 名患者。透過與護理標準進行比較，我們允許醫生利用他們的標準做法來治療 AH 患者，除了支持性護理（例如液體、營養支持和感染抗生素）之外，還可以使用皮質類固醇。總共，我們對 307 名患有嚴重酒精相關性肝炎的患者進行了隨機分組。這些患者的 MELD 評分範圍為 21 至 30，Maddrey 判別函數評分大於或等於 32。

We enroll patients in AHFRIM through a global network of clinical sites, including leading hospitals in the United States, Australia, EU, and the UK. Our sites included reknowned liver centers, and we had the honor of working with some of the world's preeminent thought leaders in AH. The top-line results in the key secondary endpoint of mortality at 90 days, showed a 41% reduction with the 30 milligram dose of larsucosterol and a 35% reduction with a 90 milligram dose of larsucosterol, as compared with the standard of care.

我們透過全球臨床中心網絡（包括美國、澳洲、歐盟和英國的領先醫院）招募病患加入 AHFRIM。我們的網站包括著名的肝臟中心，我們有幸與 AH 中的一些世界傑出思想領袖合作。 90 天關鍵次要終點死亡率的最重要結果顯示，與標準護理相比，30 毫克劑量的 larsucosterol 可使死亡率降低 41%，90 毫克劑量的 larsucosterol 可使死亡率降低 35%。

We also reported a numerical improvement in the primary endpoint of reduction in mortality or liver transplant at 90 days. So neither the primary or the key secondary endpoint achieved results that was statistically significant. Impressive results were found in the US population, which comprised three quarters of the total enrollment in AHFRIM. That was 232 out of 307 patients.

我們也報告了 90 天死亡率或肝臟移植降低的主要終點的數字改善。因此，主要終點或關鍵次要終點均未取得具有統計顯著性的結果。美國人口的結果令人印象深刻，佔 AHFRIM 總入學人數的四分之三。這是 307 名患者中的 232 名。

In the US patients, we saw reductions of mortality at 57% and 58% for the 30 and 90 milligram arms, respectively, compared with the standard of care. Although not a part of the original trial statistical analysis plan, the p-values reduced these results were both approximately 0.01. Very importantly, larsucosterol exhibited an excellent safety profile, with no serious adverse events in either arm and greater than 20% reductions in the number of treatment emergent adverse events for both active arms of these severely ill patients when compared with the standard of care.

在美國患者中，與標準治療相比，30 毫克組和 90 毫克組的死亡率分別降低了 57% 和 58%。儘管不屬於原始試驗統計分析計畫的一部分，但這些結果的 p 值均約為 0.01。非常重要的是，larsucosterol 表現出出色的安全性，與標準治療相比，任一臂均未出現嚴重不良事件，並且這些重症患者的兩個活躍臂的治療緊急不良事件數量減少了 20% 以上。

Ultimately, these clinically meaningful reductions in mortality, coupled with the reduction in adverse events in these severely ill patients, reinforce the compelling risk-reward proposition for the continued advancement of larsucosterol as the first approved treatment for AH. We look forward to meeting with the FDA in the first quarter of 2024, to discuss the AHFIRM data and the path forward to seek approval of larsucosterol in AH, including design for a potential registrational Phase 3 trial using mortality is the primary endpoint. As a reminder, the FDA has granted our larsucosterol AH program fast track designation.

最終，這些具有臨床意義的死亡率降低，再加上這些重症患者不良事件的減少，強化了將 larsucosterol 作為第一個批准的 AH 治療方法的持續發展的令人信服的風險回報主張。我們期待在 2024 年第一季與 FDA 會面，討論 AHFIRM 數據以及尋求批准 larsucosterol 在 AH 中的前進道路，包括以死亡率為主要終點的潛在註冊 3 期試驗的設計。謹此提醒，FDA 已授予我們的 larsucosterol AH 專案快速通道資格。

AH has a cause of more than 158,000 hospitalizations each year in the United States, with a 90-day mortality rate of approximately 30% and is responsible for tens of thousands of deaths each year. There are no effective treatments for AH. If we were able to gain approval for larsucosterol, it would likely be the first FDA approved treatment for this disease. In addition to its high mortality rate, AH represents a significant cost to the US health care system.

在美國，AH 每年導致超過 158,000 例住院患者，90 天死亡率約為 30%，每年導致數萬人死亡。 AH 沒有有效的治療方法。如果我們能夠獲得 larsucosterol 的批准，這可能是 FDA 批准的第一個治療這種疾病的方法。除了高死亡率之外，AH 也為美國醫療保健系統帶來了巨大的成本。

Hospitalizations attributed to AH in care costs of $62,000 to $167,000 each, a total cost to hospitals of approximately $10 billion annually in the United States. As a result, larsucosterol represents a potential multibillion-dollar opportunity in the US alone and could simultaneously provide overall cost savings to the health care system. We look forward to the possibility of bringing this potential life-saving therapeutic to patients with no effective therapies available today.

AH 導致的住院治療費用為每次 62,000 至 167,000 美元，美國醫院每年的總費用約為 100 億美元。因此，僅在美國，larsucosterol 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整體成本。我們期待將這種潛在的救命療法帶給目前尚無有效療法的患者。

We attended the AASLD conference in Boston, this is the US liver meeting, over the weekend and had the opportunity to discuss the top-line results with many of our investigators from AHFIRM, and with more than a dozen influential KOLs. The reaction of this physician community has been overwhelmingly positive and enthusiastic about larsucosterol's prospects. These physicians expressed their frustration with the lack of effective treatment. They recognize that the type of mortality benefit and safety profile suggested by larsucosterol from our AHFIRM data, would potentially bring a major advancement in the standard of care for these severely ill patients. We'd now like to take any questions you might have.

我們週末參加了在波士頓舉行的 AASLD 會議，這是美國肝臟會議，並有機會與 AHFIRM 的許多研究人員以及十幾位有影響力的 KOL 討論了最重要的結果。該醫生群體的反應非常積極，並且對 larsucosterol 的前景充滿熱情。這些醫生對缺乏有效的治療表示沮喪。他們認識到，根據我們的 AHFIRM 數據，larsucosterol 所建議的死亡率益處和安全性特徵可能會為這些重症患者的護理標準帶來重大進步。我們現在想回答您可能提出的任何問題。

(Operator Instructions) François Brisebois, Oppenheimer.

（操作員指令）François Brisebois，Oppenheimer。

Hi, thanks for taking the question, just a couple here. So in terms of the mortality, can you remind us what it was that mortality that was seen in the trial? I know there was a fear that maybe the trial would not or AH patients did not have quite the mortality that that people expected. Can you just maybe remind us what you saw in the trial? And was it in line with what you thought?

您好，感謝您提出問題，這裡只有幾個。那麼就死亡率而言，您能否提醒我們試驗中看到的死亡率是什麼？我知道有人擔心試驗可能不會進行，或者 AH 患者的死亡率沒有達到人們預期的水平。您能否提醒我們您在審判中看到了什麼？以及是否符合你的想法呢？

Absolutely. Yes. For the overall trial, the global trial, we saw a-- 25% mortality and we had powered it for a 30% mortality. So it was a little bit lower than we had expected, and that was, in all likelihood, the primary the primary reasons why we slightly missed that endpoint. Our biostatisticians tell me if we'd had X number of 15-plus more patients or something, we would have been able to possibly hit that endpoint.

絕對地。是的。對於整個試驗，即全球試驗，我們看到死亡率為 25%，而我們為其提供了 30% 的死亡率。因此，它比我們的預期要低一些，這很可能是我們稍微錯過該終點的主要原因。我們的生物統計學家告訴我，如果我們有 X 位 15 位以上的患者或其他什麼情況，我們就有可能達到終點。

It's interesting when we look at the subset of the data, which is three quarters of the data from the United States, we see a mortality endpoint rate of 28% in the United States, as compared to 12% in the two active arms. So that certainly was almost 60%, so that was highly statistically significant. So in the US, it hit right, when we look globally, it didn't. And that's unfortunately hits.

有趣的是，當我們查看數據子集（即來自美國的數據的四分之三）時，我們發現美國的死亡率終點率為 28%，而兩個活躍組的死亡率終點率為 12%。所以肯定接近 60%，因此具有高度的統計顯著性。因此，在美國，它是正確的，但當我們放眼全球時，卻並非如此。不幸的是，這很受歡迎。

We moved from this small four patient from group study to 100 patient groups in the 2b, but it would bring in so much information. And to have a trial that had this kind of signal, when we spent the weekend -- as you know, Frank, in Boston with these investigators, they were quite excited about the data we have.

我們從 4 名患者的小型小組研究轉移到 2b 中的 100 名患者小組，但它會帶來很多資訊。為了進行具有這種信號的試驗，當我們在波士頓與這些研究人員一起度過週末時，弗蘭克，您知道，他們對我們擁有的數據感到非常興奮。

Okay, great. No, that's very -- and then in terms of speaking to a lot of physicians over the weekend and whatnot, -- what are the thoughts in terms of their hypothesis to maybe there were differences in the US versus ex-US population? Is it too early to see? Anything you can share there or should we wait for more information about the potential differences there? Thank you.

好的，太好了。不，那是非常的——然後就週末與許多醫生交談以及諸如此類的事情而言——他們的假設是，美國人口與前美國人口之間可能存在差異，他們的想法是什麼？現在看還太早嗎？您可以在那裡分享什麼，還是我們應該等待有關那裡潛在差異的更多資訊？謝謝。

Yeah, certainly. There's certainly were some things that they focused on and we are investigating more thoroughly and the first thing that they focused on were the differences in age. We saw the age of the US patient population and 43, and to a person, they are saying, yes, these are the patients we're seeing, they're younger. I had a number of them quote back that kind of numbers we've been talking about.

是的，當然。他們當然專注於一些事情，我們正在更徹底地調查，他們關注的第一件事是年齡差異。我們看到美國患者群體的年齡是 43 歲，他們對一個人說，是的，這些就是我們看到的患者，他們更年輕。我讓他們中的一些人引用了我們一直在談論的那種數字。

20-something percent of their patients are young women in their 20s and 30s without cirrhosis and we certainly saw that in our trials. We saw younger people, -- 43 was the mean age in the United States and ex-US it was 50, even higher in Europe as it goes 52. And there was a physician from Southern California from USC who we spoke to, who talked about some papers that he'd written showing that, if you were over the age of 44, you had a much greater chance of dying from this disease. So we know in a lot of diseases, the older you are, the more susceptible you are to dying.

他們的患者中有 20% 左右是 20 多歲和 30 多歲的年輕女性，沒有肝硬化，我們在試驗中確實看到了這一點。我們看到年輕人的平均年齡是 43 歲，美國以外地區的平均年齡是 50 歲，歐洲的平均年齡是 52 歲。我們採訪了一位來自南加州大學的南加州醫生，他與我們進行了交談他寫的一些論文表明，如果你超過44 歲，你死於這種疾病的機會就會大得多。所以我們知道，在很多疾病中，年紀越大，就越容易死亡。

And certainly, in this population, that's the case. And so that was one component that we learned. The other thing that they focused on was the amount of cirrhosis. The US population had 76% cirrhosis, which means fits with being younger, you have less cirrhosis. But the ex-US population was, especially for the EU, it's biopsy-confirmed 90% cirrhosis, which means, basically, means much less liver available to respond to the drug unfortunately.

當然，在這個人群中，情況就是如此。這就是我們學到的一個組成部分。他們關注的另一件事是肝硬化的數量。美國人口中有 76% 患有肝硬化，這意味著越年輕，肝硬化就越少。但前美國人口，尤其是歐盟人口，經活檢證實 90% 患有肝硬化，這意味著，不幸的是，基本上，意味著可用於對該藥物做出反應的肝臟要少得多。

But we're still easing out the differences because the other differences there were much smaller population of patients and they were divided and randomized across Australia, the UK, and the EU. And so you can also get into a mismatching of balancing of that as well, which can lead to greater variability.

但我們仍在消除這些差異，因為其他差異是患者群體要小得多，而且他們在澳洲、英國和歐盟進行了劃分和隨機分配。因此，您也可能會陷入平衡不匹配的情況，這可能會導致更大的可變性。

Thank you.

謝謝。

Sure.

當然。

Carl Byrnes, Northland Capital Markets.

卡爾‧伯恩斯，北國資本市場。

Great. Thanks for the question. I'm wondering if there's any rationale for the FDA to not allow mortality as a primary endpoint in the Phase 3 trial, considering you have a limited number of liver of organs available for transplantation, the mortality benefit that you saw, particularly in the US population, and then the safety profile, which was clearly better than the standard of care, which is something we simply don't see? Thanks.

偉大的。謝謝你的提問。我想知道 FDA 是否有任何理由不允許將死亡率作為 3 期試驗的主要終點，考慮到可用於移植的肝臟或器官數量有限，您看到的死亡率益處，特別是在美國人口，然後是安全狀況，這顯然比護理標準更好，這是我們根本看不到的？謝謝。

Yeah, I think first of all, the FDA is happy to, from the correspondence that I've been associated with them, they would prefer mortality over anything else, quite frankly, and that will be. If another trial is required for approval, we will do a trial looking at survival. So if you look at the secondary endpoint, if you look at the US population, those would be good surrogate populations and analyses that we would do if we were required to do another Phase 3 or a Phase 3 trial for this drug.

是的，我認為首先，FDA 很高興，從我與他們聯繫的信件來看，坦白說，他們更喜歡死亡率而不是其他任何事情，事實就是如此。如果需要另一次試驗才能獲得批准，我們將進行一次生存試驗。因此，如果你看看次要終點，如果你看看美國人口，這些將是很好的替代人群，如果我們被要求對該藥物進行另一項 3 期或 3 期試驗，我們就會進行分析。

Because you're right: the mortality is terrific and transplant, there's less than 2% of these patients are going to be transplanted in the US or quarter liver transplants, but that's about 2000 livers and their 158,000 of these hospitalizations as of a couple of years ago, probably growing at about 4%, 5% a year. So they always lag behind their actual data with what we can get from the government literature. So there are probably 98% of these patients in the United States never have a chance to a liver. And their only option then is what is out there today.

因為你是對的：死亡率非常高，而且在移植方面，只有不到2% 的患者將在美國接受移植或四分之一的肝臟移植，但這大約有2000 個肝臟，截至最近幾年，其中有158,000 例住院治療。幾年前，每年大概增加4%、5%左右。因此，他們總是落後於我們從政府文獻中獲得的實際數據。所以在美國這些患者中可能有98%從來沒有機會獲得肝臟。他們唯一的選擇就是今天的選擇。

So their only option is to potentially die at a rate of what we saw in this trial in the US: 28% or 30%, depending on how you look historically. So it's a horrible circumstance and these physicians were so excited about the data we have and the ones who were involved with the trial were telling us stories about patients that -- really, after having the week where we had to talk about the data that we had, it was really heartening and really lifted up the spirits of everyone who's there, really good.

因此，他們唯一的選擇就是可能以我們在美國這項試驗中看到的死亡率死亡：28% 或 30%，這取決於你過去的樣子。所以這是一個可怕的情況，這些醫生對我們擁有的數據感到非常興奮，那些參與試驗的人向我們講述了關於患者的故事——真的，在經歷了一周我們不得不談論我們的數據之後確實很令人振奮，也確實鼓舞了在場每個人的士氣，真的很好。

Great. So, on that thought, drug done, I'm wondering, is there any possibility or do you think there's any possibility that larsucosterol can be used on a compassionate basis given the safety profile in the meantime?

偉大的。因此，考慮到這一點，藥物完成後，我想知道，考慮到安全性，是否有任何可能性，或者您認為是否有可能在富有同情心的基礎上使用拉糖甾醇？

Compassionate use is a possibility, but what we'll do is we'll go have a conversation with them. We'll talk about the potential for an accelerated review as a possibility as well. So we're just going to have a conversation with the FDA about what we have. This is certainly a highly lethal condition with no therapy.

同情使用是可能的，但我們要做的是與他們對話。我們還將討論加速審查的可能性。因此，我們將與 FDA 就我們所掌握的情況進行對話。這無疑是一種高度致命的疾病，無需治療。

As you said, it's got a very clean profile, if not -- I would just leave it at that from a very nice profile from an adverse event standpoint. So we'll have that conversation with the FDA in first quarter and find out what the next steps will be.

正如你所說，它有一個非常乾淨的配置文件，如果不是的話，我會從不良事件的角度來看，從一個非常好的配置文件中保留它。因此，我們將在第一季與 FDA 進行對話，並了解接下來的步驟。

Got it. Thanks. And then just one last question. There's been some concern about not seeing a dose response, but if we look at the US-only population, again, you explained some of the nuances with respect to mismatching, but clearly you did see a dose response. I think it was like 58% of the 90 mg dose versus 57.1% in the 30 mg dose. So is that correct? And then what's your thought on some of the comments are out there in terms of not seeing dose response? And that's my final question. Thank you.

知道了。謝謝。最後一個問題。人們對看不到劑量反應存在一些擔憂，但如果我們再次觀察僅限美國的人群，您解釋了一些與不匹配有關的細微差別，但顯然您確實看到了劑量反應。我認為 90 毫克劑量的比例為 58%，而 30 毫克劑量的比例為 57.1%。那麼這是正確的嗎？那麼您對一些沒有看到劑量反應的評論有何看法？這是我的最後一個問題。謝謝。

Yeah, thank you, Carl. I think what we can glean first from the fact that both doses showed very well is, first of, both doses showed very well, right? So that means you grab a population of 100 people dosing with the drug, phenomenal result, almost 60%. Grabbing another 100 people, check them against standard of care, once again, another phenomenal response, almost 60%.

是的，謝謝你，卡爾。我認為我們首先可以從兩種劑量都表現得很好的事實中得知，首先，兩種劑量都表現得很好，對嗎？所以這意味著你對 100 個人服用該藥物進行了調查，結果非常驚人，幾乎達到了 60%。再抓起 100 個人，根據護理標準對他們進行檢查，再次出現了另一個驚人的反應，幾乎 60%。

You can't really tease out the difference between 57 and 58 nor can you really between 35 and 41. These are -- what they're showing is the drug is having an effect and so most likely, biologically, we're probably if you think about a curve, it will probably at the asymptotic component of the curve. We're just near the top of that. So one dose versus another dose is not going to make an appreciable difference there.

你無法真正分辨出 57 和 58 之間的差異，也無法真正分辨出 35 和 41 之間的差異。這些是 - 他們所顯示的是藥物正在發揮作用，因此從生物學角度來看，我們很可能你考慮一條曲線，它可能會在曲線的漸近分量處。我們剛剛接近頂峰。因此，一種劑量與另一種劑量不會產生明顯的差異。

And so that will be a conversation with the FDA. We certainly know a lot more about how the drug works in various animal models and other studies we've done. We know it's an inhibitor of DNMT, DNA methyltransferases. We know it reduces hypomethylation. We know these patients have elevated levels of these enzymes.

這將是與 FDA 的對話。我們當然更了解該藥物在各種動物模型中的作用以及我們所做的其他研究。我們知道它是 DNMT（DNA 甲基轉移酶）的抑制劑。我們知道它可以減少低甲基化。我們知道這些患者的這些酵素水平升高。

And so all that is well understood from a scientific standpoint. And that the finer points of which dose to be selected, will be a conversation we have with the agency at the end of the day, and we're prepared to use either dose going forward.

因此，從科學的角度來看，這一切都是很好理解的。至於選擇哪種劑量的細節，將是我們在一天結束時與該機構進行的對話，我們準備繼續使用任一劑量。

Great. Thanks again.

偉大的。再次感謝。

Thank you.

謝謝。

(Operator Instructions) Ed Arce, H.C. Wainwright.

（操作員說明）Ed Arce, H.C.溫賴特。

Hi, everyone, this is Thomas Yip asking a couple of questions for Ed. Thank you for taking our questions. First question, based on what you've learned from AHFRIM so far, can you discuss what are some inherent favorability of the liver transplant endpoint in your study?

大家好，我是 Thomas Yip，向 Ed 問幾個問題。感謝您接受我們的提問。第一個問題，根據您迄今為止從 AHFRIM 了解到的情況，您能否討論一下您的研究中肝臟移植終點有哪些固有的優勢？

Well, -- when you look at transplant, and it's just inherently variable. That's the reality of it. It's available, as I said earlier, to less than 2% of the patients who have this disease. And the administration of the transplant is very variable as well. It depends on which center you're at. It depends on what is your level of insurance coverage, whether or not you have a match, how aggressive your surgical team is, and it also depends on how sick you are.

嗯，當你觀察移植時，你會發現它本質上是可變的。這就是事實。正如我之前所說，只有不到 2% 的患有這種疾病的患者可以獲得這種治療。移植的管理也有很大差異。這取決於你在哪個中心。這取決於您的保險範圍、您是否有比賽、您的手術團隊的積極性，也取決於您病情的嚴重程度。

There are a number of patients who are too sick when they first come in to get a transplant. So we think about the use of larsucosterol in this setting. Certainly, in a survival trial, a trial where you're looking at mortality, there are a certain number of patients who would be in the standard of care group, who would get a transplant and survive, and that's true. But witness the fact that we -- a mortality signal even considering those.

有許多患者在剛來接受移植手術時就病得很重。因此，我們考慮在這種情況下使用 larsucosterol。當然，在生存試驗中，即關注死亡率的試驗中，有一定數量的患者屬於標準護理組，他們會接受移植並存活下來，這是事實。但請見證這樣一個事實：即使考慮到這些，我們也是一個死亡信號。

And I believe, from talking to some of the people and understanding the path for some of the patients in this trial, what we're also seeing is, for lack of a better term, a bridge to transplant, where some of these patients are severely ill at the beginning may not be alive long enough to get a transplant, but because they were dosed with larsucosterol, they were then potentially able to get a transplant six or eight, 10 weeks later. So that's another component of it all. And rather than trying to separate that out and tease that out would be very difficult to do. We're simply just going to look at mortality and let transplants fall where they may.

我相信，透過與一些人交談並了解本次試驗中一些患者的路徑，我們也看到，由於缺乏更好的術語，移植的橋樑，其中一些患者正在那裡一開始病情嚴重的患者可能活不了足夠長的時間來進行移植，但由於他們服用了larsucoterol，因此他們有可能在六到八週（即10週後）進行移植。這是這一切的另一個組成部分。而不是試圖將其分離出來並梳理出來，這將是非常困難的。我們只是專注於死亡率，然後讓移植手術減少。

And so that's how we're going to deal with that. Because there are so many factors that influence transplant that the drug can't influence. The only thing the drug really can do towards transplant is keep you alive and make you a little healthier, so that you might be still around if the liver, by chance, came up, as rare as it is.

這就是我們要處理的方式。因為影響移植的因素太多，藥物無法影響。這種藥物對移植真正能起到的唯一作用就是讓你活下去，讓你更健康一點，這樣，即使肝臟偶然出現，儘管這種情況很少見，你也可能還活著。

Understood. That makes sense. And then perhaps just one more question from us on. So you discussed a little bit earlier how the US operations with lower mean age and also a low percentage, cirrhosis. So wonder how we look at potential of materials markets, perhaps our discussions with the EMA. Is that on the table?

明白了。這就說得通了。也許接下來我們還會提出一個問題。因此，您之前討論了美國如何以較低的平均年齡和較低的比例進行肝硬化手術。因此，想知道我們如何看待材料市場的潛力，也許是我們與 EMA 的討論。那是在桌子上嗎？

No. I mean, we will be talking with the EMA as we go forward. We're just now starting to take the additional cuts of the data and look at that, and we will look at the data for a number of different reasons, for all these different characteristics and try to understand how it responds, because I'm certain that both the FDA and the EMA will want to understand that. My sense is it will be able to help patients with doses in Child-Pugh C patients who are dying or their livers are failing and for other indications orally.

不，我的意思是，我們將在前進過程中與 EMA 進行對話。我們現在才開始對數據進行額外的削減並進行研究，我們將出於多種不同的原因、所有這些不同的特徵來研究數據，並嘗試了解它的反應，因為我FDA 和EMA 肯定都想理解這一點。我的感覺是，它將能夠幫助那些瀕臨死亡或肝臟衰竭的 Child-Pugh C 患者以及其他口服適應症的患者。

It's awesome, nice improvements in these patients, just single dose, safety studies but saw some interesting biomarker changes and the like. So I do think there's the potential to help these patients. That being said, we're going to drive forward for approval in the US based on the US data. And then we'll take on the rest of the world in these more severely ill patients as time goes on. (multiple speakers) we've got a long ways to go and it's early days in analysis.

這太棒了，這些患者的改善很好，只是單劑量的安全性研究，但看到了一些有趣的生物標記變化等。所以我確實認為有潛力幫助這些患者。話雖這麼說，我們將根據美國的數據推動美國的批准。隨著時間的推移，我們將在這些病情更嚴重的患者身上與世界其他地區競爭。 （多位發言者）我們還有很長的路要走，現在還處於分析的早期階段。

Okay. Yeah, thank you for taking our questions. We look forward to the [SA] meeting in the first quarter activity.

好的。是的，謝謝您回答我們的問題。我們期待第一季的[SA]會議活動。

As do we. Thank you.

我們也一樣。謝謝。

Ladies and gentlemen, with that, we will conclude today's question-and-answer session. I'd like to turn the floor back over to Jim Brown for any closing remarks.

女士們、先生們，今天的問答環節就到此結束。我想請吉姆·布朗發表結束語。

I just would like to thank you all for your time today and for your support. And as always, if you have any further questions, please reach out to Tim and myself or others on the team that you know, and we're happy to get on the phone and talk to you. Thanks a lot and take care.

我只想感謝大家今天抽出寶貴的時間和支持。像往常一樣，如果您還有任何其他問題，請聯繫蒂姆和我本人或您認識的團隊中的其他人，我們很高興透過電話與您交談。非常感謝並保重。

Ladies and gentlemen, with that, we'll conclude today's conference call and presentation. We thank you for joining. You may now disconnect your lines.

女士們先生們，我們今天的電話會議和演示就到此結束。我們感謝您的加入。現在您可以斷開線路。