Galmed Pharmaceuticals Ltd (GLMD) 2021 Q4 法說會逐字稿

Good day and welcome to the Galmed conference call to discuss financial results for the fourth quarter and year end 2021. Today's conference is being recorded. Before we begin, please note that we will be making certain forward-looking statement on today's call, including those regarding financial results, statements and focus regarding anticipated time lines and expectations with respect to our regulatory and clinical development programs, as well as other statements that relate to future events.

大家好，歡迎參加 Galmed 電話會議，討論 2021 年第四季和年終的財務業績。今天的會議正在錄製中。在我們開始之前，請注意，我們將在今天的電話會議上做出某些前瞻性聲明，包括有關財務業績、有關我們的監管和臨床開發計劃的預期時間表和期望的聲明和重點，以及與未來事件有關的其他聲明。

These statements are based on the beliefs and expectations of management as of today and actual results trends, time lines and projections relating to our financial position and projected development programs and pipeline could defer materially. We urge all investors to read carefully, the risk and uncertainties disclosed in our filings with the SEC including without limitation the risk under the heading risk factors described in our latest annual report on form 20F filed with the SEC. Galmed assumes no applications to update any forward-looking statements or information, which speak as of the respective dates only.

這些聲明是基於管理層今天的信念和期望，與我們的財務狀況和預期的開發計劃及管道相關的實際結果趨勢、時間表和預測可能會有重大延遲。我們敦促所有投資者仔細閱讀我們向美國證券交易委員會提交的文件中披露的風險和不確定性，包括但不限於我們向美國證券交易委員會提交的最新 20F 表年度報告中所述的風險因素項下的風險。 Galmed 不承擔更新任何前瞻性陳述或資訊的應用，這些陳述或資訊僅代表相應日期的觀點。

I will now like to turn the call over to Allen Baharaff, president and chief executive officer. Allen, Please go ahead.

現在，我想將電話轉給總裁兼執行長艾倫·巴哈拉夫 (Allen Baharaff)。艾倫，請繼續。

Thank you, Peter. Good morning and thank you for joining us on today's conference call. I'm pleased to be here today with our Chief Scientific Officer, Dr. Liat Hayardeny; our Chief Financial Officer, Doron Cohen; and Chief Accounting Officer, Yohai Stenzler to provide you with an update on our clinical development programs, as well as report to you on our financial results for the 2021 fourth quarter and full year financial results. As always, we'll be happy to take any question you may have at the conclusion of our prepared remarks. On April 28th, Galmed published interim results from the open label part of the ARMOR phase 3 study.

謝謝你，彼得。早安，感謝您參加今天的電話會議。我很高興今天能與我們的首席科學官 Liat Hayardeny 博士一起來到這裡；我們的首席財務官 Doron Cohen；和首席會計官 Yohai Stenzler 向您提供我們臨床開發計劃的最新情況，並向您報告我們 2021 年第四季度和全年財務業績。像往常一樣，我們很樂意在發言結束時回答您的任何問題。 4 月 28 日，Galmed 發布了 ARMOR 第 3 期研究開放標籤部分的中期結果。

As a quick reminder, for those of you who are new to our story, the open label part of the ARMOR study was designed to explore the effect size of the higher dose of Aramchol for NASH induced fibrosis and the kinetics of histological outcome measure as a function of treatment duration in preparation for the registrational double blind placebo control part of the study. In simple words, the aim of the open label study was to explore the speed and the extent of fibrosis reduction testing the hypothesis that higher Aramchol exposure results in an improved efficacy profile.

快速提醒一下，對於那些剛了解我們故事的人來說，ARMOR 研究的開放標籤部分旨在探索較高劑量的 Aramchol 對 NASH 誘導的纖維化的效果大小和組織學結果測量的動力學作為治療持續時間的函數，為研究的註冊雙盲安慰劑對照部分做準備。簡而言之，開放標籤研究的目的是探索纖維化減少的速度和程度，以驗證以下假設：更高的 Aramchol 暴露會導致療效改善。

Acknowledging the complexity, variability and moderate (inaudible) in liver pathology reading, the open label part was also used to further assess different methodologies that may support and improve fibrosis scoring. All slides were assessed using 3 histopathological reading methodologies. A central pathology committee scored a biopsy according to the conventional formal NASH CRN scoring system, F1 to F4. Scoring was initially performed individually by the 3 independent pathologists followed by consensus reading by the committee.

考慮到肝臟病理學讀數的複雜性、多變性和中等（聽不清楚），開放標籤部分也用於進一步評估可能支持和改善纖維化評分的不同方法。使用 3 種組織病理學讀取方法評估所有投影片。中央病理委員會根據常規正式的 NASH CRN 評分系統 F1 至 F4 對活檢進行評分。評分最初由 3 位獨立病理學家分別進行，然後由委員會達成共識。

Since BARD reading maybe reflect real world pathological assessment, the same central committee was also asked to perform a rank assessment, improvement, worsening, stable of BARD pre and post treatment biopsies, scramble and blinded to sequence, i.e., not knowing which is the baseline and which is the post baseline. Furthermore, artificial intelligence, AI based tools are at the forefront of the development of a more sensitive automated continuous scoring system for the detection of fibrosis change for future NASH and fibrosis clinical trials. Accordingly, the same slide were also read using FibroNest, a quantity, digital pathology image AI analysis, providing continuous fibrosis composite severity score FCS, which allows identifying fibrosis improvement that may be missed by the formal scoring as well as the statistical quantification of change from baseline.

由於 BARD 讀數可能反映現實世界的病理評估，因此也要求同一中央委員會對 BARD 治療前後活檢進行等級評估、改善、惡化、穩定，對序列進行打亂和盲測，即不知道哪個是基線，哪個是治療後基線。此外，人工智慧和基於 AI 的工具處於開發更敏感的自動連續評分系統的前沿，用於檢測未來 NASH 和纖維化臨床試驗的纖維化變化。因此，也使用 FibroNest（一種數量、數位病理影像 AI 分析）讀取了同一張幻燈片，提供了連續的纖維化綜合嚴重程度評分 FCS，這可以識別正式評分可能遺漏的纖維化改善以及從基線變化的統計量化。

Results of post baseline biopsies performed either 24 weeks or 48 weeks from 46 subjects with NASH and F1 to 3 that received Aramchol support the antifibrotic effect of Aramchol and reinforced the favorable safety profile of Aramchol. Treatment with Aramchol 300 milligram BID resulted in a high rate of subjects with fibrosis improvement across the 3 separate pathology reading methods. Both BARD and AI evaluations identified most subjects with fibrosis improvement indicating greater sensitivity to detect change versus categorial scoring. For all methods, treatment effect was larger at 48 compared to 24 weeks. At week 48, fibrosis improvement was identified in 40%, 65% and 100% of patients, according to NASH CRN, BARD and AI respectively.

對接受 Aramchol 治療的 46 名患有 NASH 和 F1 至 3 的受試者在 24 週或 48 週後進行的基線活檢結果支持了 Aramchol 的抗纖維化作用，並強化了 Aramchol 的良好安全性。使用 Aramchol 300 毫克 BID 治療後，在 3 種不同的病理讀數方法中，纖維化改善率較高。 BARD 和 AI 評估均發現大多數受試者的纖維化有所改善，顯示與分類評分相比，檢測變化的敏感度更高。對於所有方法，48 週的治療效果都比 24 週的治療效果更好。在第 48 週，根據 NASH CRN、BARD 和 AI 分別確認 40%、65% 和 100% 的患者纖維化得到改善。

Quantification of change from baseline by AI demonstrated that reduction in fibrosis was statistically significant, both at week 24 P of 0.017 and at week 48 P value smaller than 0.0001. Further analysis based on AI have been prepared for publications in upcoming scientific conferences. Altogether, we believe the results highlight the need to reassess histological analysis in future NASH studies. With regard to the initiation of the double blind placebo control registrational part of the phase 3 study, it is our current assessment that despite considerable efforts from the scientific community and regulatory agencies, there are significant uncertainties that remain unresolved.

透過 AI 對基線變化進行量化表明，纖維化的減少具有統計意義，第 24 週 P 為 0.017，第 48 週 P 值小於 0.0001。已經準備好基於人工智慧的進一步分析，以便在即將舉行的科學會議上發表。總之，我們認為研究結果強調了在未來的 NASH 研究中重新評估組織學分析的必要性。關於啟動第 3 階段研究的雙盲安慰劑對照註冊部分，我們目前的評估是，儘管科學界和監管機構做出了巨大努力，但仍存在尚未解決的重大不確定性。

These include dependence on biopsies as the primary surrogate endpoint with all the complexities described above. No significant progress in validation of non-invasive biomarkers and a high screen failure rate that remains a substantial burden for NASH studies. In addition, Galmed is considering a more robust changes to its development program for NASH. Changes may include focusing on higher risk patients, F3, evaluating patients with compensated cirrhosis, F4 as well as change to study design, such as 2 smaller studies instead of one pivotal study and the addition of a combination arm.

其中包括依賴活檢作為主要替代終點，以及上述所有複雜性。非侵入性生物標記的驗證沒有取得重大進展，且篩檢失敗率高，這仍然是 NASH 研究的沉重負擔。此外，Galmed 正在考慮對其 NASH 開發計劃進行更有力的變更。變化可能包括關注高風險患者 F3、評估患有代償性肝硬化的患者 F4，以及改變研究設計，例如進行 2 項小型研究而不是一項關鍵研究，並增加一個組合組。

Taking all the above into consideration, Galmed has decided to move the initiation of the double blind placebo control part of the study with Aramchol meglumine until second half of 2023, subject to, among other things, the results of our open label part, sufficient funding and clarification of the regulatory approval process for NASH drugs at which time a de-risk scrutinized clinical development plan can be put in place. Importantly, as you may remember, on January, 2022, we announced that the United States Patent and Trademark Office, USPTO granted Galmed new patents related to the use of Aramchol for the treatment of fibrosis and for the treatment for modulating gut microbiota.

考慮到以上所有因素，Galmed 決定將 Aramchol 葡甲胺雙盲安慰劑對照研究部分的啟動時間推遲到 2023 年下半年，但前提是，我們的開放標籤部分的結果、足夠的資金以及 NASH 藥物監管審批流程的明確，屆時可以製定去風險審查的臨床開發計劃。重要的是，您可能還記得，2022 年 1 月，我們宣布美國專利商標局 (USPTO) 授予 Galmed 新的專利，涉及使用 Aramchol 治療纖維化和調節腸道菌群的治療。

With these latest patents, Galmed is strengthening and extending the IP protection of its lead compound Aramchol until December, 2038. This broad patent protection and the clinical data for NASH induced fibrosis is broadening the potential of Aramchol in fibrosis treatment. The past 12 months have been an exciting time for Galmed, as we reported positive interim data from the open label part of the more phase 3 study. And we continue to advance our pipeline compound Amilo-5MER. Amilo-5MER is synthetic peptide consisting of 5 amino acids that exert anti-inflammatory effects by binding to proinflammatory amyloid proteins, preventing polymerization of serum amyloid A, SAA, monomers and thereby interfering with SAA-induced immune cell activation.

憑藉這些最新專利，Galmed 正在加強和延長其主要化合物 Aramchol 的智慧財產權保護至 2038 年 12 月。這種廣泛的專利保護和 NASH 誘導纖維化的臨床數據正在拓寬 Aramchol 在纖維化治療中的潛力。過去的 12 個月對 Galmed 來說是令人興奮的一年，因為我們報告了第 3 階段研究開放標籤部分的積極中期數據。我們將繼續推進我們的產品線化合物 Amilo-5MER。 Amilo-5MER 是一種由 5 種氨基酸組成的合成勝肽，透過與促炎澱粉樣蛋白結合，阻止血清澱粉樣蛋白 A、SAA 單體聚合，從而乾擾 SAA 誘導的免疫細胞活化，發揮抗炎作用。

On January, 2022, we announced positive results from the first in human phase on clinical trial of Amilo-5MER in healthy volunteers. Galmed is currently assessing a number of potential proof of concept studies designed to rapidly generate data that will drive the next steps of the Amilo-5MER clinical program with a clear and efficient route forward. We intend to provide more detail in the next few months. Along with an update on our planned activities, we are pleased to welcome the (inaudible) as our newly appointed CFO. (inaudible) brings more than 25 years of experience in the global financial markets, including significant experience on the buy side of life science companies.

2022年1月，我們宣布了在健康志願者中進行的Amilo-5MER首次人體臨床試驗取得了積極成果。 Galmed 目前正在評估一些潛在的概念驗證研究，旨在快速產生數據，以明確有效的途徑推動 Amilo-5MER 臨床計劃的下一步發展。我們打算在接下來的幾個月提供更多細節。除了更新我們計劃的活動之外，我們還很高興地歡迎（聽不清楚）擔任我們新任命的財務長。 (聽不清楚) 在全球金融市場擁有超過 25 年的經驗，包括在生命科學公司買方的豐富經驗。

Now let me transfer the call to our Chief Accounting Officer, Yohai Stenzler.

現在，讓我將電話轉接給我們的會計長 Yohai Stenzler。

Thank you, Allen. This morning, I will be providing you with our financial results for the fourth quarter in the year ended December 31st, 2021. For more information, please refer to our report on form 20F filed earlier today with the SEC, which among other things provide the summary of such financial results. Our net loss for the 3 and 12 months ended December 31st, 2021, totaled $7.5 million and $32.5 million respectively, compared with the net loss of $10.3 million and $28.8 million for the corresponding period in 2020. As a result, our loss per share for the 3 and 12 months and then December 31st, 2021 was $0.13 per share and $1.32 per share respectively as compared to $0.48 and $1.35 for the corresponding periods in 2020. Research and development expenses for the 3 and 12 months and December, 2021, totaled $6.3 million and $27.2 million. This compares with $9 million and $26.1 million for the corresponding period in 2020.

謝謝你，艾倫。今天上午，我將向您提供我們截至 2021 年 12 月 31 日的第四季度的財務業績。有關更多信息，請參閱我們今天早些時候向美國證券交易委員會提交的 20F 表報告，其中除其他內容外還提供了此類財務結果的摘要。截至 2021 年 12 月 31 日的 3 個月和 12 個月，我們的淨虧損分別為 750 萬美元和 3,250 萬美元，而 2020 年同期的淨虧損為 1,030 萬美元和 2,880 萬美元。因此，我們 2021 年 3 個月、12 個月和 12 月 31 日的每股虧損分別為每股 0.13 美元和每股 1.32 美元，而 2020 年同期分別為 0.48 美元和 1.35 美元。 2021 年 3 個月、12 個月和 12 月的研發費用總計 630 萬美元和 2,720 萬美元。相較之下，2020 年同期分別為 900 萬美元和 2,610 萬美元。

Turning now to G&A, our general and administrative expenses for the 3 and 12 months ended December, 2021 totaled $1.2 million and $5.7 million respectively versus $1.3 million and $4.1 million for 2020. During the 3 and 12 months ended December 31st, 2021, we had a net financial income of $0.05 million and $0.4 million respectively versus $0.1 million and $1.4 million during 2020. Our cash balance as of December 31st, 2021, which includes cash, cash equivalent, restricted cash and marketable security totaled $34.9 million. This compares with $51 million on December 31st, 2020. With that said operator, please provide instructions for the Q&A portion of our call.

現在談談一般及行政開支，截至 2021 年 12 月的 3 個月和 12 個月，我們的一般及行政開支分別為 120 萬美元和 570 萬美元，而 2020 年分別為 130 萬美元和 410 萬美元。截至 2021 年 12 月 31 日的 3 個月和 12 個月，我們的淨財務收入分別為 0.05 萬美元和 0.4 萬美元，而 2020 年分別為 0.1 萬美元和 140 萬美元。截至 2021 年 12 月 31 日的現金餘額，包括現金、現金等價物、受限現金和有價證券，總計 3,490 萬美元。相比之下，2020 年 12 月 31 日這一數字為 5,100 萬美元。話雖如此，接線生請提供有關我們通話問答部分的說明。

(Operator Instructions) Our first question is from the line of Steven Seedhouse with Raymond James.

（操作員指示）我們的第一個問題來自 Raymond James 的 Steven Seedhouse。

Can you hear me?

你聽得到我嗎？

Yes, we can hear you now, Steve.

是的，我們現在可以聽到你的聲音，史蒂夫。

Sorry about that guys. Technical difficulties. Appreciate you taking the question I wanted to ask about the histology data. I noticed you had 2 cohorts 24 weeks and also greater than 48 weeks. And I wanted to ask if that meant patients just showing up a week or 2 late for the 48-week biopsy or if in fact that combines 48 to 72 week paired biopsies. And if so, could you break out sort of how many of each you had and maybe what data from 72-week biopsies would be forthcoming?

我很抱歉，各位。技術困難。感謝您回答我關於組織學數據的問題。我注意到您有 2 個 24 週的隊列和超過 48 週的隊列。我想問的是，這是否意味著患者在進行 48 週活檢時會晚一周或兩週，或者實際上是否結合了 48 週至 72 週的配對活檢。如果是的話，您能否詳細說明每種情況有多少，以及 72 週活檢將提供哪些數據？

Sure. So most of the patients came from the 48 weeks. We did combine the 48 and 72 groups. Approximately, 5 patients came from the 72 and most of them came from the 48.

當然。所以大多數病人都是從48週開始的。我們確實將 48 組和 72 組合併了。大約有 5 名患者來自這 72 名患者，其中大多數來自這 48 名患者。

Can you comment on just the relative fibrosis improvement rates between 48 and 72 weeks?

您能否評論一下 48 週和 72 週之間的相對纖維化改善率？

We think the numbers are too small for 5 patients to draw any conclusion. But in general, what we've seen before in the small numbers of the 20 patient, we see that also later on, but we can't draw any real conclusions from 5 patients. So we prefer to group it together.

我們認為，5 名患者的數量太少，無法得出任何結論。但總的來說，我們之前在 20 名患者中的少數患者中看到的情況，我們後來也看到了，但我們無法從 5 名患者中得出任何真正的結論。所以我們更喜歡將其歸為一組。

Our next question is from line of Kristen Kluska with Cantor Fitzgerald.

我們的下一個問題來自 Cantor Fitzgerald 的 Kristen Kluska。

The first one I wanted to ask was on the second half of 2023 guidance in terms of the registrational study. So some of the factors that you cited are things that, of course you, as the company could control, like understanding which patient population to evaluate, but then some of the factors you cited were things out of your control. So you know, for example, understanding the biopsies as the primary surrogate endpoint. So just wanted to understand a little bit about this time line and what you hope to understand from the field more broadly by the time you plan to start this study next year.

我想問的第一個問題是關於 2023 年下半年註冊研究的指導。因此，您提到的某些因素當然是您作為公司可以控制的，例如了解要評估哪些患者群體，但您提到的某些因素是您無法控制的。例如，將活檢視為主要替代終點。所以只是想了解一點關於這個時間線的情況，以及當您計劃明年開始這項研究時，您希望從更廣泛的領域中了解什麼。

So we believe that the field is developing in the right direction and very recently, there was a Liver forum where the FDA presented and many of the pharma companies involved in the NASH space also participated. So we certainly see a very positive development and AI in particular is a very important one. But we feel that it is still from- as I said, I mean, with all the enormous efforts and work that are done by a number of consortiums both from academia and industry, trying to develop biomarkers and the better understanding of the biopsy reading, it is too risky now to initiate a registrational study when the primary endpoint is not very well defined. And we feel that we should wait and look and we believe by the time that we plan the re-initiation.

因此，我們相信該領域正在朝著正確的方向發展，最近有一個肝病論壇，FDA 出席了論壇，許多涉及 NASH 領域的製藥公司也參加了論壇。因此，我們確實看到了非常積極的發展，其中人工智慧是非常重要的發展。但是我們認為，正如我所說的，儘管來自學術界和工業界的許多聯盟已經付出了巨大的努力和工作，試圖開發生物標誌物並更好地理解活檢讀數，但在主要終點尚未明確定義的情況下啟動註冊研究風險太大。我們覺得我們應該等待並觀察，並相信到那時我們就可以計劃重新啟動。

To reinitiate the study in the second half of 2023 means that we have to start working on that already early 2023. I hope that at that time we'll see some positive signs coming from all these efforts that many participants are advancing. And that will give us sufficient time to have a meeting with the FDA to discuss all these concerns and information, to show it in the information. The FDA is extremely supportive. And we would like to show them, the data that we have. I don't know if there are many companies that do this effort of reading the biopsies in 3 different methodologies. So this is very important data. We've submitted this data as a late breaker for Easel and it's very valuable data for all NASH companies.

在 2023 年下半年重新啟動這項研究意味著我們必須在 2023 年初就開始著手這項工作。我希望到那時我們會看到許多參與者正在推進的所有這些努力中出現一些積極的跡象。這將給我們足夠的時間與 FDA 開會討論所有這些擔憂和訊息，並在訊息中顯示出來。 FDA 非常支持。我們想向他們展示我們掌握的數據。我不知道是否有許多公司採用 3 種不同的方法讀取活檢結果。所以這是非常重要的數據。我們已將這些數據作為 Easel 的最新動態提交，這對所有 NASH 公司來說都是非常有價值的數據。

Okay. And then wanted to ask how some of the recent data that you shared last week, how you're thinking it could correlate to the one daily Aramchol meglumine profile in light of some of the early PK work that you shared between the 2 drugs?

好的。然後想問一下，您上週分享的一些最新數據，根據您在兩種藥物之間分享的一些早期 PK 研究，您認為它如何與每日 Aramchol 葡甲胺概況相關聯？

So as you recall, Aramchol meglumine is circulated as Aramchol. So the (inaudible) Aramchol. We're just talking about a different kind of formulation or a different dose. The advantage of Aramchol meglumine is that we'll be able to get to the same exposure that we see now with the twice daily 300 mg with once daily 300 and something, 380 about milligram of Aramchol once daily. So this is a great advantage both in terms of compliance, in terms of patients- cost of good and the patents, of course. This has a very long patent as I alluded before. So simultaneously, we continued the development of the meglumine preparing it for the initiation of the double blind, but I don't really see any difference between the data between the 2 formulations, Aramchol and Aramchol meglumine.

正如您所記得的，Aramchol 葡甲胺以 Aramchol 的名稱流通。所以（聽不清楚）Aramchol。我們只是在討論不同類型的配方或不同的劑量。 Aramchol 葡甲胺的優點是，我們能夠獲得與現在每天兩次 300 毫克相同的劑量，而每天一次 300 毫克左右，每天一次約 380 毫克的 Aramchol。因此，無論從合規性、病患成本或專利角度而言，這都是一個巨大的優勢。正如我之前提到的，這個專利很長。因此，我們同時繼續開發葡甲胺，為啟動雙盲試驗做準備，但我真的沒有看到 Aramchol 和 Aramchol 葡甲胺這兩種配方之間的數據有任何差異。

Okay. And then the last question for me was just on Amilo-5MER. You highlighted that over the next couple months, you might share some plans in terms of proof of concept studies, but I just wanted to ask if you're still looking to first assess IBD. I know when you first introduced Amilo-5MER, you had discussed a number of potential programs. Thank you.

好的。我的最後一個問題是關於 Amilo-5MER 的。您強調說，在接下來的幾個月裡，您可能會分享一些概念驗證研究方面的計劃，但我只是想問您是否仍希望先評估 IBD。我知道當您第一次介紹 Amilo-5MER 時，您已經討論了許多潛在的計劃。謝謝。

Indeed. We developed the first formulation for Amilo-5MER is an intracolonic oral formulation and this is developed for IBD. Now we look carefully at the space and the competitive landscape and we are trying to create an edge for Amilo-5MER in this competitive landscape. So one of the possibility would be a combination with another compound, which will ease the recruitment, because we know that recruitment is very challenging, almost as much as challenging for NASH trials, but we can solve that if we do a combination treatment and also the population, which population are we targeting, mild to moderate, moderate to severe. At the same time, we are also looking for the systemic exposure of Amilo-5MER. And once we will confirm that it will open for us a variety of other indications, which serum amyloid play crucial rule. One for instance is FMS, Familial Mediterranean Fever, but I can name others which is highly relevant for us. And we are trying to- looking for this inflammatory indication where Amilo-5MER can play important role.

的確。我們開發的第一個 Amilo-5MER 配方是一種結腸內口服配方，專為 IBD 開發。現在我們仔細研究了空間和競爭格局，並試圖在這種競爭格局中為 Amilo-5MER 創造優勢。因此，其中一種可能性是與另一種化合物聯合使用，這將簡化招募工作，因為我們知道招募工作非常具有挑戰性，幾乎與 NASH 試驗一樣具有挑戰性，但如果我們進行聯合治療，我們就可以解決這個問題，同時還可以確定人群，我們針對的是哪些人群，輕度到中度，中度到重度。同時，我們也在尋找 Amilo-5MER 的系統暴露。一旦我們確認了這一點，它就會為我們揭示多種其他適應症，其中血清澱粉樣蛋白起著至關重要的作用。例如，家族性地中海熱（FMS）就是其中一種，但我也可以說出其他與我們高度相關的疾病。我們正在嘗試尋找 Amilo-5MER 可以發揮重要作用的炎​​症指徵。

Our next question is from the line of Naz Rahman with Maxim Group.

我們的下一個問題來自 Maxim Group 的 Naz Rahman。

I have a few. First, I'm going to start on your recent data on how you used the 3 different methodologies. Could you just sort of talk about what you sort of see as a clinical value of the different methodologies and have you had any conversation with like KOLs or DFD on these methodologies, seeing how the rates of fibrosis improvement were so different? Did you find that like KOLs are potentially updated and would prefer like a more stricter CRN methodology versus the AI methodology?

我有幾個。首先，我將從您最近的數據開始介紹您如何使用這 3 種不同的方法。能否簡單談談您認為不同方法的臨床價值？您是否與 KOL 或 DFD 就這些方法進行過交流，以了解纖維化改善率有何不同？您是否發現 KOL 可能會更新，並且更喜歡更嚴格的 CRN 方法而不是 AI 方法？

Yes. So thank you for the excellent question. All these methodologies are relevant to the question of sensitivity. And we need to really discuss the data with the FDA. Galmed is under the opinion and together with the KOLs, I mean, this is something, of course we are consulting with the KOLs. The AI company we use was highly recommended to us by our KOL. I know that there are 8 other abstract, which these companies are going to present at Easel for other NASH companies. So clearly, they are the forefront of AI. We believe that there is and I think this is data that also presented, but it certainly will be presented during Easel is the correlation between the AI and peer reading, for instance and the high correlation between AI and peer reading.

是的。非常感謝您提出這個非常好的問題。所有這些方法都與敏感度問題相關。我們需要與 FDA 認真討論數據。 Galmed 是根據意見並與 KOL 一起制定的，我的意思是，這當然是我們正在與 KOL 協商的事情。我們使用的AI公司是我們的KOL強烈推薦的。我知道還有其他 8 份摘要，這些公司將在 Easel 上為其他 NASH 公司展示。顯然，他們是人工智慧的前沿。我們相信有，而且我認為這也是所呈現的數據，但它肯定會在 Easel 期間呈現，例如人工智慧與同伴閱讀之間的相關性以及人工智慧與同伴閱讀之間的高度相關性。

And this is important because peer reading is the closest methodology that we see for real life. And if we can support the peer reading together with AI, that would, I think a combination of the 2 and potentially that can be also validated by biomarkers, non-invasive biomarkers, all of that can bring the NASH space and in particular, the fibrosis effect into a different category. Simply, the NASH CRN is limited by definition. And as you may recall, in the hepatitis C studies, the ranking was not done through NASH CRN. It was done by peer readings. We are going back to the traditional "reading" that was used in hep C clinical studies supported by the very novel AI technologies, which shows the improvement that is normally missed by the human eye. We are very excited and we try as much as possible to move away from categorical reading, i.e., F1, 2, 3 into a continuous method, which is much more accurate.

這很重要，因為同伴閱讀是我們所看到的最接近現實生活的方法。如果我們能夠支持同行評審和人工智慧，那麼我認為這兩者的結合可能也可以透過生物標記、非侵入性生物標記進行驗證，所有這些都可以將 NASH 領域，特別是纖維化效應帶入不同的類別。簡單地說，NASH CRN 受到定義限制。您可能還記得，在C型肝炎研究中，排名不是透過 NASH CRN 進行的。這是透過同行閱讀完成的。我們將回歸到在非常新穎的人工智慧技術支援下的丙型肝炎臨床研究中使用的傳統“讀數”，它顯示了人眼通常無法察覺的改善。我們非常興奮，我們盡可能地嘗試擺脫分類閱讀，即 F1、2、3，轉而採用更準確的連續方法。

You actually brought up another point I was going to ask. This is for analysis. Did you find any biomarker correlation with the AI readings or like any sensitive correlations with biomarkers on AI readings?

您實際上提出了我要問的另一個問題。這是為了分析。您是否發現生物標記與 AI 讀數之間存在相關性，或與 AI 讀數上的生物標記之間有任何敏感相關性？

So I can't talk too much because otherwise, Easel would not give me my late-breaker. So unfortunately, I have to be very careful with the information that I disclose, but I can tell you, these are very, very interesting. I think the interesting point is, again, as far as I know, our abstract is the first time that you have both the clinicians, the key, the KOLs and clinicians together with the leading histopathologists on one paper agreeing and raising the main issues and concerns and basically putting it in a very open and frank way, the biopsy reading challenges and hopefully that would support the entire space.

所以我不能說太多，因為否則，Easel 就不會給我晚間休息時間。所以不幸的是，我必須非常小心地披露訊息，但我可以告訴你，這些資訊非常非常有趣。我認為有趣的一點是，據我所知，我們的摘要是第一次讓臨床醫生、關鍵人物、KOL 和臨床醫生以及領先的組織病理學家在一篇論文中達成一致並提出主要問題和擔憂，並且基本上以非常開放和坦率的方式提出活檢閱讀挑戰，希望這能夠支持整個領域。

Just one last question, Amilo-5MER, have you considered or are you considering potentially partnering the product for future development and non-diluted sources of financing?

最後一個問題，Amilo-5MER，您是否考慮過或正在考慮與該產品合作，以實現未來的發展和非稀釋的融資來源？

Absolutely. Absolutely. And thank you again, Justin, for this- sorry (inaudible) for this question. Galmed is I think what we've demonstrated over the years is our core competence is to advance those pre-clinical assets quickly into clinical preferably phase one and proof of concept studies. For longer studies and phase 3 studies collaborating with other biotech or pharma companies, I think especially nowadays is the right way to move forward. And we will continue and this is what we are trying to do is, form coalitions of partners that have the same ideas to advance the assets as much as quickly as we can into advanced medical studies, no matter whether it is a pharma or another biotech company.

絕對地。絕對地。再次感謝你，賈斯汀，抱歉（聽不清楚）提出了這個問題。我認為，Galmed 多年來已經證明了我們的核心競爭力，即將這些臨床前資產迅速推進到臨床階段，最好是第一階段和概念驗證研究。對於與其他生物技術或製藥公司合作的長期研究和第 3 階段研究，我認為尤其是在當今，這是正確的前進方式。我們將繼續努力，組成擁有相同想法的合作夥伴聯盟，盡快將資產推進到高級醫學研究中，無論是製藥公司還是其他生技公司。

Our next question is from the line of Ed Arce.

我們的下一個問題來自 Ed Arce。

Can you hear me?

你聽得到我嗎？

Yes, Ed.

是的，埃德。

Great. First, I joined a bit late, but I understand that you were moving the time lines for the phase 3 portion of our (inaudible) second half of next year and having to do at least in part with defining of the primary endpoint and working with the FDA. Could you perhaps just give us a bit more detail on some of the criteria that you were reviewing as you were considering pushing this back, just to give a better sense for why you thought this was necessary?

偉大的。首先，我加入得有點晚，但我知道你們正在調整我們（聽不清楚）明年下半年第三階段的時間表，並且至少有一部分與定義主要終點和與 FDA 合作有關。您能否向我們詳細介紹一下您在考慮推遲這一決定時所審查的一些標準，以便更好地說明您為什麼認為這是必要的？

So thank you, Ed. So to start with the screen failure, when you look at other NASH studies, including our study, the screen failure for the NASH studies is about between 80% to 90%. It means you have to biopsy 10 patients in order to get one eligible patient. I don't think that in order to run 1000 patients (inaudible) you would need to biopsy 10,000 patients. This is something which I don't think no one should expect. And we should wait and see and find together with everyone who is working on biomarkers, validated biomarkers, how we can reduce these numbers into a sensible number not only for the cost of the study, but also (inaudible) the patients.

所以謝謝你，埃德。因此，從篩檢失敗開始，當您查看其他 NASH 研究（包括我們的研究）時，您會發現 NASH 研究的篩檢失敗率約為 80% 到 90%。這意味著你必須對 10 名患者進行活檢才能找到一名符合條件的患者。我認為，為了對 1000 名患者進行檢查（聽不清楚），你不需要對 10,000 名患者進行活檢。我想這是任何人都不會想到的事情。我們應該拭目以待，與所有致力於生物標記、經過驗證的生物標記研究的人一起，共同尋找如何將這些數字減少到一個合理的數字，不僅適用於研究成本，也適用於（聽不清楚）患者。

All these patients that need to do these unnecessary biopsies and the frustration of the PI and the patient. And we are looking for a method with a better sensitivity that will allow a smaller sample size. For instance, AI. So this is to start with the screen. And then I'm moving to the end of the study, the results. You can't run a study when the rules of the, how do you say, we started playing basketball and we are moving and playing hockey or cricket. I mean, this is something which is again, when you see the discrepancy between the different methodologies and there is no clear guidance, which one is the one that we should use.

所有這些患者都需要進行這些不必要的活檢，這讓 PI 和患者都感到沮喪。我們正在尋找一種靈敏度更高、可以使用更小樣本的方法。例如人工智慧。所以這是從螢幕開始的。然後我將進入研究的最後階段，討論結果。當你遵守規則時，你無法進行研究，你怎麼說呢，我們開始打籃球，然後我們正在打曲棍球或板球。我的意思是，當你看到不同方法之間存在差異並且沒有明確的指導時，我們應該使用哪一種。

This is probably the reason why we see so many NASH studies have failed. So these 2 by itself, I think, demand in addition to what I've said earlier, the ability to better design the study, think about the population, whether we should go for more advanced population, whether we should go for 2 smaller studies, whether the one large pivotal study, whether we should test combination and there's still no guidance on combination, how do you include a combination arm in this kind of pivotal study? So I hope that by the time that we initiate- reinitiate the double blind part of the study, we will get answers to all these questions.

這或許就是我們看到如此多的 NASH 研究失敗的原因。因此，我認為，除了我之前所說的之外，這兩項本身就要求能夠更好地設計研究，考慮人群，我們是否應該針對更先進的人群，是否應該進行兩項小型研究，是否進行一項大型關鍵研究，是否應該測試組合，並且仍然沒有關於組合的指導，如何在這種關鍵研究中納入組合組？因此我希望，當我們啟動或重新啟動雙盲研究部分時，我們能夠得到所有這些問題的答案。

Okay, great. So the next question is regarding your data, your initial data out of FibroNest and the fibrosis composite score. Obviously, truly compelling data on the reduction of at least 0.3 units over that time period. And I understand that this does not correlate well with the NASH CRN definition of histology. And fact, if you were really trying to devise a better method, you wouldn't necessarily want to have it correlate to histology. So you in the end have- the space has had for several years sort of catch-22, trying to move away from histology and yet still having to correlate to it. So the question is with this data in hand, are you intending to have discussions with the FDA (inaudible) say basically, moving to essentially a better method and not having to continue to tie things to biopsy, or is the FDA more inclined to listen to some of these groups like in the US and Europe that are large data of patients that are being worked on over several years.

好的，太好了。所以下一個問題是關於您的數據，即 FibroNest 的初始數據和纖維化綜合評分。顯然，在這段時間內減少至少 0.3 個單位的數據才真正令人信服。而且我知道這與 ​​NASH CRN 組織學定義不太相關。事實上，如果您真的想設計更好的方法，您不一定希望它與組織學相關。因此，你最終會——這個領域幾年來一直處於一種第 22 條軍規的狀態，試圖擺脫組織學但仍然必須與之相關。所以問題是，有了這些數據，您是否打算與 FDA（聽不清楚）進行討論，基本上是轉向一種更好的方法，而不必繼續將事情與活檢聯繫起來，或者 FDA 是否更傾向於聽取一些團體的意見，比如美國和歐洲的團體，他們擁有多年來一直在研究的大量患者數據。

So thank you, Ed. I think this is a very important question. We are trying to move from a categorical method into a sequential method, which by definition is more sensitive and more accurate. And hence we could also demonstrate a P value, which you cannot demonstrate in a categorical number. Now I think that in the first stage, it would be a combination- with the AI support. You know that FDA has now already allowed to use of AI as a post reader. (inaudible) and there's another AI reading, but this is not good enough because that keeps us with the NASH CRN and create additional noise. We are not alone. As I said, there are 8 other abstracts (inaudible). Other companies, large pharma and trying to better time and together with the FDA, find ways that we can still use the biopsies because I don't see in the near future, any validated biomarker can replace the biopsies. So still use the biopsies, but using it in a different way, like I said before, for instance, a combination of the BARD and AI. Now we expect top plan correlations between methods. So for example, the 24 is better than 48. So there is very clear dataset that we already see from these numbers, notwithstanding the fact that we are using 3 different methodologies. This is, by the way, across all methodologies, the 48 better than 24- the direction is the same. So whether it's CRN, BARD or AI, you see the direction is the same and this gives a lot of confidence in the BARD and AI themselves.

所以謝謝你，埃德。我認為這是一個非常重要的問題。我們正在嘗試從分類方法轉向順序方法，從定義上講，後者更加敏感，也更加準確。因此我們也可以證明 P 值，而這是無法用分類數證明的。現在我認為在第一階段它將是一個結合——與人工智慧支援。您知道 FDA 現在已經允許使用 AI 作為貼文閱讀器。 （聽不清楚）還有另一個 AI 讀數，但這還不夠好，因為這會讓我們保留 NASH CRN 並產生額外的噪音。我們並不孤單。正如我所說，還有其他 8 篇摘要（聽不清楚）。其他公司和大型製藥公司也在嘗試更好地掌握時機並與 FDA 一起尋找仍然可以使用活檢的方法，因為我不認為在不久的將來任何經過驗證的生物標誌物可以取代活檢。因此仍然使用活檢，但以不同的方式使用，就像我之前說的，例如，BARD 和 AI 的組合。現在我們期望方法之間頂級計劃的相關性。例如，24 比 48 好。因此，儘管我們使用了 3 種不同的方法，但我們已經從這些數字中看到了非常清晰的數據集。順便說一句，在所有方法中，48 都比 24 好，方向是相同的。因此，無論是 CRN、BARD 還是 AI，您都會發現方向都是相同的，這給了 BARD 和 AI 本身很大的信心。

Thank you. Ladies and gentlemen, we have reached the end of the question and answer session and I would now like to turn the call back to Allen Baharaff for closing remarks.

謝謝。女士們、先生們，問答環節已經結束，現在我想請艾倫·巴哈拉夫作結束語。

So thank you very much, everyone for joining our today's call. As always we're available for any follow-up question and we look forward to seeing you on 2023 first quarter call, which is just around the corner- sorry, 2022 first quarter call. Thank you all. Bye-bye.

非常感謝大家參加我們今天的電話會議。像往常一樣，我們隨時可以回答任何後續問題，我們期待在即將到來的 2023 年第一季度電話會議上見到您 - 抱歉，是 2022 年第一季電話會議。謝謝大家。再見。

Thank you. This concludes today's teleconference. You may now disconnect your lines at this time. Thank you for your participation.

謝謝。今天的電話會議到此結束。現在您可以斷開您的線路了。感謝您的參與。