Madrigal Pharmaceuticals Inc (MDGL) 2022 Q1 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Madrigal Pharmaceuticals First Quarter 2022 Conference Call. (Operator Instructions) As a reminder, this call may be recorded. I would now like to introduce your host for today's conference, Dr. Paul Friedman, Chairman and Chief Executive Officer of Madrigal. Dr. Friedman, you may begin.

女士們、先生們，美好的一天，歡迎參加 Madrigal Pharmaceuticals 2022 年第一季電話會議。 （操作員說明）謹此提醒，此通話可能會被錄音。現在我想介紹一下今天會議的主持人，Madrigal 董事長兼執行長 Paul Friedman 博士。弗里德曼博士，您可以開始了。

Thank you. Good morning, and thanks to all of you for joining us on the call. Here's the fine print dealing with our forward-looking statements. Please see today's press release and our SEC filings for forward-looking statement and risk factor considerations associated with these statements and our business. With me on today's call are Becky Taub, President of R&D and Chief Medical Officer; Remy Sukhija, Chief Commercial Officer; and Alex Howarth, Chief Financial Officer.

謝謝。早安，感謝大家加入我們的電話會議。以下是有關我們前瞻性陳述的細則。請參閱今天的新聞稿和我們向 SEC 提交的文件，以了解前瞻性聲明以及與這些聲明和我們的業務相關的風險因素考慮因素。與我一起參加今天電話會議的是研發總裁兼首席醫療官 Becky Taub；蘇希賈 (Remy Sukhija)，商務長；和財務長 Alex Howarth。

We also have Dr. Stephen Harrison joining us to provide his perspective on the MAESTRO program updates we're announcing today. This morning, we issued a press release outlining a number of important clinical development program updates, including the acceptance of 4 resmetirom abstracts as oral presentations at EASL's International Liver Congress next month additional positive data from the Phase III MAESTRO-NAFLD-1 safety study and a new outcomes trial that will evaluate resmetirom for the treatment of NASH patients with compensated cirrhosis.

Stephen Harrison 博士也加入我們，就我們今天宣布的 MAESTRO 計劃更新提供他的觀點。今天早上，我們發布了一份新聞稿，概述了許多重要的臨床開發計畫更新，包括在下個月的EASL 國際肝臟大會上接受4 份瑞美羅摘要作為口頭報告，來自III 期MAESTRO-NAFLD-1安全性研究的額外正面數據，以及一項新的結果試驗將評估瑞美羅治療代償性肝硬化 NASH 患者的效果。

We also announced that Madrigal secured a term loan facility, which puts us in a strong financial position for the road ahead. The decision to expand our clinical development program and raise additional capital reflects our conviction in the potential of resmetirom to be a transformational therapy for patients with NASH. The emerging data for MAESTRO-NAFLD-1 safety study including the results we're announcing today continue to support that conviction, and we look forward to sharing additional data in our late-breaker presentation at EASL.

我們還宣布 Madrigal 獲得了定期貸款融資，這使我們在未來的道路上處於強大的財務狀況。擴大我們的臨床開發計劃並籌集額外資金的決定反映了我們對瑞美羅姆成為 NASH 患者變革療法的潛力的信念。 MAESTRO-NAFLD-1 安全性研究的新數據（包括我們今天宣布的結果）繼續支持這一信念，我們期待在 EASL 的最新演示中分享更多數據。

Now Becky is going to review the design of the new MAESTRO-NASH outcome study in more detail in a few minutes, but I'd like to say a few words about the medical and commercial rationales for the study.

現在，貝基將在幾分鐘內更詳細地回顧新的 MAESTRO-NASH 結果研究的設計，但我想談談該研究的醫學和商業原理。

First, -- and I think fairly obviously, patients with compensated cirrhosis are at significantly elevated risk of progressing to negative clinical outcomes, and there's a high unmet need for an approved therapy to treat these patients. Second, resmetirom has been well tolerated in this population and early efficacy results are quite encouraging. Third, we believe this study can be conducted in a timely manner, and since in this more advanced population, events will accrue faster, it can provide an alternative path to an early full approval in noncirrhotic NASH than our ongoing clinical outcome studies in MAESTRO-NASH. And finally, by substantially expanding the NASH market opportunity to include patients with compensated cirrhosis to therapeutic and commercial value of resmetirom for Madrigal and potential business development partners should be strengthened.

首先，我認為很明顯，代償性肝硬化患者進展為陰性臨床結果的風險顯著升高，並且對治療這些患者的批准療法的需求很高，但未得到滿足。其次，瑞美羅在該族群中具有良好的耐受性，早期療效結果非常令人鼓舞。第三，我們相信這項研究可以及時進行，並且由於在這個更先進的人群中，事件發生的速度會更快，因此與我們正在進行的MAESTRO 臨床結果研究相比，它可以為非肝硬化NASH的早期完全批准提供另一種途徑-納什。最後，透過大幅擴大 NASH 市場機會，將代償性肝硬化患者納入 Resmetirom 的治療和商業價值，對於 Madrigal 和潛在的業務開發合作夥伴來說，應該得到加強。

As we've gained increasing confidence that we'll achieve both NASH resolution and the fibrosis improvement end points in the MAESTRO-NASH biopsy study, we are moving 1-point fibrosis reduction up the hierarchy to a primary endpoint along with NASH resolution. The dual primary end points now for MAESTRO-NASH, NASH resolution without worsening of fibrosis or fibrosis improvement without worsening of NASH. And while we fully expect to achieve both endpoints making either endpoint is compatible with the subpart H NDA submission according to FDA's draft guidance.

隨著我們越來越有信心在 MAESTRO-NASH 活檢研究中實現 NASH 消退和纖維化改善終點，我們正在將 1 點纖維化減少與 NASH 消退一起提升到主要終點。 MAESTRO-NASH 現在的雙重主要終點是 NASH 消退而不惡化纖維化或纖維化改善而不惡化 NASH。雖然我們完全期望實現這兩個終點，但根據 FDA 的指南草案，任一終點都與 H NDA 子部分提交的內容相容。

Importantly, our planned MAESTRO-NASH outcome study and the move to a dual primary endpoint in the biopsy study do not alter our time line assumptions for readout of the biopsy study in Q4 for subpart H NDA submission in non-cirrhotic NASH next year. The term loan financing we announced today will help fund the expansion of the resmetirom clinical development program and reinforces Madrigal's solid financial position.

重要的是，我們計劃的MAESTRO-NASH 結果研究和活檢研究中向雙重主要終點的轉變不會改變我們在第四季度讀出活檢研究的時間線假設，以提交明年非肝硬化NASH 的H 子部分NDA。我們今天宣布的定期貸款融資將有助於為 resmetirom 臨床開發計劃的擴展提供資金，並鞏固 Madrigal 穩健的財務狀況。

As of March 31, Madrigal had cash, cash equivalents and marketable securities of $220 million an additional $50 million of drawn at closing of the new loan agreement, Alex will share additional details shortly. As we noted in our press release, MAESTRO and NAFLD-1 double-blind data were submitted as a late-breaking abstract to EASL and accepted as an oral presentation at the International Liver Congress next month. So while we'd like to share the full data set with you, we're not going to be able to provide you with any additional data beyond today's update because the data are now under embargo. Our team is looking forward to EASL, the first major in-person hepatology conference since 2011. I'd like to thank our R&D team for the work they've done in generating multiple accepted abstracts for the meeting, including the MAESTRO-NAFLD-1 late-breaker. We'll be conducting an investor event after the new data are presented at EASL-- so please reach out to us if you plan to be in London for the meeting. And now I'll turn the call over to Becky.

截至 3 月 31 日，Madrigal 擁有 2.2 億美元的現金、現金等價物和有價證券，並在新貸款協議結束時額外提取 5000 萬美元，亞歷克斯將很快分享更多細節。正如我們在新聞稿中指出的，MAESTRO 和 NAFLD-1 雙盲數據作為最新摘要提交給 EASL，並在下個月的國際肝臟大會上被接受作為口頭報告。因此，雖然我們希望與您分享完整的數據集，但我們無法向您提供今天更新之外的任何其他數據，因為這些數據現在處於禁運狀態。我們的團隊期待 EASL，這是自 2011 年以來的第一次大型面對面肝病學會議。遲到者。在 EASL 上公佈新數據後，我們將舉辦投資者活動 - 因此，如果您計劃前往倫敦參加會議，請與我們聯繫。現在我將把電話轉給貝基。

Good morning. So on Slide 7, Here's a summary of the data that we've presented at the January 31 webcast when we announced the top line data from MAESTRO-NAFLD. Resmetirom was safe and well tolerated, the top dose of 100 milligrams as well as 80 milligrams in MAESTRO-NAFLD. Key secondary endpoints in MAESTRO-NAFLD are both aiming a 100-milligram in those groups, including PDFF, LDL cholesterol, ApoB and triglyceride reductions, which are consistent with the parallel randomized 100-milligram open-label arm that had been from the same study that had been presented at AASLD in earlier in November 2021.

早安.在投影片 7 中，這是我們在 1 月 31 日網路廣播中公佈的數據摘要，當時我們宣布了 MAESTRO-NAFLD 的頂線數據。 Resmetirom 安全且耐受性良好，最高劑量為 100 毫克，MAESTRO-NAFLD 的最高劑量為 80 毫克。 MAESTRO-NAFLD 的關鍵次要終點均針對這些組別中的 100 毫克劑量，包括 PDFF、LDL 膽固醇、ApoB 和三酸甘油酯降低，這與來自同一研究的平行隨機 100 毫克開放標籤組一致已於2021 年11月稍早在AASLD 上提出。

The safety and efficacy of the study are in line with the expectations from the Phase II liver biopsy study and the randomized parallel open-label 100-milligram arm of MAESTRO-NAFLD. And positive results from this trial support our conviction that resmetirom has the potential to be the first medication approved for the treatment of NASH patients with liver fibrosis.

研究的安全性和有效性符合 II 期肝臟切片研究和 MAESTRO-NAFLD 隨機平行開放標籤 100 毫克組的預期。這項試驗的積極結果支持了我們的信念，即瑞美羅有可能​​成為第一個被批准用於治療肝纖維化 NASH 患者的藥物。

Next slide. Now there will be multiple presentations of Madrigal's program data at EASL's International Liver Congress, including a late-breaking presentation primary data analysis of MAESTRO-NAFLD, 52-week double-blind placebo-controlled Phase III clinical trial of resmetirom in patients with NAFLD. We will also be presenting 3 other oral abstracts the impact of resmetirom mediated reductions in liver volume and steatosis compared with placebo on the quantification of fibrosis using second harmonic generation in a serial liver biopsy. This refers to a technique using artificial intelligence to read fibrosis on the liver biopsy slides. We will present an abstract utility of FIB-4 thresholds to identify patients with at-risk F2-F3 NASH based on screening data from a 2,000-patient liver biopsy. Cohort of our Phase III clinical trial, MAESTRO-NASH, and a fourth presentation, biomarkers, imaging and safety in a well-compensated NASH cirrhotic cohort treated with resmetirom, a thyroid hormone receptor beta agonist for 52 weeks.

下一張投影片。現在，Madrigal 的計畫數據將在EASL 的國際肝臟大會上進行多次演示，包括MAESTRO-NAFLD 的最新演示主要數據分析，這是一項為期52 週的瑞美替羅治療NAFLD 患者的雙盲安慰劑對照III 期臨床試驗。我們還將介紹另外 3 篇口頭摘要，介紹瑞美羅介導的肝臟體積和脂肪變性減少與安慰劑相比對連續肝臟活檢中使用二次諧波生成量化纖維化的影響。這是指使用人工智慧讀取肝臟切片載玻片上的纖維化情況的技術。我們將根據 2,000 名患者肝臟活檢的篩檢數據，提出 FIB-4 閾值的抽象實用程序，用於識別高風險 F2-F3 NASH 患者。我們的III 期臨床試驗隊列，MAESTRO-NASH，以及第四次演示，在補償良好的NASH 肝硬化隊列中使用瑞美羅（一種甲狀腺激素受體β 激動劑）治療52 週的生物標記、影像學和安全性。

And we also have 2 posters: one, looking at the Association of FIB-4 with health care costs and a second using a different AI methodology to review our slides, it confirms the significant treatment induced changes in histologic features of NASH from our Phase II study. There's an additional satellite symposium, which will discuss identifying, managing and treating patients with NASH in significant fibrosis. So on the next slide, Slide 9, additional data from the MAESTRO-NAFLD trial as Dr. Friedman mentioned detailed results of this trial are under Argo until the late-breaking presentation at EASL.

我們還有2 張海報：一張是FIB-4 與醫療保健成本的關聯，第二張是使用不同的AI 方法來審查我們的幻燈片，它證實了II 期治療引起的NASH 組織學特徵的顯著變化學習。還有一個額外的衛星研討會，將討論識別、管理和治療患有嚴重纖維化的 NASH 患者。因此，在下一張投影片（投影片 9）中，Friedman 博士提到的 MAESTRO-NAFLD 試驗的其他數據在 Argo 下，直到 EASL 上的最新演示為止。

However, we will focus on some of the important results here, similar to what was reported for the 100-milligram open-label arm in November of 2021. Patients in the parallel arms 80-milligram and 100-milligram treated with resmetirom, achieved reductions from baseline in ALT that P equals 0.002 and less than 0.0001 relative to placebo. Transient ALT increases that were greater than 3x the upper limit of normal occurred in 0.61% in the resmetirom 80-milligram group, 0.31% in the 100-milligram group and 1.6% of patients in the placebo group indicating that, if anything, there was a lower increase in patients treated with resmetirom.

然而，我們將在這裡重點關註一些重要的結果，類似於 2021 年 11 月報道的 100 毫克開放標籤組的結果。來看，相對於安慰劑，P 等於0.002 且小於0.0001。 resmetirom 80 毫克組、100 毫克組和安慰劑組分別有 0.61%、0.31% 和 1.6% 的患者出現短暫 ALT 升高超過正常上限 3 倍的情況，這表明，如果有的話，接受瑞美羅治療的患者數量增幅較低。

And this was across the entire 52 weeks of the study. treatment emergent adverse events of greater than Grade 3, greater than or equal to Grade 3 occurred in 7.6% of patients in the resmetirom 80 mg, 9% in the 100 mg group and 9.1% in the placebo group.

這貫穿了整個 52 週的研究。治療中出現的大於3級、大於或等於3級的不良事件發生率在resmetirom 80 mg組為7.6%，在100 mg組為9%，在安慰劑組為9.1%。

This was data that we also presented in January withdrawals due to adverse events were very low in the study. 2.4% in the 80-milligram group, 2.8% in the 100-milligram group and 1.3% in the placebo group. The GI-related adverse events that we had shown at the end of January were increased in the drug arms relative to placebo. Further analysis has shown that these increases in GI adverse events, diarrhea and nausea, did not occur after the first few weeks of therapy.

這是我們在一月份提供的數據，該研究中由於不良事件而退出的比例非常低。 80 毫克組為 2.4%，100 毫克組為 2.8%，安慰劑組為 1.3%。我們在一月底顯示的與胃腸道相關的不良事件在藥物組中相對於安慰劑增加。進一步的分析表明，胃腸道不良事件（腹瀉和噁心）的增加並沒有在治療的最初幾週後發生。

Next slide, Slide 10. Endpoints related to a fiber scan were evaluated in the study. Patients had a screening or prescreening FibroScan that then allow them to screen for the study based on the cap and kPa values. And then they had a second FibroScan at week 52. The FibroScan CAP score, which is reflective of hepatic fat, were statistically significantly reduced p<0.0001 in the resmetirom arm as compared with placebo. FibroScan, liver stiffness reductions were presented for the 100-milligram open-label arm in November of 2021 and showed a marked reduction from baseline and these reductions were similar in the 100-milligram open-label and double-blind arms. Responder analyses of the fiber scan VCTE reduction or kPa reduction and percent reduction from baseline comparing resmetirom 100-milligram open-label and the 2 double-blind arms with placebo showed a significant increase in responders in the treatment arm around 44%.

下一張投影片，投影片 10。患者接受了 FibroScan 篩檢或預篩檢，然後根據上限和 kPa 值篩選研究。然後他們在第 52 週進行了第二次 FibroScan。 FibroScan 於 2021 年 11 月提出了 100 毫克開放標籤組的肝臟硬度降低情況，顯示較基線顯著降低，且這些降低在 100 毫克開放標籤組和雙盲組中相似。纖維掃描VCTE 降低或kPa 降低以及相對於基線的降低百分比的應答者分析，比較resmetirom 100 毫克開放標籤和2 個雙盲組與安慰劑相比，顯示治療組中的應答者顯著增加約44% 。

Average across resmetirom arms compared with the placebo, and this was statistically significant. There appeared to be some dose relationship between the 180-milligram doses in this study. If we examine the mean reduction in FibroScan liver stiffness in the resmetirom double-blind arms. These were numerically greater than placebo but not statistically significant in this study.

瑞美羅治療組與安慰劑組的平均值相比，具有統計學意義。本研究中 180 毫克劑量之間似乎存在某種劑量關係。如果我們檢查 Resmetirom 雙盲組中 FibroScan 肝臟硬度的平均減少。這些在數值上大於安慰劑，但在本研究中不具有統計意義。

I will note also at this point that the threshold for a eligible FibroScan was 7.2 kPa, which is consistent with approximately F1 to F2 fibrosis stage compared to liver biopsy historically in the literature, and this was a fraction of the patients in the MAESTRO-NAFLD study, which was in general, an earlier population in MAESTRO-NASH. MRE responders as measured by kPa reduction. We're also significantly greater in resmetirom treated groups compared with placebo and showed a similar level of responders in all resmetirom dose arms.

此時我還要指出，合格 FibroScan 的閾值為 7.2 kPa，與文獻中歷史上的肝臟活檢相比，這與大約 F1 至 F2 纖維化階段一致，並且這是 MAESTRO-NAFLD 患者的一小部分研究，總的來說，MAESTRO-NASH 中的早期人群。 MRE 響應者以 kPa 降低來衡量。與安慰劑相比，瑞美羅治療組的反應率也明顯較高，且所有瑞美羅劑量組的反應水準相似。

So that would be 100-milligram open-label, 100-milligram, double line and 80-milligram double-blind arm showed a similar reduction in MRE and this was in patients who had at least a 2.9 kPa at baseline. The intrinsic variability of FibroScan 35% to 40% in the -- which has been confirmed many times in the literature, limited use as a sole measure to diagnose or follow NASH patients, but it is an excellent office space enrichment test and it was an excellent enrichment test In both of our MAESTRO studies, enabling us to rule out patients without significant fibrosis and identify potential NASH fibrosis patients.

因此，100 毫克開放標籤、100 毫克雙線和 80 毫克雙盲組顯示出類似的 MRE 降低，而且這是在基線至少有 2.9 kPa 的患者中。 FibroScan 的內在變異性為35% 至40%，這已在文獻中多次得到證實，作為診斷或追蹤NASH 患者的唯一措施的使用有限，但它是一種出色的辦公空間豐富測試，並且是一種出色的富集測試 在我們的兩項 MAESTRO 研究中，使我們能夠排除沒有明顯纖維化的患者並識別潛在的 NASH 纖維化患者。

We will be presenting additional data on FibroScan and other eligibility criteria to diagnose NASH in one of our oral abstracts at EASL. However, a few of the highlights are shown here, the screening FibroScan of greater than 8.5 kPa in MAESTRO NASH, predicted significant fibrosis on biopsy, and approximately 50%, and a high percentage of positive fiber scans did not have significant liver fibrosis. The MRE of 2.9, which was not used as a prescreening test, but we have data from the study that predicts significant fibrosis on screening biopsy and about 80% of the MAESTRO-NASH population.

我們將在 EASL 的口頭摘要中提供有關 FibroScan 和診斷 NASH 的其他資格標準的更多數據。然而，這裡顯示了一些亮點，在 MAESTRO NASH 中篩選大於 8.5 kPa 的 FibroScan，預測活檢時出現顯著纖維化，大約 50%，並且高比例的陽性纖維掃描沒有顯著肝纖維化。 MRE 為 2.9，未用作預篩選測試，但我們從研究中獲得的數據預測，篩選活檢時會出現顯著纖維化，約 80% 的 MAESTRO-NASH 族群會出現纖維化。

The intrinsic variability of the MRE is approximately 19%, so lower than the fiber scan, and we believe that additional biomarkers and there is a huge amount of work going on this in the field, including composites or more specific imaging tests like MRE and MRI-PDFF with the FibroScan may increase the accuracy in diagnosing and monitoring patients with NASH. In the MAESTRO-NASH outcome study, that we are planning to start over the next few months.

MRE 的內在變異性約為 19%，因此低於纖維掃描，我們相信額外的生物標記以及該領域正在進行大量工作，包括複合材料或更具體的成像測試，如 MRE 和 MRI -使用FibroScan 進行PDFF可以提高診斷和監測NASH 患者的準確性。在 MAESTRO-NASH 結果研究中，我們計劃在未來幾個月內開始。

Just to give you some brief comments on the study design. It's a randomized, double-blind, placebo-controlled study in approximately 70 patients with early NASH cirrhosis to allow for noninvasive monitoring a progressive to liver decompensation events.

只是給您一些關於研究設計的簡短評論。這是一項隨機、雙盲、安慰劑對照研究，受試者約 70 名早期 NASH 肝硬化患者，可對進行性肝臟失代償事件進行非侵入性監測。

Just to make this clear, these are patients who have never decompensated. So they have early NASH cirrhosis. They're very similar -- this is a similar population to an ongoing open-label arm of more than 180 patients with well-compensated NASH cirrhosis from our MAESTRO-NAFLD study. The FDA has publicly stated that an outcome study in NASH cirrhosis patients can support full approval of noncirrhotic NASH and Madrigal met with FDA to confirm the strategy and study sign. MAESTRO-NASH outcome is designed to assess the rate of disease progression in early NASH cirrhosis patients and enhance the statistical power of MAESTRO trials to assess clinical benefit the decompensation events that will be assessed, include development of ascites, bleeding varices, hepatic encephalopathy and increased MELD>=15 and are expected to occur at a rate that is higher than in MAESTRO-NASH. This is because the MAESTRO-NASH patients who are past week 52 and are assessed out to month 54 are noncirrhotic. And these are in MAESTRO-NASH outcomes, these are early NASH cirrhotic patients.

需要澄清的是，這些患者從未失代償。所以他們患有早期 NASH 肝硬化。他們非常相似——這與我們的 MAESTRO-NAFLD 研究中正在進行的開放標籤組相似，該組包含 180 多名補償良好的 NASH 肝硬化患者。 FDA 公開表示，針對 NASH 肝硬化患者的結果研究可以支持非肝硬化 NASH 的完全批准，Madrigal 與 FDA 會面以確認該策略和研究標誌。 MAESTRO-NASH 結果旨在評估早期NASH 肝硬化患者的疾病進展率，並增強MAESTRO 試驗的統計能力，以評估將評估的失代償事件的臨床益處，包括腹水、靜脈曲張出血、肝性腦病變和增加的失代償事件。這是因為過去第 52 週且評估到第 54 個月的 MAESTRO-NASH 患者是非肝硬化。這些是 MAESTRO-NASH 結果，這些是早期 NASH 肝硬化患者。

And so the rate of decompensation will be higher in this population. Importantly, liver biopsies, not an endpoint. In MAESTRO-NASH outcomes the outcome portion of the trial of MAESTRO-NASH, the liver biopsy study, there is a third liver biopsy that occurs at month 54. So here in MAESTRO-NASH outcomes, the invasiveness and the variability of liver biopsy is avoided. Several biomarker and imaging techniques will also be employed to assess correlates with disease progression. We will be presenting additional data on the open-label study of more than 180 patients with well-compensated NASH cirrhosis at EASL. And these data support the potential of resmetirom in this patient population. We have reported data from this patients with NASH cirrhosis at international meetings and demonstrated that resmetirom reduces liver fat, liver enzymes, liver volume, fibrosis markers and atherogenic lipids in this population.

因此，該族群的失代償率會更高。重要的是，肝臟切片不是終點。在 MAESTRO-NASH 結果中，MAESTRO-NASH 試驗的結果部分（肝臟活檢研究）在第 54 個月進行了第三次肝臟活檢。避免了。也將採用幾種生物標記和影像技術來評估與疾病進展的相關性。我們將在 EASL 上提供有關 180 多名補償良好的 NASH 肝硬化患者的開放標籤研究的更多數據。這些數據支持了瑞美羅在該患者群體中的潛力。我們在國際會議上報告了這些 NASH 肝硬化患者的數據，並證明瑞美羅可以降低該族群的肝臟脂肪、肝臟酵素、肝臟體積、纖維化標記和致動脈粥狀硬化脂質。

So before asking Remy to give us a commercial update. I'd like to ask Dr. Harrison for his perspectives on the planned MAESTRO-NASH outcome study.

因此，在要求雷米向我們提供商業更新之前。我想詢問 Harrison 博士對計劃中的 MAESTRO-NASH 結果研究的看法。

Thanks, Paul. So first of all, I think this is incredibly important. I think it shows progression in the development of resmetirom to kind of address all the different aspects of what the FDA is looking for. So I think this is the final piece. The MAESTRO-NASH outcomes trial in a well-compensated group of over 700 cirrhotic patients. So I think the unique thing about this study that I find incredibly important and encouraging is the fact that we're able to use noninvasive techniques to enroll the patient population.

謝謝，保羅。首先，我認為這是非常重要的。我認為它顯示了瑞美羅姆開發的進展，以解決 FDA 所尋求的所有不同方面的問題。所以我認為這是最後的作品。 MAESTRO-NASH 結果試驗在一個由 700 多名肝硬化患者組成的良好補償組中進行。因此，我認為這項研究的獨特之處在於，我們能夠使用非侵入性技術來招募患者群體，這一點非常重要且令人鼓舞。

And so here, for the first time in a very large study, we're able to move away from liver biopsy. And so I think that provides an additional positive point relative to the study. So the outcomes are well validated. They're known development of ascites, bleeding varices, hepatic encephalopathy increase in the MELD score greater than or equal to 15%. So I think this sets everything up very nicely to augment the MAESTRO-NASH program and also extend benefit potentially into cirrhotic patients as well. So just -- I think it's I think it's exactly what we needed.

因此，在一項大型研究中，我們第一次能夠擺脫肝臟切片檢查。所以我認為這為這項研究提供了一個額外的積極點。因此，結果得到了很好的驗證。已知他們出現腹水、靜脈曲張出血、肝性腦病，MELD 評分增加大於或等於 15%。因此，我認為這一切都非常好，可以增強 MAESTRO-NASH 計劃，也可以為肝硬化患者帶來潛在的益處。所以，我認為這正是我們所需要的。

Okay. Thanks very much, Stephen. I appreciate that. I'll turn the call now over to Remy to provide a commercial update.

好的。非常感謝，史蒂芬。我很欣賞這一點。我現在將把電話轉給雷米，以提供商業更新。

Thank you, Paul. Good morning, everyone. NASH is a truly exciting commercial opportunity, and I feel both fortunate and privileged to lead our team's commercial planning efforts for a potential first-to-market launch in the category. As a reminder, we view this as a specialty product launch focused on the NASH specialists, who we define as a subset of hepatologists, gastroenterologists and endocrinologists who already manage a substantial number of patients that are living with NASH with fibrosis.

謝謝你，保羅。大家早安。 NASH 是一個真正令人興奮的商業機會，我感到非常幸運和榮幸能夠領導我們團隊的商業規劃工作，以實現該類別的潛在首次上市。提醒一下，我們認為這是針對NASH 專家的專業產品發布，我們將他們定義為肝病學家、胃腸病學家和內分泌學家的子集，他們已經治療了大量患有纖維化的NASH 患者。

To create the NASH therapeutic market, we are engaging with all key stakeholders so far in 2022, we have gained a deep understanding of market dynamics with the health care provider, payer and patient lenses based on extensive market research and advice from thought leaders. And we have advanced health economics and outcomes research that will inform future value assessments of resmetirom and held disease education sessions with U.S. payers that together cover roughly 80% of all branded prescriptions in the U.S. You can see examples of our market development activities on this slide.

為了創建NASH 治療市場，我們正在與所有主要利益相關者進行接觸，到2022 年為止，基於廣泛的市場研究和思想領袖的建議，我們對醫療保健提供者、付款人和患者鏡片的市場動態有了深入的了解。我們擁有先進的健康經濟學和結果研究，將為瑞美羅的未來價值評估提供信息，並與美國付款人舉行疾病教育課程，這些課程涵蓋了美國約80% 的品牌處方藥。幻燈片上看到我們的市場開發活動的範例。

For the remainder of the year, we will have a particular focus on education initiatives at U.S. Medical Congresses like DDW, ACE, AGA and of course, AASLD. Our first major digital disease education campaign for the health care provider audience, NASH, reimagined, will be launching in the U.S. in the coming weeks. We remain heavily focused on partnering discussions. As we have stated previously, our plan is to establish an ex U.S. commercial partnership following Phase III MAESTRO-NASH data readout. And we have already begun discussions with multiple potential partners. Overall, I'm pleased with the progress we made so far in 2022 and the momentum we have established with our commercial strategy and execution. With that, I will turn it over to Alex for a financial update.

在今年剩下的時間裡，我們將特別關注美國醫學大會上的教育計劃，例如 DDW、ACE、AGA，當然還有 AASLD。我們針對醫療保健提供者受眾的第一個大型數位疾病教育活動 NASH 重新設計，將於未來幾週在美國推出。我們仍然高度重視合作討論。正如我們之前所說，我們的計劃是在第三階段 MAESTRO-NASH 數據讀出後建立美國以外的商業合作夥伴關係。我們已經開始與多個潛在合作夥伴進行討論。總體而言，我對 2022 年迄今的進展以及我們在商業策略和執行方面建立的勢頭感到滿意。這樣，我會將其轉交給亞歷克斯以獲取最新的財務資訊。

Thanks, Remy, and good morning, everyone. Based on our cash position and term loan facility announced today, Madrigal is on solid financial footing for the road ahead. As of March 31, 2022, Madrigal had cash, cash equivalents and marketable securities of $220 million compared to $270.3 million at December 31, 2021. Operating expenses were $57.6 million for the 3-month period ended March 31, 2022, which comprised research and development expenses of $47.9 million and G&A expenses of $9.7 million.

謝謝雷米，大家早安。根據我們今天宣布的現金狀況和定期貸款安排，Madrigal 為未來的道路奠定了堅實的財務基礎。截至2022 年3 月31 日，Madrigal 擁有現金、現金等價物和有價證券為2.2 億美元，而2021 年12 月31 日為2.703 億美元。為5,760 萬美元，其中包括研究和支出開發費用為 4,790 萬美元，一般管理費用為 970 萬美元。

The operating cash burn for the period was $49.9 million. Please refer to this morning's press release and 10-Q filing, if you would like additional details on Q1 financial results. I'll now turn to the term loan facility. Madrigal has secured a $250 million term loan facility with Hercules Capital, Inc. The committed capital strengthens Madrigal's balance sheet, providing an additional source of funding to support strategic priorities including the new MAESTRO-NASH outcome study. Under the terms of the credit facility, $50 million was drawn at closing.

該期間的營運現金消耗為 4,990 萬美元。如果您想了解有關第一季度財務業績的更多詳細信息，請參閱今天上午的新聞稿和 10-Q 報告。我現在談談術語貸款工具。 Madrigal 已從Hercules Capital, Inc. 獲得了2.5 億美元的定期貸款融資。 。根據信貸安排的條款，交易結束時已提取 5,000 萬美元。

Madrigal may also draw an additional $125 million in 2 separate tranches upon achievement of resmetirom clinical and regulatory milestones. An additional $75 million may be drawn by Madrigal to support operational activities subject to the approval of Hercules Capital. With our existing cash access to the term loan, our existing ATM facility and other potential financing sources, we are well positioned to execute on our strategic objectives for Resmetirom. With that, I'll now turn the call back to Paul.

在實現 resmetirom 臨床和監管里程碑後，Madrigal 還可能分兩期額外提取 1.25 億美元。經 Hercules Capital 批准，Madrigal 可能會額外提取 7,500 萬美元用於支援營運活動。憑藉我們現有的定期貸款現金、現有的 ATM 設施和其他潛在的融資來源，我們有能力執行 Resmetirom 的戰略目標。現在，我將把電話轉回給保羅。

Thanks, Alex. So we've delivered quite a bit of news today. I'm sure you have questions you would like addressed. We're going to open the call momentarily for Q&A. I just wanted to let you know that the company has a hard stop at 9:00. So we have 30 minutes. We'll answer as many questions as we can in that time. Operator, please open the call for Q&A.

謝謝，亞歷克斯。今天我們發布了很多消息。我確信您有一些問題想要解決。我們將立即開始電話問答。我只是想讓您知道，公司將於 9:00 硬停。所以我們有 30 分鐘的時間。屆時我們將盡可能回答問題。接線員，請打開電話問答。

(Operator Instructions) Our first question comes from Ritu Baral with Cowen.

（操作員說明）我們的第一個問題來自 Ritu Baral 和 Cowen。

I'll keep it brief. So is it fair to say that now that you've incorporated fibrosis that you've got a hierarchical non-gating analysis as the prior NASH company did. And since this isn't in interim, is the assumption that you guys have full alpha 0.05 of Alpha to spend on that primary endpoint?

我會保持簡短。因此，可以公平地說，既然您已經納入了纖維化，您就可以像之前的 NASH 公司一樣進行分層非門控分析。由於這不是臨時的，是否假設你們有 0.05 的 Alpha 完整 alpha 值用於該主要終點？

So this is Becky. Thank you, Ritu. I think that your comment showed an excellent understanding of what we said. We are in the process of the finalization of the statistical analysis plan. And so the details of the alpha and the hierarchy, et cetera. We aren't discussing. But the idea is that this is similar to really every other NASH study where there are dual endpoints both fibrosis and NASH resolution dual primary endpoints, so that's achievement if either of those 2 endpoints can lead to a successful study.

這就是貝基。謝謝你，瑞圖。我認為您的評論表明您對我們所說的內容有很好的理解。我們正在最終確定統計分析計劃。阿爾法和層次結構的細節等等。我們不討論。但我們的想法是，這與其他所有 NASH 研究類似，其中都有雙重終點，即纖維化和 NASH 解決雙重主要終點，因此，如果這兩個終點中的任何一個能夠導致研究成功，那就是成就。

So we're not requiring achievement of both of NASH resolution and fibrosis, although we believe that both endpoints will be achieved.

因此，我們並沒有要求同時實現 NASH 消退和纖維化，儘管我們相信這兩個終點都會實現。

And what drove inclusion? Was it FDA payer import or the data, the MRE data that you generated?

是什麼推動了包容性？是 FDA 付款人進口還是您產生的數據、MRE 數據？

We've actually had this plan for quite some time, and it was a matter of consolidating the entire MAESTRO development plan and finalizing it at this point in time.

實際上，我們制定這個計劃已經有一段時間了，這是一個整合整個 MAESTRO 開發計劃並在此時最終確定的問題。

The -- as we mentioned on the call, the FDA providing the opportunity for the MAESTRO-NASH outcomes in the early NASH cirrhosis population helps support the statistical power for determining clinical benefit. And so I think that also helped us in terms of statistical plan for MAESTRO-NASH week 52 biopsy.

正如我們在電話會議中提到的，FDA 為早期 NASH 肝硬化族群提供 MAESTRO-NASH 結果的機會有助於支持確定臨床獲益的統計能力。因此，我認為這對 MAESTRO-NASH 第 52 週活檢的統計計劃也有幫助。

Our next question comes from Thomas Smith SVB Securities.

我們的下一個問題來自 Thomas Smith SVB 證券。

I guess first on the MAESTRO-NAFLD detailed data that we're expecting at EASL. I understand you're under embargo and kind of limited in what you can say in terms of the additional data sets, but maybe if you could help set the stage for what other data sets we can expect to see from this presentation at the meeting?

我想首先是我們在 EASL 上期待的 MAESTRO-NAFLD 詳細數據。我知道您受到禁運，並且在附加資料集方面您能說的內容受到限制，但也許您可以幫助為我們期望在會議上的演示中看到哪些其他資料集奠定基礎？

I think it is a primary presentation of the data. from MAESTRO-NAFLD and will include the primary endpoint and the key secondary endpoints and as well as additional safety and more exploratory endpoints of the study. Beyond that, I don't want to get into more detail, but I think that it will provide a lot of information about the clinical trial, much of which we've already presented.

我認為這是數據的主要呈現方式。來自 MAESTRO-NAFLD 的數據，將包括主要終點和關鍵次要終點，以及研究的額外安全性和更具探索性的終點。除此之外，我不想透露更多細節，但我認為它將提供大量有關臨床試驗的信息，其中大部分我們已經介紹過。

So in fact, we have said that in terms of the safety that the only AE that was disproportionate in the MAESTRO resmetirom arms were the early diarrhea and nausea, the GI-related AEs that were self-limited and did not lead to study discontinuation.

因此，事實上，我們說過，就安全性而言，MAESTRO resmetirom 組中唯一不成比例的 AE 是早期腹瀉和噁心，這些與胃腸道相關的 AE 是自限性的，不會導致研究中止。

Okay. Great. Well, we'll look forward to more color there. And then just one on the new MAESTRO-NASH outcome study. Can you talk a little bit more about the level of regulatory engagement here if you were putting the other plans for the study? And then can you comment at all on the potential time lines, the data and the estimated cost for this additional study?

好的。偉大的。好吧，我們期待那裡有更多的顏色。然後是關於新的 MAESTRO-NASH 結果研究的一篇。如果您要製定其他研究計劃，您能在這裡多談談監管參與的程度嗎？那麼您能否對這項額外研究的潛在時間表、數據和估計成本發表評論？

I can comment on some of this. So the FDA really was last year. publicly commented on what they call the parallel path for full approval in noncirrhotic NASH where they showed a study design in noncirrhotic NASH. It's very similar to the liver biopsy portion of Maestro NASH with a baseline biopsy and then a follow-up liver biopsy after 1 year to 1.5 years.

我可以對此發表一些評論。 FDA確實是去年的。公開評論了他們所謂的非肝硬化 NASH 完全批准的平行路徑，他們展示了非肝硬化 NASH 的研究設計。它與 Maestro NASH 的肝臟活檢部分非常相似，先進行基線活檢，然後在 1 至 1.5 年後進行後續肝臟活檢。

And that would be a completed study and then they showed a parallel study outcome study for clinical benefit in an early NASH cirrhosis cohort and commented that those 2 studies would support positive outcome from those 2 studies would support a full approval for noncirrhotic NASH and that it would have the additional benefit of also a potential for approval in cirrhotic in early cirrhotic NASH.

這將是一項完整的研究，然後他們展示了一項針對早期NASH 肝硬化隊列臨床獲益的平行研究結果研究，並評論說這兩項研究將支持這兩項研究的積極結果將支持非肝硬化NASH 的完全批准，並且它還將具有額外的好處，即還有可能被批准用於治療早期肝硬化 NASH。

And so we followed up with them with an inquiry and solicited advice and then had a direct meeting to discuss the strategy and the potential protocol and that we plan to initiate in the next few months. And the cost of the study is consistent with what you would expect for a 700-patient study that would go on for 2 to 3 years.

因此，我們對他們進行了調查並徵求建議，然後召開了一次直接會議來討論我們計劃在未來幾個月內啟動的策略和潛在協議。研究的費用與您對 700 名患者進行為期 2 至 3 年的研究的預期一致。

It has noninvasive imaging and biomarkers. But otherwise, it's a fairly simple design. And so really not as expensive as some other studies like the early portion of the MAESTRO-NASH study. And does impact the numbers of patients that need to be enrolled in the MAESTRO-NASH study for the long-term 54-month readout. So the total costs, we haven't absolutely calculated, but we think there are some cost offsets from the study for the total program.

它具有非侵入性成像和生物標記。但除此之外，這是一個相當簡單的設計。因此，實際上並不像其他一些研究（例如 MAESTRO-NASH 研究的早期部分）那麼昂貴。並且確實會影響需要參加 MAESTRO-NASH 研究以進行長期 54 個月讀數的患者數量。因此，我們還沒有絕對計算出總成本，但我們認為整個計劃的研究可以抵銷一些成本。

Yes, I mean just -- again, just to reinforce what Becky is saying, the details of the study are less onerous in terms of the biopsy work, et cetera. So overall, the costs are more modest compared to the early portion of the MAESTRO-NASH study, but we won't go into specifics, obviously, the details of the totality of the study costs. That's just not something we will do.

是的，我的意思是——再次強調，為了強化貝基所說的，該研究的細節在活檢工作等方面並不那麼繁重。因此，總體而言，與 MAESTRO-NASH 研究的早期部分相比，成本更為適中，但我們不會詳細介紹研究成本總體的細節。那不是我們會做的事情。

Thomas, just to emphasize one thing. We had said we would enroll up to 2,000 people in the NASH 54-week biopsy study and we won't go that far. I think Becky alluded to that, but we don't have to recruit as many patients there now that we have this second study to start in a couple of months. And this study should end well before the current outcome study that's ongoing in MAESTRO-NASH.

湯瑪斯，只是想強調一件事。我們曾說過，我們將招募多達 2,000 人參加為期 54 週的 NASH 活檢研究，但我們不會走那麼遠。我認為貝基提到了這一點，但我們不必在那裡招募那麼多患者，因為我們將在幾個月後開始第二項研究。這項研究應該早於 MAESTRO-NASH 正在進行的當前結果研究結束。

Okay. Understood. And just one last question on MAESTRO-NASH outcomes. Are you planning to take forward 1 dose arm, the 100-milligram dose or 2 dose arms into the study?

好的。明白了。最後一個問題是關於 MAESTRO-NASH 結果的。您是否計劃將 1 個劑量組、100 毫克劑量或 2 個劑量組推進到研究中？

The dosing of this patient population, it is something that it's under consideration in the final details of the protocol. But I will note that in the ongoing NASH cirrhosis cohort, the well compensated NASH cirrhosis cohort where we enrolled more than 180 patients. The starting dose is 80 milligrams in that population, and there are patients who then receive 100 milligrams. So this design, as I said, is under discussion, but we have precedent from our ongoing NASH cirrhosis open-label cohort.

該患者群體的劑量，正在方案的最終細節中考慮。但我要指出的是，在正在進行的 NASH 肝硬化隊列中，在補償良好的 NASH 肝硬化隊列中，我們招募了 180 多名患者。該族群的起始劑量為 80 毫克，有些患者隨後接受 100 毫克。因此，正如我所說，這種設計正在討論中，但我們有正在進行的 NASH 肝硬化開放標籤隊列的先例。

Our next question comes from John Wolleben with JMP Securities.

我們的下一個問題來自 JMP 證券的 John Wolleben。

I was hoping you could just remind us of your reading methodology for biopsies in the Phase II study and how you're doing it in MAESTRO-NASH, please?

我希望您能提醒我們您在 II 期研究中的活檢閱讀方法以及您在 MAESTRO-NASH 中是如何進行的？

So we haven't discussed the entire detail of the biopsy review. And as you know, there's been a lot of recent theories about practices for biopsy review, none of which are, by the way, validated. We are using 2 central readers, the same 2 central readers that read our Phase II biopsy and had consistent results between the 2 readers, and we believe we have a good methodology to gain agreement on the final outcome of the study based on these 2 central leasing to central readers. So that's the bottom line.

所以我們還沒有討論活檢審查的全部細節。如你所知，最近有很多關於活檢審查實踐的理論，順便說一句，這些理論都沒有得到驗證。我們使用2 個中心閱讀器，這2 個中心閱讀器讀取了我們的II 期活檢，並且2 個閱讀器之間的結果一致，我們相信我們有一個很好的方法來就基於這2 個中心的研究的最終結果達成一致。這就是底線。

Just to again mention how this has played out in the past. The same 2 central readers, Red, our Phase II. There was a primary central leader, and then there was a second reader who read the entire Phase II study. We showed their results at an oral presentation a couple of years ago. at EASL, Dr. Rohit Loomba, presented their data. And we showed an excellent correlation between the determination of NASH resolution between the 2 readers who were both blinded and they were blinded to each other's scoring.

只是再次提及過去的情況。相同的 2 個中心讀者，紅色，我們的第二階段。有一位主要的中央領導，然後有一位閱讀整個二期研究的第二位讀者。幾年前，我們在口頭報告中展示了他們的結果。在 EASL，Rohit Loomba 博士展示了他們的數據。我們發現，兩位讀者之間的 NASH 分辨率測定之間存在極佳的相關性，這兩位讀者都對彼此的評分不知情。

And subsequently in every component of NASH fibrosis reduction, inflammation and steatosis was greater in patients with a PDFF response, which was one of the highlights of our Phase II Subsequently, we had this approach validated and will be another one of our presentations in EASL from the Path AI where they also read the Phase II biopsy study using artificial intelligence and got the same result as the 2 biopsy readers.

隨後，在NASH 纖維化減少的每個組成部分中，PDFF 反應的患者中的炎症和脂肪變性更大，這是我們II 期的亮點之一隨後，我們驗證了這種方法，並將成為我們在EASL 中的另一個演示Path AI，他們還使用人工智慧讀取了 II 期活檢研究，並得到了與 2 個活檢讀取器相同的結果。

So we believe between that precedent and what we're doing now that we have a very good plan to get a convincing read of the liver biopsy study in MAESTRO-NASH.

因此，我們相信，在這個先例和我們現在正在做的事情之間，我們有一個非常好的計劃來獲得令人信服的 MAESTRO-NASH 肝臟活檢研究結果。

That's helpful. And one more, if I may. You discussed the expansion in the cirrhotic population. Can you give us some thoughts about how you're thinking about that commercial opportunity versus the earlier stage NASH that was the earlier primary target?

這很有幫助。如果可以的話，再來一張。您討論了肝硬化人口的擴張。您能否給我們一些關於您如何看待該商業機會與早期主要目標的早期 NASH 的想法？

Remy, do you want to handle that one?

雷米，你想處理那個嗎？

Sure thing, Paul. So when you think about commercial opportunity, there's probably 3 things, generally speaking, you got to think about. One, the addressable patient population to unmet need three, what your competitive set looks like. So when you look at NASH with compensated cirrhosis, the prevalence of the disease, if you look at ST publication that we all seem to look at is around 2 million is the prevalence, 2 million people in the U.S. today, probably right in to 3.5 million by the end of this decade.

當然可以，保羅。因此，當您考慮商業機會時，一般來說，您可能需要考慮三件事。第一，未滿足需求的可尋址患者群體第三，您的競爭群體是什麼樣的。因此，當您查看代償性肝硬化NASH 時，如果您查看ST 出版物，我們似乎都在關注該疾病的患病率，那麼患病率約為200 萬，今天美國有200 萬人，可能正好達到3.5到本十年末將達到 100 萬。

Now we've got to balance that by saying, hey, listen, most of these patients are not identified right now. because there's really nothing to do with them. But as NASH drugs enter the market, that diagnosis rate should go up. So overall, the addressable patient population could be quite large unmet need.

現在我們必須平衡這一點，說，嘿，聽著，大多數患者的身份目前還沒有確定。因為確實與他們無關。但隨著 NASH 藥物進入市場，診斷率應該會上升。因此總體而言，可解決的患者群體可能存在相當大的未滿足需求。

We've talked to both payers and the NASH specialists. I mean these patients are on the cusp of very bad things. I mean, to point out the obvious, liver transplant death, hospitalization. So there is a high unmet need. We look at the pipeline, it's pretty smart, especially compared to national fibrosis. So when you put it all together, I mean, we're quite bullish about the commercial potential for resmetirom, assuming it gains an indication for NASH with compensated roses.

我們已經與付款人和 NASH 專家進行了交談。我的意思是這些病人正處於非常糟糕的事情的風口浪尖。我的意思是，指出顯而易見的事實，肝臟移植死亡、住院治療。因此，存在著很高的未滿足需求。我們看看管道，它非常聰明，特別是與全國纖維化相比。因此，當你把所有這些放在一起時，我的意思是，我們非常看好瑞美羅的商業潛力，假設它通過補償玫瑰獲得了 NASH 的適應症。

Our next question comes from Yasmeen Rahimi with Piper Sandler.

我們的下一個問題來自 Yasmeen Rahimi 和 Piper Sandler。

A few questions for you. Maybe the first place to start off, are you seeing some improvements in event rates in your open-label cirrhosis cohort that motivated you to wanting to run this parallel design studies, if you could kind of comment on that?

有幾個問題想問你。也許首先要考慮的是，您是否看到開放標籤肝硬化隊列的事件發生率有所改善，這促使您想要進行這項平行設計研究，如果您能對此發表評論嗎？

And then I have a second question.

然後我還有第二個問題。

So I don't think we mentioned event rates in our ongoing open-label active as cirrhosis cohort because there is no placebo control group in that study. But we will say that the patient population is done very well, and the safety has been excellent. And -- but I think it's always important if you're going to talk about event rates to have a relevant control group in the study.

因此，我認為我們在正在進行的開放標籤活性肝硬化隊列中沒有提到事件發生率，因為該研究中沒有安慰劑對照組。但我們要說的是，患者群體做得很好，安全性也非常好。而且——但我認為，如果你要談論事件發生率，那麼在研究中設定相關的對照組總是很重要的。

So the other thing I would add to that is over the time that we've treated the population, statistically you would have expected to see some hepatic decompensation events.

因此，我要補充的另一件事是，隨著我們治療人群的時間的推移，從統計數據來看，您預計會看到一些肝臟代償失調事件。

Which -- I mean, in other words, what he's saying is that the rate is extremely low to nonexistent in the study so far. But again, we will defer to having a placebo-controlled study to measure the event rate. I don't know Dr. Harrison, if you want to comment at all on this topic?

換句話說，我的意思是，他所說的是，到目前為止，該研究中的比率極低，甚至不存在。但同樣，我們將延後進行安慰劑對照研究來衡量事件發生率。我不知道哈里森博士，您是否想對這個主題發表評論？

Yes. I mean I think you hit on all the right points. Yasmeen, I mean, we're just -- we don't have a placebo control, but what we can say is that the event rate is incredibly low, but that's not necessarily inconsistent with the disease state. I mean these events take time to accumulate. So just I don't think that's necessarily the reason for pushing into this trial.

是的。我的意思是我認為你說得對。 Yasmeen，我的意思是，我們只是——我們沒有安慰劑對照，但我們可以說的是，事件發生率非常低，但這並不一定與疾病狀態不一致。我的意思是這些事件需要時間累積。所以我認為這不一定是推進這項試驗的原因。

I think it's more to align with the FDA around the parallel trial design so that we don't have to wait forever for the NASH -- MAESTRO-NASH trial to read an outcome. We can move forward with a noninvasive assessment of these well-compensated cirrhotics to try to get to an end point quicker. And so I think that's the reason for doing it.

我認為在平行試驗設計方面更應該與 FDA 保持一致，這樣我們就不必永遠等待 NASH——MAESTRO-NASH 試驗來讀取結果。我們可以對這些補償良好的肝硬化進行非侵入性評估，以更快達到終點。所以我認為這就是這樣做的原因。

And then I acknowledge that the FibroScan and MRE measurements were in the MAESTRO-NAFLD study is an earlier patient population and maybe didn't reach stat sig based on all the reasons you outlined. But -- are you able to comment on whether those 2 noninvasive biomarkers tend to really remarkable differences at least in the cirrhosis cohort?

然後我承認，MAESTRO-NAFLD 研究中的 FibroScan 和 MRE 測量是早期患者群體，根據您概述的所有原因，可能沒有達到統計數據。但是，您能否評論一下這兩種非侵入性生物標記是否至少在肝硬化隊列中確實存在顯著差異？

I think investors might struggle with why -- what evidence do we have for all the data that's going to be presented on its antifibrotic activity given that those 2 measures, unfortunately, did not hit stat sig. And I appreciate any color you can give us.

我認為投資者可能會困惑為什麼——鑑於不幸的是，這兩項措施沒有達到統計數字，我們有什麼證據來證明將要提供的所有有關其抗纖維化活性的數據。我很感激你能給我們的任何顏色。

Well, I mean I don't mind starting there, Becky, you kind of like. I mean, so first of all, I mean what you -- what was mentioned is that they're in a responder analysis, I think there is statistical significance. There is a difference -- and remember that there is significant coefficient variance in FibroScan from 1 point to 0.2 in the same patient over time. So to be able to have a responder analysis where we're actually showing a significant difference, I think, is significant even in this milder disease state population of MAESTRO-NAFLD-1. As far as looking at other biomarkers, I think MRE is more specific.

好吧，我的意思是我不介意從這裡開始，貝基，你喜歡的。我的意思是，首先，我的意思是您所提到的，他們處於響應者分析中，我認為存在統計顯著性。存在差異 - 請記住，隨著時間的推移，同一患者的 FibroScan 中的係數差異顯著，從 1 點到 0.2 點。因此，我認為，即使在 MAESTRO-NAFLD-1 這種疾病狀態較輕的人群中，能夠對我們實際上顯示出顯著差異的反應者進行分析也很重要。就其他生物標記而言，我認為 MRE 更具體。

It picks up more accurately the amount of collagen that's in the liver. And if you look at those scans that were abnormal, defined as like greater than 2.9, there was a nice reduction in MRI and in more or less geography. So I think -- I don't know from an investor perspective, I'm not sure what you would take from that as a clinician, I get -- that's very, very positive data. So I'll just stop there, but I think it's looking very good.

它可以更準確地獲得肝臟中膠原蛋白的量。如果你看看那些異常的掃描，定義為大於 2.9，MRI 和或多或少的地理方面都有很大的減少。所以我認為——我不知道從投資者的角度來看，我不確定作為臨床醫生你會從中得到什麼——這是非常非常積極的數據。所以我就到此為止，但我認為它看起來非常好。

Yes. One of the things that I would add is in the evaluation of an improvement in fibrosis in the Phase III NASH biopsy study. The way that's done is a responder analysis. Ergo, we have statistical significance for a responder analysis even in this earlier population.

是的。我要補充的一件事是評估 III 期 NASH 活檢研究中纖維化的改善。完成的方法是響應者分析。因此，即使在這個早期族群中，我們對應答者分析也具有統計意義。

Yes. I just also think that one of the things that we -- like for example was setting up was trying to understand the value of these biomarkers and how we have to analyze them. And to Paul's comment, when resmetirom is approved as a therapy. The clinicians are not going to be looking at the average response on FibroScan or MRE, they're going to be looking at an individual patient.

是的。我還認為，我們正在做的事情之一就是試圖了解這些生物標誌物的價值以及我們如何分析它們。對於保羅的評論，當瑞美羅被批准作為一種療法。臨床醫生不會關注 FibroScan 或 MRE 的平均反應，他們會關注個別患者。

And so it may well be that a responder analysis for these tests is a more important way and a better way to do the analysis.

因此，這些測試的響應者分析很可能是更重要、更好的分析方法。

Our next question comes from Andrea Tan with Goldman Sachs.

我們的下一個問題來自高盛的 Andrea Tan。

Remy, maybe just one for you. I would love to hear you speak more on the market dynamics that you've been learning from this additional work, anything new or different than what you were previously thinking?

雷米，也許只是一個適合你的。我很想聽您更多地談論您從這項額外工作中學到的市場動態，有什麼新的或與您之前的想法不同的嗎？

Yes. Andrea, is your question relative to just NASH overall or NASH cirrhotic population specifically?

是的。 Andrea，您的問題是僅與 NASH 整體相關還是與 NASH 肝硬化族群相關？

NASH overall.

總體而言，NASH。

Yes. So Andrea, I think key things that we can talk about that we probably haven't in the past is considering NASH is a nascent therapeutic area, the question is are patients actually being identified?

是的。因此，Andrea，我認為我們可以討論但過去可能沒有討論過的關鍵問題是，考慮到 NASH 是一個新興的治療領域，問題是患者是否真的得到了識別？

So we've done that sort of work looking at patient claims data, insurance claims data. And quite surprisingly, we found that about 1 million people may have already been identified and coated with ICD-10 code for NASH. And that's pretty exciting for therapies coming to market because they would have -- one can expect a pool of patients that physicians can actively determine if the drug that's approved is right for them. So it doesn't take away our responsibility to continue to educate the market, but it's a good finding that we've had as of late.

因此，我們已經完成了此類工作，查看患者索賠數據、保險索賠數據。令人驚訝的是，我們發現大約 100 萬人可能已經被識別並塗上 NASH 的 ICD-10 代碼。這對於即將上市的療法來說是相當令人興奮的，因為人們可以預期，醫生可以主動確定批准的藥物是否適合他們的一群患者。因此，這並沒有免除我們繼續教育市場的責任，但這是我們最近的一個很好的發現。

And Remy, let me -- this is Dr. Harrison. Let me just add to that. So just to provide a little bit more color on the progression of the prevalence of more significant NASH, NASH with F2 or greater fibrosis. Now I published 2 papers, 2 prevalence papers, 1 in gastro in 2011 and 1 in J hepatology in 2021. So over that decade of difference, we've seen a rise in moderate to severe fibrosis of -- from like 1.9% to 6% in a cohort of patients. So we're beginning to see in real life play out what's happened in the modeling of disease progression and prevalence over time. And so on top of diagnosing more and beginning to spread the disease awareness news, we're seeing an increase in the prevalence of more disease as well.

雷米，讓我——這是哈里森博士。讓我補充一下。因此，只是為了提供更多關於更顯著的 NASH 盛行率、具有 F2 或更嚴重纖維化的 NASH 盛行率進展的顏色。現在我發表了2 篇論文，2 篇盛行率論文，2011 年發表了1 篇《胃腸病學》論文，2021 年發表了1 篇《J 肝病學》論文。中，我們看到中度至重度纖維化增加——從1.9% 上升到6% % 在一組患者中。因此，我們開始在現實生活中看到隨著時間的推移疾病進展和盛行率建模中發生的情況。因此，除了診斷更多疾病並開始傳播疾病意識新聞之外，我們還看到更多疾病的盛行率增加。

So all in all, Andrea, I think this market is ready for NASH therapies. We're excited to be the lead horse at this point. If current time lines hit, resmetirom could be on the market 2, 3 years ahead of any other products. So when you think about it all, I mean, again, we have to look at MAESTRO-NASH data. We expect it to be positive. If resmetirom is the first drug to the market, it could be the backbone of NASH treatment, considering it has 2 to 3 years' lead. So it's an exciting place to be.

總而言之，Andrea，我認為這個市場已經為 NASH 療法做好了準備。我們很高興能成為此時的領頭羊。如果按照目前的時間表，resmetirom 可能會比任何其他產品提前 2、3 年上市。因此，當您考慮到這一切時，我的意思是，我們必須再次查看 MAESTRO-NASH 數據。我們預計它會是積極的。如果瑞美羅是第一個上市的藥物，考慮到它有 2 到 3 年的領先優勢，它可能會成為 NASH 治療的支柱。所以這是一個令人興奮的地方。

Perfect. Remy, maybe just one follow-up to what you were just saying, how are you guys thinking about potential combination therapies at this point?

完美的。雷米，也許只是你剛才所說的後續行動，現在如何考慮潛在的聯合療法？

Maybe Dr. Harrison or Becky will want to elaborate on this. At this point, we are excited about the program, the way it's shaping up. The data that is shaping up. We see significant commercial potential for resmetirom as monotherapy. So no worries there. But I think as we look at some of the emerging data, we find that resmetirom actually has -- provides additional efficacy or it works even better in patients that are on background type 2 diabetes therapy.

也許哈里森博士或貝基會想詳細說明這一點。此時此刻，我們對這個計劃以及它的形成方式感到興奮。正在形成的數據。我們看到瑞美羅作為單一療法的巨大商業潛力。所以不用擔心。但我認為，當我們查看一些新出現的數據時，我們發現瑞美羅實際上具有——提供額外的功效，或者它對接受背景 2 型糖尿病治療的患者效果更好。

So in a way, that data is are you pointing to beneficial effect of resmetirom on top of type 2 diabetes patients -- sorry, therapies. But maybe Dr. Harrison or Becky, do you want to elaborate further on that when it comes to the combo question.

因此，從某種程度上來說，這些數據表明了瑞美羅對第 2 型糖尿病患者的有益作用——抱歉，是療法。但也許哈里森博士或貝基博士，當涉及組合問題時，您想進一步詳細說明嗎？

Yes. I would just simply say that we have -- are doing combos. I mean these are patients, NASH patients are on many, many drugs. More than half of them were diabetic as Remy alluded to. And a significant fraction are taking drugs such as SGLT2 inhibitors or GLPs that cause some degree of weight loss. So they're on the stable background therapy that allows us to look at whether resmetirom has an enhanced effect in combination with those drugs.

是的。我只想簡單地說，我們正在做組合。我的意思是這些患者，NASH 患者正在服用很多很多藥物。正如雷米所提到的，其中超過一半患有糖尿病。其中很大一部分人正在服用 SGLT2 抑制劑或 GLP 等藥物，這些藥物會導致一定程度的體重減輕。因此，他們正在進行穩定的背景治療，使我們能夠了解瑞美羅與這些藥物合併使用是否會增強療效。

So those are some of the things that we will be -- we've talked about a little bit in the past with our open-label study, but we'll also be talking about it from the MAESTRO-NAFLD data set. Stephen, did you want to add any comments to that?

這些是我們將要做的一些事情——我們過去已經在開放標籤研究中討論過一些問題，但我們也將從 MAESTRO-NAFLD 資料集中討論它。史蒂芬，您想對此添加任何評論嗎？

Well, just to say that -- look, we understand that one size doesn't necessarily fit all. And ultimately, we want to get at as many patients as we can with this disease. And where we're able to combine therapies, we think there is a role, in my opinion, for a THR beta like Madrigal resmetirom to be a backbone drug. But it doesn't mean we can't continue to look at that synergistic benefit. And to me, the ideal NASH drug is one that's oral, it's well tolerated, it's safe that can be given for the long haul.

好吧，只是說——聽著，我們知道一種尺寸不一定適合所有人。最終，我們希望盡可能多地治療這種疾病的患者。在我看來，在我們能夠結合療法的地方，我們認為像 Madrigal resmetirom 這樣的 THR beta 可以成為骨幹藥物。但這並不意味著我們不能繼續關注這種協同效益。對我來說，理想的 NASH 藥物是一種口服藥物，它具有良好的耐受性，並且安全，可以長期服用。

And not only does it have histopathologic benefit on NASH resolution and fibrosis improvement, but you also get after the extra hepatic manifestations of disease the atherogenic lipids, the glycemic control, the lipotoxic fat, and all those are critically important. So where we're able to leverage the benefit of resmetirom targeting the majority of what I just mentioned and augment that a little bit, as Becky mentioned, with potentially diabetic therapy that are -- we've already shown synergistic effects with relative to some of the outcomes we're looking for.

它不僅對 NASH 消退和纖維化改善具有組織病理學益處，而且在疾病的額外肝臟表現後，您還可以獲得致動脈粥樣化脂質、血糖控制、脂毒性脂肪，所有這些都至關重要。因此，正如貝基所提到的，我們能夠利用瑞美羅的優勢來針對我剛才提到的大部分目標，並透過潛在的糖尿病治療來稍微增強這一點，我們已經顯示出與某些藥物的協同效應。

I think that's important. It doesn't mean that there aren't other combinations that might work well together, but just taking it 1 step at a time. First, figure out how effective your drug is, how effective is resmetirom. We'll know that from the data that we're generating in MAESTRO-NAFLD-1 MAESTRO-NASH and MAESTRO-NASH outcomes as well as open-label extension of the MAESTRO-NAFLD-1 trial. Huge amounts of data being generated to really get at, What is the foundational answer? What can resmetirom do by itself and then begin to look at iterative steps to improve.

我認為這很重要。這並不意味著沒有其他組合可以很好地協同工作，而只是一次邁出一步。首先，弄清楚你的藥物有多有效，瑞美羅有多有效。我們將從 MAESTRO-NAFLD-1 MAESTRO-NASH 和 MAESTRO-NASH 結果以及 MAESTRO-NAFLD-1 試驗的開放標籤擴展中產生的數據知道這一點。產生大量數據才能真正了解基本答案是什麼？ resmetirom 本身可以做什麼，然後開始考慮迭代步驟來改進。

Our last question from Liisa Bayko with Evercore ISI.

我們的最後一個問題來自 Evercore ISI 的 Liisa Bayko。

Trials before I've looked at co-primary endpoints very similar to what you're looking at. Why the change now? Is there anything in the that you've observed in the NAFLD, the MAESTRO-NAFLD-1 study that makes you more or less confident around NASH resolution and fibrosis. And then do you expect these -- I guess, you're going to have alignment between FDA and EMA and any power changes? How does it affect powering and whatnot that you have kind of now 2 shots on goal in a way?

在我研究共同主要終點之前的試驗與您所看到的非常相似。為什麼現在要改變？您在 NAFLD（MAESTRO-NAFLD-1 研究）中觀察到的任何內容是否使您對 NASH 消退和纖維化或多或少有信心？然後你是否期望這些——我想，你會在 FDA 和 EMA 之間達成一致以及任何權力變化嗎？從某種程度上來說，你現在有 2 次射門，這對你的力量有什麼影響？

Yes. So I think one of the kind of little confusing word is the word co-primary versus dual primary Co-primary means you have to make both primary endpoints. This is not what this is. Obviously, we are going to evaluate the percentage of patients that achieve both fibrosis reduction in NASH resolution, but that's not the endpoint. So this is dual primaries. And if either end point is achieved -- either primary endpoint is achieved, then there is an opportunity to submit for approval. We made a decision on including this endpoint quite a while ago when we believe based on our data and from the Phase II data and from the continuing data that we've seen that resmetirom is lowering fibrosis biomarkers. We know and just biomarkers and fibrosis on biopsy.

是的。因此，我認為其中一個令人困惑的詞是“共同主要”與“雙重主要”一詞，“共同主要”意味著您必須制定兩個主要終點。這不是這個。顯然，我們將評估在 NASH 消退中實現纖維化減少的患者百分比，但這不是終點。所以這是雙重初選。如果實現了任一終點——任一主要終點，那麼就有機會提交審批。我們很久以前就決定納入這一終點，當時我們相信，根據我們的數據、II 期數據以及我們看到的瑞美羅正在降低纖維化生物標記的持續數據。我們只知道活檢中的生物標記和纖維化。

And we've discussed many times that the Phase II study was not powered, there weren't a sufficient number of patients to observe the fibrosis endpoint. There was an increase in fibrosis responders, particularly actually on both AI technologies. And so we believe that the fibrosis endpoint will be achieved in the Phase III, and this gives us an opportunity to evaluate both endpoints.

我們已經多次討論過，II 期研究沒有動力，沒有足夠數量的患者來觀察纖維化終點。纖維化反應者增​​加，尤其是在兩種人工智慧技術上。因此，我們相信纖維化終點將在第三階段實現，這使我們有機會評估這兩個終點。

So Liisa, what I would just add is while we're not going to get into details of our SAP, we have gained statistical power by virtue of committing to the second outcome study, which makes the alpha situation for having a second primary pretty much a wash. So it's entirely logical to move fibrosis up into a primary endpoint slot based on the power that we've gained by virtue of doing the second study.

所以 Liisa，我要補充的是，雖然我們不打算詳細介紹 SAP，但我們透過致力於第二次結果研究獲得了統計能力，這使得進行第二次初選的 alpha 情況幾乎成為可能洗一洗。因此，根據我們透過第二項研究獲得的力量，將纖維化移至主要終點位置是完全合乎邏輯的。

Okay. And then just a commercial question for Remy. I think investors have been asking a lot about sort of the kind of fusion of the obesity market, with the NASH market and kind of the rising use of GLP-1s and interest there. And can you maybe talk about how these markets may kind of overlap or what you think the use of GLP-1 and any influence of that on the opportunity for resmetirom in NASH?

好的。接下來是雷米的一個商業問題。我認為投資者一直在詢問肥胖市場與 NASH 市場的融合以及 GLP-1 的日益增長的使用和興趣。您能否談談這些市場可能如何重疊，或者您認為 GLP-1 的使用以及它對 NASH 中瑞美羅姆機會的影響？

Yes, I think the answer is similar to the sort of question and the answer we gave around combo therapies. So with the current sort of treatment paradigm for type 2 diabetes and obesity, when we talk to the treaters, there's very high unmet need. So I mean it's one of those things physicians are actively waiting for NASH-specific drugs, drugs that work in the liver that are approved by the FDA. So our patient is going to be on background therapy for type 2 diabetes and obesity by the time resmetirom launches. The answer is yes. But the attractiveness, the commercial potential is not diminished by any of that.

是的，我認為答案類似於我們針對組合療法給出的問題和答案。因此，對於當前第 2 型糖尿病和肥胖症的治療模式，當我們與治療者交談時，發現存在非常高的未滿足需求。所以我的意思是，這是醫生們正在積極等待 FDA 批准的 NASH 特異性藥物、對肝臟起作用的藥物之一。因此，當瑞美羅上市時，我們的患者將接受第 2 型糖尿病和肥胖症的背景治療。答案是肯定的。但吸引力和商業潛力並沒有因此而減弱。

And also remember, I mean, NASH as far as unmet need and patients the size of the population. I mean it's going to support multiple drugs. And we really got to think about different solutions for different patients, but being a lead horse being the first to market in a high unmet need market across the continuum of NASH seems like as far as our Phase III trials. It's a good place to be.

我的意思是，還要記住，NASH 就未滿足的需求和病患人口規模而言。我的意思是它將支持多種藥物。我們確實必須為不同的患者考慮不同的解決方案，但就我們的 III 期試驗而言，成為 NASH 連續體中未滿足的高需求市場中第一個上市的領頭羊似乎是這樣。這是一個好地方。

So what I would add to that is we have a significant number of patients who are on stable doses of SGLT2s and GLP-1s in the Maestro NASH study. which means that on biopsy after being on the drug for 6 months or more that they still had NASH. So we have to just see ultimately what those drugs show in their own Phase III studies. But that doesn't, in any way, go against what Remy just said about the commercial opportunity in any event.

因此，我要補充的是，在 Maestro NASH 研究中，我們有大量患者正在服用穩定劑量的 SGLT2 和 GLP-1。這意味著在服用藥物 6 個月或更長時間後進行活檢時，他們仍然患有 NASH。因此，我們最終必須看看這些藥物在他們自己的 III 期研究中顯示出什麼結果。但這無論如何都不違背雷米剛才所說的商業機會。

Thank you. I would now like to turn the call back over to Dr. Friedman for closing remarks.

謝謝。我現在想將電話轉回給弗里德曼醫生進行總結發言。

Okay. Thanks. I want to first thank Dr. Harrison for spending some time with us today. This is a pivotal time for Madrigal. I'm pleased with the progress that we've made. Our clinical development program continues to advance with the multiple data presentations at EASL followed by top line results for the biopsy study in the fourth quarter. The new outcomes trial we announced today further strengthens the program, we think both clinically and commercially. And we're in a strong financial position for the road ahead. So I want to thank all of you for tuning in today, and we look forward to seeing many of you in London for the EASL meeting.

好的。謝謝。我首先要感謝哈里森博士今天與我們一起度過了一些時間。對馬德里加爾來說，這是一個關鍵時刻。我對我們所取得的進展感到高興。我們的臨床開發計劃繼續推進，在 EASL 上展示了多項數據，隨後在第四季度獲得了活檢研究的頂線結果。我們今天宣布的新結果試驗進一步加強了該計劃，我們認為無論是在臨床還是商業上。我們在未來的道路上處於強大的財務狀況。因此，我要感謝大家今天的收看，我們期待在倫敦參加 EASL 會議。

Thank you for participating. You may now disconnect.

感謝您的參與。您現在可以斷開連線。