Inventiva SA (IVA) 2022 Q4 法說會逐字稿

Thank you, operator, and welcome to everybody to this full year 2022 financial results. As usual, I will be making with my colleague forward-looking statements so please have a look at the regulatory documentation that is available on our website.

謝謝業者，歡迎大家閱讀 2022 年全年財務表現。像往常一樣，我將與我的同事一起發表前瞻性聲明，因此請查看我們網站上提供的監管文件。

In terms of speakers today, I'm very happy as usual to have Pierre with us, our CSO and Co-Founder. Michael, our CMO, will go through an update on our three important clinical trials with lanifibranor, of course, the Phase III, but also the two Phase II that are ongoing. And then Jean will conclude the presentation with an update on the financials. Of course, at the end of the session, we will have a Q&A session.

就今天的演講者而言，我像往常一樣很高興有我們的 CSO 兼聯合創始人 Pierre 與我們在一起。我們的首席行銷長 Michael 將介紹我們三個重要的 lanifibranor 臨床試驗的最新情況，當然是 III 期試驗，還有正在進行的兩項 II 期試驗。然後，吉恩將以財務狀況的最新情況來結束演講。當然，在會議結束時，我們還會有一個問答環節。

So let me give you, first of all, some highlights for the full year. So let's start with our lead program, lani, in NASH and start with NATiV3 where we've been, I would say, very happy to work and extend, develop the Phase III in 23 countries. And now we have more than 350 clinical sites that are active and more than 300 that have screened at least the patient. We have throughout the year, and we continue to do so, implemented a series of measure to boost enrollment, and I would say that this continue throughout 2023.

首先，讓我先為大家介紹一下全年的一些亮點。因此，讓我們從 NASH 領域的主導計畫 lani 開始，然後從 NATiV3 開始，我想說，我們非常高興在 23 個國家開展第三階段的工作和擴展。現在我們有 350 多個活躍的臨床中心，其中 300 多個至少已經對患者進行了篩檢。我們全年實施了一系列措施來提高入學率，並將繼續這樣做，我想說，這種情況將持續到 2023 年。

We have done many things, and I'm very proud of those and grateful to our team. We have reviewed and implemented the new process to speed up our biopsy or analyzed.

我們做了很多事情，我對此感到非常自豪，並對我們的團隊表示感謝。我們已經審查並實施了新流程，以加快我們的活檢或分析速度。

We have trained site. We've put in place incentives. We have included site networks, which are specialized. We have a strong NASH expertise, and we also have closed sites that were not performing to what we -- to our expectations.

我們有培訓現場。我們已經制定了激勵措施。我們已經包括了專門的站點網路。我們擁有強大的 NASH 專業知識，我們也關閉了那些表現不符合我們預期的站點。

We have developed patient material, including opening recently the patient website. We have provided support to pre-screening activities to sites, including providing a screening algorithm to better identify patients. We have organized and we're currently organizing investigator meetings and also made several protocol improvements. All of that, I would say, make us confident that we will achieve our target to have the last patient first visit as targeted for the second half of 2023.

我們開發了患者材料，包括最近開放了患者網站。我們為站點的預篩檢活動提供了支持，包括提供篩檢演算法以更好地識別患者。我們已經組織了並且目前正在組織研究者會議，並且還對協議進行了一些改進。我想說，所有這些都讓我們充滿信心，我們將實現 2023 年下半年實現最後一位患者首次就診的目標。

We have also, and when Michael will go through that, developed a new design for NATiV3, which is much more patient centric. We have started to implement this new protocol. It has been submitted, and we're very pleased to see that it has been approved in key countries including the US.

我們也為 NATiV3 開發了一種新的設計，當 Michael 將會經歷這個過程時，它會更加以患者為中心。我們已經開始實施這個新協議。它已經提交，我們很高興看到它已經在包括美國在內的主要國家獲得批准。

This morning, Akero announced their design for the Phase III. And we're very pleased to see that Akero is working on our footsteps with a design, which is very close to ours. And especially, they've selected the same primary endpoint as our primary endpoint in NATiV3.

今天早上，Akero 宣布了他們的第三期設計。我們很高興看到 Akero 正在追隨我們的腳步，其設計與我們非常接近。特別是，他們選擇了與我們在 NATiV3 中的主要端點相同的主要端點。

On the other trial, I think it's important to point out that LEGEND, we have activated the first clinical site in US, in Europe. And of course, we are randomizing in all of the countries where LEGEND is open.

在另一項試驗中，我認為重要的是要指出，傳奇，我們已經在美國和歐洲啟動了第一個臨床站點。當然，我們在 LEGEND 開放的所有國家/地區進行隨機分配。

And then finally, we're looking forward to the results of the investigation study conducted by Professor Cusi from the University of Florida. The last patient was enrolled in September '22. We recently exchanged with Professor Cusi, is going through the database, finalizing the last cleanup, and getting ready for the database log. So we're looking to be able to publish those results by middle of Q2 '23.

最後，我們期待佛羅裡達大學 Cusi 教授進行的調查研究的結果。最後一位患者於 22 年 9 月入組。我們最近和Cusi教授交流，正在遍歷資料庫，完成最後一次清理，準備資料庫日誌。因此，我們希望能夠在 23 年第二季中期之前發布這些結果。

The '22 has also been very active in terms of partnership. Very proud of having secured a strong partner with Sino Biopharm after an extensive due diligence from their part, which prove that our drug is well positioned in China, which, as you know, is a very promising market for NASH, given the prevalence of the disease in China. It has allowed us to secure close to EUR13 million of upfront payment, and we're eligible to additional milestone that can reach to under EUR290 million on top of royalties. You know that depending on various discussion and interaction with Sino Biopharm we'll have with the regulatory authorities, they'll be -- they can join the NATiV3 trial.

'22 在合作方面也非常活躍。經過中國生物製藥的廣泛盡職調查，我們非常自豪能夠與中國生物製藥建立一個強大的合作夥伴，這證明我們的藥物在中國處於有利地位，正如您所知，鑑於NASH 的流行，中國是一個非常有前景的NASH 市場中國的疾病。它使我們能夠獲得近 1300 萬歐元的預付款，並且我們有資格獲得額外的里程碑，在特許權使用費之外，可以達到 2.9 億歐元以下。你知道，根據我們將與監管機構進行的與中國生物製藥的各種討論和互動，他們將可以加入 NATiV3 試驗。

And then finally, I would point out that we're very pleased like major strategy of finding partners in Asia. This allows to speed up the development and the entry to market. And we continue exploring other potential commercialization of lanifibranor in Asia. And then finally, in terms of IP, we have secured in the US a patent that strengthen our IP estate, especially in patient with -- efficiency cirrhotic patients.

最後，我想指出，我們對在亞洲尋找合作夥伴的重大策略感到非常高興。這可以加快開發和進入市場的速度。我們將繼續探索 lanifibranor 在亞洲的其他潛在商業化。最後，在智慧財產權方面，我們在美國獲得了一項專利，該專利可以加強我們的智慧財產權財產，特別是對於患有高效肝硬化患者的患者。

Looking at the other program in term of AVVB-157, unfortunately, you know that we received -- we were notified by AbbVie that the following, I mean, expected tox result in a long-term tox study, they have decided to hold to this program. We received the notification in October. On odiparcil, we have a very constructive discussion with the FDA over the summer. They confirm that we can move with this drug in children, given the safety profile of the drug, and also have validated that a single Phase II/III trial in children would be sufficient to secure if positive accelerated market approval.

不幸的是，看看 AVVB-157 方面的其他計劃，您知道我們收到了艾伯維 (AbbVie) 的通知，我的意思是，長期毒性研究中的預期毒性結果，他們決定堅持這個程序。我們十月就收到了通知。關於奧迪帕西，我們在夏天與 FDA 進行了非常有建設性的討論。他們確認，鑑於該藥物的安全性，我們可以在兒童中使用該藥物，並且還驗證了在兒童中進行的單一 II/III 期試驗將足以確保如果積極加速市場批准。

Financially, we've been very active as well. We've secured the EUR50 million loan from EIB, one of the largest for biotech in Europe. Out of those EUR50 million, still EUR25 million are to be used and are not included in our cash runway.

在財務方面，我們也非常積極。我們已從歐洲投資銀行 (EIB) 獲得了 5000 萬歐元的貸款，該貸款是歐洲最大的生物技術貸款之一。在這 5000 萬歐元中，仍有 2500 萬歐元將被使用，並且不包含在我們的現金跑道中。

On top of the EUR13 million or close to EUR13 million we received from Sino, we also raised close to EUR10 million from our ATM program and also secure additional facilities backed by the French government of close to or actually a bit more than EUR5 million. And then of note, we were selected to have shown a very limited number of players to be part of the Euronext Tech Leaders segment. And also, we're very pleased to welcome Dr. Lucy Lu as a new Board member.

除了我們從信諾收到的1300 萬歐元或接近1300 萬歐元之外，我們還從ATM 計劃中籌集了近1000 萬歐元，並獲得了法國政府支持的接近或實際上略高於500 萬歐元的額外設施。值得注意的是，我們被選中展示了極少數參與者成為泛歐交易所科技領導者細分市場的一部分。此外，我們非常高興地歡迎 Lucy Lu 博士成為新的董事會成員。

So let's talk a little bit about lanifibranor. And before I give the floor to Michael, let me just to remind you some key features of lanifibranor.

讓我們來談談 lanifibranor。在請邁克爾發言之前，讓我提醒您 lanifibranor 的一些主要功能。

Very importantly, the profile of the drug is really unique. We are, to our knowledge, the only pan-PPAR that currently in development in NASH. And this profile is really important because the strong result we were able to show during the Phase IIb that granted breakthrough therapy, a role is, according to AbbVie, there's really ability to activate the three isoforms. We also remind you that we are not a TZD, that we have not seen any of the typical liabilities that characterize TZD, especially during the preclinical program.

非常重要的是，該藥物的概況確實很獨特。據我們所知，我們是目前唯一在 NASH 中開發的泛 PPAR。這個特徵非常重要，因為我們在 IIb 期試驗中能夠展示出突破性療法的強大結果，根據艾伯維的說法，一個作用是，確實有能力激活三種亞型。我們也提醒您，我們不是 TZD，我們沒有看到任何 TZD 所特有的典型責任，特別是在臨床前計畫期間。

The safety continues to be in our mind, very favorable. Recently, we had the DSMB in our NATiV3 and the conclusion rules for the previous DSMB we have had throughout the course of the history of lanifibranor that we can continue the trial with no changes.

我們仍然牢記安全性，非常有利。最近，我們在 NATiV3 中加入了 DSMB，並且我們在 lanifibranor 的整個歷史過程中對先前的 DSMB 的結論規則，我們可以繼續進行試驗，無需進行任何更改。

I mentioned the very strong result of the Phase IIb. I think it's important to try to position lanifibranor compared to the potential competitors. This is, of course, very difficult because trials are, of course, different.

我提到了 IIb 期的非常強烈的結果。我認為嘗試將 lanifibranor 與潛在競爭對手進行比較很重要。當然，這是非常困難的，因為試驗當然是不同的。

And also, we have reported our data, giving the ITT population because this seems to ask the relevant population because this is the one that is considered by regulatory authorities while most of our competitors only reported data for protocol. But I think it gives an idea that lanifibranor, when we look on NASH resolution and no worsening of fibrosis and a very compelling data, certainly, with that profile, very competitive and probably superior to the other oral drugs in development and also competitive profile versus injectables.

此外，我們還報告了我們的數據，向 ITT 人群提供了信息，因為這似乎是在詢問相關人群，因為這是監管機構考慮的人群，而我們的大多數競爭對手僅報告了協議數據。但我認為它給出了一個想法，當我們觀察NASH 解決情況和纖維化沒有惡化以及非常令人信服的數據時，lanifibranor 具有非常強的競爭力，並且可能優於正在開發的其​​他口服藥物，並且與其他口服藥物相比也具有競爭力注射劑。

This is even more true when we look at fibrosis improvement, which for us remains given the disease and given what we want to achieve, which is a patient with NASH avoid to become cirrhotic. We see that on fibrosis. We have a very compelling profile, very competitive even with injectables.

當我們考慮纖維化的改善時，情況更是如此，對我們來說，纖維化的改善仍然是考慮到疾病和我們想要實現的目標，即 NASH 患者避免變成肝硬化。我們在纖維化方面看到了這一點。我們擁有非常引人注目的形象，即使在註射劑方面也非常有競爭力。

And lastly, I also would like to show very briefly the primary endpoint we have selected and that also Akero has selected for the Phase III. You see that this primary endpoint was made by both our low dose and high dose, 800 milligram and 1,200, and that was 3 to 4 times more responders.

最後，我還想非常簡要地展示我們選擇的主要終點以及 Akero 為 III 期選擇的主要終點。您會看到，這個主要終點是由我們的低劑量和高劑量（800 毫克和 1,200 毫克）實現的，這是反應者的 3 到 4 倍。

Lastly, I also would like to point out that this is, I think, a compelling endpoint because it enables to really reduce the placebo. We have 7%; you see that Akero was 5%. So you really see that with this approach, we are able to reduce the noise of the placebo effect.

最後，我還想指出，我認為這是一個令人信服的終點，因為它能夠真正減少安慰劑的使用。我們有7%；你看 Akero 是 5%。所以你確實看到，透過這種方法，我們能夠減少安慰劑效應的噪音。

Finally, let's talk of the interaction we have had with the FDA, a positive interaction that have led to the new design Michael will present. And I think this is a very good step for all the field with this approach to have a trial based on surrogate histology endpoint in patients with non-cirrhotic NASH, and then enabled the possibility to secure full approval with an outcome trial in patients with compensated cirrhotic NASH.

最後，讓我們談談我們與 FDA 的互動，這種積極的互動導致了邁克爾將展示的新設計。我認為這對所有領域來說都是非常好的一步，採用這種方法在非肝硬化NASH 患者中進行基於替代組織學終點的試驗，然後使在補償性NASH 患者中進行結果試驗獲得完全批准成為可能。肝硬化 NASH。

I think that makes the development more feasible, also, from a timing point of view, shorter development to secure full approval. And also, in our case, it would expand the population that we could address. I also including patients with compensated cirrhosis.

我認為這使得開發更加可行，而且從時間的角度來看，開發時間更短以確保獲得充分批准。而且，就我們而言，它將擴大我們可以解決的人口。我還包括代償性肝硬化患者。

So that's for my brief introduction. And I will now turn to Michael that will give you an update NATiV3 and also the other two Phase II that are ongoing.

這就是我的簡短介紹。我現在請 Michael 為您提供 NATiV3 的更新以及正在進行的其他兩個第二階段。

Thank you, Frédéric, and good morning, good afternoon to everybody. I'm on slide 15 now which summarizes the development program for lanifibranor. On the left, in green, we have the completed study that was summarized by Frédéric just a minute ago, so the Phase II study. And I would just highlight also that this was a six-month treatment with a very robust efficacy on histology, both NASH activity and fibrosis, which is a testimony to the efficacy of the compound to have that degree of effect on fibrosis after a short treatment period for a fibrosis evaluation.

謝謝你，Frédéric，大家早安，下午好。我現在正在觀看第 15 張投影片，其中總結了 lanifibranor 的開發計劃。左邊的綠色部分是 Frédéric 一分鐘前總結的已完成的研究，即第二階段研究。我還要強調的是，這是一個為期六個月的治療，對組織學、NASH 活性和纖維化都具有非常強大的功效，這證明了該化合物在短期治療後對纖維化有一定程度的影響的功效纖維化評估期。

Based on these data, the efficacy and safety of the compound, the FDA has granted breakthrough therapy designation for lanifibranor in NASH. On the right, in orange, the Phase III study, which is currently ongoing. We are in the midst of the Phase III study as you know and as I also speak about two earlier Phase II studies that Frédéric also mentioned.

基於這些數據以及該化合物的功效和安全性，FDA 已授予 lanifibranor 治療 NASH 的突破性療法稱號。右側橙色部分是目前正在進行的 III 期研究。如您所知，我們正處於 III 期研究之中，而且我也談到了 Frédéric 也提到過的兩項早期 II 期研究。

On slide 16, as you heard, we have updated the design of the study to make it more attractive to patients, investigators. The move to seven-years, placebo-controlled treatment period and had very good interactions with the FDA on this change. And as you know, the FDA has also made public communications that correspond to this, to the overall development approach that we currently have in place.

在投影片 16 上，如您所聽到的，我們更新了研究的設計，使其對患者和研究人員更具吸引力。轉向七年安慰劑對照治療期，並就這一變化與 FDA 進行了良好的互動。如您所知，FDA 也針對我們目前採用的整體開發方法進行了相應的公開溝通。

So what are the main changes in NATiV3? The readout for the surrogate efficacy endpoint, which is histology after 72 weeks of treatment, has remained unchanged. We have two active arms and a placebo arm. And there will be two biopsies, one at baseline, maybe historical. But one biopsy at baseline and one at the end of treatment for a total of about 950 patients.

那麼NATiV3主要有哪些變化呢？替代療效終點（即治療 72 週後的組織學結果）的讀數保持不變。我們有兩個主動組和一個安慰劑組。將會有兩次活檢，一次是基線，也許是歷史性的。但總共約 950 名患者在基線時進行了一次活檢，在治療結束時進行了一次活檢。

After that, patients will remain in the study, but they will be re-randomized to an active treatment arm. So they will not be receiving placebo beyond that time, which is seen by everybody as a very positive approach. And the active treatment extension will be at least 48 weeks after that readout for the secondary or after the second biopsy. So that will provide, also, data on longer-term treatment with lanifibranor.

之後，患者將繼續參與研究，但他們將被重新隨機分配到積極治療組。因此，超過這個時間他們就不會再接受安慰劑，每個人都認為這是一種非常積極的方法。主動治療延長時間將是在二次活檢或第二次活檢讀數後至少 48 週。因此，這也將提供有關拉尼布諾長期治療的數據。

In addition, and this is also a new aspect, we will enable patients who screen failed because of histology, but who have NASH and fulfill all the other inclusion criteria to enroll in an exploratory cohort of about 200 patients, again, using the two doses and placebo controlled. And this exploratory cohort will, for example, enroll patients who are staged for the fibrosis by SF3B1 pathologists for -- by the second one. And the tiebreaker [data force] these patients would have very early cirrhosis and would be eligible to enter into the exploratory cohort. That's just one example.

此外，這也是一個新的方面，我們將讓因組織學篩檢失敗但患有 NASH 並滿足所有其他納入標準的患者再次使用兩種劑量加入約 200 名患者的探索性隊列中和安慰劑對照。例如，這個探索性隊列將招募由 SF3B1 病理學家對第二個纖維化進行分期的患者。決勝局[數據力量]這些患者將患有非常早期的肝硬化，並且有資格進入探索性隊列。這只是一個例子。

So the main changes are really the shorter duration of exposure to placebo and two biopsies instead of three. And the exploratory cohort also will not have a second biopsy supplement. So on the next slide, number 17.

因此，主要的變化實際上是安慰劑暴露時間的縮短和兩次活檢而不是三次。探索性隊列也不會進行第二次活檢補充。在下一張投影片上，編號為 17。

The readout of the histology at 72 weeks is the basis for submission for accelerated approval in United States with the FDA and the corresponding conditional approval by the European Medicines Agency, the EMA. And this is with regard to the FDA corresponding to several communications that they have made and their continued support for accelerated approval in the field of NASH.

72 週時的組織學讀數是向美國 FDA 提交加速批准以及歐洲藥品管理局 (EMA) 相應有條件批准的基礎。這是針對 FDA 所進行的多次溝通以及他們對 NASH 領域加速批准的持續支持。

The principal investigators are Dr. Francque from Antwerp and Dr. Sanyal from Richmond, Virginia, two very well-known leading experts in the field of NASH. And the main inclusion criteria, of course, have remained the same. So result patients within the degree of activity based on the SAF scoring, which is the scoring system for the degree of tissue injury, ballooning, and inflammation, and fibrosis stages F2-F3. So patients with advanced fibrosis, but not proceeded to the degree of the stage of cirrhosis.

主要研究人員是來自安特衛普的 Francque 博士和來自維吉尼亞州里士滿的 Sanyal 博士，他們是 NASH 領域的兩位非常知名的領先專家。當然，主要的納入標準保持不變。因此，根據 SAF 評分得出患者的活動程度，SAF 評分是組織損傷、氣球膨脹、發炎以及纖維化階段 F2-F3 程度的評分系統。因此患者出現晚期纖維化，但並未進展到肝硬化階段的程度。

We do and allow patients who have a stable dose of a GLP-1 receptor agonist. They have to be at least three months on a stable dose, and I think this will also be very important for enrollment. And to get data of this -- the treatments of those two compounds. So that's, I think, an important aspect, especially since GLP-1 receptor agonist have become -- have an increasing uptake in patients with metabolic disorders.

我們這樣做並允許服用穩定劑量的 GLP-1 受體激動劑的患者。他們必須至少服用三個月的穩定劑量，我認為這對入學也非常重要。並取得這兩種化合物的治療數據。因此，我認為這是一個重要的方面，特別是自從 GLP-1 受體激動劑在代謝性疾病患者中的使用量不斷增加以來。

We have randomization according to Type 2 Diabetes in fibrosis stage. The study is powered based on the Phase II data, which were very positive. So we have 90% power for the primary efficacy endpoint.

我們根據第 2 型糖尿病纖維化階段進行隨機分組。該研究是基於第二階段的數據，這些數據非常積極。因此，我們對主要療效終點有 90% 的功效。

And then of note, the biopsy reading is very robust. We use three expert pathologists, and it's based on the fact that every biopsy is read by two of them. And in case of non-agreements on certain aspects that affect eligibility, the third pathologist is the tiebreaker.

值得注意的是，活檢讀數非常穩健。我們聘請了三名病理專家，這是基於每次活檢都由其中兩名進行讀取這一事實。如果在某些方面無法達成一致而影響資格，則由第三位病理學家決定。

So the primary efficacy endpoint is again based on the Phase II data, both NASH resolution and fibrosis improvement, which is, of course, also relays on the clinical benefits, which is significant compared to having only one and also corresponds to the mechanism of action of the compound, the lanifibranor treating all aspects of the disease biology. So we do have an effect on all these aspects of NASH.

所以主要療效終點還是基於II期數據，NASH消退和纖維化改善，當然，這也依賴於臨床獲益，這與只有一個相比是顯著的，也對應於作用機制該化合物的lanifibranor 可以治療疾病生物學的各個面向。所以我們確實對 NASH 的所有這些方面都有影響。

And then there are several secondary endpoints. Here, the key secondary endpoints are listed, which are NASH solution, no worsening of fibrosis, and the other way around, fibrosis improvement and no worsening of NASH. But we also have a larger amount of secondary endpoints that relate to the beneficial effect of NASH on the metabolic immune markers of NASH. And of course, also, safety and tolerability to have the good benefit risk ratio, which is the basis for approval.

然後還有幾個次要終點。這裡列出了關鍵的次要終點，即 NASH 解決、纖維化不惡化，反之，纖維化改善且 NASH 不惡化。但我們還有大量次要終點與 NASH 對 NASH 代謝免疫標記物的有益影響有關。當然，還有安全性和耐受性，具有良好的效益風險比，這是批准的基礎。

Going to slide 18, the current NATiV3 updates provide the data for accelerated approval. In order to get full approval thereafter, we have to have data on the outcome benefits and our plan.

轉到投影片 18，目前的 NATiV3 更新提供了加速批准的資料。為了獲得全面批准，我們必須獲得有關結果效益和計劃的數據。

And this is, again, in agreement with the communications of the FDA. It will be coming from an outcome study in patients with NASH who have compensated cirrhosis. So at four, but early, without any decompensation at study entry.

這再次與 FDA 的溝通一致。它將來自一項針對代償性肝硬化 NASH 患者的結果研究。四點鐘，但是很早，進入研究時沒有任何失代償。

There are a lot of data that inform us about the natural course of patients with early cirrhosis, in other words, when decompensation events will occur. So that enables us to predict the sample size of such a study quite well. We plan to have about 900 patients, select one dose of lanifibranor, and of course, placebo controlled. The outcome will be event driven. And this study then will provide data for full approval based on outcome benefits, which is defined as essentially an improvement of the decompensation events -- in the hepatic decompensation events.

有大量數據告訴我們早期肝硬化患者的自然病程，換句話說，什麼時候會發生失代償事件。因此，這使我們能夠很好地預測此類研究的樣本量。我們計劃約有900名患者，選擇一劑lanifibranor，當然還有安慰劑對照。結果將由事件驅動。然後，這項研究將提供基於結果益處的完全批准數據，結果益處被定義為本質上是失代償事件的改善——在肝失代償事件中。

The first ones that appear in patients with cirrhosis are hepatic encephalopathy; progression of portal hypertension with either bleeding from varices or the need to prophylactically treat these varices, which is common practice today; and the new onset ascites that is symptomatic, in other words, that requires treatment. Also, all-cause mortality, worsening of liver function, emission by the MELD score of 15 or more, which is quite by degree of worsening of liver function, and the need for liver transplantation in that period. So the trial is expected to last up to three years. And it, as I mentioned, an outcome benefit study for full approval.

肝硬化患者首先出現的是肝性腦病變；門靜脈高壓進展，伴隨靜脈曲張出血或需要預防性治療這些靜脈曲張，這是當今的常見做法；新出現的腹水是有症狀的，換句話說，需要治療。此外，全因死亡率、肝功能惡化、MELD評分達到15或以上的排放（這與肝功能惡化的程度相當）以及該時期是否需要進行肝臟移植。因此，審判預計將持續長達三年。正如我所提到的，這是一項獲得完全批准的結果效益研究。

So going to slide 19. In NATiV3, the study is conducted quite on a quite worldwide scale. As you can see, we have several studies on both sides of the Atlantic, the Americas, Europe, also some sites in South Africa, and Australia. And as Frédéric mentioned, through our partnership with [HDQ], we also have sites in China before the end of August that is currently ongoing. So quite on the global approach.

轉到幻燈片 19。在 NATiV3 中，這項研究是在全球範圍內進行的。正如您所看到的，我們在大西洋兩岸、美洲、歐洲以及南非和澳洲的一些地點進行了多項研究。正如 Frédéric 所提到的，透過我們與 [HDQ] 的合作，我們將於 8 月底之前在中國建立站點，目前正在進行中。所以完全是全球性的做法。

Next slide, number 20, with regard to the timelines. In the second half of 2023, the last patient first visit targets of the circa 900 patients is planned. So completion of enrollment essentially at the end of this year. And then in the first half of 2025, we'll have, for the current design of the study, last patient last visit, and that will bring us to a top-line data in the second half of 2025, and an NDA submission for accelerated approval with the FDA coming at the beginning of 2026.

下一張投影片，第 20 號，關於時間表。計劃在 2023 年下半年實現最後一次首次就診目標，約 900 名患者。因此，招生工作基本上會在今年底完成。然後在 2025 年上半年，對於目前的研究設計，我們將獲得最後一位患者的最後一次訪問，這將使我們在 2025 年下半年獲得頂線數據，並提交 NDA FDA 將於 2026 年初加速批准。

Going to slide 21, I'll say a few words about the two Phase II studies. The first one is study in patients with NAFLD non-histologically defined and who also have Type 2 Diabetes. It is a study that has completed enrollment last year. It is, as Frédéric also mentioned, the study that is sponsored by the University of Florida and conducted by Dr. Cusi.

轉到投影片 21，我將簡單介紹這兩項 II 期研究。第一項研究是針對非組織學定義的 NAFLD 且同時患有第 2 型糖尿病的患者進行的。這是一項去年已完成入組的研究。正如 Frédéric 也提到的那樣，這項研究由佛羅裡達大學贊助並由 Cusi 博士進行。

And it is truly a mechanistic study that will provide much more granularity and data more the effects of lanifibranor as a pan-PPAR agonist to really address all the metabolic events that occur in the cascade of NASH development and also in Type 2 Diabetes, two which have very similar common underlying disease biology, which is really in its upstream mechanism, evolving around insulin resistance in multiple tissues and the corresponding dysregulation of lipid metabolism and accumulation of toxic lipid intermediaries that lead to the inflammation and tissue injury and fibrosis in the liver, but also to an atherogenic lipid profile that causes atherosclerosis, et cetera. So many of these disease biology aspects will be evaluated in this study. And I think, therefore, it will be giving us a wealth of information about the benefits of lanifibranor in addition to the hepatic benefits which we have described and published earlier.

這確實是一項機制研究，將提供更多粒度和更多數據，說明lanifibranor 作為泛PPAR 激動劑的作用，以真正解決NASH 發展級聯以及2 型糖尿病（這兩種疾病）中發生的所有代謝事件。具有非常相似的常見基礎疾病生物學，實際上是在其上游機制中，圍繞多個組織中的胰島素阻抗以及相應的脂質代謝失調和有毒脂質中間體的積累而演變，從而導致肝臟發炎、組織損傷和纖維化，而且還涉及導致動脈粥狀硬化等的致動脈粥樣硬化脂質譜。本研究將評估許多疾病生物學方面的內容。因此，我認為，除了我們之前描述和發表的對肝臟的益處之外，它還將為我們提供有關拉尼夫拉諾益處的大量資訊。

The NASH and NAFLD and Type 2 Diabetes occur very much in parallel as you know. And the more advanced the disease becomes, that's true for both, the Type 2 Diabetes and NASH. The more frequent the overlap becomes, which has to do by the fact that both diseases reinforce one another.

如您所知，NASH 和 NAFLD 以及第 2 型糖尿病非常並行發生。疾病進展得越嚴重，2 型糖尿病和 NASH 都是如此。重疊變得越頻繁，這與兩種疾病相互強化有關。

So it is a very significant medical issue. And I think, therefore, studying lanifibranor in patients with these overlapping conditions helps us understanding the disease and its medical value quite a bit.

所以這是一個非常重要的醫學問題。因此，我認為，研究患有這些重疊病症的患者的 lanifibranor 有助於我們了解這種疾病及其醫學價值。

So it has to do with insulin resistance and lipid metabolism as I mentioned. So Dr. Cusi has enrolled 30 patients who had Type 2 Diabetes, with a fasting glucose level below 250 milligrams per deciliter and an HbA1c below 9.5%. So they were controlled, but with an amount of hepatic steatosis defined by MR spectroscopy of 10% or more and stable weight. The randomization was 1:1 active 800 milligram versus placebo, and they had a treatment of half a year.

正如我所提到的，這與胰島素阻抗和脂質代謝有關。因此，Cusi 博士招募了 30 名第 2 型糖尿病患者，這些患者的空腹血糖值低於 250 毫克/分升，而糖化血紅素 (HbA1c) 低於 9.5%。因此，它們得到了控制，但透過 MR 波譜確定的肝脂肪變性量為 10% 或更多，體重穩定。隨機分組為 1:1 活性藥物 800 毫克與安慰劑，治療時間為半年。

If you go to the next slide, just mentioned that in summary, the site uses spectrum of state-of-the-art imaging technology to evaluate truly the fat amount in the liver, fat distribution, and also inflammation and fibrosis in the liver through various software methods that we have today available based on MRI, as well as ultrasound FibroScan. And then, also, very sophisticated ways to measure insulin resistance using the hyperinsulinemic clamp, and the use of stabilizer dose to measure glucose uptake by muscle, et cetera. So to get really in a very detailed picture of the effects of lanifibranor on insulin resistance.

如果你看下一張幻燈片，剛才提到，總而言之，該網站使用最先進的成像技術，透過以下方式真實評估肝臟中的脂肪量、脂肪分佈以及肝臟中的發炎和纖維化：我們今天擁有基於MRI 以及超音波FibroScan 的各種軟體方法。然後，還有使用高胰島素鉗測量胰島素抗性的非常複雜的方法，以及使用穩定劑劑量來測量肌肉對葡萄糖的攝取等。因此，要真正詳細了解拉尼布諾對胰島素抗性的影響。

And the primary efficacy endpoint that Phase II have just define the sample size calculation. It is based on the reduction of intrahepatic triglycerides measured by MR spectroscopy at week 34 (sic - see slide 23, "24"). But there are these really wealth of secondary endpoints that will gives us that of I think profile of lanifibranor on its -- with regard to its broad metabolic beneficial effects in NASH as I mentioned.

而II期的主要療效終點只是定義了樣本數的計算。它基於第 34 週時通過 MR 光譜測量的肝內甘油三酯的減少（原文如此 - 參見幻燈片 23，“24”）。但正如我所提到的，有大量的次要終點可以讓我們了解 lanifibranor 對 NASH 的廣泛代謝有益作用。

So this study is fully enrolled. Since September, it's on -- the last patient was enrolled. And in Q2 2023, in other words, the next weeks, we'll have the results, the top-line results of these analysis.

所以這項研究已經全部入組。自九月以來，最後一名患者已入組。換句話說，在接下來的幾週，我們將在 2023 年第二季獲得結果，即這些分析的主要結果。

And then a few words about the combination of lanifibranor and empagliflozin in another Phase II study, which is run by Inventiva, the sort of LEGEND study, also in patients with NASH and Type 2 Diabetes. The rationale for combination treatment in disease like NASH, of course, has been discussed in many fora. And there's a strong rationale given the biology of the disease stretching from metabolism all the way to fibrosis and cancer. So with regard to lanifibranor, based on its mechanism of action, there is a good rationale to combine it with compounds such as GLP-1 receptor agonist and SGLT2 receptor agonist -- SGLT2 inhibitor, sorry.

接著簡單介紹 Inventiva 進行的另一項 II 期研究中的 lanifibranor 和 empagliflozin 聯合用藥，該研究屬於 LEGEND 研究，也是針對 NASH 和 2 型糖尿病患者。當然，對於 NASH 等疾病進行聯合治療的基本原理已經在許多論壇上進行了討論。考慮到這種疾病的生物學特性，從新陳代謝一直延伸到纖維化和癌症，這是有充分理由的。所以關於lanifibranor，基於它的作用機制，有一個很好的理由將它與GLP-1受體激動劑和SGLT2受體激動劑——SGLT2抑制劑等化合物結合起來，抱歉。

Lanifibranor in itself, of course, addresses all aspects of the disease. And so in many patients, it will probably be adequate as a treatment. But some patients may have an additional benefit from the combination treatment.

當然，Lanifibranor 本身可以解決該疾病的各個方面。因此，對於許多患者來說，它可能足以作為一種治療方法。但有些患者可能會從聯合治療中獲得額外的益處。

And the other aspect is that with lanifibranor, at certain percentage, roughly about one-third, if you define it as 5% or more, patients will have an increasing weight. We know that weight increase with lanifibranor is metabolically healthy. That has been clear from all the data that we have from NATIVE and that we have published, yet it is maybe an issue for some patients. And therefore, I think it is important to show that with combination such as with an SGLT2 inhibitor, that weight gain can be balance out.

另一方面是，用lanifibranor，在一定比例下，大約三分之一左右，如果你定義為5%或更多，患者的體重就會增加。我們知道，服用 lanifibranor 增加體重對新陳代謝是健康的。從我們從 NATIVE 獲得並已發布的所有數據中可以清楚地看出這一點，但這對某些患者來說可能是一個問題。因此，我認為重要的是要表明，透過與 SGLT2 抑制劑等組合，可以平衡體重增加。

Let's go to the next slide, number 26. So we know from at least four-randomized trials that have been published that when you combine pioglitazone with SGLT2 inhibitor, that you do see an improvement of metabolic markers. So further improvements such as lowering of HbA1c, and that the weight gain that you see with pioglitazone, which is PPAR agonist is, as I mentioned before, disappearing. So there's no further -- no weight increase, which maybe of an important aspect for some patients.

讓我們來看看下一張投影片，即第26 號投影片。因此，我們從至少已發表的四項隨機試驗中得知，當您將吡格列酮與SGLT2 抑制劑聯合使用時，您確實會看到代謝標誌物的改善。因此，進一步的改善，例如降低 HbA1c，以及您在吡格列酮（PPAR 激動劑）中看到的體重增加，正如我之前提到的，正在消失。所以體重不會再增加，這對某些患者來說可能是一個重要方面。

And these data are quite robust. They are robust. They are based on the four last studies, as I mentioned, about 1,400 patients in different parts of the world. So this is a good foundation for our approach, and there has been no safety concerns for the combination of PPAR agonist with an SGLT2 inhibitor.

而且這些數據都是相當穩健的。它們很堅固。正如我所提到的，它們基於最後四項研究，涉及世界不同地區的約 1,400 名患者。因此，這是我們方法的良好基礎，且 PPAR 激動劑與 SGLT2 抑制劑的組合不存在安全問題。

And slide 27 gives some more information about the LEGEND trial. I summarize to you the rationale. We will have information from that study, which is currently ongoing as well, about the distribution of fat because we use imaging as well, so MultiScan. And we will have information about the additional metabolic benefits and the effect of the combination has on the weight change.

投影片 27 提供了有關 LEGEND 試驗的更多資訊。我給你總結一下理由。我們將從目前正在進行的這項研究中獲得有關脂肪分佈的信息，因為我們也使用成像技術，即 MultiScan。我們將獲得有關額外代謝益處以及組合對體重變化的影響的資訊。

So this study is based on the effect of lanifibranor on HbA1c that is used for the sample size calculation. And we have those data from NATIVE. The HbA1c, of course, is also, as it underlies insulin resistance, an important market for NASH as well as for Type 2 Diabetes that provides a good rationale to use this marker as an endpoint -- as primary efficacy endpoint. But the true information -- the true importance of this study is really it will give us an amount of information about the benefits of the combination on the metabolic immune markers of NASH, as well as the hepatic health markers assessed non-invasively.

因此，本研究是基於 lanifibranor 對樣本量計算的 HbA1c 的影響。我們有來自 NATIVE 的這些數據。當然，HbA1c 也是胰島素阻抗的基礎，因此也是 NASH 和 2 型糖尿病的重要市場，這為使用該標記作為終點（主要療效終點）提供了良好的理由。但真正的資訊——這項研究的真正重要性在於，它將為我們提供大量關於該組合對 NASH 代謝免疫標記物以及非侵入性評估的肝臟健康標記物的益處的資訊。

And slide 28, some more details. We ran this study in four countries. The primary -- the principal investigators are Dr. Holleboom from the Academic Medical Center in Amsterdam and Dr. Lai from Harvard, Beth Israel in Boston.

第 28 張投影片提供了更多細節。我們在四個國家進行了這項研究。主要研究人員是阿姆斯特丹學術醫學中心的 Holleboom 博士和波士頓貝斯以色列哈佛大學的 Lai 博士。

And it's an ongoing study, so our top-line results are planned to be available this year. As you could see, it's on half-year treatment as well.

這是一項正在進行的研究，因此我們計劃在今年提供最重要的結果。正如你所看到的，它也接受了半年的治療。

We have one dose of lanifibranor and one dose of empagliflozin. That's the SGLT2 inhibitor that we choose in one arm. In another arm is lanifibranor 800 milligram, and it's a placebo-controlled study.

我們有一劑拉尼夫拉諾和一劑恩格列淨。這就是我們在一隻手臂中選擇的 SGLT2 抑制劑。另一組的 lanifibranor 劑量為 800 毫克，這是一項安慰劑對照研究。

I've covered the endpoints already, so I can go to slide 29, which will then be covered by Jean.

我已經介紹了端點，因此我可以轉到投影片 29，Jean 將介紹該投影片。

Good morning and good afternoon, everyone. So we will get to the key information on our financial landscape. I'm happy to answer, of course, your questions later on if you have further questions.

大家早安，下午好。因此，我們將獲得有關我們金融環境的關鍵資訊。當然，如果您還有其他問題，我很樂意稍後回答您的問題。

So first of all, in terms of the shareholder base, no significant change. It's really stable, and therefore, still with us with our key partner. We have recently extended our analyst coverage with Stifel that came recently.

所以首先，就股東基礎而言，沒有重大變動。它非常穩定，因此仍然與我們和我們的主要合作夥伴在一起。我們最近擴大了對 Stifel 的分析師覆蓋範圍。

I wouldn't like to elaborate too much about our market cap, which appears disconnected from what is the potential of the lanifibranor asset. But at least, at the moment, the consensus is still positive, and at significant spread process, the current market cap.

我不想過度闡述我們的市值，這似乎與 lanifibranor 資產的潛力無關。但至少，目前，共識仍然是積極的，並且在顯著的傳播過程中，當前的市值。

In terms of the financial statements, three takeaways to mark. First of all, in terms of revenues, I guess it's the first time we reached this level of EUR12.2 million in sales. And the good thing is it's the same cash white because we recorded also this amount with the upfront from the CCTQ, Sino Biopharm partnership in China where we're talking about.

就財務報表而言，需要注意三個要點。首先，就收入而言，我想這是我們第一次達到 1,220 萬歐元的銷售額水準。好處是，它是同樣的現金，因為我們也記錄了這筆金額，其中包括我們正在談論的中國生物製藥合作夥伴 CCTQ 的預付款。

The second point important is a continuous effort. And we have seen some of the actions to boost the enrollment and continue to match our operational target on NATiV3. This explains the significant increase in R&D expense.

第二點重要的是持續的努力。我們已經看到了一些旨在提高註冊人數並繼續實現我們在 NATiV3 上的營運目標的行動。這解釋了研發費用大幅增加的原因。

We should, in '23, continue this trend to reach a plateau. It could speed in '23 as expected to match again our objective by the end of the year.

我們應該在 23 年繼續這種趨勢並達到穩定水平。它可能會在 23 年加速，正如預期的那樣，到年底再次達到我們的目標。

And then third point in a very difficult market. This year, on the financial field, you would see we have secured a short term close to EUR80 million, principally with the European Investment Bank deal, to tranche of the EUR25 million. One have been raised in the first quarter. And we've also used our at-the-market program with EUR9 million plus.

然後是在非常困難的市場中的第三點。今年，在金融領域，您會看到我們已經獲得了接近 8000 萬歐元的短期資金，主要是透過歐洲投資銀行的交易，其中一部分是 2500 萬歐元。第一季已籌集了一筆資金。我們還使用了超過 900 萬歐元的市場計劃。

Also, in June, remaining $58 million on the shelf. And we have optimized, also, kind of the state-backed loan niche with the $5 million plus, also, cashed in this year. So all in all, we finished the year with a close to EUR8 million without considering, let's say, the cash cartridge of the EUR25 million second tranche of the EIB, which allow us to operate until the end of '23.

此外，6 月份，還剩下 5,800 萬美元。我們也優化了國家支持的貸款利基，今年也兌現了 500 萬美元以上。總而言之，我們以接近 800 萬歐元結束了這一年，而不考慮歐洲投資銀行第二批 2500 萬歐元的現金，這使我們能夠運營到 23 年底。

Great. Thank you, Jean. So on the catalyst of the near term. So it's, as you understood, for us, is closing and obtaining the data from Professor Cusi on the Phase II. We're looking always relatively confident on this trial.

偉大的。謝謝你，讓。因此，這是近期的催化劑。所以，正如你所理解的，對我們來說，正在關閉並從庫西教授那裡獲取第二階段的數據。我們對這次試驗總是相對有信心。

And we think it's going to be an important data for position lani patient with Type 2 Diabetes. And of course, I mentioned all the effort what we are doing, and we target, and we continue to target an end of enrollment for NATiV3 for the second half of this year. That will be also, I think, a very important achievement and positive news. And then the last one is, of course, the work we are doing on LEGEND with the data expected in the second half.

我們認為這將成為第 2 型糖尿病患者的重要數據。當然，我提到了我們正在做的所有努力和我們的目標，我們繼續以今年下半年結束 NATiV3 的註冊為目標。我認為這也將是一項非常重要的成就和正面的消息。最後一項當然是我們在 LEGEND 上所做的工作以及預計下半年的數據。

So this is for a quick update of the 2022 financials and the achievements. I give now the floor to the operator that will providing instruction to ask your questions.

這是為了快速更新 2022 年的財務狀況和成就。我現在請接線生發言，接線員將指導您提問。

(Operator Instructions) Seamus Fernandez, Guggenheim Securities.

（操作員指示）Seamus Fernandez，古根漢證券公司。

Great. Thanks so much for the question. So a couple of quick questions.

偉大的。非常感謝您的提問。有幾個簡單的問題。

The first one is really hoping if there will be a disclosure of baseline characteristics of the patients now that the next or the first Phase III trial that's going to readout in 2025 is likely -- if those are likely to be presented and shared with investors, I think that's definitely an important dynamic as we think about the differentiation of this clinical trial versus some of the other competitor opportunities.

第一個真正希望的是，現在是否會披露患者的基線特徵，因為下一個或第一個 III 期試驗很可能會在 2025 年公佈——如果這些可能會被提交並與投資者分享，我認為，當我們考慮該臨床試驗與其他一些競爭對手機會的差異時，這絕對是一個重要的動態。

And then the second question is just what your hoped-for results or the opportunity is, to really share some with investors the opportunity that you see from the Phase II clinical studies? I think, Michael, you provided a lot of detail in your prepared remarks. Just hoping to better understand what or how those results are likely to be presented, whether it's in a press release with a formal primary endpoint assessment, or if it's more exploratory analyses that will be provided and perhaps presented at a medical meeting specifically? Thanks.

那麼第二個問題就是你希望的結果或機會是什麼，能夠真正與投資人分享你從二期臨床研究中看到的機會嗎？我認為，邁克爾，您在準備好的發言中提供了很多細節。只是希望更好地了解這些結果可能會呈現什麼或如何呈現，無論是在帶有正式主要終點評估的新聞稿中，還是將提供並可能專門在醫學會議上呈現更具探索性的分析？謝謝。

Thank you, Seamus. So maybe I'll take the first question, and then for the communication strategy of the Phase II with Professor Cusi, maybe I'll let Pierre or Michael summarize the discussion we've had with [this].

謝謝你，西莫。所以也許我會回答第一個問題，然後對於第二階段與 Cusi 教授的溝通策略，也許我會讓皮埃爾或邁克爾總結我們與 [this] 的討論。

Concerning your first question about disclosing the baseline characteristic, it's actually a good suggestion. Honestly, we have not thought about that, and we're not able to answer. But yes, it is feasible; that could be interesting to do.

關於你的第一個問題，關於揭露基線特徵，這實際上是一個很好的建議。老實說，我們沒有考慮過這個問題，也無法回答。但是，是的，這是可行的；這可能很有趣。

Of course, we have looked at the patients that have been enrolled. And Michael maybe can correct me, but from what we have seen is that, of course, we are not changing patient population from the previous Phase IIb. And so we're really looking for patient, of course, F2, F3 with a moderate to severe level of inflammation and ballooning always selected with the same approach with an activity score of at least two or three.

當然，我們已經研究了已入組的患者。麥可也許可以糾正我，但從我們所看到的情況來看，我們當然不會改變之前 IIb 期的患者群體。因此，我們確實在尋找具有中度至重度發炎和氣球樣變的 F2、F3 患者，並且總是使用相同的方法選擇活動評分至少為 2 或 3 的患者。

What we have seen is maybe a bit more patient with Type 2 Diabetes. I think with approximately 40% in the Phase II, now we're more at 60%. So I don't know what it is due to. I don't think it's -- if it means anything, we have seen that the drug is as efficacious in both populations for -- patient with NASH or patient with NASH and Type 2 Diabetes.

我們看到的可能是第 2 型糖尿病患者更有耐心。我認為第二階段大約有 40%，現在我們已經達到 60%了。所以我不知道這是因為什麼。我認為，如果這意味著什麼的話，我們已經看到該藥物對 NASH 患者或 NASH 合併第 2 型糖尿病患者同樣有效。

But otherwise, they are good suggestions maybe to disclose the baseline characteristic once we are fully enrolled. Maybe Michael or Pierre, you want to talk about communication strategy for the Phase II?

但除此之外，他們是很好的建議，也許可以在我們完全註冊後披露基線特徵。也許邁克爾或皮埃爾，你想談談第二階段的溝通策略嗎？

Yeah, sure. For the study that is sponsored by University of Florida, we will have -- once the data are available and press release on the top-line results. And then, of course, the details of the data, the primary efficacy endpoint and all the secondary efficacy endpoints will be presented, made it public at scientific conferences in the first place by Dr. Cusi's team.

好，當然。對於佛羅裡達大學贊助的這項研究，一旦數據可用並發布有關主要結果的新聞稿，我們將立即發布。當然，數據的詳細資訊、主要療效終點和所有次要療效終點將首先由 Cusi 博士的團隊在科學會議上公開。

Great. And then maybe just as one follow-up, should we anticipate those results likely in terms of the medical meetings that you would be targeting? Is that more of an EASD conference just because this is a diabetic patient population or a little bit more along the lines of AASLD remaining focused on the liver-focused patient population? I know there's a blend of marketing to endocrinologist and to liver specialists.

偉大的。然後，也許作為一項後續行動，我們是否應該根據您所針對的醫療會議來預測這些結果？這更像是一場 EASD 會議，只是因為這是一個糖尿病患者群體，還是更像 AASLD 的路線，仍然專注於以肝臟為中心的患者群體？我知道內分泌學家和肝臟專家的營銷是混合的。

Absolutely. And so we aim for both actually, and we are doing that now. We have done a great deal of analysis of the metabolic immune markers of the NATIVE study and present those does to both liver conferences, so AASLD, EASL, but also to the ADA. We also have a presentation this year at ADA.

絕對地。所以我們實際上是兩者的目標，而且我們現在正在這樣做。我們對 NATIVE 研究的代謝免疫標記進行了大量分析，並將這些結果提交給兩次肝臟會議，包括 AASLD、EASL，以及 ADA。今年我們還在 ADA 上做了一次演講。

And with the conclusion, of course, we will discuss that together. And the goal is to certainly also cover the endocrinology conferences. But that does not -- we also stay active with the liver conferences. I think that's enough --

當然，有了結論，我們將一起討論。我們的目標當然是涵蓋內分泌學會議。但事實並非如此——我們也積極參與肝臟會議。我想這就夠了——

(multiple speakers)

（多個發言者）

Yeah, enough material to cover both conferences.

是的，足夠的材料來涵蓋這兩個會議。

Okay. Thank you.

好的。謝謝。

Annabel Samimy, Stifel.

安娜貝爾·薩米米，斯蒂菲爾。

Hi. Thanks for taking my question and the tremendous details that you provided for the Phase II. I guess I wanted to look a little bit bigger picture. When we think about the Phase II trials that you're conducting, is the intention to potentially make lanifibranor available to all patients you are trying to gear towards the Type 2 diabetic patient, which it seems to have some tremendous benefit for?

你好。感謝您提出我的問題以及您為第二階段提供的大量詳細資訊。我想我想看得更遠。當我們考慮您正在進行的 II 期試驗時，是否有意向您試圖針對 2 型糖尿病患者的所有患者提供 lanifibranor，因為它似乎對這有一些巨大的好處？

And then also on the LEGEND trial. So you're looking at it in combination (inaudible) but it seems that a number of these patients or a number of the physicians believe that these patients were already beyond some background with one. So I'm just wondering, again, bigger picture, how do you envision some of these combinations to play out in real world?

然後也在傳奇審判中。因此，您將其結合起來（聽不清楚），但似乎其中一些患者或許多醫生認為這些患者已經超越了某些背景。所以我只是想知道，從更大的角度來看，您如何設想其中一些組合在現實世界中發揮作用？

And are you intending to try to find another combination treatment to optimize lani? Or is it too -- that's may be oral and more suitable for the population that you're targeting? Or is it just to potentially manage some of the weight gain issues, or whatever, optimize its profile in general? So I guess I'm trying to understand how it works out with the GLP-1 as well as the combination trials that you're looking at right now. Thanks.

您是否打算嘗試尋找另一種組合療法來優化拉尼？或者也是——這可能是口頭的，更適合您的目標群體？或者只是為了潛在地管理一些體重增加問題，或者其他什麼，總體上優化其形象？所以我想我正在嘗試了解 GLP-1 以及您現在正在考慮的組合試驗的效果如何。謝謝。

Okay. So maybe on the Phase III. So currently, of course, we have patient F2, F3, and we stratify for patient with NASH and Type 2 Diabetes. Clearly, our intention and our belief that lani addresses both populations, and that has been shown in the Phase IIb. It's effective in patient with NASH, and it's also effective in patient with NASH and Type 2 Diabetes.

好的。所以也許在第三階段。當然，目前我們有病患 F2、F3，我們將 NASH 和第 2 型糖尿病患者進行分層。顯然，我們的意圖和信念是拉尼針對這兩種人群，這已在 IIb 階段中得到了體現。它對 NASH 患者有效，對 NASH 和 2 型糖尿病患者也有效。

Where and why we work a lot on the anti-diabetic properties of lani? It's because we look at competition. And when we look at competitors, we believe we are the only one that have this direct insulin sensitizer of properties.

我們在哪裡以及為什麼對拉尼的抗糖尿病特性進行了大量研究？這是因為我們著眼於競爭。當我們審視競爭對手時，我們相信我們是唯一擁有這種直接胰島素增敏劑特性的公司。

And so if you position yourself from the patient perspective and you have NASH and Type 2 Diabetes, if you're treated with lani, not only you would improve in NASH, reduce your fibrosis, but on top of that, you would -- lani would help further control your HbA1c. So it's really a perfect drug for these patients, and we also have published that when we look at patient with pre-diabetes treated with lani during the Phase IIb. Those patients, during the course of the trial, had seen their diabetes stop progression. So clearly, it's a patient population that we like.

因此，如果您從患者的角度定位自己，並且您患有 NASH 和 2 型糖尿病，如果您接受 lani 治療，您不僅會改善 NASH，減少纖維化，而且最重要的是，您會 - lani將有幫助於進一步控制您的HbA1c。因此，對於這些患者來說，它確實是一種完美的藥物，當我們在 IIb 期研究中觀察使用拉尼治療的糖尿病前期患者時，我們也發表了這一點。在試驗過程中，這些患者的糖尿病停止了進展。很明顯，我們喜歡的是這樣的患者群。

And then ultimately, when we talk to endocrinologists, we realize that they have huge amount of patient that are sitting in their offices that have NASH. And so developing and producing the type of data we'll be generating for Professor Cusi I think will help position the drug among endocrinologists.

最終，當我們與內分泌科醫生交談時，我們意識到他們辦公室裡有大量患有 NASH 的患者。因此，我認為開發和產生我們將為 Cusi 教授產生的數據類型將有助於在內分泌學家中定位該藥物。

Now maybe for the GLP-1, I'll let Michael or Pierre answer. Just one comment just to point out that in the current NATiV3, the Phase III, we are allowing patient under GLP-1 under a stable dose of GLP-1 for three months. And so we are including patient with GLP-1 in the trial. And that will help us, of course, generate data about combining lani and GLP-1.

現在也許對於 GLP-1，我會讓 Michael 或 Pierre 來回答。僅一則評論指出，在目前的 NATiV3（III 期）中，我們允許接受 GLP-1 治療的患者接受穩定劑量的 GLP-1 治療三個月。因此，我們將患有 GLP-1 的患者納入試驗中。當然，這將有助於我們產生有關 lani 和 GLP-1 組合的數據。

Maybe Michael or Pierre, do you want to add something about the LEGEND and combination with the GLP-1?

也許 Michael 或 Pierre，您想添加一些有關 LEGEND 以及與 GLP-1 組合的內容嗎？

Yeah. So I think the -- in these diseases, it's also a non-cardiovascular disease, and diabetes treatment paradigms change as new treatments become available. And semaglutide, specifically, is a GLP-1 receptor agonist that certainly have or changing that paradigm. And other GLP-1 receptor agonists becoming or have become first-line treatment in Type 2 Diabetes. So I think that's something that we adapt to. I don't think -- I think that's actually an opportunity.

是的。所以我認為，在這些疾病中，它也是一種非心血管疾病，隨著新療法的出現，糖尿病治療模式也會改變。具體而言，索馬魯肽是一種 GLP-1 受體激動劑，它肯定具有或改變了這種模式。其他 GLP-1 受體激動劑正在成為或已成為第 2 型糖尿病的第一線治療藥物。所以我認為這是我們適應的事情。我不認為——我認為這實際上是一個機會。

And we do allow patients who are on a stable dose to be enrolled in NATiV3. We may also, since Frédéric refer to that, consider to get and use that opportunity to update LEGEND if you wish, and that's something that we are discussing.

我們確實允許服用穩定劑量的患者參加 NATiV3。既然 Frédéric 提到了這一點，我們也可以考慮獲得併利用這個機會來更新圖例（如果您願意的話），這也是我們正在討論的事情。

But I think lanifibranor remains a very distinct drug from the other compounds and that it has a pan-PPAR agonist. It does have this effect on metabolism, as well as on inflammation, as well as on fibrosis. And so for disease like NASH and Type 2 Diabetes, that go hand in hand or approval will be fore NASH.

但我認為 lanifibranor 仍然是一種與其他化合物非常不同的藥物，而且它具有泛 PPAR 激動劑。它確實對新陳代謝、發炎和纖維化有這種作用。因此，對於 NASH 和 2 型糖尿病等疾病，它們是齊頭並進的，或者批准將先於 NASH。

But many patients will have Type 2 Diabetes. And even those who don't have over Type 2 Diabetes, many of those have pre-diabetes, which the diabetology community also recommends to treat. So this is an advantage I think that we have in the NASH field.

但許多患者會患有第 2 型糖尿病。即使是沒有患有第 2 型糖尿病的人，其中許多人也患有糖尿病前期，糖尿病學界也建議對其進行治療。所以我認為這是我們在 NASH 領域的一個優勢。

And the fact that the treatment field for Type 2 Diabetes is changing, something that we use to our advantage to position lanifibranor in combination with these newer treatments as well. So I think that's how our studies are currently designed. And I think that lanifibranor will have an attractive position in this field.

事實上，2 型糖尿病的治療領域正在發生變化，我們利用這一點將 lanifibranor 與這些新療法結合。所以我認為這就是我們目前研究的設計方式。我認為 lanifibranor 將在這一領域佔據有吸引力的地位。

Okay, great. Thank you.

好的，太好了。謝謝。

Ed Arce, H.C. Wainwright.

埃德·阿爾塞，H.C.溫賴特。

Great. Thanks for taking my questions, and congrats on the continued progress.

偉大的。感謝您提出問題，並祝賀我的持續進步。

A few from me. Firstly, just wanted to ask if you can disclose how many patients are currently enrolled in NATiV3? And then turning to the outcomes trial, I think you mentioned 900 patients is the total target, but I think there's 800 on the slide. Just wanted to confirm the total number there. And then lastly, also with outcomes, which dose of lani are you planning to use for that trial? And then I have a couple of follow-ups.

我的一些。首先，我想問您是否可以透露目前有多少患者參加了 NATiV3？然後轉向結果試驗，我認為您提到 900 名患者是總目標，但我認為幻燈片上有 800 名患者。只是想確認那裡的總數。最後，關於結果，您計劃在該試驗中使用哪種劑量的拉尼？然後我有一些後續行動。

Okay. So let's take the first two. I think on the outcome trial (multiple speakers) disclose the number of patients that we have randomized and enrolled. No, we have not.

好的。那我們就來看前兩個。我認為在結果試驗（多名發言者）中披露了我們隨機分組和入組的患者數量。不，我們沒有。

As a practice, of course, we monitor the situation daily. And we're very pleased with the enrollment, with the screen failure I mentioned. We have, let's say, battled or anyway had to concentrate, including the screen failure, which was higher than what we expected. That is something that is general in the industry.

當然，作為一種做法，我們每天都會監控情況。我們對註冊以及我提到的螢幕故障感到非常滿意。比如說，我們經歷過戰鬥，或者無論如何都必須集中註意力，包括螢幕故障，這比我們的預期要高。這是產業內的普遍現象。

But we've been really working out, and we see the screen failure going down regularly for the past several months. So that's very positive. As I mentioned, we have quite a large number of sites that are screening, inactive screening. So that gives us confident that we can meet our target of end of enrollment for the second half of this year.

但我們一直在努力鍛煉，並且在過去的幾個月裡我們發現螢幕故障經常出現。所以這是非常積極的。正如我所提到的，我們有相當多的網站正在篩選、非活躍篩選。這讓我們有信心實現今年下半年招生結束的目標。

Then on the third question on the dose, maybe, Michael, you want to give a highlight of the discussion we've had with FDA?

那麼關於劑量的第三個問題，邁克爾，也許你想強調我們與 FDA 的討論？

Yeah. If I understand the question correctly, correct me if I'm wrong, it was about the total number of patients that we enrolled in the outcome study. So our estimate is about 800 with two arms, one dose of lanifibranor and placebo. And the 950 or 960 is for the NATiV3, the study that we are currently running that is providing data for accelerated approval. So did I answer your question?

是的。如果我正確理解了這個問題，如果我錯了，請糾正我，這是關於我們參加結果研究的患者總數。因此，我們估計兩隻手臂、一劑 lanifibranor 和安慰劑的患者人數約為 800 人。 950 或 960 用於 NATiV3，我們目前正在進行的研究正在為加速批准提供數據。那我回答你的問題了嗎？

Actually, Michael, the other part of the question was which dose would you be using -- intend to use for the outcomes study? Which dose of (inaudible)

實際上，邁克爾，問題的另一部分是您將使用哪種劑量——打算用於結果研究？哪種劑量（聽不清楚）

We have not decided yet, but we will choose one dose. I think when we finalize the design, we'll take all information into consideration, which includes the clinical pharmacology data, but also the data that we get from NATiV3, depending on where we are.

我們還沒決定，但我們會選擇一劑。我認為當我們最終確定設計時，我們將考慮所有信息，其中包括臨床藥理學數據，還包括我們從 NATiV3 獲得的數據，具體取決於我們所處的位置。

Okay, great. And as a follow-up, I just wanted to ask furtherly, I think you mentioned at the beginning of your remarks some work that's been done more recently on speeding up biopsies. I wondered if you could expand upon those activities and what you've done and how that's helped the study?

好的，太好了。作為後續行動，我只是想進一步詢問，我認為您在演講開頭提到了最近在加速活檢方面所做的一些工作。我想知道您是否可以擴展這些活動以及您所做的事情以及這對研究有何幫助？

And then lastly, I just wanted to ask about the financials. I think you said cash right now is runway to the end of the year. If you could confirm that, and also what's the remaining amount on the ATM? Thanks so much.

最後，我只是想問一下財務狀況。我想你說過現金現在是到年底的跑道。如果您能確認的話，ATM 上的餘額是多少？非常感謝。

Okay. So on the biopsy process, so there has been many activities going on and improving that process --improving the screening process. So by speeding up, I meant that the process between making a biopsy in a site and the time it takes for the reviewer to give their appraisal, it's a long process. So I think we have now speed up and optimize that process.

好的。在活檢過程中，已經開展了許多活動來改進這個過程—改善篩檢過程。因此，我所說的加快，是指從現場進行活檢到審稿人給予評估所需的時間之間的過程，這是一個漫長的過程。所以我認為我們現在已經加快並優化了這個過程。

And then secondly, the big change we made is that you know that we follow the FDA guidelines to have a biopsy reviewed by three pathologists with a tiebreaker. We started to trial with two pathologists involved. And if one of these two pathologist is agreed or did not evaluate in the same way as the other one, the biopsy, the patient would be excluded. And now we have introduced a tiebreaker also for the baseline.

其次，我們做出的重大改變是，您知道我們遵循 FDA 指南，由三名病理學家進行活檢，並進行決勝負。我們開始與兩名病理學家一起進行試驗。如果這兩位病理學家中的一位同意或沒有以與另一位病理學家相同的方式（活檢）進行評估，則患者將被排除在外。現在我們也為基線引入了決勝局。

And so now, when there is a disagreement between the two biologists, there is a tiebreaker. So the pathologists that have the tiebreaker. So that also has been introduced in all along the way.

所以現在，當兩位生物學家之間出現分歧時，就會出現決勝局。所以病理學家有決勝局。所以這一點也一直被引入。

Also, we have introduced training alignment, training between these three pathologists so that they really work as a team. And that's also something that has taken up some time, and we see now good alignment between these three pathologists.

此外，我們還引入了培訓協調，在這三位病理學家之間進行培訓，以便他們真正作為一個團隊工作。這也花了一些時間，我們現在看到這三位病理學家之間的良好一致性。

And then on cash and all of that, I let to Jean answer about the ATM and the cash.

然後關於現金和所有這些，我讓吉恩回答有關 ATM 和現金的問題。

So EUR88 million as we've seen in the end of '23 and very important without considering the second tranche of the EIB which present cartridge of the EUR25 million. And we have still USD58 plus million on the shelf for the at-the-market program.

因此，正如我們在 23 年底看到的那樣，8,800 萬歐元非常重要，但不考慮歐洲投資銀行 (EIB) 的第二批資金，其中包括 2,500 萬歐元。我們還有 58 多萬美元用於市場計劃。

Great. Thanks so much.

偉大的。非常感謝。

Frédéric Gomez, Pharmium Securities.

Frédéric Gomez，Pharmium 證券公司。

Thanks for taking the questions. One on the LEGEND study -- yes, can you hear me?

感謝您提出問題。關於傳奇研究的一項——是的，你聽得到我說話嗎？

Yes.

是的。

Yes.

是的。

(inaudible)

（聽不清楚）

Hello. We hear you very well.

你好。我們很清楚地聽到你的聲音。

Can you hear me?

你聽得到我嗎？

Yes.

是的。

Okay. Perfect. Yeah, perfect.

好的。完美的。是的，完美。

So the first question is on the LEGEND study, the primary will be the HbA1c. Can you maybe clarify a little bit the statistical analysis plan, or you will perform the analysis between the combo arm and the lani arm? Yeah, I'm just wondering are you will say that the study is positive because we should expect an effect on the primary with the lani alone versus the placebo.

所以第一個問題是關於 LEGEND 研究的，主要是 HbA1c。您能否澄清一下統計分析計劃，或者您將在組合臂和拉尼臂之間進行分析？是的，我只是想知道你是否會說這項研究是積極的，因為我們應該預期單獨使用拉尼與安慰劑相比會對主要效果產生影響。

And just to follow-up a little bit on this analysis of biopsies and the change in the number of pathologists that will have a look at the biopsies. You started at two now; it says three pathologists. Does it -- I'm curious to hear you about the potential impact on the outcome and also the baseline data because this shift may have an impact overall on the trial itself if more patients have been looked by three pathologists versus two. Can you maybe elaborate a little bit more on the potential impact of this change?

只是為了跟進活組織檢查的分析以及將檢查活組織檢查的病理學家數量的變化。你現在兩點就開始了；上面寫著三位病理學家。是嗎——我很想聽聽您對結果和基線數據的潛在影響，因為如果更多的患者接受三名病理學家而不是兩名病理學家的檢查，這種轉變可能會對試驗本身產生整體影響。您能否詳細說明一下這項變化的潛在影響？

Sure. So for the LEGEND, we can start with that. And maybe even for the tiebreaker, maybe, Michael, you can address that.

當然。所以對於LEGEND，我們可以從這裡開始。也許即使是決勝局，邁克爾，你也可以解決這個問題。

Sure. Yes. I think to start with LEGEND, we actually have based the sample size calculation and the power on the data that we have from [NATiV2]. On the effect on HbA1c, I don't have it in my head now, but those numbers we have. And also, on the additional benefits that you expect when you combine pioglitazone with one of the SGLT2 inhibitors.

當然。是的。我認為從圖例開始，我們實際上已經基於我們從 [NATiV2] 獲得的數據進行了樣本量計算和功效。關於對 HbA1c 的影響，我現在還沒有想到，但我們有這些數字。此外，當您將吡格列酮與 SGLT2 抑制劑結合使用時，您會期望獲得額外的好處。

And as I mentioned, there are four large, randomized trials that give actually a consistent picture that you have an additional benefit on the decrease of HbA1c after half year of treatment or longer. But most of these studies was half year. And that provides the basis of to define an effect size that we should see and a power calculation to have the p-value that is adequate. That's what it's based.

正如我所提到的，有四項大型隨機試驗實際上給出了一致的結果，即在治療半年或更長時間後，您對 HbA1c 的降低有額外的好處。但這些研究大多是半年的。這為定義我們應該看到的效應大小和功效計算提供了基礎，以獲得足夠的 p 值。這就是它的基礎。

Now it is a proof-of-concept study. So I like to point out that this is really because we -- this is the way we do it. But the main importance of the of the study is really to show that there is an additional benefit of the combination on metabolic markers for those patients who may need it, and also, on weight, for those patients who may find this important.

現在它是一項概念驗證研究。所以我想指出，這實際上是因為我們——這就是我們做事的方式。但這項研究的主要重要性實際上是表明，對於那些可能需要它的患者來說，這種組合對代謝標記物有額外的好處，對於那些可能認為這一點很重要的患者來說，對於體重也有額外的好處。

I can only repeat that to weight gain with PPAR agonist is distinct from weight gain that results from poor lifestyle. But that may still be an issue for patients who are obese. Not all patients with NASH or NASH and Type 2 Diabetes are obese. So it will actually not be an issue for all patients. For some, it may be, and this is what it's based on.

我只能重複一遍，PPAR 激動劑導致的體重增加與不良生活方式導致的體重增加不同。但這對於肥胖患者來說可能仍然是一個問題。並非所有患有 NASH 或 NASH 合併第 2 型糖尿病的患者都是肥胖的。因此，這實際上並不是所有患者的問題。對某些人來說，可能是這樣，這就是它的基礎。

So we really see the value of this study in providing that set of data on the additional benefits that the combination we have in certain patients for whom this may be important. And it's in line also with how metabolic treatments -- sorry, metabolic diseases are treated such as Type 2 Diabetes. And physicians will start with the treatment and then see how the patient evolves and may add another treatment, if necessary, in certain patients.

因此，我們確實看到了這項研究的價值，因為它提供了一組數據，說明我們的組合對某些可能很重要的患者俱有額外的益處。這也符合代謝治療的方式——抱歉，代謝疾病的治療方式，例如第 2 型糖尿病。醫生將從治療開始，然後觀察患者的病情進展，如有必要，可能會對某些患者添加另一種治療方法。

So with regard to the biopsy, it was always our intention to start with three biopsy -- with three expert pathologists. And we have started with two and have -- as soon as a third one was onboard contractually, may the tiebreaker process put it in place.

因此，就活檢而言，我們始終打算從三名病理學家專家的三次活檢開始。我們從兩個人開始，一旦第三個人按照合約加入，願決勝局程序將其落實到位。

That does not really affect the patients that we enroll as eligible. In fact, we have looked at patients who was screened failed based on the initial two biopsies and see which patients would be eligible, if the -- or when the third one comes in as a tiebreaker, and some of these patients would then be eligible again or would become eligible.

這並不會真正影響我們登記為合格的患者。事實上，我們已經研究了根據最初的兩次活檢篩選失敗的患者，看看哪些患者符合資格，如果——或者當第三次活檢出現時，其中一些患者將符合資格再次或將有資格。

But the key point is that either the tiebreaker system gives a degree of stability, I think, in the histology scoring. That's an important aspect, of course. But for the evaluation of efficacy at the end of the 72-week treatment period, all histology will be reread. So the histology at inclusion and the histology at the end of treatment will be evaluated again by the three pathologists according to this pattern. So for the entire study, if you look at the evaluation of efficacy, then the reading will be consistent. (multiple speakers)

但關鍵是，我認為，決勝局系統在組織學評分方面提供了一定程度的穩定性。當然，這是一個重要的面向。但為了在72週治療期結束時評估療效，將重新讀取所有組織學結果。因此，納入時的組織學和治療結束時的組織學將由三位病理學家根據此模式再次評估。所以對於整個研究來說，如果你看療效的評價，那麼讀數就會是一致的。 （多個發言者）

We have no further questions at this time. I'll hand back the conference to Mr. Cren for closing remarks. Thank you.

目前我們沒有進一步的問題。我將把會議交還給克倫先生做閉幕詞。謝謝。

Yes. So thank you very much for attending. We have, in front of us, a very exciting 2023. NASH is a very exciting space. It was not the case last year, and we see now a much more renewed interest. There're going to be quite a lot of events this year, especially with the FDA, the Intercept and the Madrigal submission.

是的。非常感謝您的出席。我們面前有一個非常令人興奮的 2023 年。NASH 是一個非常令人興奮的領域。去年的情況並非如此，我們現在看到了更多新的興趣。今年將會有許多活動，特別是 FDA、Intercept 和 Madrigal 提交。

And concerning lanifibranor, we remain confident. We have in our -- and a drug that can make it to the finish line. And this year, operationally, we know we have to deliver the NATiV3. And as I mentioned, it seemed that we're on the right track.

對於 lanifibranor，我們仍然充滿信心。我們有一種藥物可以到達終點。今年，在營運方面，我們知道我們必須提供 NATiV3。正如我所提到的，我們似乎走在正確的軌道上。

And then we'll also be looking forward with, let's say, the crucial optimism to the data that will be generated by Professor Cusi in the Type 2 Diabetes study, and also, of course, in the LEGEND study. And that will keep us busy. And as usual, thank you very much for attending, and I look forward to seeing all of you in future meetings.

然後，我們也將期待 Cusi 教授在 2 型糖尿病研究中，當然還有 LEGEND 研究中產生的數據的至關重要的樂觀情緒。這會讓我們很忙。像往常一樣，非常感謝你們的出席，我期待在以後的會議中見到你們所有人。