Genfit SA (GNFT) 2023 Q2 法說會逐字稿

Good day, and welcome to the GENFIT Conference Call. Today's call is being recorded. At this time, I would like to turn the conference over to Stefanie Magner. Please go ahead.

美好的一天，歡迎參加 GENFIT 電話會議。今天的通話正在錄音。這次，我想把會議交給史蒂芬妮·馬格納（Stefanie Magner）。請繼續。

Hello, everyone. Thank you for joining us on our 2023 Half Year Earnings Call and Corporate Update, following publication of our half year results press release. Our press release can be accessed via our website at ir.genfit.com in the News tab. Joining me on this call today are Pascal Prigent, CEO; and members of the management team.

大家好。感謝您在半年度業績新聞稿發布後參加我們的 2023 年半年度財報電話會議和公司最新動態。您可以透過我們網站 ir.genfit.com 的「新聞」標籤存取我們的新聞稿。今天加入我的電話會議的是執行長 Pascal Prigent；以及管理團隊的成員。

Before we begin, I'd like to remind everyone that statements made during this conference call, including the Q&A session relating to GENFIT's expected future performance, business prospects, events are planned, including ability to meet and obtain milestones through our licensing agreements, obtained regulatory approvals, anticipated time lines for clinical development, study enrollment and data release dates as well as expected cash used in our operational activities and cash runway are forward-looking statements as defined under the U.S. Private Securities Litigation Reform Act of 1995 that based on our management's current assumptions and estimates, which although believe to be reasonable, are subject to numerous known and unknown risks and uncertainties, which could cause actual results to differ materially from those expressed in or implied or projected by the forward-looking statements. For a further discussion of the material risks and other important factors that could affect our business operations and financial results, please refer to those contained in our most recent filings with the SEC and AMS.

在我們開始之前，我想提醒大家，在本次電話會議期間發表的聲明，包括與GENFIT 的預期未來業績、業務前景、計劃的活動（包括透過我們的許可協議實現和獲得里程碑的能力）相關的在問答環節，已獲得監管部門批准、臨床開發的預期時間表、研究註冊和資料發布日期以及我們營運活動和現金跑道中使用的預期現金均為前瞻性陳述，根據1995 年美國私人證券訴訟改革法案定義，該法案基於我們的管理層目前的假設和估計雖然被認為是合理的，但受到許多已知和未知的風險和不確定性的影響，這些風險和不確定性可能導致實際結果與前瞻性陳述中明示、暗示或預測的結果有重大差異。有關可能影響我們業務營運和財務表現的重大風險和其他重要因素的進一步討論，請參閱我們最近向 SEC 和 AMS 提交的文件中包含的內容。

These forward-looking statements speak only as of the date of this webcast. Other than as required by applicable law, the company does not undertake any obligation to update or revise any forward-looking information or statements, whether as a result of new information, future events or otherwise. Following the prepared remarks, we'll open the call up for questions that will be addressed by GENFIT management. Please limit yourself to one initial question to allow time for others. I now turn the call over to our CEO, Pascal Prigent.

這些前瞻性陳述僅代表截至本網路廣播當天的情況。除適用法律要求外，本公司不承擔任何更新或修改任何前瞻性資訊或聲明的義務，無論是由於新資訊、未來事件或其他原因。在準備好的發言之後，我們將開始徵求問題，由 GENFIT 管理階層解決。請只回答一個初始問題，以便為其他人留出時間。我現在將電話轉給我們的執行長 Pascal Prigent。

Thank you, Stefanie. Well, this is an exciting time for GENFIT as we are now entering a new era for the company. Indeed, we are now pivoting from a model that was centered on elafibranor to one where we will be focusing on the development of a promising portfolio of drug candidates targeting primarily ACLF. Elafibranor was discovered at GENFIT, and the company took it all the way from drug discovery to Phase III. These years of development culminated earlier this year when at the end of June, we announced positive data from the 52-week double-blind treatment period of the pivotal ACLF Phase III trial of elafibranor in PBC.

謝謝你，斯蒂芬妮。嗯，這對 GENFIT 來說是一個令人興奮的時刻，因為我們現在正在進入公司的新時代。事實上，我們現在正在從以 elafibranor 為中心的模式轉向專注於開發主要針對 ACLF 的有前景的候選藥物組合。 Elafibranor是在GENFIT發現的，該公司將其從藥物發現一路推進到III期臨床。這些年的發展在今年早些時候達到了頂峰，6 月底，我們宣布了 elafibranor 在 PBC 中的關鍵 ACLF III 期試驗的 52 週雙盲治療期的積極數據。

As a reminder, the trial met its primary endpoint with a statistically significant higher percentage of patients achieving a clinically meaningful cholestasis response compared to placebo. Indeed, 51% of patients on elafibranor 80-milligram achieved a cholestasis response compared with 4% on placebo. It means that we saw a strong treatment effect with approximately 13x more responders on the active arm compared to placebo.

提醒一下，該試驗達到了主要終點，與安慰劑相比，達到有臨床意義的膽汁淤積反應的患者比例在統計學上顯著更高。事實上，服用 elafibranor 80 毫克的患者中有 51% 達到了膽汁淤積緩解，而服用安慰劑的患者只有 4% 出現了膽汁淤積緩解。這意味著我們看到了很強的治療效果，與安慰劑相比，主動臂上的反應者增加了約 13 倍。

We hit the first key secondary endpoint, normalization of ALP at week 52, which was also highly statistically significant. Although the other key secondary endpoint did not reach statistical significance, we observed the trend for prudent improvement. The study showed that elafibranor was generally well tolerated with a safety profile consistent with that observed in previously reported studies. We believe these findings already demonstrate that elafibranor can be a very valuable option for patients with PBC.

我們達到了第一個關鍵的次要終點，即第 52 週時 ALP 的正常化，這也具有高度的統計顯著性。儘管其他關鍵次要終點未達到統計顯著性，但我們觀察到了謹慎改善的趨勢。研究表明，elafibranor 通常具有良好的耐受性，其安全性與先前報告的研究中觀察到的結果一致。我們相信這些發現已經證明 elafibranor 對於 PBC 患者來說是一個非常有價值的選擇。

We have seen some analysis speculating about the competitiveness of elafibranor relative to other alternative in development. But we believe it is an exercise of limited value at this stage. Comparing partial high-level results across different studies without a full understanding of potential design differences or population differences is not scientifically sound. Much more meaningful conclusions might be possible after more data is released at upcoming scientific conferences.

我們已經看到一些分析推測 elafibranor 相對於其他開發替代品的競爭力。但我們認為，現階段這種做法的價值有限。在沒有充分了解潛在的設計差異或人群差異的情況下比較不同研究的部分高水平結果在科學上是不合理的。在即將舉行的科學會議上發布更多數據後，可能會得出更有意義的結論。

As far as GENFIT is concerned, we are now finalizing for the transfer of the elafibranor program to Ipsen that is now fully responsible for the next steps, including scientific communication, regulatory filing, commercialization and potential additional development. We are very pleased by Ipsen's continued commitment to the program. We believe that their strong commercial track record and international footprint will enable them to make the most of the opportunity and achieve significant commercial success.

就 GENFIT 而言，我們現在正在最終確定將 elafibranor 項目轉移給 Ipsen，Ipsen 現在全面負責後續步驟，包括科學交流、監管備案、商業化和潛在的額外開發。我們對易普生對該計劃的持續承諾感到非常高興。我們相信，他們強大的商業記錄和國際足跡將使他們能夠充分利用機會並取得重大商業成功。

As elafibranor becomes an Ipsen program, it essentially turns into a potential source of revenue for GENFIT. As per our agreement with Ipsen, we are eligible for up to EUR 360 million of milestone payments, and the first payment could start as early as later this year. Of course, the potential approval and successful launch would trigger additional milestones and a regular stream of revenues through the royalties.

隨著 elafibranor 成為 Ipsen 項目，它實質上變成了 GENFIT 的潛在收入來源。根據我們與 Ipsen 的協議，我們有資格獲得高達 3.6 億歐元的里程碑付款，第一筆付款最早可能在今年稍後開始。當然，潛在的批准和成功推出將觸發額外的里程碑和透過特許權使用費產生的定期收入流。

As I was alluding to earlier in this call, we are now shifting our strategic focus from a single program to a diversified portfolio of programs. The development of elafibranor bought us two things. First, over the years, we built R&D knowledge, capabilities, networks and strong partnerships in the field of liver disease. Second, the successful PBC program and subsequent partnership with Ipsen pour us the funding to build and now to develop a diversified pipeline that we have strategically put together over the last 18 months.

正如我在本次電話會議早些時候提到的，我們現在正在將策略重點從單一計劃轉向多元化的計劃組合。 elafibranor 的開發為我們帶來了兩件事。首先，多年來，我們在肝病領域建立了研發知識、能力、網絡和強大的合作關係。其次，成功的 PBC 計劃以及隨後與 Ipsen 的合作夥伴關係為我們提供了資金，用於建立和現在開發一個多元化的管道，我們在過去 18 個月中戰略性地整合了該管道。

GENFIT's focus now fully turns to our expanded pipeline in rare and severe liver diseases with a high unmet medical need with a primary focus on ACLF syndrome, also known as acute on chronic liver failure, where we are running multiple programs with several key inflection milestones to look forward to. Our ACLF franchise now comprises 5 assets, all based on differentiated mechanism of action, leveraging complementary pathways through different modes of administration.

GENFIT 的重點現在完全轉向我們在罕見和嚴重肝臟疾病方面的擴展產品線，這些疾病的醫療需求未得到滿足，主要關注ACLF 綜合徵，也稱為急性慢性肝衰竭，我們正在運行多個項目，其中有幾個關鍵的拐點里程碑期待。我們的 ACLF 特許經營權現在包括 5 項資產，全部基於差異化的行動機制，透過不同的管理模式利用互補途徑。

So we have VS-01, NTZ as well as a newly in-licensed SRT-015 that we licensed from Seal Rock Therapeutics in Seattle and CLM-022 that we licensed in from Celloram in Cleveland as well as VS-02 in hepatic encephalopathy, which is a condition closely associated with ACLF. Development stages of these different programs range from preclinical to Phase II.

因此，我們有 VS-01、NTZ 以及新近獲得許可的 SRT-015（從西雅圖的 Seal Rock Therapeutics 獲得許可）和 CLM-022（從克利夫蘭的 Celloram 獲得許可）以及用於肝性腦病的 VS-02，這是與ACLF 密切相關的病症。這些不同項目的開發階段從臨床前到第二階段。

So let's start with VS-01, our potential first-in-class liposomal-based therapeutic. It's currently being evaluated in the international unveiled IT Phase II open-label, randomized, controlled multicenter proof-of-concept study to assess its efficacy, safety and tolerability in addition to standard of care compared to standard of care alone in adult patients with ACLF Grade 1 and 2 with ascites.

那麼，讓我們從 VS-01 開始，它是我們潛在的一流脂質體治療藥物。目前正在國際上公佈的 IT II 期開放標籤、隨機、對照多中心概念驗證研究中對其進行評估，以評估其療效、安全性和耐受性以及治療標準與單獨治療 ACLF 成人患者的標準相比1 級和2 級有腹水。

The first patient was randomized in early July, and we expect interim data to be available in the first half of 2024. Given the high unmet need in this indication Orphan Drug Designation obtained from the U.S. FDA for VS-01, it is expected that the program may qualify for some of the expedited regulatory pathways provided by health authorities. In May 2023, we presented positive data at the Digestive Disease Week 2023 from an NTZ Phase I study demonstrating that it was generally well [curated] with a favorable safety profile in subjects with moderate and severe hepatic impairment. Preliminary data from a similar Phase I study conducted in subjects with renal impairment also support a favorable safety and tolerability profile. So those studies enable us to move forward. But for NTZ in ACLF, GENFIT has decided to pursue the development of a new nitazoxanide formulation, which will permit greater dosing flexibility. We have, therefore, revised the expected launch date of a Phase II clinical trial to the first half of 2025.

第一個患者於 7 月初被隨機分配，我們預計中期數據將在 2024 年上半年獲得。資格獲得衛生當局提供的一些快速監管途徑。 2023 年5 月，我們在2023 年消化疾病週上公佈了一項NTZ I 期研究的積極數據，表明該研究總體上經過精心策劃，在中度和重度肝功能損害受試者中具有良好的安全性。在腎功能不全受試者中進行的一項類似 I 期研究的初步數據也支持良好的安全性和耐受性。因此，這些研究使我們能夠繼續前進。但對於 ACLF 中的 NTZ，GENFIT 決定開發一種新的硝唑尼特製劑，這將允許更大的劑量彈性。因此，我們將二期臨床試驗的預計啟動日期修改為2025年上半年。

In the first half of this year, we further expanded our ACLF franchise by in-licensing 2 additional exciting programs. In May, it was SRT-015, an ASK1 inhibitor in an injectable formulation. And more recently, in July, CLM-022, which is a 13 class inflammasome inhibitor that we licensed, as I was saying from Celloram. So ASK1 inhibition has shown several potentially beneficial effects that may be relevant in ACLF such as blocking LPS associated impair inflammatory response, reducing immune response, reducing apoptosis, reducing release of a poor inflammatory cytokines, reducing fibrosis and protecting macrophage mitochondrial function.

今年上半年，我們透過引入另外 2 個令人興奮的項目的許可，進一步擴大了我們的 ACLF 特許經營權。 5 月，它是 SRT-015，一種注射製劑中的 ASK1 抑制劑。最近，即 7 月份，CLM-022，這是我們獲得許可的 13 類炎性體抑制劑，正如我在 Celloram 所說的那樣。因此，ASK1 抑制顯示出可能與ACLF 相關的幾種潛在有益作用，例如阻斷LPS 相關的損害發炎反應、減少免疫反應、減少細胞凋亡、減少不良發炎細胞因子的釋放、減少纖維化和保護巨噬細胞粒線體功能。

A 30 human study is planned for SRT-015 in the second half of 2024 to support a proof-of-concept study in ACLF patients as early as 2025. CLM-022 enables GENFIT to develop a potential of an inflammasome inhibitor into liver disease indication for the first time. We will provide updates on this program as it moves closer to an IND. The last asset in this franchise is VS-02, which is a urease inhibitor, which is being developed in hepatic encephalopathy, which is one of a major complication of advanced liver disease and portal hypertension and is closely associated to ACLF.

計畫於 2024 年下半年對 SRT-015 進行 30 名人體研究，以支持最早於 2025 年在 ACLF 患者中進行概念驗證研究。 。當該計劃接近 IND 時，我們將提供該計劃的最新資訊。該系列的最後一個資產是 VS-02，它是一種脲酶抑制劑，正在針對肝性腦病變開發，肝性腦病變是晚期肝病和門靜脈高壓的主要併發症之一，與 ACLF 密切相關。

IND-enabling studies are targeted to be completed in 2025. We are very pleased to have created a unique portfolio in ACLF. There is a very high unmet medical need, and we believe our deep pipeline provides us with a unique opportunity to drive value rapidly and potentially bring new hope for these patients. Besides ACLF, we are running our Phase Ib/IIa program for the treatment of advanced KRAS-mutated cholangiocarcinoma, evaluating our novel clinical stage autophagy inhibitor called GNS561.

支持 IND 的研究預計於 2025 年完成。未滿足的醫療需求非常高，我們相信我們深厚的產品線為我們提供了一個獨特的機會，可以快速推動價值，並有可能為這些患者帶來新的希望。除了 ACLF 之外，我們還在運行治療晚期 KRAS 突變膽管癌的 Ib/IIa 期項目，以評估我們的新型臨床階段自噬抑制劑 GNS561。

The first patient is expected to be screened in the last quarter of 2023. And the first biomarker data expected to be available as early first half of 2024, should support preparation of further evaluation of efficacy with the optimal doses of GNS561 and trametinib in the Phase IIa part of the study. Other than ACLF and CCA, we have an earlier stage program underway with VS-01. This time develop for acute (inaudible) crisis associated with (inaudible) metabolism in urea cycle disorders, an organic acidemia where IND-enabling studies are targeted to be completed in 2024. Last but not least, we will continue to explore partnerships opportunity for NIS2+ technology with a goal to release an IVD test powered by NIS2+ on the U.S. and European markets. We believe this market is bound to grow now that approval of NASH drugs seem to be on the horizon. In 2023, we've continued to have scientific publication and presentation at scientific events on NII.

預計於2023 年最後一個季度對第一位患者進行篩檢。 。除了 ACLF 和 CCA 之外，我們還有一個早期階段的專案 VS-01 正在進行中。這次是針對與尿素循環障礙（聽不清楚）代謝相關的急性（聽不清楚）危機，這是一種有機酸血症，其中支持IND 的研究目標是在2024 年完成。重要的一點是，我們將繼續探索NIS2+ 的合作機會技術，目標是在美國和歐洲市場發布由 NIS2+ 支援的 IVD 測試。我們相信，既然 NASH 藥物的批准似乎即將到來，這個市場必然會成長。 2023 年，我們繼續在 NII 的科學活動中發表科學出版物和演示。

In conclusion, I'd like to say just a few words about GENFIT corporate social responsibility as this was recognized by 3 independent stakeholders. In January, we were granted a prime status by ISS. In June, GENFIT was classified by other research as best-in-class for ESG based on our 2 main criteria; activity impact and ESG maturity. In July, GENFIT was awarded a gold medal by EthiFinance and ranked 2 out of 75 companies in the biopharmaceutical sector in France. This recognition are a testament to a company-wide effort in implementing CSR initiatives and ensuring transparent communication about that. In the second half of 2023, GENFIT will continue to reaffirm its commitment to social responsibility and sustainable development.

最後，我想簡單談談 GENFIT 的企業社會責任，因為這一點得到了 3 個獨立利害關係人的認可。一月份，我們被國際太空站授予了首要地位。 6 月，根據我們的 2 個主要標準，GENFIT 被其他研究評為 ESG 領域最佳；活動影響和 ESG 成熟度。 7月，GENFIT榮獲EthiFinance金獎，在法國生物製藥領域75家企業中排名第2。這項認可證明了全公司在實施企業社會責任計畫和確保透明溝通方面所做的努力。 2023年下半年，GENFIT將持續重申對社會責任和永續發展的承諾。

I will now highlight a few key financial elements from today's press release, but I won't get into details since all numbers were already described in the documentation provided. So as of June 30, 2023, GENFIT had EUR 111.8 million in cash and cash equivalents compared to EUR 140.2 million as of December 31, 2022. The decrease in cash, cash equivalents and current financial instruments between December 31, 2022, and June 30, 2023, is largely the result of our research and development efforts, notably for Phase III clinical trial of elafibranor in PBC, unveil IT of Phase II clinical trial for VS-01 in ACLF, the study for GNS561 as part of our cholangiocarcinoma program as well as the continued development of NTZ in ACLF.

我現在將重點介紹今天新聞稿中的一些關鍵財務要素，但我不會詳細介紹，因為所有數字都已在提供的文件中進行了描述。截至2023年6月30日，GENFIT的現金及現金等價物為1.118億歐元，而截至2022年12月31日為1.402億歐元。金融工具減少2023 年，主要是我們研發工作的結果，特別是 elafibranor 在 PBC 的 III 期臨床試驗，公佈了 VS-01 在 ACLF 中的 II 期臨床試驗，GNS561 的研究作為我們膽管癌計劃的一部分以及NTZ在ACLF中的持續發展。

As we continue to advance our current product candidates, conduct preclinical studies as well as clinical trials, we expect that our cash used in operational activities will amount to about EUR 60 million in 2023. This amount does not include potential expenses (inaudible) in future business development activities, such as in-licensing. GENFIT's finances remain secure until the fourth quarter of 2024 based on current assumptions, excluding exceptional events and in particular, excluding potential milestone payments, which GENFIT can expect to receive following the positive interim readout of ELATIVE.

隨著我們繼續推進現有的候選產品、進行臨床前研究以及臨床試驗，我們預計到2023 年，我們用於營運活動的現金將達到約6000 萬歐元。不清）業務開發活動，例如引進許可。根據當前假設，排除特殊事件，特別是排除潛在的里程碑付款，GENFIT 的財務狀況在 2024 年第四季度之前保持安全，在 ELATIVE 的中期讀數積極後，GENFIT 預計將收到這筆付款。

If GENFIT were to receive milestones related to a successful ELATIVE study according to potential regulatory submission approval as well as potential commercialization. We expect that company funding may be secured far beyond 2024, obviously, assuming that [all plan] outcomes are favorable. So I guess we are now ready to take questions. So operator, I'll let you give the instructions to the audience. Thank you.

根據潛在的監管提交批准以及潛在的商業化，GENFIT 能否獲得與成功 ELATIVE 研究相關的里程碑。顯然，假設[所有計劃]結果都是有利的，我們預計公司的資金可能會在 2024 年後得到保障。所以我想我們現在準備好回答問題了。那麼接線員，我會讓你向觀眾發出指示。謝謝。

(Operator Instructions) Our first question will come from the line of Evan Wang with Guggenheim Securities.

（操作員說明）我們的第一個問題將來自古根漢證券公司的 Evan Wang。

I just have a question on elafibranor. It seems like both GENFIT and Ipsen are pretty confident in some nuance heading into AASLD. So just interested to hear what kind of analysis we could look forward to at AASLD, whether it be on baseline characteristics, different measures with biochemical response or different cuts in (inaudible)?

我只是有一個關於 elafibranor 的問題。看來 GENFIT 和 Ipsen 對進入 AASLD 的一些細微差別都非常有信心。所以只是有興趣聽聽我們可以在 AASLD 上期待什麼樣的分析，無論是基線特徵、生化反應的不同測量還是不同的削減（聽不清楚）？

Well, at this point, we can't really comment further. I think both, (inaudible) as well as Ipsen are going to present more data at upcoming conferences, and it has the sort of full that is made available. People will have a better idea about how the 2 product profile are. I think at this point, we just can't comment on what Ipsen going to present, but AASLD is not too far out. So there's not much time to wait.

好吧，在這一點上，我們無法進一步發表評論。我認為（聽不清楚）和 Ipsen 都將在即將舉行的會議上提供更多數據，並且它具有可用的完整數據。人們將對這兩種產品的概況有更好的了解。我認為目前我們還無法評論 Ipsen 將要展示的內容，但 AASLD 也離我們不遠了。所以沒有太多時間等待。

Got it. And if I could ask one follow-up. Great to see the (inaudible) inflammatory trial is underway. Does that trial provide an opportunity to look at pruritus in a larger patient population?

知道了。如果我可以問一個後續問題。很高興看到（聽不清楚）發炎試驗正在進行中。 該試驗是否提供了在更多患者群體中觀察搔癢症的機會？

So this trial -- I mean, obviously, as you know, the [inflammatory] study is primarily designed to show the impact of the treatment on the [half]clinical end point to demonstrate that the target that are in the Phase III are indeed (inaudible) of clinical end point. That being said, it is also an opportunity to gather much more data from a larger group of patients. So I fully expect Ipsen to be communicating on various elements for this study.

所以這個試驗——我的意思是，顯然，正如你所知，[發炎]研究主要是為了顯示治療對[一半]臨床終點的影響，以證明處於 III 期的目標確實是（聽不清楚）臨床終點。話雖這麼說，這也是一個從更大的患者群體中收集更多數據的機會。因此，我完全期望 Ipsen 能夠就這項研究的各個要素進行交流。

We will take our next question from the line of Sushila Hernandez with Van Lanschot Kempen.

我們將從 Sushila Hernandez 和 Van Lanschot Kempen 回答下一個問題。

First of all, could you just repeat when you expect the first milestones to come in from Ipsen and what triggers them? And as a second question, are you expecting to further build out your ACLF franchise?

首先，您能否重複一下您預計 Ipsen 何時會實現第一個里程碑以及觸發這些里程碑的因素？第二個問題，您是否期望進一步擴大您的 ACLF 特許經營權？

Thank you, Sushila. Well, actually, we hope to get the first milestone -- or we have to meet the first milestone before the end of the year. And the first milestone is linked to regulatory filing in the U.S. and in Europe. As far as your second question is concerned, no, I think we now have a pretty deep portfolio in ACLF. As far as I know, no other company has more than one program in ACLF, and we have now 5. So the idea is not to continue to build that, but try to execute on the development of the program.

謝謝你，蘇西拉。嗯，實際上，我們希望能夠實現第一個里程碑——或者說我們必須在年底前實現第一個里程碑。第一個里程碑與美國和歐洲的監管備案有關。至於你的第二個問題，不，我認為我們現在在 ACLF 中有相當深入的投資組合。據我所知，沒有其他公司在 ACLF 中有超過一個項目，而我們現在有 5 個。

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

我們的下一個問題來自 Ed Arce 和 H.C.溫賴特。

Great. Congratulations on the data earlier in the quarter. Wanted to ask about your growing ACLF portfolio. You have this new ASK1 inhibitor with data potentially in 2025. I'm just curious you just brought this in. I'm wondering if you can explain to us what specific aspects to the profile of this asset gives you confidence in ACLF? And how does this sort of inconclusive data previously with this target in NASH have anything to do, if at all, in ACLF? And then I have a follow-up.

偉大的。恭喜本季早些時候的數據。想詢問您不斷成長的 ACLF 投資組合。你們有這種新的ASK1 抑制劑，其數據可能會在2025 年提供。信心？先前在 NASH 中與該目標相關的不確定資料與 ACLF 有何關係（如果有的話）？然後我有一個後續行動。

Yes. So I'll let Dean comment on this specific ASK1 inhibitor and how it differed from the one that was tested in NASH (inaudible). I just wanted to maybe preface Dean's comment by talking just a little bit about the importance of the unmet medical need in ACLF. I mean, as we know, all liver disease sort of lead to cirrhosis regardless of etiology, right? It could be NASH. It could be alcohol related. It could (inaudible) related. They all lead to cirrhosis, first compensated and then decompensated (inaudible).

是的。因此，我將讓 Dean 評論一下這種特定的 ASK1 抑制劑，以及它與 NASH 中測試的抑制劑有何不同（聽不清楚）。我只是想在 Dean 的評論前先談談 ACLF 中未滿足的醫療需求的重要性。我的意思是，正如我們所知，無論病因如何，所有肝臟疾病都會導致肝硬化，對吧？可能是 NASH。這可能與酒精有關。它可能（聽不清楚）相關。它們都會導致肝硬化，首先是代償期，然後是失代償期（聽不清楚）。

In the U.S., it's about 300,000 hospitalized compensated cirrhosis per year. And about 1/3 of those or 100,000 go to ACLF. That's Stage 3. So you should just look at ACLF 1 and 2, it's about 80,000 ACLF episodes every year in the U.S. and probably about 150,000 in Europe. The mortality is really high, 25% fatalities at 28 days for ACLF 1, 50% for ACLF 2. And currently, there is no approved product in -- for this condition.

在美國，每年約有 30 萬人因代償性肝硬化而住院。其中約 1/3 或 10 萬人參加了 ACLF。那是第三階段。死亡率確實很高，ACLF 1 的 28 天死亡率為 25%，ACLF 2 的死亡率為 50%。

So the unmet need is really high. The cost to public health is also really high since (inaudible) obviously monetize a lot of IT resources. So it's really important to try and address this. So yes, [ASK1] is underway. And then we brought this to asset, and I'll let Dean comment on -- specifically on SRT-015 and ASK1 inhibition.

所以未滿足的需求確實很高。公共衛生成本也非常高，因為（聽不清楚）顯然需要大量 IT 資源來貨幣化。因此，嘗試解決這個問題非常重要。所以，是的，[ASK1] 正在進行中。然後我們將其轉化為資產，我將讓 Dean 發表評論——特別是 SRT-015 和 ASK1 抑制。

Ed, thank you for the question. So the SRT-015, as you just mentioned, is inhibitor of ASK1. I think the audience probably know ASK1 inhibitor is best positioned in NASH and is positioned in NASH. I think most of the focus was looking at the inhibitors to be able to impact on fibrosis. However, I think when you look at the mechanism of the ASK1 pathway, we know that when ASK1 is activated, it leads to activation of downstream pathways like P38 junk.

艾德，謝謝你的提問。因此，正如您剛才提到的，SRT-015 是 ASK1 的抑制劑。我想觀眾大概都知道ASK1抑制劑最好定位在NASH，並且定位在NASH。我認為大多數關注點都在於尋找能夠影響纖維化的抑制劑。然而，我認為當你研究 ASK1 路徑的機制時，我們知道當 ASK1 被活化時，它會導致 P38 垃圾等下游路徑的活化。

And that pathway when it is chronically activated, which is what you have in chronic liver diseases, including cirrhosis and late-stage cirrhosis, decompensated cirrhosis, beyond the fibrosis, there's going to be benefits because this pathway impacts on inflammation, and we know that systemic high, systemic inflammation is a real hallmark of ACLF patients.

當該途徑被長期激活時，這就是慢性肝病的情況，包括肝硬化和晚期肝硬化、失代償性肝硬化，除了纖維化之外，還會有好處，因為該途徑會影響炎症，我們知道全身性高、全身性發炎是ACLF 患者的真正標誌。

And the other important activity of an ASK1 inhibitor is that it impacts on cell death. And as we realize that ACLF hallmarks of which is, as I mentioned, systemic inflammation, but also organ failures, multiple organ failures. So that combination of activities on fibrosis, inflammation as well as cell death, I think, is going to be a potent combination to be used to address for the treatment of ACLF patients.

ASK1 抑制劑的另一個重要活性是它會影響細胞死亡。正如我所提到的，我們意識到 ACLF 的標誌是全身性炎症，但也包括器官衰竭、多重器官衰竭。因此，我認為，針對纖維化、發炎和細胞死亡的活性組合將成為治療 ACLF 患者的有效組合。

The SRT-015 molecule itself, I think, has a wider therapeutic window than the molecules, which -- and I'm talking about (inaudible), than what was used in NASH. And I think also -- so Seal Rock also has done a lot of work looking at the activity of this molecule in different disease models things like acute liver failure, drug-induced liver failure and so on, and there is some very nice positive data looking at that, which, of course, is aligned with some data looking at specifically at the ability of inhibiting ASK1 with SRT-015 that impact on key steps within the pathway. I hope that answers your question, Ed.

我認為，SRT-015 分子本身比 NASH 中使用的分子（我說的是（聽不清楚））具有更寬的治療窗口。我也認為，Seal Rock 也做了很多工作來研究這種分子在不同疾病模型中的活性，例如急性肝衰竭、藥物引起的肝衰竭等，並且有一些非常好的積極數據當然，這與一些數據是一致的，這些數據專門研究了SRT-015 抑制ASK1 的能力，該能力影響通路中的關鍵步驟。我希望這能回答你的問題，艾德。

I think maybe we can add that I think, generally, what people think happened with (inaudible) is that the drug -- the dose was too low maybe to show efficacy. And that was because at a higher dose, there was some safety concerns. And I think the folks at Seal Rock have really made a convincing case that this issue does not exist with SRT-015, which enables them to dose it at the right level for efficacy.

我想也許我們可以補充一點，我認為，一般來說，人們認為發生的事情（聽不清楚）是藥物劑量太低，可能無法顯示療效。那是因為在較高劑量下，存在一些安全性問題。我認為 Seal Rock 的人員確實提出了令人信服的案例，證明 SRT-015 不存在這個問題，這使他們能夠以正確的劑量劑量發揮功效。

Great. That's very helpful. One follow-up, if I may, before I get back in the queue. And this is sticking with your proprietary pipeline beyond elafibranor. Given that the first biomarker data out of the CCA program is probably the nearest coming up here in the first half of '24, I'm wondering if you could give a little more detail about what exactly we can expect with that data readout.

偉大的。這非常有幫助。如果可以的話，在我回到隊列之前進行一次後續行動。這與 elafibranor 之外的專有管道保持一致。鑑於 CCA 計劃中的第一個生物標記數據可能是最接近的，將在 24 年上半年出現，我想知道您是否可以提供更多詳細信息，說明我們對該數據讀出的具體期望。

Ed, I'll let Dean comment on what we can expect to see. I would just say that the first data we'll have is likely to be VS-01. Of course, it will depend on the rhythm of enrollment, but that I think 2 will be really close next year. So Dean, I'll let you comment on GNS561.

艾德，我會讓迪恩評論一下我們可以期待看到的情況。我只想說，我們擁有的第一個數據很可能是 VS-01。當然，這取決於招生節奏，但我認為明年 2 會非常接近。 Dean，我讓你對 GNS561 發表評論。

Yes. So Ed, as you probably remember, GNS561 is an inhibitor of autophagy. And as an inhibitor of autophagy, it specifically inhibits PPT1, which is an enzyme towards the later stage of the whole autophagy pathway. So I think some key markers, which we'll be assessing is the ability of this molecule to decrease the expression of PPT1, for example. So there's different steps throughout the autophagy pathway downstream of PPT1, we'll be looking at, but I think that was a particular one, which will be a prime interest.

是的。 Ed，您可能還記得，GNS561 是一種自噬抑制劑。作為自噬抑制劑，它特異性抑制PPT1，PPT1是整個自噬途徑後期的酵素。因此，我認為我們將評估的一些關鍵標記是該分子降低 PPT1 表現的能力。因此，我們將研究 PPT1 下游的自噬途徑中存在不同的步驟，但我認為這是一個特定的步驟，這將是我們最感興趣的。

Our next question comes from the line of Evan Wang with Guggenheim Securities.

我們的下一個問題來自古根漢證券公司的 Evan Wang。

I just wanted to ask a follow-up specific to the VS-01 program. Great to see some of the progress there, and it sounds like we're on track for a first half '24 interim read. So just wanted to get a sense on how enrollment is tracking. And can you talk through some scenarios that would allow for expedited pathways, is the trial site sufficient for a potential (inaudible) approval?

我只是想問 VS-01 計劃的具體後續情況。很高興看到那裡的一些進展，聽起來我們正在按計劃進行 24 年上半年的臨時閱讀。所以只是想了解一下註冊情況是如何追蹤的。您能否談談一些可以加快途徑的場景，試驗地點是否足以獲得潛在（聽不清楚）批准？

Evan, so in terms of enrollment, I mean, it's still early days. I mean, right now, we're still on track. We hope to open more sites in the U.S. that are going to come online later this year. And that obviously help with accelerating performance, so we're hopeful. Obviously, we're breaking a little bit new ground here, because there have not been a lot of ACLF trial up until now, but we're confident, and we'll update you as we go along.

埃文，就招生而言，我的意思是，現在還處於早期階段。我的意思是，現在我們仍然走在正軌上。我們希望在美國開設更多網站，這些網站將於今年稍後上線。這顯然有助於提高性能，所以我們充滿希望。顯然，我們在這裡開闢了一些新天地，因為到目前為止還沒有進行大量的 ACLF 試驗，但我們有信心，我們會隨時向您通報最新情況。

In terms of accelerated approval, it will obviously depend on what we are able to show. I think the view is if we can make a case that there is efficacy, there will be openness from the authorities because of the very high medical needs and the fact that we got the Orphan Drug Designation. Right now, we have -- and I'll let Dean comment about the design, but we have an (inaudible) design where the primary is CLIF score, which is a score developed (inaudible) at the organ function. But we are also obviously looking at survival. And obviously, if we can show something here, that would be a very strong argument to get accelerated approval. Dean, do you want to comment on the design of the study?

就加速批准而言，這顯然取決於我們能夠展示什麼。我認為，我們的觀點是，如果我們能夠證明其療效，當局就會持開放態度，因為醫療需求非常高，而且我們獲得了孤兒藥資格。現在，我們有——我會讓 Dean 對設計進行評論，但我們有一個（聽不清楚）設計，其中主要是 CLIF 評分，這是根據器官功能製定的評分（聽不清楚）。但我們顯然也在關註生存問題。顯然，如果我們可以在這裡展示一些東西，這將是獲得加速批准的一個非常有力的論點。 Dean，您想對這項研究的設計發表評論嗎？

Sure. Yes, before I get to that, I think another important point, and this is what we're seeing as we engage with different investigation centers as well as the investigators themselves. I think there's a lot of excitement and motivation from the different investigators with whom we have met and with whom we're reaching out to. I think, as you know, that's going to be a key point to be able to drive recruitment of any trial.

當然。是的，在我談到這一點之前，我認為還有一個重要的點，這就是我們在與不同的調查中心以及調查人員本身接觸時所看到的。我認為我們遇到的以及我們正在接觸的不同研究人員都非常興奮和動力。我認為，正如您所知，這將是推動任何試驗招募的關鍵點。

This trial, it's not an easy trial, but I think it's viewed as technology as an engineered liposome and the mode of administration and all of that, I think, is seen as a technology that really has potential to be groundbreaking and be a real game changer. I think all these different things taken together, also based on what has been seen in terms of results in the first in human trial with some very compelling results, I think, drives a lot of excitement.

這次試驗，這不是一個簡單的試驗，但我認為它被視為一種技術，如工程脂質體和管理模式，所有這些，我認為，被視為一項真正具有突破性潛力並成為真正遊戲的技術改變者。我認為所有這些不同的事情加在一起，也基於在第一次人體試驗中所看到的結果，我認為，一些非常引人注目的結果會帶來很多興奮。

So right now, the study is in Phase II. We have different centers opened in Europe, and the design is to recruit a total of 60 patients. So we'll have 30 patients on treatment with VS-01 on top of standard of care versus the control group, which is standard of care. Pascal mentioned, the primary endpoint will be the CLIF ACLF score. So the CLIF ACLF score is something that was developed by the CLIF Consortium. And this was published, we think back in 2014. I invite anyone who is interested to really look at that paper, I think, that's published in the Journal of Hepatology, really describing the development of the CLIF score, the strength of the CLIF score and also the ability of the CLIF score to be prognostic and inform on risk of mortality of these different patients.

目前，該研究正處於第二階段。我們在歐洲開設了不同的中心，設計總共招募60位病患。因此，我們將有 30 名患者在標準護理的基礎上接受 VS-01 治療，而對照組則為標準護理。 Pascal 提到，主要終點將是 CLIF ACLF 評分。所以 CLIF ACLF 分數是由 CLIF 聯盟所發展出來的。回想一下，這篇文章是在2014 年發表的。評分的優勢以及 CLIF 評分的預測能力並提供這些不同患者的死亡風險資訊。

So the CLIF score is basically a score, it's an algorithm, which looks at organ system function, which is composed of liver, the kidney, the brain, coagulation, circulatory as well as respiratory and the 2 other components, which is it captures age and white blood cell count to form an (inaudible) inflammation. So again, it's a score which has been developed and tested quite extensively. And you'll see that in the publication that it does have a lot of evidence supporting it. So that's the primary end point. And of course, the secondary end point, which is equally important concerns mortality.

所以 CLIF 分數基本上是一個分數，它是一種演算法，它著眼於器官系統功能，它由肝臟、腎臟、大腦、凝血、循環以及呼吸和其他兩個組成部分組成，它捕獲了年齡和白血球計數形成（聽不清楚）發炎。再說一遍，這是一個經過廣泛開發和測試的分數。你會在出版物中看到它確實有很多證據支持它。這就是主要終點。當然，同樣重要的次要終點是死亡率。

In terms of the timing of this, so the protocol itself is that we will introduce the VS-01 technology into the intraperitoneal space and leave it in there up for 4 hours. So it's a 4-hour dwelling time. We then drain it back out, and we do this once a day for 4 consecutive days. And then we follow up with the patients to look -- we keep them in the hospital up to 7 days. And then we follow up at day 14, 20 and 90. And at day 90, it is the end of study.

就時間而言，協議本身是我們將 VS-01 技術引入腹膜內空間，並將其留在那裡 4 小時。所以這是一個4小時的停留時間。然後我們將其排出，連續 4 天每天一次。然後我們對患者進行追蹤觀察——我們讓他們住院 7 天。然後我們在第 14 天、第 20 天和第 90 天進行追蹤。

Our next question comes from the line of Thomas Smith with Leerink Partners.

我們的下一個問題來自 Thomas Smith 和 Leerink Partners 的電話。

Congrats for all the progress. Just a couple of questions from our end. I guess, first on elafibranor. We've seen a competitor post study in patients who are above upper limited normal, but below the 1.67x upper limited normal criteria. I guess can you just remind us how the future elafibranor development plans are going to be implemented with Ipsen? Do they drive all of the clinical development decisions here?

祝賀所有的進步。我們最後只提出幾個問題。我想，首先是 elafibranor。我們已經看到一項競爭對手的後期研究，患者的病情高於正常上限，但低於 1.67 倍正常上限標準。我想您能否提醒我們未來的 elafibranor 開發計劃將如何與 Ipsen 一起實施？他們是否推動這裡所有的臨床開發決策？

Or are you working with them to help structure that? And how do you think about running a study in that patient population to perhaps expand -- either expand the label or expand the addressable patient population? And then just a second question on the overall strategy. Can you just give us an update on sort of your latest thoughts on business development? Are you still out there evaluating some of these other rare liver disease programs and looking to bring an additional assets? Or do you feel like you've kind of completed the pipeline build at this point you're more in sort of an execution mode?

或者您正在與他們合作來幫助建立這一點？您如何看待在該患者群體中進行一項研究，以擴大其範圍——要么擴大標籤，要么擴大可尋址的患者群體？然後是關於總體戰略的第二個問題。您能為我們介紹一下您對業務發展的最新想法嗎？您是否仍在評估其他一些罕見肝病項目並尋求帶來額外的資產？或者您覺得您已經完成了管道構建，此時您更多地處於執行模式？

Tom, look, so first of all, in terms of the development for elafibranor, Ipsen is now responsible for everything. So that would include the open-label part of the Phase III as well as the confirmatory study. And obviously, any new indication, either in PBC similar to what (inaudible) is doing to expand that market. Or in other indications, I think Ipsen has communicated that they started study in (inaudible) and also potentially in combination, for example.

湯姆，你看，首先，就 elafibranor 的開發而言，Ipsen 現在負責一切。因此，這將包括第三階段的開放標籤部分以及驗證性研究。顯然，任何新的跡象，無論是在中國人民銀行，都類似於（聽不清楚）正在採取的擴大該市場的措施。或者在其他方面，我認為 Ipsen 已表示他們開始研究（聽不清楚），並且也可能進行組合研究。

So that's 100% Ipsen decision. The only sort of impact for us is should it be successful, then elafibranor in other indications (inaudible) will also give rights to royalties for (inaudible). But whatever choices made there is entirely up to Ipsen. That being said, I mean, obviously, we know the product very well. So if they have any question, we are 100% here to help, but that's their decision how they want to pursue that.

這就是 100% Ipsen 的決定。對我們來說唯一的影響是，如果它成功，那麼 elafibranor 在其他適應症（聽不清楚）中也將授予特許權使用費（聽不清楚）。但無論做出什麼選擇，都完全取決於 Ipsen。話雖如此，我的意思是，顯然我們非常了解該產品。因此，如果他們有任何問題，我們 100% 會提供幫助，但這取決於他們想要如何解決。

In terms of the -- your second question, now we feel that from a BD standpoint, we want to pause. We have built -- as I was saying earlier, we have built a portfolio in ACLF that's really unique. Nobody else has anything close to that in terms of its depth and in terms of the company's commitment to ACLF. But now, I mean, we can't keep adding.

關於你的第二個問題，現在我們覺得從 BD 的角度來看，我們想暫停一下。正如我之前所說，我們已經在 ACLF 中建立了一個非常獨特的投資組合。就其深度以及公司對 ACLF 的承諾而言，沒有其他公司可以與之相提並論。但現在，我的意思是，我們不能繼續添加。

So first of all, we feel that we've covered the more sort of promising pathways and also we need to now really be focused on execution, and we don't have the bandwidth to do much more than that. So no, don't expect anything else from a BD standpoint. We'll obviously be continuing -- continuously monitoring the environment. And if we -- if there's something really promising, we might change the vision. But in terms of strategy, we feel we have something that's really exciting, and we want to develop that.

因此，首先，我們認為我們已經涵蓋了更有希望的途徑，而且我們現在需要真正專注於執行，但我們沒有足夠的頻寬來做更多的事情。所以，從 BD 的角度來看，不要期待任何其他事情。顯然，我們將繼續持續監測環境。如果我們——如果有一些真正有前途的事情，我們可能會改變願景。但就策略而言，我們覺得我們有一些真正令人興奮的東西，我們希望發展它。

Got it. That's super helpful. And maybe just one quick follow-up, if I could, on elafibranor. And I was just wondering if you could comment on, I guess, whether there are any outstanding data sets that would potentially serve as a gating factor, basically turning them over, I suppose, to Ipsen for the regulatory submission or whether at this point, essentially everything has been turned over, and it's just a matter of Ipsen preparing the NDA and submitting the NDA on their end?

知道了。這非常有幫助。如果可以的話，也許只是對 elafibranor 進行一次快速跟進。我只是想知道你是否可以評論一下，我想，是否有任何未完成的數據集可能會成為一個門控因素，基本上將它們移交給 Ipsen 進行監管提交，或者是否在這一點上，基本上一切都已經移交了，只是Ipsen 準備NDA 並最終提交NDA 的問題？

Yes. We have completed the transfer. So now it's really Ipsen in the driver seat for the filing for -- and also for the presentation of a much more complete data set in conferences.

是的。我們已經完成了轉帳。因此，現在 Ipsen 確實佔據了主導地位，負責歸檔以及在會議上展示更完整的資料集。

Got it. Okay. Great. That's super helpful. Looking forward to seeing the detailed data at AASLD, and congrats again on all the progress.

知道了。好的。偉大的。這非常有幫助。期待在 AASLD 上看到詳細數據，並再次祝賀所有進展。

This does conclude today's question-and-answer session. I will now turn the call back to Pascal Prigent for any additional or closing remarks.

今天的問答環節到此結束。現在，我將把電話轉回給帕斯卡·普里金特（Pascal Prigent），詢問任何補充或結束語。

Thank you, and thank you all for joining. So in conclusion, I'll just reiterate that the positive results for our ELATIVE Phase III study in PBC means that GENFIT is now entering a new era. And we pivot from a focus on a single program to the development of a robust portfolio of exciting programs with a focus on ACLF. Additional ELATIVE data will be released in the coming months, and we are confident that this data will further demonstrate that elafibranor has a very competitive profile and the potential to add significant value to patients with PBC.

謝謝大家，也謝謝大家的加入。因此，總而言之，我只想重申，我們在 PBC 中的 ELATIVE III 期研究的積極結果意味著 GENFIT 現在正在進入一個新時代。我們從專注於單一專案轉向開發一系列以 ACLF 為重點的令人興奮的專案。更多 ELATIVE 數據將在未來幾個月內發布，我們相信這些數據將進一步證明 elafibranor 具有非常有競爭力的形象，並有可能為 PBC 患者增加顯著價值。

We are very pleased to see the commitment of our partner, Ipsen, and we believe that they will make the most of the opportunity. And for GENFIT, essentially, this means a potential first milestone met in 2023. And if elafibranor is approved in PBC, additional milestone and regular revenue stream for royalty payments. These potential revenues would be used to finance the development of our pipeline with 7 different programs now, ranging from preclinical to Phase II.

我們很高興看到我們的合作夥伴 Ipsen 的承諾，我們相信他們將充分利用這個機會。對於 GENFIT 來說，本質上來說，這意味著 2023 年可能會實現第一個里程碑。這些潛在收入將用於資助我們目前有 7 個不同項目的管道開發，從臨床前到第二階段。

And as I was saying, in particular, 5 distinct programs in ACLF, where the medical need is really significant. So looking forward to our next corporate update at AASLD in mid-November. Thank you and goodbye.

正如我所說，特別是 ACLF 的 5 個不同項目，這些項目的醫療需求確實非常重要。因此，期待我們 11 月中旬在 AASLD 上發布的下一次企業動態。謝謝，再見。

This concludes today's call. Thank you for your participation, and you may now disconnect.

今天的電話會議到此結束。感謝您的參與，您現在可以斷開連接。