Inventiva SA (IVA) 2026 Q2 法說會逐字稿

Good day, and thank you for standing by. Welcome to Inventiva's first half of 2026 financial results conference call. (Operator Instructions) As a reminder, today's conference call is being recorded.

各位好，感謝您耐心等候。歡迎參加 Inventiva 2026 年上半年財務業績電話會議。(接線員指示) 提醒各位，今天的電話會議將被錄音。

I would now like to hand the call over to David Nikodem, Head of Investor Relations for Inventiva. Please go ahead.

現在我想把電話交給 Inventiva 投資人關係主管 David Nikodem。請開始。

Thank you. Good morning, good afternoon. Thank you for joining Inventiva's first half 2026 financial results and business update. This morning, we issued our press release reporting our full financial results for the first half of 2026. A replay of this webcast will be available in the Investor section of our website following the call.

謝謝。各位早安、午安。感謝各位參加 Inventiva 2026 年上半年財務業績與業務更新說明會。今天上午，我們已發布新聞稿，公布 2026 年上半年完整財務業績。本次網路直播的重播將於會後在我們網站的「投資人」專區提供。

Before we begin, a quick reminder that the statements we make today, including during the Q&A, may include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements reflect our views only as of today and should not be relied upon at any later date. Please refer to slide 2 and to our filings with the SEC and the AMF for a discussion of the associated risks.

在開始之前，先簡要提醒：我們今天所作的陳述（包括問答環節）可能包含《1995 年私人證券訴訟改革法》所定義的前瞻性陳述。這些陳述僅反映我們截至今日的觀點，日後不應再加以依賴。有關相關風險的討論，請參閱投影片第 2 頁，以及我們向 SEC 與 AMF 提交的文件。

Joining me today are Andrew Obenshain, our Chief Executive Officer; Dr. Jason Campagna, our Chief Medical Officer and President of R&D; and Axel-Sven Malkomes, our Chief Financial Officer. Chris Benecchi, our recently appointed Chief Operating Officer, will be joining us for the Q&A portion of the call.

今天與我一同出席的有：我們的執行長 Andrew Obenshain；我們的首席醫療長暨研發總裁 Jason Campagna 博士；以及我們的財務長 Axel-Sven Malkomes。我們新近任命的營運長 Chris Benecchi 也將在本次電話會議的問答部分加入。

With that, I'll turn the call over to Andrew.

接下來，我把電話交給 Andrew。

Thank you, David, and welcome everyone. Today, I'll start by providing an update on the company and our priorities. Jason will overview our lanifibranor development program. Axel will walk through our first half of 2026 financial highlights, and then we will open the call for Q&A. The first half of 2026 has been a defining period for Inventiva. We have stayed focused on our near-term objectives, advancing lanifibranor toward the Phase 3 top-line results readout in MASH expected in Q4 2026, preparing for regulatory filing while building the organization to support a potential commercial launch.

謝謝你，David，也歡迎各位。今天我將先就公司近況與我們的優先事項提供最新進展。Jason 將概述我們的 lanifibranor 開發計畫。Axel 將帶大家回顧 2026 年上半年的財務重點，之後我們將開放問答。2026 年上半年對 Inventiva 而言是關鍵的時期。我們持續聚焦於短期目標，推進 lanifibranor 朝向預計於 2026 年第四季公布的 MASH 第三期主要（top-line）結果，同時在建立組織以支援潛在商業上市之際，也為法規申請做準備。

Let me start with why we believe in the potential of lanifibranor and why a potential new therapy for MASH is so important. It comes down to three key elements, differentiation, late-stage validation, and market opportunity.

我先談談為何我們相信 lanifibranor 的潛力，以及為何 MASH 的潛在新療法如此重要。這可歸結為三個關鍵要素：差異化、後期臨床驗證，以及市場機會。

Let's begin with differentiation. MASH is driven by both intrahepatic and extrahepatic processes, and lanifibranor is designed to address both through a single once-daily oral therapy. In our NATIVE Phase 2b study, lanifibranor showed improvement across all key histological endpoints. Next is validation. We designed the NATiV3 Phase 3 trial to build on the foundation established in our positive Phase 2b study.

先從差異化談起。MASH 同時受到肝內與肝外機制所驅動，而 lanifibranor 的設計是透過每日一次的口服單一療法，同時處理這兩者。在我們的 NATIVE 第二期 b 臨床試驗中，lanifibranor 在所有關鍵組織學終點上均顯示改善。接著是驗證。我們設計 NATiV3 第三期試驗，是為了在第二期 b 正向結果所建立的基礎上再向前推進。

We look forward to reporting top-line data in the fourth quarter of this year. Finally, market opportunity. The market is being built in front of us. If lanifibranor is approved, we will enter an established therapeutic area with a market potential expected to exceed $15 billion by 2035. However, significant unmet need remains, and this represents a meaningful opportunity for Inventiva to bring a potentially differentiated treatment option with lanifibranor to people diagnosed with MASH, if approved.

我們期待在今年第四季公布主要（top-line）數據。最後是市場機會。市場正在我們眼前逐步成形。若 lanifibranor 獲得核准，我們將進入一個已建立的治療領域，且其市場潛力預計到 2035 年將超過 150 億美元。然而，仍存在顯著未被滿足的需求；因此，若獲核准，這將為 Inventiva 帶來重要機會，將 lanifibranor 作為一項可能具差異化的治療選項提供給被診斷為 MASH 的患者。

Let me take each in turn and then lay out our priorities for the year ahead. Let's start with differentiation, and it begins with understanding the biology of the disease. MASH is not simply a liver problem. It is the hepatic expression of a broader systemic metabolic dysfunction. As slide 6 shows, the disease is driven by multiple interconnected pathways, both outside and inside the liver. These include insulin resistance, adipose dysfunction, and dyslipidemia on the extrahepatic side, and steatosis, inflammation, and fibrosis within the liver itself. That has clear implications for treatment. If the disease is driven by several processes at once, there is an opportunity for next-generation treatment to target more than just one driver. That is the unmet need we believe lanifibranor could address if approved.

接下來我將逐一說明，並闡述我們未來一年的優先事項。先從差異化開始，而這要從理解疾病生物學著手。MASH 不僅僅是肝臟問題。它是更廣泛全身性代謝功能失調在肝臟的表現。如投影片第 6 頁所示，該疾病由多條彼此相互連結的途徑所驅動，涵蓋肝外與肝內。肝外方面包括胰島素阻抗、脂肪組織功能失調與血脂異常；肝內方面則包括脂肪變性、發炎與纖維化。這對治療具有明確意涵。若疾病同時由多種機制驅動，下一代治療便有機會不只針對單一驅動因子。這正是我們相信 lanifibranor 若獲核准可望滿足的未被滿足需求。

Our aim is not only to target the liver, it is to modulate pathways across both the metabolic and hepatic components of the disease and bring a differentiated treatment option to patients with MASH. The differentiated mechanism of lanifibranor modulating both pathways is reflected in compelling clinical data.

我們的目標不僅是針對肝臟，而是調節涵蓋疾病代謝與肝臟兩個組成面向的相關途徑，為 MASH 患者帶來具差異化的治療選項。lanifibranor 同時調節兩類途徑的差異化機轉，也反映在具說服力的臨床數據中。

In our Phase 2b study, after six months, lanifibranor delivered an 18% placebo-adjusted improvement in fibrosis, 26% on MASH resolution, and 24% on the composite endpoint. Those results were the foundation for NATiV3, where we are now testing the same approach in a larger control Phase 3 population of patients with F2 and F3. That is what makes NATiV3 so impactful. It was designed to confirm at pivotal scale the biology and activity we observed in our Phase 2b study, and we are pursuing this in a market with substantial and growing unmet need.

在我們的第二期 b 研究中，治療六個月後，lanifibranor 在纖維化方面達到相較安慰劑調整後 18% 的改善；在 MASH 緩解方面為 26%；在複合終點方面為 24%。這些結果奠定了 NATiV3 的基礎；目前我們正以更大規模、具對照的第三期受試者族群（F2 與 F3 患者）來檢驗相同策略。這也是 NATiV3 影響力之所在。其設計目的，是在關鍵性（pivotal）規模下確認我們在第二期 b 研究中觀察到的生物學與活性；同時，我們也在一個未被滿足需求龐大且持續成長的市場中推進此計畫。

As slide 8 shows, there are an estimated 18 million Americans living with MASH, yet only 10% are diagnosed. That is changing fast. As the treatment landscape has matured, diagnosis has increased, up roughly 25% versus 2024, and that is translating into a larger population being actively identified and managed. Today, approximately 374,000 patients with F2 or F3 disease are already in treatment or under the care of a physician. The picture is clear. A large prevalent patient population expanding rapidly as awareness and testing improve, and a compelling opportunity for lanifibranor if approved.

如投影片第 8 頁所示，估計美國約有 1,800 萬人罹患 MASH，但僅有 10% 被診斷出來。這種情況正在快速改變。隨著治療版圖日趨成熟，診斷率已提升，較 2024 年約增加 25%，並轉化為更大規模的族群被積極辨識與管理。目前，約有 374,000 名 F2 或 F3 疾病患者已在接受治療或由醫師照護中。情勢相當清楚。隨著認知與檢測改善，龐大的現存患者族群正快速擴大；若獲核准，這也為 lanifibranor 帶來極具吸引力的機會。

Turning to slide 9. To see where lanifibranor may fit in the treatment paradigm, it helps to think about MASH in terms of two factors that are top of mind for physicians, the severity of fibrosis and the cardiometabolic factors that can influence the risk of disease progression. Put fibrosis on one axis and cardiometabolic risk on the other, and four clinically distinct populations come into view. Start with the lower right quadrant. We have patients with F3 MASH and cardiometabolic risk, such as Type 2 diabetes. This is a population with high unmet medical need, where the mechanism of action of lanifibranor could be compelling in that it targets both the liver and the metabolic drivers simultaneously.

接著看投影片第 9 頁。要了解 lanifibranor 可能在治療架構中扮演的角色，可從兩個醫師最關注的因素來思考 MASH：纖維化的嚴重程度，以及可能影響疾病進展風險的心代謝因素。將纖維化作為一個軸、心代謝風險作為另一個軸，便可看出四個在臨床上截然不同的族群。先從右下象限開始。這裡是 F3 MASH 且具有心代謝風險（例如第二型糖尿病）的患者。這是一個未被滿足醫療需求很高的族群；lanifibranor 的作用機轉可能相當具吸引力，因為它可同時針對肝臟與代謝驅動因子。

In our Phase 2b trial, lanifibranor demonstrated an 18% placebo-adjusted improvement in fibrosis at just six months. Similarly, in the lower left, although these patients have earlier stage F2 fibrosis, their cardiometabolic risk factors can put them at risk for more rapid disease progression. For these patients, physicians may also want to act urgently, and lanifibranor could potentially offer an opportunity to intervene earlier in the course of the disease if approved.

在我們的第 2b 期試驗中，lanifibranor 在僅六個月內即展現出相較安慰劑調整後 18% 的纖維化改善。同樣地，在左下象限，儘管這些患者屬於較早期的 F2 纖維化，但其心代謝風險因子可能使其面臨更快速的疾病進展風險。對於這些患者，醫師也可能希望緊急介入；若獲核准，lanifibranor 可能提供在疾病進程較早期即進行介入的機會。

Moving to the top right quadrant. By extension, lanifibranor could be well-positioned in patients with F3 fibrosis without significant cardiometabolic risk. Here, the fibrosis itself is the primary concern, and lanifibranor may have the potential to address the underlying liver disease before it progresses. Taken together, these three quadrants represent a large population with significant unmet need, and if approved, we believe lanifibranor has the potential to play an important role in addressing the needs of these patients.

接著看右上象限。延伸而言，lanifibranor 可能非常適用於沒有顯著心代謝風險的 F3 纖維化患者。在此，纖維化本身是主要關切點，而 lanifibranor 可能有潛力在疾病惡化之前處理其潛在的肝臟疾病。綜合來看，這三個象限代表一個龐大且存在顯著未被滿足需求的人群；若獲核准，我們相信 lanifibranor 有潛力在滿足這些患者需求方面扮演重要角色。

With that overview of why we believe in the potential of lanifibranor, let me lay out three key priorities we are focused on to unlock new opportunities for patients with MASH. First, the NATiV3 trial. We remain on track to report top-line data in the fourth quarter of 2026. Earlier this month, the last patient completed their final 72-week visit. The main cohort enrolled 1,009 participants, all with biopsy-confirmed non-cirrhotic MASH and F2 or F3 fibrosis.

在概述了我們為何相信 lanifibranor 具備潛力之後，讓我說明我們目前聚焦的三項關鍵優先事項，以為 MASH 患者開啟新的機會。第一，NATiV3 試驗。我們仍按計畫在 2026 年第四季公布主要（top-line）數據。本月稍早，最後一位患者已完成其最終的 72 週回診。主要隊列共納入 1,009 名受試者，皆為經活檢確認之非肝硬化 MASH 且具有 F2 或 F3 纖維化。

Second, regulatory readiness. We are advancing our preparations now to support a potential NDA submission with the FDA in the first half of 2027, positioning us to move quickly into regulatory interactions if the top-line data read out as positive. Third, commercial readiness. We are building a commercial organization with the depth and breadth of experience with the best in disease products to be ready for the potential launch in 2028. We believe we are moving forward with lanifibranor from a position of strength and with a potential for a differentiated profile, a late-stage validation opportunity with NATiV3, and a significant market opportunity if approved. I am truly energized by the potential to make a real difference for millions of people living with this serious disease.

第二，法規準備度。我們正加速推進相關準備，以支持在 2027 年上半年向 FDA 提交潛在的 NDA 申請；若主要數據讀出為正向，將使我們能迅速進入法規互動。第三，商業化準備度。我們正在建立商業組織，並延攬在疾病領域產品方面具備深度與廣度經驗的頂尖人才，以因應 2028 年潛在上市。我們相信，我們正以優勢地位推進 lanifibranor，並具備差異化特徵的潛力、透過 NATiV3 取得後期驗證的機會，以及若獲核准所帶來的重大市場機會。我確實因有機會為數百萬名罹患此嚴重疾病的人帶來真正改變而深受鼓舞。

With that, let me hand it over to Jason to take you through the science behind lanifibranor and our clinical program. Jason?

接下來，讓我把時間交給 Jason，由他帶各位了解 lanifibranor 背後的科學以及我們的臨床計畫。Jason？

Thank you, Andrew, and greetings, everyone. I will spend a few minutes on four aspects of our lanifibranor development program in MASH. One, how lanifibranor is designed to address the spectrum of disease. Two, what we have observed in the positive NATIVE Phase 2b clinical trial. Third, how our NATiV3 Phase 3 trial is built to confirm that Phase 2 study. Lastly, where we are thinking of taking the program next.

謝謝你，Andrew，各位好。我將用幾分鐘談談我們在 MASH 中 lanifibranor 開發計畫的四個面向。第一，lanifibranor 的設計如何用以涵蓋疾病光譜。第二，我們在正向的 NATIVE 第 2b 期臨床試驗中觀察到的結果。第三，我們的 NATiV3 第 3 期試驗如何設計以確認第 2 期研究。最後，我們對於下一步計畫走向的思考。

Let me start with the molecule. As slide 11 shows, lanifibranor is a potential novel new chemical entity, structurally and mechanistically distinct from both fibrates and thiazolidinediones, and recognized by the FDA with both breakthrough therapy and Fast Track designations. It was informed by decades of research on PPAR biology and the development learnings of prior compounds, and it rests on one critical concept, balance.

我先從分子本身談起。如投影片 11 所示，lanifibranor 是一個潛在的新型新化學實體（NCE），在結構與作用機轉上皆不同於 fibrates 與 thiazolidinediones，並已獲 FDA 授予突破性療法與快速審查（Fast Track）資格。它奠基於數十年對 PPAR 生物學的研究與先前化合物的開發經驗，其核心建立在一個關鍵概念：平衡。

Lanifibranor engages all three PPAR isoforms, alpha, delta, and gamma, in a low-potency balanced manner such that no single receptor biology dominates. It was also engineered to have only partial agonism of the PPAR gamma receptor. The combination of this balanced low-potency pharmacology and partial PPAR gamma agonism are the keys to our differentiation. It is what lets lanifibranor modulate in harmony the metabolic, inflammatory, and anti-fibrotic pathways of MASH combined rather than forcing one mechanism or receptor at the expense of the others.

Lanifibranor 以低效價且平衡的方式同時作用於三種 PPAR 同功型：alpha、delta 與 gamma，使得不會由任何單一受體的生物學效應主導。它也被設計為僅對 PPAR gamma 受體具有部分致效作用（partial agonism）。這種平衡的低效價藥理特性與部分 PPAR gamma 致效作用的組合，是我們差異化的關鍵。這使得 lanifibranor 能夠協調調節 MASH 的代謝、發炎與抗纖維化途徑，而非以犧牲其他機制或受體為代價去強推單一機轉或受體。

The two charts on the right illustrate this designed pharmacology. On the first panel, we see the balanced activation profile and the approximately 80% gamma activation with lanifibranor. While on the far right, the cofactor recruitment fingerprint that sets lanifibranor apart from full TZD gamma agonists. The result is a once-daily oral therapy intended to deliver a physiologic balance between achieving pan-PPAR activation and avoiding any one receptor dominance.

右側兩張圖表說明了這種設計出的藥理特性。在第一個圖板中，我們看到平衡的活化輪廓，以及 lanifibranor 約 80% 的 gamma 活化。而在最右側，則顯示其輔因子招募指紋（cofactor recruitment fingerprint），使 lanifibranor 有別於完全型 TZD gamma 致效劑。其結果是一種每日一次的口服療法，旨在於達成泛 PPAR 活化與避免任何單一受體主導之間取得生理性的平衡。

Moving now to our Phase 2b NATIVE clinical trial data. Andrew shared our overall histology efficacy data, but that included patients with lower risk earlier F1 disease. When we exclude these patients with earlier stage disease, we continue to see robust effects across all three histologic endpoints, showing that the drug worked equally well in both early and later stage disease. These results were achieved after only six months of treatment. Looking more closely at the data for the composite endpoint, you can see that treated patients were roughly 8 times more likely than placebo patients to achieve dual histologic improvement in the Type 2 diabetes subgroup.

接著談我們第 2b 期 NATIVE 臨床試驗數據。Andrew 分享了我們整體的組織學療效數據，但其中包含風險較低、較早期的 F1 疾病患者。當我們排除這些較早期疾病患者後，仍可在三個組織學終點上看到強勁效果，顯示該藥在早期與較晚期疾病中的效果同樣良好。這些結果是在僅六個月治療後達成。更仔細看複合終點的數據可見，在第 2 型糖尿病亞組中，接受治療的患者達成雙重組織學改善的可能性約為安慰劑患者的 8 倍。

This tells us that spontaneous regression of the disease was uncommon and that the treatment effect of lanifibranor was strong. Together with the early and late-stage data, these results underscore the potential of lanifibranor to perform across the disease spectrum, including in patients with the most urgent disease.

這告訴我們，自發性疾病逆轉並不常見，而 lanifibranor 的治療效果相當強。結合早期與晚期分期的數據，這些結果凸顯 lanifibranor 有潛力在整個疾病光譜中發揮作用，包括在病情最為迫切的患者身上。

Let me now turn to safety and tolerability. On slide 13, we show the most frequently reported adverse events by investigators in our NATIVE Phase 2b clinical trial. Lanifibranor was generally well-tolerated across the totality of our Phase 2 program, but the adverse event profile in NATIVE 2b tracked closely with the underlying scientific design of lanifibranor. Consistent with our preclinical toxicology data, we saw minimal classic alpha or delta toxicities. On gamma-related effects, weight gain, edema, and hemoglobin decline, these were present but attenuated relative to the full TZD class gamma agonists.

現在我轉到安全性與耐受性。在投影片 13，我們呈現研究者在 NATIVE 第 2b 期臨床試驗中最常回報的不良事件。在我們第 2 期計畫的整體資料中，lanifibranor 一般而言耐受性良好；但 NATIVE 2b 中的不良事件特徵與 lanifibranor 的科學設計高度一致。與我們的臨床前毒理數據一致，我們觀察到典型的 alpha 或 delta 毒性極少。至於與 gamma 相關的影響——體重增加、水腫與血紅素下降——雖然存在，但相較於完全型 TZD 類別的 gamma 致效劑有所減輕。

The weight gain we observed in patients treated with lanifibranor is biphasic. Early on, the partial PPAR gamma activation acts on a sodium channel in the kidney, resulting in sodium and water retention. While in a later phase, that same partial PPAR gamma activation drives improved insulin sensitization and adipose remodeling, reflected in the rise in adiponectin, which is itself tied to histologic efficacy.

我們在接受 lanifibranor 治療的患者中觀察到的體重增加呈雙相（biphasic）。在早期，部分 PPAR gamma 活化作用於腎臟的鈉通道，導致鈉與水分滯留。而在較後期，同樣的部分 PPAR gamma 活化會促進胰島素敏感性改善與脂肪組織重塑，反映在脂聯素（adiponectin）上升；而脂聯素本身與組織學療效相關。

Both phases are consistent with the known pharmacology of PPAR gamma engagement. Based on our LEGEND study, these gamma-related effects were mitigated by adding an SGLT2 inhibitor, empagliflozin, while also preserving the metabolic benefit of lanifibranor. This brings me to NATiV3. This is a Phase 3 global registrational trial, and it was deliberately designed to build on our Phase 2b. The same two doses, a similar patient population, and a primary composite endpoint of MASH resolution and at least one-stage fibrosis improvement in the same patient.

兩個階段皆與已知的 PPAR gamma 作用機轉一致。根據我們的 LEGEND 研究，透過加入一種 SGLT2 抑制劑 empagliflozin，可減輕這些與 gamma 相關的效應，同時保留 lanifibranor 的代謝效益。這帶我進入 NATiV3。這是一項第 3 期全球註冊性試驗，並且是刻意設計用來延續我們的第 2b 期研究。採用相同的兩個劑量、相近的病人族群，以及以同一位病人達成 MASH 緩解並且纖維化至少改善一個分期的主要複合終點。

Secondary endpoints include MASH resolution and fibrosis improvement of one stage or more. The trial enrolled approximately 1,400 patients across two cohorts, a placebo-controlled randomized portion consisting of 1,009 patients with biopsy-confirmed F2 or F3 MASH, and an exploratory cohort of 410 patients with predominantly F1 or F4 disease. Both cohorts were treated for 72 weeks. All patients who completed the trial are eligible for an active treatment extension to support a longer-term view of the safety and tolerability of lanifibranor.

次要終點包括 MASH 緩解，以及纖維化改善一個分期或以上。本試驗共納入約 1,400 名病人，分為兩個隊列：一個為安慰劑對照的隨機分派部分，包含 1,009 名經活檢證實為 F2 或 F3 的 MASH 病人；以及一個探索性隊列，包含 410 名以 F1 或 F4 疾病為主的病人。兩個隊列皆治療 72 週。所有完成試驗的病人皆符合資格進入主動治療延伸期，以支持對 lanifibranor 安全性與耐受性更長期的觀察。

The main cohort will serve as the basis for global marketing registration, and the primary endpoint is powered at 90% on deliberately conservative assumptions with a higher placebo response and a lower treatment effect than we observed in the Phase 2b NATIVE trial. It is stratified by fibrosis stage and diabetes status. This main cohort also reflects the real world. The NATiV3 population is a contemporary MASH population with higher diabetes prevalence, more advanced fibrosis, and more use of GLP-1s and SGLT2 inhibitors compared to our Phase 2b trial. As Andrew noted, it has been fully recruited, and the last patient visit for the week 72 portion of the trial was completed earlier this month. And as Andrew shared, we are excited for top-line data in the fourth quarter of this year.

主要隊列將作為全球上市註冊的基礎，而主要終點在刻意保守的假設下，以 90% 的檢定力設計：假設安慰劑反應較高、治療效果較低，均低於我們在第 2b 期 NATIVE 試驗中所觀察到的結果。並依纖維化分期與糖尿病狀態進行分層。此主要隊列也反映真實世界。NATiV3 的受試者為當代的 MASH 族群，與我們的第 2b 期試驗相比，糖尿病盛行率更高、纖維化更進展，且使用 GLP-1 與 SGLT2 抑制劑的比例更高。如 Andrew 所提，已完成全數招募，本月稍早也已完成試驗 72 週部分的最後一位病人訪視。也如 Andrew 所分享，我們期待在今年第四季取得主要結果（top-line data）。

Subject to positive Phase 3 results, we intend to file for accelerated approval with the FDA and conditional approval with the EMA. We will also be initiating a confirmatory clinical outcomes trial designed to evaluate the effects of lanifibranor in patients with more advanced disease. That's worth pausing on because everything I've described targets the core pathophysiology of MASH. But that same pathophysiology also underlies compensated advanced chronic liver disease, or CACLD, due to MASH.

若第 3 期結果為正向，我們計畫向 FDA 申請加速核准，並向 EMA 申請附條件核准。我們也將啟動一項確認性臨床結局試驗，旨在評估 lanifibranor 對於疾病更進展病人的影響。這點值得稍作停留，因為我所描述的一切都鎖定 MASH 的核心病理生理機轉。但同樣的病理生理機轉也構成由 MASH 所致之代償性進展期慢性肝病（CACLD）的基礎。

These are patients who have progressed to advanced fibrosis or early histologic cirrhosis, yet they remain clinically compensated but have evidence of clinically significant portal hypertension, the primary driver of adverse liver-related outcomes. This subgroup of patients has no approved disease-modifying therapy. It is a significant area of high unmet need in the disease. We believe that lanifibranor is mechanistically compelling in CACLD because the same PPAR isoforms that drive the histologic and metabolic effect in the non-cirrhotic MASH population also act on the vascular biology that underpins portal hypertension in this more advanced group.

這些病人已進展至高度纖維化或早期組織學肝硬化，但臨床上仍維持代償狀態，然而已有臨床上顯著的門脈高壓證據，而門脈高壓是導致不良肝相關結局的主要驅動因素。此一病人亞群目前沒有任何已核准的疾病修飾治療。這是該疾病領域中一個高度未被滿足的重大需求。我們認為 lanifibranor 在 CACLD 具有機轉上的吸引力，因為在非肝硬化 MASH 族群中驅動組織學與代謝效應的相同 PPAR 同功型，也會作用於血管生物學，而血管生物學正是此更進展族群門脈高壓的基礎。

And in CACLD, portal pressure matters because as the disease advances, portal hypertension and not fibrosis alone becomes a key driver of these hard clinical outcomes, including bleeding, ascites, and liver transplant. We recently published an analysis of our Phase 2b NATIVE trial showing a correlation in patient biopsies with vascular remodeling we've observed preclinically.

在 CACLD 中，門脈壓力之所以重要，是因為隨著疾病進展，門脈高壓而非僅僅纖維化，會成為這些硬性臨床結局的關鍵驅動因素，包括出血、腹水與肝臟移植。我們近期發表了第 2b 期 NATIVE 試驗的一項分析，顯示病人活檢結果與我們在臨床前所觀察到的血管重塑之間存在相關性。

These are exploratory analysis, but they add to our conviction to pursue further advanced disease states in MASH. With that, I'll hand it over to Axel.

這些屬於探索性分析，但進一步強化了我們在 MASH 中推進至更進展疾病狀態的信心。接下來我把時間交給 Axel。

I will pick up for Axel here.

我在這裡代替 Axel 接續說明。

I'm sorry, I lost my text. Please go ahead.

抱歉，我的稿子不見了。請繼續。

Yes. So this morning we issued our press release reporting our full financial results for the first half of 2026. Axel will focus on the key financial highlights and our financial position as we approach the NATiV3 top line readout. Axel, are you ready to take over?

好的。今天早上我們發布新聞稿，報告 2026 年上半年完整財務結果。Axel 將聚焦於主要財務重點，以及在我們接近 NATiV3 主要結果揭露之際的財務狀況。Axel，你準備好接手了嗎？

Not yet.

還沒。

Okay. As of June 30, 2026, we had EUR233.9 million of combined cash equivalents, and short-term deposits. We significantly strengthened our financial position through the comprehensive capital structure optimization that we announced in June. Under that, we bought back approximately 60% of the EIB warrants with anti-dilution protection for EUR50 million, and repaid our EIB loans for EUR63 million. In addition, the remaining EIB warrants with anti-dilution protection were canceled. Inventiva issued new EIB warrants in exchange, as described in the July 9, 2026, press release.

好的。截至 2026 年 6 月 30 日，我們的現金及約當現金與短期存款合計為 2.339 億歐元。我們透過 6 月宣布的全面性資本結構優化，顯著強化了財務狀況。在該方案下，我們以 5,000 萬歐元買回約 60% 具反稀釋保護的 EIB 認股權證，並以 6,300 萬歐元償還 EIB 貸款。此外，其餘具反稀釋保護的 EIB 認股權證已被取消。Inventiva 另行發行新的 EIB 認股權證作為交換，如 2026 年 7 月 9 日新聞稿所述。

I am ready to take over.

我準備好接手了。

Please go ahead.

請開始。

As part of this optimization, we secured new debt financing of up to EUR130 million in three committed tranches, subject to conditions with an initial drawdown of two tranches of EUR75 million gross, plus an additional uncommitted tranche of up to EUR20 million, as described in our press release of June 2, issued earlier this year. We also completed an underwritten public offering of our American depositary shares, generating gross proceeds of EUR103 million.

作為此項優化的一部分，我們取得最高可達 1.30 億歐元的新債務融資，分為三個已承諾的分期撥款（須符合相關條件），其中初始動用為兩個分期合計 7,500 萬歐元（總額），另有一個最高可達 2,000 萬歐元的額外未承諾分期，如我們於今年稍早 6 月 2 日發布的新聞稿所述。我們也完成了美國存託股份的承銷公開發行，募集總額 1.03 億歐元。

Together, these actions strengthened our balance sheet, extended the maturity of our debt, and simplified our capital structure. Our current financing assumptions, existing resources, and completed financing transactions provide cash runway until the end of the second quarter of 2027, seeing us through key milestones, the Phase 3 top-line data readout, and potential NDA filing.

綜合上述行動，我們強化了資產負債表、延長了債務到期年限，並簡化了資本結構。依據我們目前的融資假設、既有資源與已完成的融資交易，我們的現金可支應至 2027 年第二季末，足以支撐關鍵里程碑、第 3 期主要結果揭露，以及潛在的 NDA 申請。

Assuming full exercise of Tranche 3 warrants on the back of a positive top-line result, as well as successful completion of Tranche C of the debt financing transaction, our cash runway would extend to the start of the first quarter of 2028. R&D expenses were EUR46.2 million in the first half of 2026, brought in line with the prior year and reflecting continued clinical development of lanifibranor MASH. Marketing and business development expenses increased to EUR2.6 million, and G&A expenses increased to EUR22.2 million. Overall, we entered the second half of 2026 with a strengthened balance sheet and financial visibility for the company.

若在主要結果為正向的情況下，第三分期認股權證獲得全數行使，且債務融資交易的 C 分期順利完成，我們的現金可支應期將延長至 2028 年第一季初。2026 年上半年研發費用為 4,620 萬歐元，與前一年持平，反映 lanifibranor 用於 MASH 的臨床開發持續推進。行銷與業務開發費用增加至 260 萬歐元，一般及行政費用增加至 2,220 萬歐元。整體而言，我們在 2026 年下半年以更強健的資產負債表與更清晰的財務能見度進入下半年。

With that, I'll turn the floor back to Andrew for his closing remarks.

接下來我把時間交回 Andrew，請他做結語。

Thank you, Axel. This is truly an exciting time for Inventiva. Our differentiated mechanism of action, the results we saw in the NATIVE Phase 2b trial, and the robust design of our NATiV3 Phase 3 trial provide a strong foundation as we approach the milestones ahead. The next major milestone is our NATiV3 top-line results readout, expected in the fourth quarter of this year.

謝謝你，Axel。對 Inventiva 而言，這確實是一個令人振奮的時刻。我們具差異化的作用機轉、在 NATIVE 第 2b 期試驗中看到的結果，以及 NATiV3 第 3 期試驗的穩健設計，為我們邁向接下來的里程碑奠定了堅實基礎。下一個重大里程碑是 NATiV3 的主要結果揭露，預計在今年第四季。

If positive, it could support the US regulatory filing in the first half of 2027 and a potential EU filing to follow. If approved, we're prepared for a potential US commercial launch in 2028, with the goal of bringing a new treatment option to patients with significant unmet need. We also expect to initiate an outcomes trial, which could support a potential opportunity for lanifibranor to expand into more advanced disease populations. Stepping back, what does this all mean for lanifibranor?

若結果為正面，將可支持於 2027 年上半年在美國提交監管申請，並可能隨後在歐盟提交申請。若獲核准，我們已為 2028 年在美國潛在的商業上市做好準備，目標是為具有重大未被滿足需求的患者帶來新的治療選擇。我們也預期將啟動一項結局試驗（outcomes trial），這可能支持 lanifibranor 擴展至更晚期疾病族群的潛在機會。退一步來看，這一切對 lanifibranor 意味著什麼？

Let me bring it back to where I started. Why lanifibranor and why now? Lanifibranor is designed to target both the metabolic and hepatic drivers of MASH in one oral medicine. Our pivotal top-line results readout is imminent in Q4 this year. The market is established and significant unmet need remains. We have established the foundation to build a launch-ready organization and prepare for the next stage of development. We are moving forward from a position of strength with the discipline and the urgency that people living with MASH deserve, and I'm genuinely excited about what lies ahead.

讓我回到我一開始提到的重點。為什麼是 lanifibranor，為什麼是現在？Lanifibranor 的設計是在一種口服藥物中同時針對 MASH 的代謝與肝臟驅動因素。我們的關鍵性試驗主要（top-line）結果讀出將於今年第四季即將公布。市場已建立，而重大未被滿足需求仍然存在。我們已奠定基礎，以打造具備上市準備的組織並為下一階段的開發做準備。我們以優勢地位持續推進，並以 MASH 患者所應得的紀律與緊迫感前行，我也真心對未來的發展感到振奮。

With that, let me hand it back to the operator to begin Q&A. Operator?

接下來，我把時間交還給接線員，開始問答環節。接線員？

(Operator Instructions)

（接線員指示）

Yasmeen Rahimi, Piper Sandler.

Yasmeen Rahimi，Piper Sandler。

Good morning, team. Congrats on all the updates and thank you so much for walking us through some of the key questions. Maybe, we've been lately getting questions from investors how we should be thinking about the two doses in the NATiV3 study, and whether it would even make sense commercially if both showed a clinically meaningful difference to move forward. Would love to get your thoughts.

各位早安，團隊。恭喜你們所有更新，也非常感謝你們帶我們梳理一些關鍵問題。或許我們最近一直收到投資人提問：我們應該如何看待 NATiV3 研究中的兩個劑量，以及如果兩者都顯示出具臨床意義的差異，商業上是否仍有意義繼續推進。很想聽聽你們的看法。

And maybe one other one that sometimes comes up is that the higher dose had a phenomenal histological benefit, but then when we compare the NITs, the two doses look more the same. So would love if you could maybe comment on both. That would be very helpful as it's on top of a few of the investors that have been asking us that. Thank you.

另外還有一個有時也會被提到的點是：較高劑量在組織學上有非常出色的獲益，但當我們比較 NITs 時，兩個劑量看起來更相近。所以也希望你們能就這兩點做些評論。這會非常有幫助，因為這是一些一直在問我們的投資人最關心的問題之一。謝謝。

Thank you, Yasmeen, and good morning. So two questions in there. First one, I think more of a commercial question, which I'll take, then I'll pass it on for the correlation with histology and dose to Jason in a second. First, if both doses are statistically significant positive, I think it would make sense to bring both forward in the market. It's going to depend on the data.

謝謝你，Yasmeen，早安。你這裡有兩個問題。第一個我認為比較偏商業面的問題，我先回答，接著我會把關於組織學與劑量之間相關性這部分交給 Jason。首先，如果兩個劑量都達到統計上顯著的正向結果，我認為把兩者都推向市場是合理的。這將取決於數據表現。

So we'll clearly look at what the efficacy is with each dose and the tolerability with each dose. And that there's a -- there could be scenarios in which the difference between the two makes sense to bring both to the market, potentially one for two patients or one you could think of as earlier stage patients that are less urgent and so therefore would be okay with a dose response or lower efficacy and more tolerable.

因此我們會清楚地檢視各劑量的療效以及各劑量的耐受性。而且確實可能出現某些情境：兩者之間的差異使得同時推向市場是合理的；例如可能一個更適合某類患者，或可將其中一個視為用於較早期、迫切性較低的患者，因此他們可能可以接受較低的劑量反應或較低的療效但更好的耐受性。

And if another one, if you have a tolerability difference between low and high, then a higher dose with still tolerable but a slightly different profile, we could see bringing both forward, but that really remains to see in the data. It's a little bit too early to speculate until we get the actual data to see it.

另外，如果低劑量與高劑量在耐受性上存在差異，那麼高劑量即使仍可耐受但呈現略有不同的特徵，我們也可能會考慮兩者都往前推進；但這仍需看數據而定。在拿到實際數據之前，現在推測還稍嫌過早。

Jason, let me hand the second question over to you, the correlation with NITs.

Jason，我把第二個問題交給你，關於 NITs 的相關性。

Sure. Happy to. Yasmeen, good morning. So in the NATIVE Phase 2 trial, the -- generally speaking, the histology endpoints tracked well with most, but not all of the clinical biomarker endpoints. Obviously, ALT/AST reduction was evidenced. This reflects hepatocellular injury. But moving into fibrosis, you can think of the data that we had as looking at both new scar being laid down and active scar resorption.

好的。很樂意回答。Yasmeen，早安。在 NATIVE 第二期試驗中，整體而言，組織學終點與多數（但不是全部）的臨床生物標記終點呈現良好一致性。很明顯可見 ALT/AST 的下降。這反映肝細胞損傷的改善。但進一步談到纖維化時，你可以把我們的數據理解為同時在觀察新疤痕的形成，以及既有疤痕的主動吸收。

PRO-C3 is the best example of new scar being laid down. It's a fragment of procollagen peptide, and the PRO-C3 marker actually tracked quite nicely with the 1,200-milligram histology efficacy endpoint. Similarly, when we look at ELF, the hyaluronic acid was a little noisy at baseline, but the two other components actually tracked very nicely in a dose-dependent manner, representing that we were, in this case, resorbing some existing scar.

PRO-C3 是新疤痕形成的最佳例子。它是前膠原蛋白胜肽的一段片段，而 PRO-C3 指標其實與 1,200 毫克劑量在組織學療效終點的表現相當一致。同樣地，當我們看 ELF 時，透明質酸在基線時有些雜訊，但另外兩個組成成分其實以劑量依賴的方式呈現非常一致的追蹤結果，顯示在這個情況下，我們正在吸收部分既有疤痕。

And lastly, on the TE, it's very difficult to compare trials, Yasmeen, as you know, across different sponsors. When you look at the data ranging from 6 months to 18 months, the range in TE liver stiffness measurement ranges from about a 1% placebo-adjusted change all the way up to like a high -- sorry, 1 kPa up to a high of 3 kPa. So that's somewhere around 10% to 30%. Lanifibranor came in at the lower end of that range, and it's our belief that's, one, it's just early in the disease to really have movement on liver stiffness. It's a composite view of what's going on in the liver. And more importantly, we know that lanifibranor has some confounding due to that fluid retention.

最後談到 TE（瞬時彈性成像），如你所知，Yasmeen，跨不同贊助商的試驗很難直接比較。當你看 6 個月到 18 個月的數據時，TE 肝硬度測量的範圍大約從安慰劑校正後 1% 的變化一路到大約——抱歉，是從 1 kPa 到最高約 3 kPa。因此大約相當於 10% 到 30%。Lanifibranor 的結果落在該範圍的較低端；我們認為原因之一是疾病仍偏早期，肝硬度尚不容易出現明顯變化。肝硬度是一個對肝臟狀況的綜合性觀察。更重要的是，我們知道 lanifibranor 因液體滯留而帶來一些混雜因素。

This is a known concern with liver stiffness in general, listed in the Echosens manuals about being cautious about getting liver stiffness data after a meal or in the presence of fluid loading. And at six months, the dynamic fluid flux that's still happening due to the PPARγ, we believe is likely impacting some of that. So we landed at about a 10% reduction in liver stiffness, about a 1 kPa placebo-adjusted number. And we're confident that with a longer treatment duration, the underlying fibrosis improvements will, in the end, dominate that signal by 18 months.

這是肝硬度測量本身已知的顧慮，在 Echosens 的操作手冊中也列出：在餐後或存在液體負荷時，解讀肝硬度數據需謹慎。而在 6 個月時，由於 PPARγ 造成的體液動態通量仍在發生，我們認為這很可能影響了部分結果。因此我們得到的肝硬度下降約 10%，安慰劑校正後約 1 kPa。我們有信心，隨著治療時間拉長，到 18 個月時，纖維化改善的基礎效應最終將主導並蓋過該訊號。

Thank you so much.

非常感謝。

Seamus Fernandez, Guggenheim Securities.

Seamus Fernandez，Guggenheim Securities。

Great. Thanks for the question. So just wanted to get a sense of the information that you guys have on a blinded basis as it relates to weight gain throughout the NATiV3 study. If you might be able to share what's with your expectations for potential weight gain. What we've heard from thought leaders is 18% would be a highly differentiated threshold for fibrosis change, very consistent with what you've commented on.

很好。謝謝這個問題。我想了解一下，就 NATiV3 研究期間的體重增加而言，你們在盲態（blinded）下掌握了哪些資訊。如果可以的話，能否分享你們對潛在體重增加的預期。我們從意見領袖那邊聽到的是，18% 會是纖維化變化上高度差異化的門檻，這也與你們先前的評論非常一致。

But I think there is the trade-off of potential weight gain and edema that some physicians have commented on and may have a higher bar for fibrosis difference over time. Just interested to know what information you guys have on the weight gain and edema, how patients actually feel on drug that has any meaningful impact on the durability and sustainability of the use of lanifibranor in the NATiV3 study. Thanks so much.

但我認為，確實存在一些醫師提到的潛在體重增加與水腫之間的取捨，而且對於隨時間推移纖維化差異的門檻可能會更高。我只是想了解你們掌握哪些關於體重增加與水腫的資訊、病人在用藥時實際感受如何，以及這些是否會對 NATiV3 研究中 lanifibranor 使用的耐久性與可持續性造成任何有意義的影響。非常感謝。

Yeah. So a couple elements to that question. Let me hand it to Jason to talk about the first part, which is what have we shown from a blinded basis from the Phase 3 trial on weight gain, and then I can take it from there. Jason, go ahead.

是的。這個問題包含幾個面向。我先請 Jason 來談第一部分，也就是我們從第三期試驗的盲態資料中，對體重增加顯示了什麼，接著我再補充。Jason，你請。

Yeah, sure. So Seamus, good morning. So we previously disclosed back when the structured financing back in 2024, some data on our Phase 2 clinical trial in the scleroderma population. This is a non-metabolic population treated for a year with the same doses of lanifibranor that are in the MASH program. And in that trial, we showed that the weight gain was similar up to six months to what we saw in the NATIVE Phase 2b trial and thereafter, where NATIVE 2b stopped at six months. Thereafter, the weight gain appeared to plateau right around the week 24 to week 30 and remained stable there out through to the end of the study at week 48.

好的，當然。Seamus，早安。我們先前在 2024 年進行結構性融資時，曾披露過一些在硬皮症族群之第二期臨床試驗的數據。這是一個非代謝性族群，使用與 MASH 計畫相同劑量的 lanifibranor 治療一年。在該試驗中，我們顯示體重增加在前六個月與 NATIVE 第二期 2b 試驗所見相近；而 NATIVE 2b 是在六個月時結束。之後，體重增加似乎在第 24 週到第 30 週左右進入平台期，並一直維持穩定直到第 48 週研究結束。

We're not guiding any additional data or input on NATiV3 in any manner. And I think, Andrew, to turn this over to you, I think that the data that we have in NATIVE is actually really representative of some of the questions Seamus asked, and I'll answer that and turn it back to you. Seamus, you're really getting at what's the potential impact of things like weight gain, edema? I think that that's the right question. And when you look in the NATIVE trial, about half of all patients in that trial had no weight gain defined as anything beyond plus or minus 5%.

我們不會以任何方式就 NATiV3 提供額外數據或指引。而且我想，Andrew，把這部分交給你；我認為我們在 NATIVE 的數據其實很能代表 Seamus 提出的部分問題，我先回答再交回給你。Seamus，你真正想問的是像體重增加、水腫這類因素可能造成的影響是什麼？我認為這是個正確的問題。而在 NATIVE 試驗中，大約有一半的病人沒有體重增加；其定義為體重變化在正負 5% 以內。

So among the patients, therefore, that did have weight gain, when you look at the adverse event reporting in that trial, only about 10% of the reports related to weight gain. That's consistent with the idea that weight gain is not seen by patients or providers as a safety or tolerability concern. And in that trial, we had about 30 approximately dropouts, and weight gain was not a primary driver of the tolerability concern there and discontinuing treatment. So our view is that at least from the completed NATIVE clinical trial, that weight gain is not an impediment to patients staying on treatment. And the perception of weight gain by both providers and patients is not one around safety and tolerability.

因此，在確實有體重增加的病人中，當你看該試驗的不良事件通報時，只有約 10% 的通報與體重增加相關。這與「病人或醫療提供者並不將體重增加視為安全性或耐受性疑慮」的觀點一致。而在該試驗中，我們大約有 30 位左右的退出者，體重增加並不是耐受性疑慮或停藥的主要驅動因素。所以我們的看法是，至少從已完成的 NATIVE 臨床試驗來看，體重增加不會妨礙病人持續接受治療。而且無論是醫師或病人，對體重增加的認知也不是把它當作安全性與耐受性問題。

Andrew, over to you.

Andrew，交給你。

Well, I do not think I could say it better than you, Jason. That was perfect. So I think we can move on to the next question.

嗯，我覺得我不可能比你說得更好，Jason。非常到位。所以我想我們可以進入下一個問題。

Ritu Baral, TD Cowen.

Ritu Baral，TD Cowen。

Good morning, guys. Thanks for taking the question. I guess I have the same question, in terms of edema, which is, I guess, related but separate in the sense that, I think KOLs see that less as a true safety issue, but potentially a tolerability issue. Is this something you guys have interrogated in your market research insofar as what level and severity that the edema becomes inconvenient or unacceptable to MASH patients and that risk-benefit around sort of extremitous edema, versus any potential issue of fluid load. Thanks.

各位早安。謝謝讓我提問。我想我有個類似的問題，關於水腫；我想這雖然相關但又是不同面向，因為我認為 KOL（關鍵意見領袖）較少把它視為真正的安全性問題，但可能是耐受性問題。你們是否在市場調研中深入探討過：對 MASH 病人而言，水腫到什麼程度與嚴重度會變得不方便或不可接受？以及在所謂四肢水腫的風險—效益權衡上，相對於任何可能的體液負荷問題，你們怎麼看？謝謝。

So I will start out, then I will hand it to Jason as well. So a very similar answer to before. The edema is mechanistically understood, is consistent with known PPAR gamma pharmacology. And that makes physicians, especially those who use pioglitazone in the market, very comfortable with managing those types of effects. And we are looking for in the larger NATiV3 data set to provide a more comprehensive safety characterization overall. But in general, the physicians know that they can mitigate the MFX linked to fluid retention, weight, edema, hemoglobin, by addition of an SGLT2, if they want to manage it. So we do view this as a profile that is very commercially attractive.

我先回答，然後也會交給 Jason 補充。所以答案與剛才非常類似。水腫在機轉上是可理解的，且與已知的 PPAR gamma 藥理作用一致。這讓醫師，特別是市場上有使用 pioglitazone 的醫師，對於處理這類影響感到非常安心。我們也期待在更大的 NATiV3 數據集中，提供更全面的整體安全性特徵描述。但總體而言，醫師知道若想管理，透過加用 SGLT2 來減輕與體液滯留相關的 MFX（不良影響），包括體重、水腫、血紅素等，是可行的。因此我們確實認為這是一個在商業上非常具吸引力的特徵。

Jason, do you have anything to add to that?

Jason，你還有要補充的嗎？

I do just briefly. So edema, as Andrew mentioned, is a known on-target consequence of PPAR gamma. I want to make a distinction between the prevalence of edema in the NATIVE 2 trial, the unadjusted prevalence, meaning independent of assessment, ranged between 7% and 10% on the two doses, and the drug-related edema was about 2%. Contrast that with what we know from pioglitazone in a similar MASH population, you are somewhere in the mid 20s, 20% to 25% edema range. So that is a prevalence.

我簡短補充一下。如 Andrew 提到，水腫是 PPAR gamma 已知的、靶點相關（on-target）的結果。我想區分一下：在 NATIVE 2 試驗中，水腫的發生率（未校正發生率，也就是不依賴評估方式）在兩個劑量組約介於 7% 到 10%，而被判定為與藥物相關的水腫約為 2%。相較之下，從我們對 pioglitazone 在類似 MASH 族群的了解，水腫大約落在 20% 到 25% 的區間，也就是二十幾%。所以那是一個發生率的差異。

In terms of the severity, which I think, Ritu, was where your question was headed, is that generally these events are considered mild to moderate. And going back to the NATIVE 2b clinical trial, these were not primary drivers of patients discontinuing treatment. So most of the edema in the experience of our clinical program is so-called peripheral edema.

至於嚴重度，我想 Ritu 你的問題重點在這裡：一般而言，這些事件被視為輕度到中度。回到 NATIVE 2b 臨床試驗，這些並不是病人停藥的主要驅動因素。因此，在我們臨床計畫的經驗中，多數水腫屬於所謂的周邊水腫（peripheral edema）。

It happens in the lower extremities, where present occasionally periorbital around the eyes, but generally this is a mild to moderate view. And most importantly, the difference between a pure PPAR agonist like pioglitazone, for example, is fairly large, which is consistent with our view that this is a more blunted or more attenuated gamma effect that you would see with a full TZD class agonist.

它發生在下肢；若出現，有時也會在眼周出現眼眶周圍水腫，但整體而言通常被視為輕度到中度。而且最重要的是，與例如 pioglitazone 這種純 PPAR 致效劑相比，差異相當大；這也符合我們的看法：相較於完整的 TZD 類別致效劑，你在這裡看到的是較為鈍化或較為減弱的 gamma 效應。

Would you expect it to be transient?

你會預期它是暫時性的嗎？

I'm sorry, Ritu, do I expect it to be?

抱歉，Ritu，你是問我預期它會是什麼？

Would you expect the edema to be transient, and if so, would it be during the full 18 months, and would that be communicated?

你會預期水腫是暫時性的嗎？如果是的話，會持續整個 18 個月嗎？而且這會被溝通說明嗎？

I think we're not giving any guidance on what we expect over time. I think that 18-month trials are long. The fluid is due to salt and water. So to the extent that patients may or may not have already on a pre-existing agent like SGLT2s or thiazide diuretics, that may impact it.

我想我們不會就隨時間推移的預期提供任何指引。我認為 18 個月的試驗很長。體液主要來自鹽分與水分。因此，若病人本來就有或沒有使用像 SGLT2 或噻嗪類利尿劑等既有藥物，可能會對其造成影響。

And also mild changes in diet around salt intake and/or fluid can impact that. I think our view is that the pharmacology is well understood here and the overall mechanism, and that going back to your core point, we don't view it as a tolerability concern or gating in any way to patients staying on it. Maybe I'll make the simple point. Pioglitazone is a generic therapeutic at this point. It's still used about 4 million scripts a year in the US, and that's with very minimal histologic efficacy on anything outside of MASH.

此外，飲食在鹽分攝取和／或液體攝取方面的輕微變化也可能影響到這點。我認為我們的看法是，這裡的藥理作用與整體機轉都已被充分理解；回到你提出的核心重點，我們不認為這是耐受性方面的疑慮，也不會以任何方式成為患者持續用藥的門檻。也許我用一句話簡單說明。吡格列酮（Pioglitazone）目前已是學名藥治療選項。在美國每年仍約有400萬張處方使用，而這是在其對MASH以外的任何病理學療效都非常有限的情況下。

I think the question you're really asking is, if we added an 18% one-stage improvement of fibrosis or more to that profile, would people use more or less of it? I would argue they would use more. I think even better evidence that it's much less of a tolerability concern in the market than we see it in the clinical program.

我想你真正想問的是：如果我們在這個特徵組合上再加上「纖維化改善一個分期或以上」達18%的效果，人們會更常用還是更少用？我會主張他們會用得更多。我認為這也更能證明：在市場上，耐受性其實遠沒有我們在臨床試驗計畫中看到的那麼令人擔憂。

Understood. Thank you.

了解。謝謝。

Thomas Smith, Leerink Partners.

Thomas Smith，Leerink Partners。

Hey guys, good morning. Congrats on the progress and thanks for taking our questions. First, from a compliance perspective, can you just remind us, is there any protocol or counseling that is built into the study for patients that are experiencing weight gain or edema to help them manage this and stay on the study? Also wondering if you have any visibility into the proportion of patients who have rolled over into the active treatment extension portion of NATiV3 on a blinded basis.

各位早安。恭喜進展，也謝謝回答我們的問題。首先，從依從性（compliance）的角度，能否提醒我們：對於出現體重增加或水腫的受試者，研究中是否內建任何流程或諮詢輔導，協助他們管理並持續留在試驗中？另外也想請問，你們是否掌握有多少比例的受試者在盲態下已進入NATiV3的主動治療延伸（active treatment extension）階段？

And then just a bit on your market research. You highlighted the 374,000 F2, F3 patients diagnosed under the care of a specialist. That's a bit lower than the 460,000 we have heard from a competitor. I was just wondering if you could talk a little bit about the differences there and how you are thinking about patient targeting relative to Rezdiffra. Thanks so much.

再來談一下你們的市場調研。你們提到在專科醫師照護下被診斷的F2、F3患者有374,000人。這比我們從某家競爭對手聽到的460,000人略低。想請你們談談其中差異，以及相較於Rezdiffra，你們如何思考患者鎖定策略。非常感謝。

Yeah. Thanks for the question, Thomas. So let me handle the first two, then hand it over to Jason. On the active treatment role, we are not commenting on that yet. We have not publicly disclosed that information. On the patient population, yes, there are some range of estimates out there. The 374,000 is certainly on the low end of that. We have not updated that number, but certainly, I think the real message here is that it is a very sizable population, and growing rapidly. So that number will continue to evolve. Jason, over to you on how weight gain was managed in the trial.

好的。謝謝你的問題，Thomas。我先回答前兩個，然後交給Jason。關於主動治療延伸（active treatment）納入的情況，我們目前還不評論。我們尚未公開披露該資訊。至於患者族群，是的，外界確實有一些不同區間的估算。374,000確實偏向較低端的估計。我們尚未更新這個數字，但我認為真正要傳達的是：這是一個非常龐大、且快速成長的族群。因此這個數字會持續演變。Jason，請你說明試驗中如何管理體重增加。

Yeah. Thomas, good morning. Good question. There's no formal management algorithm or treatment algorithm in the NATiV3 protocol. However, investigators are educated as to the mechanism. Generally, once they know that the protocol does allow them, if they choose to manage the weight gain, the fluid retention with the use of either diuretics or SGLT2s. Keep in mind, patients in this population are already on, many of them are already on diuretics for hypertension control, et cetera. So the providers have the opportunity to utilize therapeutics that may already be in use to manage, but there's no formal management algorithm that they're required to follow.

好的。Thomas，早安。好問題。NATiV3的試驗方案中沒有正式的管理流程或治療演算法。不過，研究者會被教育了解其作用機轉。一般而言，一旦他們了解機轉，且方案允許他們在需要時進行處置，他們可以選擇用利尿劑或SGLT2抑制劑來管理體重增加與液體滯留。請記得，這個族群的患者中，很多人本來就因為高血壓控制等原因已在使用利尿劑，等等。因此，醫療提供者有機會運用可能已在使用的治療來進行管理，但並沒有要求他們必須遵循的正式管理演算法。

Understood. Super helpful. Thanks, guys. Looking forward to the data.

了解。非常有幫助。謝謝各位。期待看到數據。

Michael Yee, UBS.

Michael Yee，瑞銀（UBS）。

Hey, guys. Good morning. This is Kyle Yang for Michael Yee. Just two for us. The first one is on the F2, F3 mix. So we did notice that NATiV3 enrolled a meaningfully higher proportion of F3 patients relative to NATIVE 2. So how do you expect that to impact both efficacy on the drug arms and placebo arm?

各位早安。早安。我是代Michael Yee提問的Kyle Yang。我們有兩個問題。第一個是關於F2、F3的組成比例。我們注意到，相較於NATIVE 2，NATiV3納入的F3患者比例明顯更高。你們預期這會如何影響藥物組與安慰劑組的療效表現？

The second question is on Group 1 droppings. So you previously disclosed roughly 10% Group 1 dropping rates during this study. How do you think that could potentially impact the outcomes on both the drug arms and placebo? Thank you.

第二個問題是關於第1組（Group 1）的退出（droppings）。你們先前披露本研究中第1組的退出率約為10%。你們認為這可能會如何影響藥物組與安慰劑組的結果？謝謝。

Yeah, absolutely. So let me just set the stage. I am going to hand it over to Jason to answer that. So on the F2, F3, the mix was indeed different in the Phase 3. We enrolled more patients in the US in the Phase 3 than we did in the Phase 2. And the patient population looks a little bit different in the US. There's more diabetes, and diabetes and F3 track together. So therefore, we had slightly more diabetic patients and slightly more F3 patients in the study. The -- we did look -- we have looked at our Phase 2 when next time we removed the F1 patients from our Phase 2.

好的，當然。我先鋪陳一下背景。我會把這題交給Jason回答。關於F2、F3的組成，第三期試驗的確不同。第三期我們在美國納入的患者比第二期更多。而美國的患者族群看起來也略有不同。糖尿病比例更高，而糖尿病與F3往往相伴。因此，我們在研究中有稍多的糖尿病患者，也有稍多的F3患者。另外——我們確實回頭看了第二期試驗，在下一次分析時把第二期中的F1患者移除。

We saw a slightly better response rate in the F2 and F3 combined than we saw in when it was combined with the F1, which gives us confidence that we are going into at least a drop in the F1s from the study will not impact the patient population. On -- I will have Jason comment in a second just on the split in F2 and F3. On the 10% drop-ins, it's actually 9% drop-ins on GLP-1s. We do not anticipate that to impact the trial as when they dropped in, they drop in on the non-MASH dose. They have dropped in on a lower dose. Jason, over to you.

我們看到F2與F3合併族群的反應率，略優於與F1合併時的反應率；這讓我們有信心，至少研究中F1比例下降不會影響患者族群的表現。至於——我稍後會請Jason就F2與F3的拆分再補充評論。關於10%的「加入」（drop-ins），其實是9%的受試者加入使用GLP-1。我們不預期這會影響試驗，因為他們加入時使用的是非MASH劑量。他們加入的是較低劑量。Jason，交給你。

Yeah. Thank you, Andrew. So just adding on to Andrew's response there around F2, F3. I agree. We don't have any expectation that the larger prevalence of F3 patients should impact the primary efficacy readout. I think three additional reasons. One, there's nothing in the biology of F2 or F3 disease that is different from each other. It's just a more advanced version of the exact same biology.

好的。謝謝你，Andrew。我補充Andrew剛才對F2、F3的回應。我同意。我們不預期F3患者比例較高會影響主要療效讀出（primary efficacy readout）。我認為還有三個額外原因。第一，F2與F3疾病在生物學上並沒有彼此不同之處。它只是同一套生物學機制更進展的版本。

I think second, that lanifibranor has direct anti-fibrotic actions to hepatic stellate cells in the liver. That direct action, meaning it does not depend on extra hepatic elements in order to achieve fibrosis. Things like weight loss or glucose metabolism, they are additive, but they are not required for fibrosis improvement. Third, the time duration of the trial actually will help to this extent. I think clearly, if the biology takes more time in an F3 patient to resolve, which is not unreasonable, a longer clinical trial should give us visibility into that. So we are pretty comfortable with that 18-month duration for NATiV3.

我認為第二點是，lanifibranor 對肝臟中的肝星狀細胞具有直接的抗纖維化作用。所謂直接作用，意思是它不需要依賴肝外因素就能達到纖維化改善。像是體重下降或葡萄糖代謝等因素是加成的，但並非纖維化改善所必需。第三，試驗的時間長度實際上將在這方面有所幫助。我認為很明顯，如果在 F3 病患身上生物學上的改善需要更多時間才能顯現（這並不不合理），那麼更長的臨床試驗應該能讓我們看得更清楚。因此，我們對 NATiV3 的 18 個月試驗期相當有信心。

And lastly, the FGF21 analogues like efruxifermin have shown similar efficacy in F2, F3, and I highlight them because those drugs, although very different mechanism of action, they actually have similar impact on both intra and extrahepatic drivers to some degree. So although not a complete overlap with pan-PPAR agonists, there are some elements that do, and I think that is support for the fact that by getting both direct action in the liver and modulating some extrahepatic drivers of disease, this difference between F2, F3 is unlikely to be a concern.

最後，像 efruxifermin 這類 FGF21 類似物在 F2、F3 中都顯示出相近的療效；我特別提到它們，是因為這些藥物雖然作用機轉非常不同，但在某種程度上對肝內與肝外的致病驅動因素都有類似的影響。因此，雖然與泛 PPAR 致效劑並非完全重疊，但確實有一些元素相同；我認為這支持了一個觀點：透過在肝臟內的直接作用，同時調節部分肝外的疾病驅動因素，F2 與 F3 之間的差異不太可能成為疑慮。

Annabel Samimy, Stifel.

Annabel Samimy，Stifel。

Hi. Thanks for taking my questions. I guess one question, with the patients on the GLP-1s and SGLT2s, are there any pre-specified analyses of these patients? And are any of those subgroups powered to show any kind of difference or statistical analysis on how those patients perform with that background of GLP-1s or SGLT2s? And I guess you touched on this before, but how you might account for any changes in the background mid-trial. And then how might that inform physicians on how to incorporate these drugs? Is there any specific protocol that you would be recommending going forward?

嗨。謝謝回答我的問題。我想問的是，對於使用 GLP-1 與 SGLT2 的病患，是否有任何預先指定（pre-specified）的分析？而且這些亞組是否有任何一組具備足夠的統計檢定力（powered），可以顯示差異或進行統計分析，來看在 GLP-1 或 SGLT2 背景用藥下這些病患的表現？另外我想你之前有提到，但你們會如何處理試驗進行中背景治療的變動？然後這會如何幫助醫師了解該如何把這些藥物納入治療？未來你們會建議任何特定的臨床流程或方案（protocol）嗎？

So on the -- thank you, Annabel, for the question. On the second, it is a little bit too early to comment on any sort of guidance to physicians by Inventiva post data. Let me go for the first part. Jason, let me hand it to you.

關於——謝謝你，Annabel，提出這個問題。第二個部分，現在要評論 Inventiva 在數據出來之後會給醫師什麼樣的指引，還稍微太早。我先回答第一個部分。Jason，我把問題交給你。

Sure. So there are several questions there. Let us go through it. Yes, there are sensitivity analyses that we have pre-specified in the SAP to allow us to look at the impact, if any. Again, as Andrew said, we do not expect any, but the analyses are there on the use of these non-MASH dose of GLP-1s and the use of SGLT2s. I think second, no, none of those groups are in any way powered. We are powered on our primary endpoint. That's the intent of the trial. As I have mentioned before, the power in detail there. Third, I think the important point I think we want to convey here is that there is nothing unusual or different that we are doing in this Phase 3 trial than any other sponsor in any other Phase 3 trial would do to account for therapeutic drop-ins.

好的。這裡面有好幾個問題。我們逐一來看。是的，我們在 SAP（統計分析計畫）中預先指定了敏感度分析（sensitivity analyses），讓我們可以評估（若有的話）其影響。同樣如 Andrew 所說，我們不預期會有影響，但分析已經納入，會針對這些非 MASH 劑量的 GLP-1 使用，以及 SGLT2 的使用進行評估。第二點，我想答案是否定的，這些族群沒有任何一組是以統計檢定力設計的。我們的檢定力是針對主要終點（primary endpoint）。這就是本試驗的目的。如我先前提過，我們在那裡已詳細說明檢定力。第三點，我認為我們想傳達的重點是：在這項第三期試驗中，為了處理治療「插入用藥」（therapeutic drop-ins），我們並沒有做任何不尋常或不同於其他任何贊助方在其他第三期試驗中會做的事情。

Even in the case of MASH, if you go back to Intercept's REGENERATE trial, the questions in that era were, what about statins and what about other antidiabetic drugs? Liraglutide had shown in the LEAN study that there was evidence that it could work. Pioglitazone. The answers there were the same answers here, that for any drop-in that may theoretically impact your concern for efficacy, sensitivity analyses are built in to give us and FDA confidence that the treatment effect we see is due to lanifibranor and not due to any other agent that may be dropped in during the course of the trial.

即使在 MASH 的情境下，如果你回頭看 Intercept 的 REGENERATE 試驗，當時大家問的是：那他汀類藥物怎麼辦？其他抗糖尿病藥物怎麼辦？在 LEAN 研究中，liraglutide 已顯示有證據可能有效。還有 pioglitazone。當時的回答與現在相同：對於任何可能在理論上影響你對療效疑慮的插入用藥，我們都會建立敏感度分析，讓我們以及 FDA 有信心，我們看到的治療效果是來自 lanifibranor，而不是來自試驗期間可能加入的其他藥物。

Okay, great. That's helpful. And if I can ask one more quick follow-up for Axel. How are you guys preparing for the launch, and have you laid out what kind of funds you might need for the launch?

好的，很棒。這很有幫助。如果我可以再快速追問 Axel 一個問題：你們正在如何為上市（launch）做準備？以及你們是否已規劃上市可能需要多少資金？

Axel, go ahead.

Axel，請。

Yeah, sure. Let's take a step back. We have done our capital transaction, as you all know, in June of this year, which gives us a solid funding until the end of Q2 2027. If we would have positive data, and we could, in addition, add the financing out of the structured financing Tranche 3 as well as the Tranche C out of the refinancing, we would extend that cash runway until the start of the beginning of Q1 2028.

好的，當然。我們先退一步看。如各位所知，我們在今年 6 月完成了資本交易（capital transaction），使我們有穩健的資金可支應到 2027 年第二季末。如果我們取得正面數據，並且另外能動用結構性融資（structured financing）的第 3 期款（Tranche 3），以及再融資（refinancing）中的 C 期款（Tranche C），我們就能把現金跑道延長到 2028 年第一季初。

So with that, we basically can fund the following catalysts. Point one, the data read out now in Q4. Point two, we are funded until the NDA filing. On top of that, we do not guide on any future raises. But with what we currently have, we believe we have strengthened the balance sheet, simplified the cap structure, prolonged the debt maturity. And with that, we are basically solidly financed prior to the data release.

因此，透過這些安排，我們基本上可以資助接下來的幾個關鍵催化事件（catalysts）。第一點，第四季的數據讀出（data readout）。第二點，我們的資金可支應到 NDA 申請遞交（filing）。此外，我們不對任何未來募資提供指引。但以我們目前的資源來看，我們相信已強化資產負債表、簡化資本結構、並延長債務到期日。因此，在數據發布之前，我們基本上已獲得相當穩健的資金支持。

Okay. Thank you.

好的。謝謝。

Prakhar Agrawal, Cantor.

Prakhar Agrawal，Cantor。

Hi. Thank you so much for taking my questions, and congratulations on all the progress. So maybe I had a couple of questions. Firstly, can you talk about the biopsy completion rate in the trial and whether that is tracking in line with some of the recent Phase 3 MASH trials? And a couple on weight gain. Maybe mechanistically, why does the weight gain plateau for lanifibranor and not for PPAR gamma pioglitazone?

嗨。非常感謝回答我的問題，也恭喜你們取得所有進展。我可能有幾個問題。首先，你們能談談試驗中的肝臟切片（biopsy）完成率，以及這是否與近期一些第三期 MASH 試驗的趨勢一致嗎？另外有幾個關於體重增加的問題。從機轉上來看，為什麼 lanifibranor 的體重增加會進入平台期（plateau），而 PPAR gamma 的 pioglitazone 不會？

And if I remember correctly, I think the company had previously shared interim weight gain data from the ongoing Phase 3 a couple of years back. Realize it was interim, but was a decent enough sample size. So why should not we use that as a reference for understanding what the weight gain profile could look like in the final analysis in the Phase 3? Thank you so much for taking my questions.

如果我沒記錯的話，我想公司先前在幾年前曾分享過正在進行的第三期試驗的期中（interim）體重增加數據。我知道那是期中資料，但樣本數也算足夠。那為什麼我們不應該把它當作參考，用來理解第三期最終分析中體重增加的可能樣貌？非常感謝回答我的問題。

Yeah. So thank you for the questions, Prakhar. So let me -- I shall address the, you asked about a biopsy completion rate. What we have guided on publicly is a dropout rate for the trial overall. So we powered the trial such that we could tolerate up to a 30% dropout rate in the trial. We have guided in, we believe it was April and May 2005, that dropout rate was below 30%, and we confirmed that that dropout rate is comfortably below 30% at that time. We are not giving more guidance beyond that.

好的。謝謝你的問題，Prakhar。我先——我來回應你問到的肝臟切片完成率。我們對外公開提供的指引是整體試驗的退出率（dropout rate）。因此，我們在試驗設計的檢定力規劃上，是以可承受最高 30% 的退出率為前提。我們曾在公開指引中提到，我們相信是在 2005 年 4 月與 5 月，當時退出率低於 30%，並且我們也確認在那個時間點退出率明顯低於 30%。除此之外，我們不再提供更多指引。

Regarding the weight gain, you had a question about the plateau and the difference pioglitazone. We are hoping Jason picked it up to be able to talk about both those points. Jason, go ahead.

關於體重增加，你問到平台期以及與吡格列酮（pioglitazone）的差異。我們希望 Jason 已經接到這個問題，能夠同時談到這兩點。Jason，你請。

Yeah, we agree. Prakhar, we will come back to the reference. We missed that. But on the question of plateau, our view is that it is a combination of the partial PPAR gamma component of lanifibranor, so not a full agonist. And that has important consequences for long-term activation of that sodium channel. And second, and more importantly, the pan-PPAR antagonism brings the alpha and delta components online, and they work to increase not to. The gamma will increase glucose storage via improved insulin sensitization, but the alpha and delta actually get to improved utilization of glucose by tissue. And that utilization actually prevents that sugar from being stored, and that you get a sort of metabolic pop from that alpha delta, which helps to keep the scale weight plateauing over time. Again, Prakhar, if you could just get to the last question, the reference part of it, we missed it.

是的，我們同意。Prakhar，我們會回到你提到的參考資料。我們剛剛漏掉了那一段。但就平台期這個問題，我們的看法是，這是 lanifibranor 的部分 PPAR gamma 成分所致，因此它不是完全致效劑（full agonist）。而這對該鈉通道的長期活化有重要影響。第二點，而且更重要的是，pan-PPAR 拮抗作用會把 alpha 與 delta 成分帶上來，而它們的作用是提高（而不是不提高）。Gamma 會透過改善胰島素敏感性來增加葡萄糖儲存，但 alpha 與 delta 實際上會改善組織對葡萄糖的利用。而這種利用會防止糖分被儲存起來；同時 alpha/delta 會帶來某種代謝上的提升，幫助體重秤上的數字隨時間維持在平台期。再一次，Prakhar，如果你能把最後一個問題，也就是參考資料那部分再說一下，我們剛剛漏掉了。

Yeah. If we remember correctly, a couple of years back, the company had previously shared blinded interim weight gain data, so on a pooled basis from the ongoing Phase 3. So it was interim, but we thought it was a very large sample size. So why shouldn't we use that as a reference for understanding the weight gain profile and the plateau effect and the time point of it for the final analysis in Phase 3? Thank you so much.

好的。如果我沒記錯的話，幾年前公司曾分享過盲態的期中體重增加資料，是來自正在進行的第 3 期試驗、以合併（pooled）方式呈現。所以那是期中資料，但我們認為樣本數非常大。那為什麼我們不應該把它當作參考，用來理解第 3 期最終分析時的體重增加特徵、平台效應以及其發生時間點呢？非常感謝。

Sure. So you are correct, Prakhar, that several years ago, something like that was done. I think just correcting language, it was no interim read of anything. It was an early look at approximately 100 blinded patients that have achieved week 72. I think to the extent that anyone on the outside world took comfort or not in that, I think those days are in the past. You ask, why do not we do that again? It is our view that utilizing blinded data from a 1,000-plus patient clinical trial is fraught with error of interpretation, and it's not something that we think would be helpful. It is more importantly, not something that we are guiding on regardless.

當然。所以你說得沒錯，Prakhar，幾年前確實做過類似的事情。我想只是修正一下用語，那並不是任何期中讀出（interim read）。那是對大約 100 名已達到第 72 週的盲態受試者所做的早期觀察。我想，外界當時是否因此感到安心或不安心，那些日子已經過去了。你問為什麼我們不再做一次？我們的看法是，在一項 1,000 名以上受試者的臨床試驗中使用盲態資料，解讀上很容易出錯，因此我們不認為那會有幫助。更重要的是，無論如何，我們也不會就此提供指引（guidance）。

Got it. Thanks for clarifying.

了解。謝謝澄清。

Srikripa Devarakonda, Truist Securities.

Truist Securities 的 Srikripa Devarakonda。

Hi, guys. Thank you so much for taking my question and congratulations on all the progress end of year. So I have a question on fibrosis expectations. How much importance should we place on not hitting the stat sig endpoint, but on the magnitude of fibrosis improvement independent of the MASH resolution? You talked earlier about lanifibranor's antifibrotic effect. So what level of response would convince you that this is a meaningful antifibrotic effect rather than improving metabolic inflammatory component of the disease? Thank you.

嗨，各位。非常感謝讓我提問，也恭喜你們在年底前取得的所有進展。我想問的是纖維化（fibrosis）的預期。對於沒有達到統計顯著（stat sig）終點這件事，我們應該放多大比重；相較之下，纖維化改善的幅度（不依賴 MASH 緩解）又應該如何看待？你們先前談到 lanifibranor 的抗纖維化效果。那麼，什麼程度的反應會讓你們相信這是一個有意義的抗纖維化效果，而不只是改善疾病的代謝性發炎成分？謝謝。

So Kripa, let me -- I think I understand the question. So we are -- we believe 18% improvement is meaningful in fibrosis to basically duplicating our Phase 2 into Phase 3. With that profile, with an 18% improvement of one stage or more in fibrosis, that is a secondary endpoint for us. We believe that we have those three segments that I discussed, the F3 diabetics or high cardiometabolic risk, the F3 non-diabetics, and the F2 diabetics as segments where that profile is an 18% fibrosis effect, this would be a differentiated product for those patients.

Kripa，我來回答——我想我理解你的問題。我們——我們認為纖維化改善 18% 是有意義的，基本上等同於把我們第 2 期的結果在第 3 期中再現。以這樣的表現來看，纖維化改善一個分期（stage）或以上、達到 18% 的改善，對我們而言是一個次要終點（secondary endpoint）。我們認為我先前提到的三個族群——F3 糖尿病患者或高心代謝風險者、F3 非糖尿病患者，以及 F2 糖尿病患者——在這些族群中，如果能呈現 18% 的纖維化效果，對這些患者而言將會是一個具差異化的產品。

Thank you.

謝謝。

Rami Katkhuda, LifeSci Capital.

LifeSci Capital 的 Rami Katkhuda。

Hi, guys. Thanks for taking my questions as well. Maybe going off a comment Jason made earlier, can you touch on the time course of lanifibranor-associated weight gain, particularly the timing of early fluid retention versus later adipose remodeling and when each typically plateaus?

嗨，各位。也謝謝讓我提問。延續 Jason 先前的一個評論，你們能否談談 lanifibranor 相關體重增加的時間進程（time course），特別是早期液體滯留（fluid retention）與後期脂肪組織重塑（adipose remodeling）的時間點，以及各自通常何時進入平台期？

And then secondly, I know it is a bit early, but how are you thinking about the design of the confirmatory outcomes trial? Are there any key learnings from ongoing studies that could help inform patient selection?

第二個問題，我知道現在可能還有點早，但你們如何思考確認性結局試驗（confirmatory outcomes trial）的設計？是否有任何正在進行的研究中的關鍵學習，可用來幫助病人篩選（patient selection）？

Yeah, thanks, Rami. So two questions there just on the time course, which I am just going to preempt it. We cannot really say much more than we have already said on this call. I think we have answered that question pretty thoroughly. So maybe we could focus Jason on the F4 and the confirmatory study and what we are thinking there.

好的，謝謝你，Rami。這裡有兩個問題，先談時間進程——我先預先說明一下。我們其實無法比今天電話會議上已經說過的內容再多說什麼。我想我們已經相當完整地回答了那個問題。所以也許我們可以請 Jason 聚焦在 F4 與確認性研究，以及我們在那方面的想法。

Yeah, I am happy to. I think, look, we are looking forward to talking more about the confirmatory study after top line. But I think for now, what we are trying to communicate is, one, that we will be focused on this CACLD, chronic advanced compensated liver disease population, those with clinically significant portal hypertension. We know now that there are very good ways to assess and identify these patients in the wild using non-invasive methodologies like a combination of liver stiffness measurements and platelets. They are captured in criteria that providers use routinely in the care of patients with advanced liver disease. So the inclusion of patients with clinically significant portal hypertension is the goal.

好的，我很樂意。我想，你看，我們期待在頂線結果（top line）之後，再更深入談確認性研究。但目前我們想傳達的是：第一，我們會聚焦在 CACLD，也就是慢性進展期代償性肝病（chronic advanced compensated liver disease）族群，也就是具有臨床顯著門脈高壓（clinically significant portal hypertension）的患者。我們現在知道，在真實世界中有非常好的方法可以用非侵入性方式評估並辨識這些患者，例如結合肝臟硬度測量（liver stiffness measurements）與血小板（platelets）。這些也已納入醫療提供者在照護進展期肝病患者時例行使用的標準中。因此，納入具有臨床顯著門脈高壓的患者是我們的目標。

Second, you ask what evidence might we have from our clinical program that will inform that trial. Good question. The exploratory cohort I mentioned during the scripted portion of the call, we have approximately 75 to 100 cirrhotic patients in that trial that will have been exposed to lanifibranor for at least 18 months, and if they complete the active treatment extension, they could be on for up to 4 years. We think that those data from a safety and tolerability perspective and pharmacology will be helpful.

第二，你問我們的臨床計畫中有哪些證據可以用來指引該試驗。這是個好問題。我在電話會議預先準備的部分提到的探索性隊列（exploratory cohort），該試驗中大約有 75 到 100 名肝硬化患者（cirrhotic patients），他們將至少接受 lanifibranor 暴露 18 個月；如果他們完成主動治療延伸（active treatment extension），用藥時間最多可達 4 年。我們認為，從安全性與耐受性（tolerability）以及藥理學（pharmacology）的角度來看，這些資料會很有幫助。

And lastly, we have completed nearly a dozen Phase 1 clinical trials with lanifibranor over the years, including dedicated hepatic impairment study in patients with Child-Pugh A, B, and C. And the results of those studies, although we have not published them, we are comfortable and confident around the safety of the drug in those Phase 1 trials at the doses we are presently using.

最後，我們多年來已完成將近一打的 lanifibranor 第 1 期臨床試驗，包括一項針對 Child-Pugh A、B、C 患者的肝功能不全（hepatic impairment）專門研究。雖然我們尚未發表這些研究結果，但就目前使用的劑量而言，我們對於該藥在這些第 1 期試驗中的安全性是安心且有信心的。

And when combined with that exploratory cohort of about 75 to 100 patients, we think we will have a really good opportunity to build and conduct a strong outcomes trial in this CACLD population.

而且，若再結合約 75 到 100 名患者的探索性隊列，我們認為將有非常好的機會在這個 CACLD 族群中建立並執行一項強而有力的臨床結局試驗。

Awesome. Thank you, guys.

太棒了。謝謝各位。

Sushila Hernandez, Van Lanschot Kempen.

Sushila Hernandez，Van Lanschot Kempen。

Hi, this is Zoe on for Sushila. Thank you so much for taking our question. So with the lanifibranor Phase 3 NATiV3 top line readout in MASH expected in the next quarter, we were wondering what kind of data we can expect at the top line. So will there be data on the treatment response in patients on GLP-1 and on SGLT inhibitor or on the weight gain? And then if I could just ask another question, we're also wondering how do you expect the placebo response to evolve with the longer treatment duration? Thank you.

嗨，我是 Zoe，代替 Sushila 發言。非常感謝你們回答我們的問題。關於 lanifibranor 在 MASH 的第三期 NATiV3 試驗，預計在下一季公布主要（top-line）結果，我們想了解在 top-line 層級可以期待看到哪些數據。例如，是否會有關於使用 GLP-1 與 SGLT 抑制劑患者的治療反應數據，或是體重增加方面的數據？另外如果我可以再問一個問題，我們也想了解，隨著治療期間拉長，你們預期安慰劑反應會如何變化？謝謝。

Great. Thank you, Zoe, for the question. We are not guiding on the top-line data right now. I think as you can tell on this call, we are very well aware of the interest in the endpoints and the tolerability profile elements I'm sure people are interested in seeing. And I'm sure we will be looking to address a lot of the questions that were on the call today. However, we're not yet guiding on what's in that readout.

好的。謝謝你，Zoe，提出這個問題。我們目前不會就 top-line 數據提供指引。我想各位從這通電話也能感受到，我們非常清楚大家對於終點指標以及耐受性特徵等要素的關注與期待。我也相信我們會希望回應今天電話會議中提出的許多問題。不過，我們目前尚未就該次讀出內容提供指引。

In terms of the placebo response, the composite endpoint was deliberately chosen as a primary endpoint, as it controls better for placebo response. It's very difficult for a placebo patient to achieve resolution by themselves on fibrosis and all the clinical endpoints of MASH. Therefore, that was why that placebo rate was chosen. Really, I'm not going to speculate on what the placebo rate will be after an 18-month trial versus a 6-month trial, but certainly it's our expectation that having that composite endpoint does help mitigate any fluctuation in placebo rates.

至於安慰劑反應，之所以刻意選擇複合終點作為主要終點，是因為它能更好地控制安慰劑反應。安慰劑組患者很難僅靠自身就同時在纖維化以及 MASH 的所有臨床終點上達到緩解。因此，這也是選擇該安慰劑比率假設的原因。我不會推測 18 個月試驗相較於 6 個月試驗的安慰劑比率會是多少，但我們確實預期，採用該複合終點有助於緩解安慰劑比率的任何波動。

Yeah. Okay. Thank you so much.

好的。了解。非常感謝。

Andy Chen, Wolfe Research.

Andy Chen，Wolfe Research。

Hi. Thank you so much. This is Jason taking it for Andy, and we just wanted to ask another question about GLP-1. And do you guys think the baseline GLP-1 subgroup is large enough to meaningfully assess whether lanifibranor provides incremental histological benefits on top of the therapy? And how would that sensitivity analysis be presented? If you could provide some color on that. Thank you.

嗨。非常感謝。我是 Jason，代替 Andy 提問，我們想再問一個關於 GLP-1 的問題。你們認為基線時使用 GLP-1 的亞組樣本量是否足夠大，能夠有意義地評估 lanifibranor 在既有治療之上是否能帶來額外的組織學獲益？另外，這類敏感性分析會如何呈現？如果可以的話，請提供一些說明。謝謝。

Yeah. So first of all, clarification, the GLP-1s drop-ins that were allowed in the trial were not at the MASH dose. So they were at a lower dose. So there should be no histological impact of the GLP-1 on the GLP-1. So I think that in terms of doing a subset analysis, I think that answers the question that we don't anticipate that there should be a histological effect of the GLP-1.

好的。首先澄清一下，本試驗允許加入（drop-in）的 GLP-1 並非使用於 MASH 的劑量。而是較低的劑量。因此，GLP-1 不應該對組織學產生影響。所以我認為，就子集分析而言，這也回答了你的問題：我們不預期 GLP-1 會帶來組織學上的影響。

Jason, would you add anything to that?

Jason，你要補充什麼嗎？

No, I do, Andrew. Andy, a good question. Just referring you back to earlier in the Q&A around the sensitivity analyses and that this question, the form of the question, how is it that other therapeutics that are dropped into a late-stage clinical trial may affect the primary endpoint? This is routinely handled in Phase 3 trials, not only outside, like in atopic dermatitis and use of steroids, but also within MASH. So the sensitivity analyses that we will run are completely routine and standard for a Phase 3 program facing those kinds of questions.

沒有，我同意，Andrew。Andy，這是個好問題。我想請你回顧一下先前 Q&A 中關於敏感性分析的討論：也就是在後期臨床試驗中加入其他治療用藥，可能如何影響主要終點的這類問題。這在第三期試驗中是例行處理的，不僅在 MASH 以外的領域（例如異位性皮膚炎中使用類固醇），在 MASH 領域內也是如此。因此，我們將執行的敏感性分析，對於面對這類問題的第三期計畫而言，完全是例行且標準的做法。

Got you. Thank you.

了解。謝謝。

Thank you. There are no further questions at this time, so I will hand the call back to Andrew for closing remarks.

謝謝。目前沒有其他問題，我將把電話交回 Andrew 作結語。

Yeah, I want to thank everyone for joining today and for the questions. Inventiva is at an inflection point right now. We are very excited to be approaching the top-line results in Q4 this year and the potential to bring a therapy forward for a large patient population with a large unmet need and bring a new therapy option. So thank you, everyone, for your interest, and we will see you, I think the next time we talk will be on the data release. Thank you.

好的，我想感謝各位今天參與以及提出的問題。Inventiva 目前正處於一個關鍵轉折點。我們非常期待在今年第四季接近 top-line 結果的公布，並有機會推進一項治療，服務龐大且仍有高度未被滿足醫療需求的患者族群，帶來新的治療選擇。因此，感謝各位的關注；我想我們下次再交流，應該就是在數據發布時。謝謝。

This concludes today's conference call. Thank you for participating. You may now disconnect.

今天的電話會議到此結束。感謝各位參與。您現在可以掛線。