Inventiva SA (IVA) 2024 Q4 法說會逐字稿

Good morning. Good afternoon, everyone. Thank you for joining us to discuss our 2024 full-year financial results. We issued the full-year press release this morning and the webcast that will be available in the Investor section of our website. I want to remind everyone that various statements that we may make today during this conference call and during the Q&A session will include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.

早安.大家下午好。感謝您加入我們討論 2024 年全年財務表現。我們今天上午發布了全年新聞稿和網路廣播，可在我們網站的「投資者」部分查看。我想提醒大家，我們今天在電話會議和問答環節中可能做出的各種聲明將包括《1995 年私人證券訴訟改革法案》所定義的前瞻性聲明。

Joining me on this call is Jean Volatier, our Chief Financial Officer; and Pierre Broqua, CSO and Co-Founder. I will first go some of the key highlights for 2024 and some recent updates of our activities before I leave the floor to Jean, who go over the full-year financial results. And of course, we'll have some time at the end of the call for a Q&A.

和我一起參加本次電話會議的還有我們的財務長 Jean Volatier；以及首席策略長兼共同創辦人 Pierre Broqua。我將首先介紹 2024 年的一些主要亮點以及我們活動的一些最新更新，然後請 Jean 介紹全年財務表現。當然，會議結束時我們會留一些時間來進行問答。

So on the highlight for '24, so '24 was ended on a very positive note, and we started 2025 strong, ready, and enthusiastic for what is ahead of us. In 2024, we've made significant strides in the clinical development of lanifibranor. And with the tremendous support and commitment of our clinical trial site, we've been able to close screening for our Phase 3 NATiV3 early January '25.

因此，2024 年的亮點在於，2024 年以非常積極的態度結束，我們以強勁、準備和熱情迎接 2025 年即將到來。2024年，我們在lanifibranor的臨床開發方面取得了重大進展。在我們臨床試驗站點的大力支持和承諾下，我們已經能夠在 2025 年 1 月初完成第 3 階段 NATiV3 的篩選。

We can therefore confirm that we target the completion of recruitment in H1 2025 as previously guided. This will start the countdown to our top-line result expect in the second half of 2026, making of lanifibranor the second oral drug that could be approved in the United States in March.

因此，我們可以確認，我們的目標是按照先前的指導在 2025 年上半年完成招募。這將啟動我們預計在 2026 年下半年公佈的頂線業績的倒數計時，使 lanifibranor 成為第二種可能在 3 月在美國獲批的口服藥物。

In addition to be very close from reaching completion of enrollment, in 2024 and in the first quarter of 2025, we had the three data monitoring committee meetings with positive recommendation to continue in NATiV3 without modification to protocol. The most recent one took place in February 2025, during which the safety data of more than 1,200 patients randomized NATiV3 were reviewed. With this progress in our Phase 3, we're truly at an inflection point in our company's journey, and we have already begun strengthening our team to ensure we're fully prepared for successful regulatory submissions and the commercialization of lanifibranor.

除了距離完成招生非常近之外，我們在 2024 年和 2025 年第一季召開了三次數據監測委員會會議，並積極建議繼續進行 NATiV3，而無需修改協議。最近一次審查是在 2025 年 2 月，期間審查了 1,200 多名隨機接受 NATiV3 治療的患者的安全性數據。隨著我們第三階段的進展，我們真正處於公司發展歷程的轉折點，我們已經開始加強我們的團隊，以確保我們為成功提交監管文件和 lanifibranor 商業化做好充分準備。

In 2024, we also reinforced our clinical data set for lanifibranor with the publication of the positive results of LEGEND, our combination proof of concept trial with lanifibranor and empagliflozin in patients with MASH and type 2 diabetes. The primary point was met with a statistically significant reduction in HbA1c with lanifibranor alone and in combination. Insulin sensitivity was improved, consistent with other study, and additional improvement was observed in combination with empagliflozin. Markers of liver injury were significantly improved, and this improvement was solely driven by lanifibranor.

2024 年，我們也發布了 LEGEND 的正面結果，加強了 lanifibranor 的臨床數據集。 LEGEND 是我們在 MASH 和 2 型糖尿病患者中使用 lanifibranor 和 empagliflozin 進行的概念驗證試驗。主要觀點是，單獨使用或合併使用 lanifibranor 均可顯著降低 HbA1c。胰島素敏感性得到改善，與其他研究一致，並且與恩格列淨聯合使用時觀察到額外的改善。肝損傷標記物得到顯著改善，而這種改善完全是由 lanifibranor 推動的。

The second goal of this trial was to look at the potential mitigation of the weight gain when adding an SGLT2 inhibitor to lanifibranor. We are very pleased to show that the combination of lani with empagliflozin completely mitigates the weight gain. Furthermore, lanifibranor alone and in combination leads to a shift towards metabolically (inaudible) deposition.

本次試驗的第二個目標是觀察在 lanifibranor 中添加 SGLT2 抑制劑是否能潛在地緩解體重增加。我們非常高興地證明，lani 與 empagliflozin 的組合完全減輕了體重增加。此外，單獨使用或與 Lanifibranor 聯合使用都會導致代謝（聽不清楚）沉積的轉變。

Finally, meta-analysis data suggests that GLP-1 have a similar effect when combined with PPAR. This study is particularly significant given the high prevalence of type 2 diabetes among patients affected by MASH. We're convinced that the profile of lani is ideal to treat patients with advanced fibrosis and diabetes, the patient population which is hard to treat and high risk to progress to cirrhosis.

最後，薈萃分析數據表明，GLP-1 與 PPAR 結合時具有類似的效果。鑑於受 MASH 影響的患者中第 2 型糖尿病的盛行率很高，這項研究具有特別重要的意義。我們確信，lani 的特性非常適合治療晚期纖維化和糖尿病患者，這類患者治療起來很困難，而且發展為肝硬化的風險很高。

We're looking forward to looking more in depth at our lani effect when combined to other drugs, particularly GLP-1, and we have randomized approximately 15% of patients on GLP-1 in the Phase 3 study.

我們期待更深入研究我們的 lani 效應與其他藥物（特別是 GLP-1）結合使用時的效果，並且我們已經在第 3 階段研究中將大約 15% 的患者隨機分配使用 GLP-1。

This year, we also announced that our partner Hepalys has launched the clinical development of lanifibranor in Japan with the initiation of a Phase 1 study. We believe that with the licensing agreement that was in place in Japan, South Korea with Hepalys, and in China with CTTQ, lanifibranor will be ideally positioned to potentially become the leading oral drug in MASH in these two important geographic areas.

今年，我們也宣布我們的合作夥伴 Hepalys 已在日本啟動 lanifibranor 的臨床開發，並啟動了第一階段研究。我們相信，憑藉在日本、韓國與 Hepalys 以及在中國與 CTTQ 達成的許可協議，lanifibranor 將有望成為這兩個重要地理區域 MASH 領域的領先口服藥物。

Looking now at the organization and at the governance. We're committed to make lani a success story for patients, and this is definitely your priority for Inventiva. We're focusing on change and challenging all our resources and efforts into achieving this goal. As part of this process, we are reinforcing our development team to ensure that we're fully prepared for regulatory filing and the potential commercial launch.

現在來看組織和治理。我們致力於讓 lani 成為患者的成功案例，這絕對是 Inventiva 的首要任務。我們正致力於變革，並投入所有資源和努力來實現這一目標。作為此過程的一部分，我們正在加強我們的開發團隊，以確保我們為監管備案和潛在的商業發布做好充分準備。

In February, following a strategic review, we announced the decision to focus all of our resources to the development of lani. Unfortunately, this decision comes with a stop of all preclinical activities not related to lani and would lead to a reduction of approximately 50% of our workforce. I want to emphasize that this was not an easy decision, and our research team has been core to Inventiva for the past 12 years and has been instrumental in the development of lani. We're currently in negotiation with the worker council, and while I'm unable to comment further at this stage, we're committed to working together through this transition.

今年 2 月，經過策略評估，我們宣布決定將所有資源集中用於 lani 的開發。不幸的是，這項決定將停止所有與 lani 無關的臨床前活動，並將導致我們裁員約 50%。我想強調的是，這不是一個容易的決定，我們的研究團隊在過去 12 年裡一直是 Inventiva 的核心，並在 lani 的開發中發揮了重要作用。我們目前正在與工人委員會進行談判，雖然我目前無法進一步發表評論，但我們致力於在這次過渡期間共同努力。

Regarding the governance of Inventiva, we also reinforced it, and we reinforced our Board of Directors with the appointment of three new Board members. The first one is Andre Turenne, the President and CEO of the Boston-based biotech Matchpoint Therapeutics and former Global Head of Business Development at Sanofi. In December, Srinivas, the Founder and Partner of Samsara Capital, joined us.

關於 Inventiva 的治理，我們也對其進行了加強，並透過任命三名新董事會成員來加強董事會。第一位是安德烈·圖雷納 (Andre Turenne)，他是波士頓生物技術公司 Matchpoint Therapeutics 的總裁兼首席執行官，曾任賽諾菲全球業務發展主管。12月，Samsara Capital創辦人兼合夥人Srinivas加入公司。

And we also nominated Mark Pruzanski as Chairman of the Board. You all know -- you all are familiar with Mark. He's been the CEO and Founder of Intercept and has shaped the MASH market over the last year. Mark brings us, of course, a wealth of experience in both MASH field and the US, along with deep expertise in financial strategy. We're excited to have him on board as we work together to achieve our mission of bringing lani to patient and driving meaningful progress in the treatment of MASH.

我們也提名馬克‧普魯贊斯基 (Mark Pruzanski) 為董事會主席。你們都知道——你們都熟悉馬克。他曾擔任 Intercept 的執行長兼創始人，並在過去一年中塑造了 MASH 市場。當然，馬克為我們帶來了 MASH 領域和美國的豐富經驗，以及深厚的金融策略專業知識。我們很高興他能加入我們，共同努力實現我們的使命，將 lani 帶給患者，並推動 MASH 治療取得有意義的進展。

Now finally, before I hand over to Jean, the financial situation in 2024, we successfully closed on several dilutive and non-dilutive financing operation, raising approximately a total of $184 million in gross proceeds. Most of these amounts come from our three-tranche financing of $125 million each. The financing came from existing and trusting investor and especially new investor. We received the first tranche in 2024, and we will be eligible to receive the second tranche following the announcement of end of randomization, and we should have then met all operational condition precedent necessary for the second tranche.

最後，在我將 2024 年的財務狀況移交給 Jean 之前，我們成功完成了幾項稀釋性和非稀釋性融資業務，籌集了總計約 1.84 億美元的總收益。其中大部分資金來自我們分三期進行的融資，每期 1.25 億美元。融資來自現有且信任的投資者，尤其是新投資者。我們在 2024 年收到了第一批款項，在隨機化結束後，我們將有資格獲得第二批款項，並且我們應該已經滿足了第二批款項所需的所有運營先決條件。

Let me now turn over to Jean, who will provide you with more details on our 2024 financial report.

現在讓我把時間交給 Jean，他將向您提供有關我們 2024 年財務報告的更多詳細資訊。

Thank you, Frederic. Good morning. Good afternoon, everyone, and thank you for joining us on this call. So yesterday I said we have issued our press release, covering the full financial results for the fiscal year '24. And of course, I will provide you with key highlights. Happy to answer more detailed questions during the Q&A time.

謝謝你，弗雷德里克。早安.大家下午好，感謝大家參加這次電話會議。所以昨天我說我們已經發布了新聞稿，涵蓋了 24 財年的全部財務表現。當然，我會向你們提供重點內容。很高興在問答時間回答更詳細的問題。

So I start with the cash position and cash flows. So we have reached at the end of '24 $96.6 million of cash position versus $36 million at the end of December '23. Therefore, a net positive variance of close to EUR61 million. As a matter of fact, this represents half a year roughly of annual OpEx. Key factors, as said by Frederic, is, of course, the USD184 million, EUR170 million of raising under different operations, dilutive and non-dilutive.

因此，我從現金狀況和現金流開始。因此，我們在 24 年底的現金部位達到 9,660 萬美元，而 23 年 12 月底的現金部位為 3,600 萬美元。因此，淨正差異接近 6,100 萬歐元。事實上，這大約相當於半年的年度營運支出。正如 Frederic 所說，關鍵因素當然是透過不同的操作（稀釋性和非稀釋性）籌集 1.84 億美元和 1.7 億歐元。

The fourth principle are, of course, the raising of the second tranche of EUR25 million drawn in January '24 from the European Investment Bank. The second in July '24 was the raising of EUR20.1 million with the issuance of YLT deals. The biggest one, of course, related to the up to EUR348 million finance structure transaction announced in October 14, '24, represent EUR116 million net proceeds received during the fourth quarter. And eventually, we received also the milestone, the first milestone of CTTQ Sino Biopharm, our Chinese partner as part of the financing in October. And you remember that there are three tranches and three milestones related to this transaction also, we can come back on that.

第四個原則當然是24年1月從歐洲投資銀行籌集第二筆2500萬歐元的資金。第二次融資於 1924 年 7 月透過發行 YLT 債券籌集 2,010 萬歐元。當然，最大的一筆涉及 24 年 10 月 14 日宣布的高達 3.48 億歐元的融資結構交易，代表第四季度收到的 1.16 億歐元淨收益。最終，我們也獲得了里程碑，即我們的中國合作夥伴 CTTQ Sino Biopharm 作為 10 月融資的一部分獲得的第一個里程碑。您還記得，這筆交易涉及三個部分和三個里程碑，我們可以回顧一下。

So therefore, we have confirmed -- we do confirm the cash runway guidance disclosed previously, meaning we can operate until September '25 without the contemplated second tranche of the financing. And after the contemplated second tranche of the financing, we should reach September '26.

因此，我們確認——我們確實確認了先前披露的現金流指引，這意味著我們可以在沒有預期的第二筆融資的情況下運營到 2025 年 9 月。在預計的第二筆融資到位後，我們應該可以達到 26 年 9 月。

Let's talk now about the key figures of the profit and loss account. So we have recorded revenues in '24 of EUR9.2 million, and it refers to the milestones I talked about earlier with CTTQ Sino Biopharm compared to EUR17.5 million in the same period in '23. The other income line is stable at EUR5.5 million compared to EUR5.7 million. It represents, as usual, essentially the R&D French tax credit.

現在我們來討論一下損益表的關鍵數據。因此，我們在 24 年的收入為 920 萬歐元，這指的是我之前與 CTTQ Sino Biopharm 談到的里程碑，而 23 年同期的收入為 1750 萬歐元。另一項收入穩定在 550 萬歐元，而之前為 570 萬歐元。像往常一樣，它本質上代表了法國研發稅收抵免。

Of course, the most important line is the R&D expenses. We still represent more than 18% of our global operation expense, so amounting to EUR19.9 million in '24 compared to EUR110 million in '23, showing a decrease of 17%, which was due to the delays we have to face in '24 to be noted that as announced during the second half of '24, these R&D expenses have started to increase again following the restart of the patient recruitment in NATiV3. The marketing and business development line is still not significant at EUR2 million, stable compared to '23. But with the approaching of the end of the Phase 3 expected to increase in the near future because we will start preparing the NDA filing and the commercialization capabilities. In terms of G&A, reaching EUR15.8 million for '24 compared to EUR13.8 million in '23, so a slight increase of 14%.

當然，最重要的一條線是研發費用。我們仍佔全球營運費用的 18% 以上，因此 24 年的支出為 1990 萬歐元，而 23 年為 1.1 億歐元，下降了 17%，這是由於 24 年我們不得不面對延誤，需要注意的是，正如 24 年下半年宣布的那樣，隨著 NATiV3 重新開始招募患者，這些研發費用又開始增加費用。行銷和業務發展線仍然不大，為 200 萬歐元，與 23 年相比保持穩定。但隨著第三階段即將結束，預計在不久的將來會增加，因為我們將開始準備 NDA 申請和商業化能力。就一般及行政費用而言，24 年達到 1,580 萬歐元，而 23 年為 1,380 萬歐元，略有成長 14%。

We have had a complex year in terms of transactions, but also we have reinforced our IP position. Therefore, we have a slight increase, in particular, in other legal and compliance fees. There is a rather unusual amount, as you can notice in the net financial loss, EUR86 million compared to EUR5 million in '23. Two items, one-off items of EUR33.4 million, which is related to a specific IFRS retreatment, non-cash related to the fair value of the second tranche to be realized, we expect very soon and has to be treated as derivative instruments since considered as a call option instruments. We also have this year EUR12.2 million of non-cash interest related to the loans and related to the royalty certificates' amortization.

就交易而言，我們度過了複雜的一年，但我們的智慧財產權地位也得到了鞏固。因此，我們的費用略有增加，特別是其他法律和合規費用。正如您在淨財務損失中所看到的，這是一個相當不尋常的數額，為 8600 萬歐元，而 23 年為 500 萬歐元。兩個一次性項目為 3340 萬歐元，與特定的 IFRS 重新處理有關，與第二批待實現的公允價值非現金相關，我們預計很快就會實現，並且必須將其視為衍生工具，因為它被視為看漲期權工具。我們今年還有 1,220 萬歐元與貸款和特許權使用費證書攤提相關的非現金利息。

Bottom line, the company's net loss for the full year was established at EUR184.2 million compared to EUR110.4 million in '23. I will now turn it over to Frederic for the conclusion and Q&A. Thank you for your attention.

總體而言，該公司全年淨虧損為 1.842 億歐元，而 23 年為 1.104 億歐元。現在我將把結論和問答環節交給 Frederic。感謝您的關注。

Merci, Jean. So we've made important improvement and significant strides, and I'm confident that we have a tremendous opportunity ahead of us with lanifibranor. If we look at 2025, we anticipate announcing the completion of randomization and the release of the second tranche of $127 million from our structure financing. Today, we are the only Phase 3 that is recruiting currently and evaluating an oral liver-targeted drug candidate. We have a robust data set, including our Phase 2, in which we observed an improvement of one-stage fibrosis in just six months of treatment.

謝謝，吉恩。因此，我們取得了重要的進步和重大的進展，我相信，lanifibranor 為我們帶來了巨大的機會。如果我們展望 2025 年，我們預計將宣布完成隨機化並從我們的結構融資中釋放第二筆 1.27 億美元。目前，我們是唯一一家正在招募和評估口服肝臟標靶候選藥物的 3 期臨床試驗公司。我們擁有一套強大的數據集，包括我們的第二階段數據，其中我們觀察到在短短六個月的治療中，單階段纖維化就得到了改善。

The demand for MASH treatment is clear, and the available treatment options are still limited today to a single mechanism of action. We believe that given the heterogeneity of the patient population and the broad prevalence of MASH, having multiple oral treatment options will be a game changer for patients.

MASH 治療的需求很明確，目前可用的治療選擇仍然僅限於單一的作用機制。我們相信，鑑於患者群體的異質性和 MASH 的廣泛流行，擁有多種口服治療選擇將為患者帶來改變。

Thank you, and we now open the floor for questions.

謝謝大家，現在開始提問。

(Operator Instructions) Ritu Baral, TD Cowen.

（操作員指示）Ritu Baral，TD Cowen。

This is [Nicole] on line for Ritu. Just a quick question. Are the background doses for the patients on background doses of GLP-1s, are they low-dose diabetic doses? Or are they also composed of a high dose for weight loss? And just a quick follow-up, how many patients do you guys estimate that you have enrolled that are on background SGLT2 inhibitors?

我是 [Nicole]，在線為 Ritu 服務。這只是一個簡單的問題。接受 GLP-1 背景劑量治療的患者的背景劑量是低劑量糖尿病劑量嗎？還是它們也含有高劑量的減肥藥？簡單問一下，你們估計已經招募了多少名正在服用 SGLT2 抑制劑的病人？

So on the first one, I'll answer, and then I'll let Pierre on the SGLT2 if you like.

因此，對於第一個問題，我會回答，然後如果您願意的話，我會讓 Pierre 回答 SGLT2。

GLP-1 is mostly antidiabetic dosing. It's not only semaglutide; it's other -- well, semaglutide is included, but you also have other GLP-1 agonists.

GLP-1 主要用於抗糖尿病藥物。不僅僅是司美格魯肽；它是其他的——嗯，包括司美格魯肽，但也有其他 GLP-1 激動劑。

And by the top of my head, you had between 6% to 8% of patients on SGLT2 inhibitors at baseline.

據我所知，基線時服用 SGLT2 抑制劑的患者比例在 6% 到 8% 之間。

Shan Hama, Jefferies.

尚哈馬，傑富瑞。

So I know you expect to complete enrollment within the first half of this year. But what's your level of confidence in randomizing that last patient in the main cohort by April 30 to secure that EUR116 million capital increase? And then secondly, given it's likely you have cash, including this second tranche just for the readout in 2H '26, what are the plans for any additional financing? And I know you previously communicated that it would make sense to post the data to have a partner. What's the level of interest here from pharma to be able to close the deal as quickly as possible?

所以我知道你預計在今年上半年完成招生。但是，您對在 4 月 30 日之前隨機抽取主要隊列中的最後一名患者以確保 1.16 億歐元的資本增加有多大信心？其次，考慮到你們可能有現金，包括僅用於 2026 年下半年讀數的第二筆現金，有什麼額外融資計劃？我知道您之前曾表示，發布數據來尋找合作夥伴是有意義的。製藥公司對盡快完成交易的興趣程度如何？

So, many questions. For the first one on the confidence of recruiting before the end of April, I would say it's high confidence, given we have communicated to all sites to stop screening at the beginning of the month of January. And we took that decision because we had sufficient patients already randomized and sufficient patients in screening to reach the target of 969 patients, which are the patients that we need to enroll in the main cohort to achieve 90% of [powering] with the assumption of the SAP. The average screen period is between 10 to 12 weeks. And so we feel very optimistic that we'll meet that end of April objective.

所以，有很多問題。對於在四月底之前招募的信心，我想說這是高度信心，因為我們已經通知所有站點在一月初停止篩選。我們做出這個決定是因為我們已經有足夠的隨機患者和足夠的篩選患者來達到 969 名患者的目標，這些患者是我們需要納入主要隊列以實現 SAP 假設的 90% 的 [動力]。平均篩檢週期為10至12週。因此，我們非常樂觀地認為我們將在四月底實現這一目標。

On your question about partnering, there is a lot of interest in the MASH market. I would say, finally, given that we've been going through a series of failures in the field, luckily, some companies have reported positive data. And more importantly, the Madrigal resmetirom drug has been approved. There is no need for biopsy to prescribe it, and the commercial launch has been very solid, and they're definitely in the direction of a blockbuster potential.

關於您提到的合作問題，人們對 MASH 市場很感興趣。最後我想說，鑑於我們在該領域經歷了一系列失敗，幸運的是，一些公司報告了積極的數據。更重要的是，Madrigal resmetirom藥物已經獲得批准。無需活檢即可開處方，而且商業推出的效果非常穩定，而且它們絕對有可能成為轟動一時的產品。

So of course, that drives a lot of interest. We believe we have a very strong package. We are the only oral drug currently in Phase 3 development. Most likely, once we will announce the end of completion, end of enrollment, we can reassert that it will be the next oral drug to be potentially approved. And given the results we had in Phase 2b, we feel extremely strong about the commercial success of lanifibranor.

因此，這當然會引起人們的極大興趣。我們相信我們擁有非常強大的一攬子計劃。我們是目前唯一處於第 3 階段開發的口服藥物。最有可能的是，一旦我們宣布完成、招募結束，我們就可以重申，這將是下一個可能獲得批准的口服藥物。鑑於我們在第 2b 階段的成果，我們對 lanifibranor 的商業成功充滿信心。

On how we manage our resources, of course, we're actively managing our financial resources, and we're confident that the step we're taking will allow us to execute the clinical trial. We work, and we are committed to advance the clinical program and ensure the long-term value of lani. And of course, while we do that, we continue evaluating all options to secure the funding needed to keep -- to achieve our objective, which is to execute the clinical trial, file for NDA, and commercialize lani first in the US and then in the European community.

關於我們如何管理資源，當然，我們正在積極管理我們的財務資源，我們相信我們正在採取的措施將使我們能夠執行臨床試驗。我們努力工作，並致力於推進臨床計劃並確保 lani 的長期價值。當然，在我們這樣做的同時，我們也會繼續評估所有選擇，以確保獲得實現我們目標所需的資金，即進行臨床試驗、申請 NDA，並首先在美國、然後在歐洲共同體將 lani 商業化。

Annabel Samimy, Stifel.

安娜貝爾·薩米 (Annabel Samimy)，Stifel。

Just on the screening again, is there any specific rate-limiting step on that screening that could derail that last person who's enrolled into becoming an actual randomized patient in the primary arm? And then secondly, I guess now that -- as you've alluded to, the MASH market appears to be forming with the first approved treatment, the profile of FGF21s are emerging, and there's additional data emerging on incretins being able to drive MASH resolution. Has the way you thought -- think about the market and the population that lani would be most appropriate for changed at all? And how do you see this market fragmenting with the potential introduction of lani?

再次進行篩選，篩選過程中是否存在任何特定的限速步驟，可能導致最後入選的人無法成為主要組的實際隨機患者？其次，我想現在——正如您所提到的，隨著第一種療法的獲批，MASH 市場似乎正在形成，FGF21 的概況正在出現，並且有更多關於腸促胰島素能夠推動 MASH 分辨率的數據出現。您對 lani 最適合的市場和人群的思考方式是否改變了？隨著 lani 的潛在引入，您如何看待這個市場的分化？

Thank you, Annabel, for this question. So it's very interesting. So to your first question, what can derail the randomization of the last patient? Once the patient is in the screening pool, we have a certain amount of period of time to complete all the examinations that are on the protocol. So during that period, we need to do all the lab tests. We need to do the biopsy. The biopsy are digitalized, and they are read centrally. And it's all that process that takes between 8 to 12 months, 12 months, or weeks. And then once the patient is randomized, there is an appointment he needs to show at the hospital and then is randomized in the study. So that's why this period takes a certain period of time.

謝謝安娜貝爾提出這個問題。所以這非常有趣。那麼對於您的第一個問題，什麼因素會導致最後一位患者的隨機化失敗？一旦患者進入篩檢池，我們就有一定的時間來完成方案上的所有檢查。因此在此期間，我們需要進行所有實驗室測試。我們需要做切片檢查。活檢被數位化，並被集中讀取。整個過程需要 8 到 12 個月、12 個月或幾週的時間。一旦患者被隨機分配，他就需要到醫院預約，然後在研究中隨機分配。所以這就是為什麼這個時期需要一定的時間。

There is a total amount of time for that period. So at a certain moment, if we see that the patient doesn't present himself to an appointment or the site is not reactive enough, and so this period of time to screen and randomize the patient is overdue. We can screen fail the patient automatically. So that's why it gives us confidence that we will randomize the last patient, as guided before the first half of H1 '25.

該期間有總時間量。因此，在某個時刻，如果我們發現患者沒有按時赴約，或者站點的反應不夠，那麼對患者進行篩選和隨機分組的這段時間就應該過了。我們可以自動篩檢失敗的病人。因此，我們有信心按照 2025 年上半年之前的指導，對最後一位患者進行隨機分組。

On your second question on where we see lani play a role in the market shape, as I said before, Madrigal launch really showed that there is a huge market. And it's even more so because we believe Madrigal is not a tremendously efficacious drug. So we believe the market will further develop when we arrive with a more efficacious drug, and also, semaglutide with the [power] commercial marketing of Novo will help enlarge the market. Where we see lani work, clearly, this is something we get extremely positive feedback.

關於你的第二個問題，即我們看到拉尼在市場形態中發揮了什麼作用，正如我之前所說，Madrigal 的推出確實表明存在一個巨大的市場。更重要的是，我們認為 Madrigal 並不是一種非常有效的藥物。因此，我們相信，當我們推出更有效的藥物時，市場將會進一步發展，而且，諾和諾德強大的商業行銷與索馬魯肽的結合將有助於擴大市場。我們看到 lani 的工作，顯然，這是我們得到非常正面的回饋。

We have a drug that is really ideal for patients that have advanced fibrosis, F2/F3, and on top of type 2 diabetes. This is a large population. We estimate that more than 50% of patients with MASH have type 2 diabetes, especially in the F2/F3 population. This is a population that has a fibrosis progression that is faster than the overall population. They are more difficult to treat, and the profile of lani where we can see fibrosis reduction in six months, we can see resolution of MASH and especially a strong insulin sensitivity activity with a drug that helps you control your diabetes is a profile that resonates very well.

我們有一種藥物，非常適合患有晚期纖維化、F2/F3 和第 2 型糖尿病的患者。這是一個龐大的群體。我們估計超過 50% 的 MASH 患者患有第 2 型糖尿病，尤其是 F2/F3 族群。這個群體的纖維化進展速度比整體群體快。它們更難治療，而 lani 的特徵是，我們可以在六個月內看到纖維化的減少，我們可以看到 MASH 的消退，特別是強大的胰島素敏感性活動，使用一種可以幫助您控製糖尿病的藥物，這是一個非常有共鳴的特徵。

Then lastly, and that's something really important to highlight, is that PPAR is a well-known mechanism with endocrinologists and diabetologists. In the US alone, you have close to 6 million prescriptions of Pio. Pio is, as you know, old PPAR gamma. Let's call it a first-generation PPAR gamma with a profile that is really less attractive than ours.

最後，需要強調的是，PPAR 是內分泌學家和糖尿病學家所熟知的一種機制。光是在美國，就有近 600 萬張 Pio 處方。如你所知，Pio 是舊版 PPAR gamma。我們稱之為第一代 PPAR 伽馬，其特性確實不如我們的有吸引力。

But still, even if generic, even if it's not prescribed, promoted, you have 6 million scripts every year written in the US, which really demonstrates that these diabetologists and endocrinologists are very familiar, very used to prescribe PPARs mechanism. And so they will be, we think, attractive by the profile of lanifibranor.

但是，即使是仿製藥，即使它沒有被開處方或推廣，美國每年也有 600 萬份處方，這確實表明這些糖尿病專家和內分泌學家非常熟悉，非常習慣於開立 PPAR 機制的處方。因此，我們認為，lanifibranor 的形象將對它們具有吸引力。

Ed Arce, HC Wainwright & Company.

阿爾斯（Ed Arce），HC Wainwright & Company。

Just a couple for me. So I just wanted to get your thoughts on R&D expenses throughout the year, considering both the impact of the recent reduction in workforce and the elimination of the early programs, but also as well the full enrollment of NATiV3 in a few months and the carrying expenses of that. And then also relatedly, just wondering if you could help us understand any potential milestone payment receipts for this year that you would expect?

對我來說只有一對。因此，我只是想了解您對全年研發費用的看法，既考慮到最近裁員和取消早期計畫的影響，也考慮到幾個月後 NATiV3 的全面招生及其附帶費用。另外，與此相關的是，我只是想知道您是否可以幫助我們了解您預期的今年任何潛在的里程碑付款收據？

Jean, do you want to take these questions?

Jean，你想回答這些問題嗎？

Sure. So for the profile, may say, of the R&D expenses this year, as I said, decreased by 17% because we know we have to face some operational problems, but we have restarted the recruitment in Q2. So the decrease versus last year and versus budget also, which was basically something like EUR20 million, represents this momentum for '24. If we talk about EUR125 million, we come back -- I would say, we come back to the normal way.

當然。因此，就今年的研發費用而言，正如我所說，下降了 17％，因為我們知道我們必須面對一些營運問題，但我們已在第二季重新開始招募。因此，與去年和預算相比有所下降，預算基本上為 2000 萬歐元，這代表了 24 年的這一勢頭。如果我們談論 1.25 億歐元，我們就會回來——我想說，我們回到正常的方式。

We expect, compared to this year, a slight increase in the expenses. As I mentioned, because we will start, and Frederic also said also, we'll start to prepare the commercial capabilities. We will also focus on the NDA filing. So it should increase, let's say, by 10% to 20% compared to this year.

我們預計，與今年相比，支出將略有增加。正如我所提到的，因為我們將開始，而且弗雷德里克也說過，我們將開始準備商業能力。我們還將重點關注保密協議 (NDA) 的提交。因此與今年相比，應該會增加 10% 到 20%。

And with regards to the expected milestones, as of today, what we know about are the milestones related in connection with the transaction, as you know, because there are three milestones expected from our Chinese partner, CTTQ. One has been collected in '24, and there is one milestone per tranche. So we are contemplating the second tranche of the financing in '25. So together with the second tranche, we may receive -- will receive the second $10 million milestones. And practically, it is paid 30 days after the last randomization disclosure.

關於預期里程碑，截至今天，我們所知道的是與交易相關的里程碑，正如您所知，因為我們的中國合作夥伴 CTTQ 預計將實現三個里程碑。'24 年已收集了一筆，每筆都有一個里程碑。因此，我們正在考慮在 25 年進行第二筆融資。因此，連同第二筆款項，我們可能會收到——將收到第二個 1000 萬美元的里程碑款項。實際上，它是在最後一次隨機化披露後 30 天支付的。

Jacob Mekhael, KBC Securities.

Jacob Mekhael，KBC 證券。

Looking ahead to the top-line data in the second half of next year, I was just wondering if you can share with us how soon after the last patient completes their treatment you will be able to share the results? And perhaps how does that tie in with your cash runway being until the end of Q3 2026?

展望明年下半年的頂線數據，我只是想知道您是否可以與我們分享，在最後一位患者完成治療後多久您將能夠分享結果？這與您到 2026 年第三季末的現金流有何關係？

So yes, so once last patient -- we have the last patient's last visit, I guess we'll need to wait for a couple of months to publish the top-line data. And then, as we said, once we will have the last patient randomized, we'll have, of course, more clarity on when that date will be. And in terms of financing, once we'll have raised the second tranche, which we expect to raise pretty soon, we'll be in a clear position to show that we have the means to deliver on our clinical objectives.

是的，一旦最後一位患者——我們有了最後一位患者的最後一次就診，我想我們需要等待幾個月才能發布頂線數據。然後，正如我們所說的，一旦我們將最後一名患者隨機分組，我們當然會更清楚地知道這個日期是什麼時候。在融資方面，一旦我們籌集到第二筆資金（我們預計很快就會籌集到），我們​​就能清楚地表明我們有能力實現我們的臨床目標。

And just maybe one more question, if you can perhaps just remind us on the deal with Hepalys in Japan, what would a Phase 3 program would look like there? And would that be entirely funded by your partner? Or do you have to contribute to that?

也許還有一個問題，您能否提醒我們一下與日本 Hepalys 的交易，那裡的第三階段計劃會是什麼樣的？這些資金全部由您的合作夥伴提供嗎？還是你必須為此做出貢獻？

Yes. So that's a very good question. All our licensing in Japan, South Korea, and China, all the clinical development that are done locally are financed by our partner. So in Japan, the current Phase 1 and the Phase 3 will be financed by Hepalys. We will have no impact on our finances. And similarly, the ongoing Phase 3 in China is totally financed by CTTQ Sino Biopharm.

是的。這是一個非常好的問題。我們在日本、韓國和中國獲得的所有許可以及在當地進行的所有臨床開發均由我們的合作夥伴資助。因此在日本，目前的第一階段和第三階段將由 Hepalys 資助。我們的財務狀況不會受到任何影響。同樣，中國正在進行的第三階段研究也完全由正大天晴生物製藥公司資助。

Rami Katkhuda, LifeSci Capital.

Rami Katkhuda，生命科學資本。

I guess, first, how are you guys thinking about the design and timing of an outcome study? Where does the FDA require you to be with it prior to the filing of an NDA for lani?

我想，首先，你們是如何考慮結果研究的設計和時間安排的？在為 lani 提交 NDA 之前，FDA 要求您去哪裡？

So yes, the outcome study. So there's been, a couple of months ago, a new guideline from the FDA, but it's very clear that the study, the outcome study, needs to be underway at the time of NDA filing. So this is exactly the plan we have internally and that we have discussed with the FDA, which is to run an outcome study in patients with compensated cirrhosis, and this trial will be underway when we file for NDA. And currently, we plan to file for NDA in the first half of '27.

是的，這是結果研究。幾個月前，FDA 發布了一項新指南，但很顯然，這項研究，即結果研究，需要在提交 NDA 時進行。這正是我們內部的計劃，我們已經與 FDA 討論過了，即對代償性肝硬化患者進行結果研究，當我們提交 NDA 時，這項試驗就會開始進行。目前，我們計劃在 27 年上半年提交保密協議 (NDA)。

And I guess, with enrollment nearly complete here, can you remind us of the powering assumptions in NATiV3 for the combined endpoint?

我想，這裡的註冊工作已經接近尾聲，您能否提醒我們 NATiV3 中針對組合端點的供電假設？

Yes. So the study is powered at 90%, and we used the data from Phase2b, which, as you know, is a six-month trial, and we have used what we believe is a cautious approach. So we looked at the placebo effect. We have increased it by some percentages. Similarly, the effect size was reduced by a couple of percentages for both doses. And that's what we used for the powering at 90%.

是的。因此，這項研究的功效為 90%，我們使用了 Phase2b 的數據，正如你所知，這是一個為期六個月的試驗，我們採用了我們認為謹慎的方法。因此我們研究了安慰劑效應。我們已將其增加了一些百分比。類似地，兩種劑量的效果都減少了幾個百分點。這就是我們用來提供 90% 電力的材料。

Why do we believe this is a prudent approach is because Phase 2b was a very successful trial. We met the primary endpoint and also the key secondary endpoint, but it was a six-month trial, and given the mechanism of action and also the data that has been published by our competitors. And if you look at data 12 or 18 months, you clearly see that with longer period of treatment, we believe the effect size of lani will actually be greater than what we saw in the Phase 2b. So to answer your question, that's how we powered the study.

我們之所以認為這是一種謹慎的做法，是因為第 2b 階段的試驗非常成功。我們達到了主要終點和關鍵次要終點，但這是為期六個月的試驗，並考慮到作用機制以及我們的競爭對手已發布的數據。如果你查看 12 或 18 個月的數據，你會清楚地看到，隨著治療時間的延長，我們相信 lani 的效果實際上會比我們在第 2b 階段看到的更大。所以回答你的問題，這就是我們進行這項研究的方式。

(Operator Instructions) Ellie Merle, UBS.

（操作員指示）Ellie Merle，瑞銀。

This is [Jasmine] on for Ellie. So a question on the combination of lani and SGLT2 inhibitors. So going forward, what are your plans to study this? Do you think you'll need to generate more data here to support this combination used by physicians? And then secondly, how important do you think the mitigation of the weight gain with this combination is going to be to physicians and patients, particularly in the segment of MASH patients that are also obese?

這是 [Jasmine] 為 Ellie 演唱的。所以關於 lani 和 SGLT2 抑制劑的組合有個問題。那麼，展望未來，您有什麼研究計畫？您是否認為需要在此產生更多數據來支持醫生使用的這種組合？其次，您認為這種組合療法減輕體重增加對醫生和患者來說有多重要，特別是對於肥胖的 MASH 患者來說？

Thank you, Ellie. So on your first question, we have no plans to develop a fixed-dose combination lani plus SGLT2 inhibitor. Why we did that study? Because I think it's important to have data that show that the metabolically healthy weight gain that you see in patients with -- that in some patients treated with lani, approximately one-third to half of the patients that gained weight. We have demonstrated that this weight gain is metabolically healthy. We have demonstrated that there is a plateau effect. So it's actually a weight gain that stabilizes after six to nine months of treatment.

謝謝你，艾莉。關於您的第一個問題，我們沒有計劃開發固定劑量組合 lani 加 SGLT2 抑制劑。我們為什麼要做這項研究？因為我認為，重要的是要有數據表明，在接受 lani 治療的患者中，大約有三分之一到一半的患者體重增加，從而呈現出健康的代謝體重。我們已經證明，這種體重增加對代謝來說是健康的。我們已經證明存在平台效應。因此，實際上體重增加會在治療六到九個月後趨於穩定。

Nevertheless, some patients probably will be looking for an approach besides the lifestyle or beside a diet to control this weight gain. So we wanted to show that if you combine lani with SGLT2 inhibitor, you manage to retain the benefit of both drug and at the same time, mitigate the weight gain that we have shown with that study. We also believe that the data that we are generating right now in the Phase 3 with patients with GLP-1 will help show that that's actually a very good combination, adding GLP-1 to lani to retain the advantages of both drugs, but also mitigate the weight gain will also be a nice combination to address the weight gain.

儘管如此，有些患者可能還會尋找生活方式或飲食以外的方法來控制體重增加。因此，我們想表明，如果將 lani 與 SGLT2 抑制劑結合使用，您既可以保留兩種藥物的益處，又可以減輕我們在該研究中顯示的體重增加。我們也相信，我們目前在第 3 階段針對 GLP-1 患者產生的數據將有助於表明這實際上是一個非常好的組合，將 GLP-1 添加到 lani 中以保留兩種藥物的優勢，同時減輕體重增加也將是解決體重增加的一個很好的組合。

There are currently no further questions. I will hand the call back to Frederic.

目前沒有其他問題。我會把電話交還給弗雷德里克。

Thank you, operator, and thank you, everybody, for attending. Great set of questions. You have understood that our next milestone is the end of randomization. It's going to be, of course, for us, a strong event but also, I think, for the MASH community because it starts the clock for an important Phase 3 that will read out. When I say important, because if you look at the profile of lani, we really have a drug that can be a game changer for patients that are suffering from MASH.

謝謝接線員，也謝謝大家的出席。很棒的一組問題。您已經了解到我們的下一個里程碑是隨機化的終結。當然，這對我們來說將是一次重大事件，但我認為，對於 MASH 社區來說，這也是一次重大事件，因為它啟動了重要的第三階段的時鐘。我之所以說它重要，是因為如果你看一下 lani 的資料，你會發現我們確實有一種藥物可以為患有 MASH 的患者帶來巨大的改變。

With that, I really thank you for your strong support over 2024, and as I said, we have ahead of us, I think, a very exciting 2025. I'm sure we will have several opportunities to discuss throughout this year. Thank you very much.

最後，我衷心感謝大家對 2024 年的大力支持，正如我所說，我認為我們即將迎來一個令人興奮的 2025 年。我相信今年我們會有多次討論的機會。非常感謝。