CymaBay Therapeutics Inc (CBAY) 2023 Q1 法說會逐字稿

Good day, ladies and gentlemen, and welcome to CymaBay's First Quarter 2023 Financial Results and Business Update Conference Call. (Operator Instructions) Please be advised that the call will be recorded at the company's request. It is also being webcast live on the Investors section at the CymaBay website at www.cymabay.com.

女士們、先生們，美好的一天，歡迎參加 CymaBay 2023 年第一季度財務業績和業務更新電話會議。 （操作員說明）請注意，根據公司的要求，將對通話進行錄音。該活動還在 CymaBay 網站 www.cymabay.com 的投資者部分進行網絡直播。

At this time, I would like to turn the call over to Mr. Paul Quinlan, General Counsel at CymaBay. Mr. Quinlan, please proceed.

現在，我想將電話轉給 CymaBay 總法律顧問 Paul Quinlan 先生。昆蘭先生，請繼續。

Thank you, operator, and good afternoon, everyone. I hope that you have had a chance to review the press release we issued announcing our first quarter 2023 financial results and business updates. You can access that release on our website under the Investors tab. Joining me on the call today are Sujal Shah, Chief Executive Officer; Chuck McWherter, Chief Scientific Officer and President of R&D; Lewis Stuart, Chief Commercial Officer; and Dan Menold, VP Finance. Following our prepared remarks, we will open the call for Q&A.

謝謝接線員，大家下午好。我希望您有機會閱讀我們發布的宣布 2023 年第一季度財務業績和業務更新的新聞稿。您可以在我們網站的“投資者”選項卡下訪問該新聞稿。今天與我一起參加電話會議的是首席執行官 Sujal Shah； Chuck McWherter，首席科學官兼研發總裁；劉易斯·斯圖爾特 (Lewis Stuart)，首席商務官；和財務副總裁 Dan Menold。在我們準備好的發言之後，我們將開始問答環節。

Before we begin, I'd like to remind everyone that statements made during this conference call, including the Q&A session relating to CymaBay's expected future performance, business prospects, events or plans, including clinical plans, regulatory approvals, funding and repayment schedules, anticipated timelines and data release dates, cash runway and planning for commercialization are forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995.

在我們開始之前，我想提醒大家，本次電話會議期間所做的聲明，包括問答環節，涉及 CymaBay 的預期未來業績、業務前景、事件或計劃，包括臨床計劃、監管部門批准、融資和還款時間表、預期時間表和數據發布日期、現金跑道和商業化規劃均屬於 1995 年《私人證券訴訟改革法案》所定義的前瞻性陳述。

Although the company believes that the expectations reflected in such forward-looking statements are based on reasonable assumptions, actual outcomes and results are subject to risks and uncertainties and could differ materially from those forecast due to the impact of many factors. The company assumes no obligation to update or supplement any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by applicable law.

儘管該公司認為此類前瞻性陳述中反映的預期是基於合理的假設，但實際結果和結果會受到風險和不確定性的影響，並且由於許多因素的影響，可能與預測存在重大差異。公司不承擔更新或補充任何前瞻性陳述的義務，無論是由於新信息、未來事件還是其他原因，除非適用法律要求。

Participants are directed to the cautionary statements set forth in today's press release as well as the risk factors set forth in CymaBay's quarterly and annual reports filed with the SEC or factors that could cause actual results to differ materially from those anticipated in the forward-looking statements. This conference call is the property of CymaBay, and any recording or rebroadcast is expressly prohibited without the written consent of CymaBay.

參與者應注意今天新聞稿中提出的警示性聲明以及 CymaBay 向 SEC 提交的季度和年度報告中提出的風險因素或可能導致實際結果與前瞻性聲明中預期存在重大差異的因素。本次電話會議屬於 CymaBay 的財產，未經 CymaBay 書面同意，明確禁止任何錄音或轉播。

At this time, I'd like to turn the call over to Sujal.

此時，我想將電話轉給 Sujal。

Thank you, Paul. Good afternoon and thank you for joining us today. 2023 continues to be an exciting year for CymaBay with only a few short months before we report results from the RESPONSE Phase III study of seladelpar in patients with primary biliary cholangitis or PBC. Conducted across 5 continents, the seladelpar development program embodies our commitment to advancing care for patients with this rare autoimmune liver disease. In service of their need for improved treatments, we have worked in close collaboration with patient advocacy groups and the world's leading disease experts to ensure that the design of the seladelpar program evaluates those aspects most important for patient needs.

謝謝你，保羅。下午好，感謝您今天加入我們。 2023 年對 CymaBay 來說仍然是激動人心的一年，距離我們報告 seladelpar 治療原發性膽汁性膽管炎或 PBC 患者的 RESPONSE III 期研究結果僅剩短短幾個月。 seladelpar 開發計劃在五大洲開展，體現了我們對促進這種罕見自身免疫性肝病患者護理的承諾。為了滿足他們對改進治療的需求，我們與患者倡導團體和世界領先的疾病專家密切合作，以確保 seladelpar 計劃的設計評估對患者需求最重要的那些方面。

Our early Q1 accomplishments included licensing of rights to develop and commercialize seladelpar in Japan to Kaken Pharmaceutical company and a follow-on equity offering. The capital we raised will fund our operating plan through Q3 of 2024. Our update today will describe our key activities, progress and accomplishments made since our last call and will share catalysts expected in the months ahead.

我們第一季度的早期成就包括向 Kaken Pharmaceutical 公司授予在日本開發和商業化 seladelpar 的權利以及後續股權發行。我們籌集的資金將為我們截至 2024 年第三季度的運營計劃提供資金。我們今天的更新將描述自上次電話會議以來我們的主要活動、進展和成就，並將分享未來幾個月預計的催化劑。

Last week, we announced the appointment of Harish Shantharam as our Chief Financial Officer. For almost 20 years, Harish led various financial functions in commercial biotech companies with a particular focus on setting strategy and building financial planning and accounting operations to prepare companies for commercial drug launch. Harish spent 11 years at Gilead Sciences, last serving as Vice President and Head of Global Commercial Finance. Prior to Gilead, he served in various roles of increasing responsibility, driving forecasting, commercial analytics and business development at Amgen. Over the course of his career, Harish has supported multiple product launches and brings his operational leadership capabilities as well as his strong strategic finance and commercial experience to CymaBay as we embark on a transformation to becoming a fully integrated commercial biotech company. We are thrilled to have him on our team and look forward to his impact on our mission to deliver seladelpar to patients with PBC.

上週，我們宣布任命 Harish Shantharam 為我們的首席財務官。近 20 年來，Harish 領導商業生物技術公司的各種財務職能，特別注重製定戰略、建立財務規劃和會計業務，為公司商業藥物上市做好準備。 Harish 在吉利德科學公司工作了 11 年，最後擔任副總裁兼全球商業金融主管。在加入吉利德之前，他曾在安進擔任過各種職務，包括增加責任、推動預測、商業分析和業務開發。在他的職業生涯中，Harish 支持了多個產品的發布，並為 CymaBay 帶來了他的運營領導能力以及豐富的戰略財務和商業經驗，幫助我們開始轉型成為一家完全一體化的商業生物技術公司。我們很高興他加入我們的團隊，並期待他對我們向 PBC 患者提供 seladelpar 的使命產生影響。

Since our last update call, we have continued to collaborate with PBC stakeholder communities. In April, we had the opportunity to be a sponsor and participant in the 10-year anniversary meeting of the Global PBC Study Group that assembled experts, advocacy groups, regulators and industry with the theme on the future of treating PBC. Emerging concepts included advancing treatment goals to include normalization of cholestatic and inflammatory markers of disease, addressing clinical symptom burden, particularly fatigue and pruritus, and leveraging inherent knowledge within real-world data to better understand risk parameters and effects of treatments on long-term outcomes.

自上次更新電話會議以來，我們繼續與 PBC 利益相關方社區合作。 4 月份，我們有機會成為全球 PBC 研究小組 10 週年紀念會議的讚助商和參與者，該會議聚集了專家、倡導團體、監管機構和行業，主題是治療 PBC 的未來。新興概念包括推進治療目標，包括疾病的膽汁淤積和炎症標誌物的正常化，解決臨床症狀負擔，特別是疲勞和瘙癢，以及利用現實數據中的固有知識更好地了解風險參數和治療對長期結果的影響。

Thanks to the advances by so many around the world, we are convinced that an important inflection point is at hand for treating patients with PBC. Novel improved treatments and growing investments by the collective community is increasing awareness and diagnosis of PBC. Our goal is to increase the number of patients treated with therapies that for the first time have the potential to both reduce the risk of disease progression while also improving quality of life.

由於世界各地的眾多進展，我們相信治療 PBC 患者的一個重要拐點即將到來。集體社區不斷改進的新穎治療方法和不斷增加的投資正在提高對 PBC 的認識和診斷。我們的目標是增加接受治療的患者數量，這些治療首次有可能降低疾病進展的風險，同時提高生活質量。

Today, I will ask Chuck McWherter, our Chief Scientific Officer and President of Research and Development, to provide important updates on our clinical progress. Lewis Stuart, our Chief Commercial Officer, will then share a brief summary of our pre-commercial planning activities before handing the call to Dan Menold, VP of Finance, to review our financials for the first quarter.

今天，我將請我們的首席科學官兼研發總裁 Chuck McWherter 提供有關我們臨床進展的重要最新信息。然後，我們的首席商務官 Lewis Stuart 將分享我們的商業前規劃活動的簡要總結，然後致電財務副總裁 Dan Menold，審查我們第一季度的財務狀況。

Chuck?

查克？

Thank you, Sujal. I'm pleased to report the progress we made this quarter in our 2 global Phase III studies of seladelpar in patients with PBC. The pivotal response study and the long-term safety ASSURE study are together currently active in more than 25 countries and more than 115 research sites and with more than 300 participants. We continue to be encouraged in both studies with patient retention. The most recently quarterly review by the RESPONSE Data Safety Monitoring Board directed that as before, the study can continue without any changes. Our team is collaborating with our partners and the sites to complete RESPONSE and then to analyze data from both studies. Our goal is to share top line results from RESPONSE in the third quarter and then to submit an NDA as soon as feasible.

謝謝你，蘇加爾。我很高興地報告我們本季度在 seladelpar 治療 PBC 患者的兩項全球 III 期研究中取得的進展。關鍵反應研究和長期安全性 ASSURE 研究目前在超過 25 個國家和超過 115 個研究中心進行，參與者超過 300 名。我們在這兩項研究中繼續受到患者保留率的鼓舞。 RESPONSE 數據安全監測委員會最近的季度審查表明，與以前一樣，該研究可以繼續進行，無需任何更改。我們的團隊正在與我們的合作夥伴和站點合作完成響應，然後分析這兩項研究的數據。我們的目標是分享第三季度 RESPONSE 的主要結果，然後儘快提交 NDA。

Our aim for RESPONSE is to confirm the significant and clinically meaningful placebo-controlled results observed in ENHANCE after 3 months. In RESPONSE, the alkaline phosphatase and bilirubin composite and alkaline phosphatase normalization endpoints are at 12 months, and the pruritus endpoint is at 6 months. The ENHANCE results were published online late last month after peer review in the AASLD flagship journal, Hepatology. The article reports results in patients with PBC having persistent elevations in alkaline phosphatase, most of whom are taking, if tolerated, first-line ursodeoxycholic acid. After 3 months in ENHANCE, nearly 80% of patients taking daily oral seladelpar 10 milligrams achieved the alkaline phosphatase bilirubin composite endpoint previously used by regulators for approval. Nearly 1 in 3 of these patients achieved normalization of alkaline phosphatase after 3 months despite having an on-average pretreatment level of 2.5x the upper limit of normal.

我們的 RESPONSE 目標是確認 3 個月後在 ENHANCE 中觀察到的顯著且具有臨床意義的安慰劑對照結果。在 RESPONSE 中，鹼性磷酸酶和膽紅素複合物以及鹼性磷酸酶正常化終點為 12 個月，瘙癢終點為 6 個月。經過同行評審後，ENHANCE 結果於上月底在線發表在 AASLD 旗艦期刊《Hepatology》上。該文章報告了 PBC 患者鹼性磷酸酶持續升高的結果，其中大多數患者在耐受的情況下正在服用一線熊去氧膽酸。經過 3 個月的 ENHANCE 治療，每天口服 seladelpar 10 毫克的患者中，近 80% 達到了監管機構此前批准的鹼性磷酸酶膽紅素複合終點。儘管平均預處理水平為正常上限的 2.5 倍，但其中近三分之一的患者在 3 個月後實現了鹼性磷酸酶的正常化。

The article further reported that in patients with prespecified baseline moderate to severe itch, those taking seladelpar 10 milligrams for 3 months, had significant improvements compared to placebo and their pruritus intensity using a daily electronic diary. ENHANCE is the first study in patients with PBC using a prespecified testing of endpoints of markers of disease activity and symptoms to achieve both significant and clinically meaningful differences on active treatment compared with placebo.

文章進一步報導，在預先設定基線中度至重度瘙癢的患者中，服用 seladelpar 10 毫克連續 3 個月的患者與安慰劑相比，通過每日電子日記的瘙癢強度有顯著改善。 ENHANCE 是第一項針對 PBC 患者的研究，使用預先指定的疾病活動和症狀標誌物終點測試，以實現積極治療與安慰劑相比的顯著且具有臨床意義的差異。

Once again, we will have a significant presence with 3 accepted abstracts to be presented at the EASL Congress in Vienna, Austria from June 21 to 24. Once the EASL embargo is lifted in June, we will be able and eager to share the insights we've gathered in an abstract titled Seladelpar Treatment resulted in correlated decreases in serum IL-31 and pruritus in patients with primary biliary cholangitis, post-hoc results from the Phase III randomized, placebo-controlled ENHANCE study to be presented by Professor, Andreas Kremer of the University of Zurich. The IL-31 pathway is a validated target associated with chronic pruritus in dermatological diseases.

我們將再次在 6 月 21 日至 24 日在奧地利維也納舉行的 EASL 大會上發表 3 份已接受的摘要。一旦 6 月 EASL 禁運解除，我們將能夠並渴望分享我們的見解。 Andreas Kremer 教授將在題為 Seladelpar 治療導致原發性膽汁性膽管炎患者血清 IL-31 和瘙癢相關降低的摘要中收集到來自 III 期隨機、安慰劑對照 ENHANCE 研究的事後結果蘇黎世大學。 IL-31 通路是與皮膚病慢性瘙癢相關的經過驗證的靶點。

A second clinical abstract to be presented by Professor Gideon Hirschfield from the University of Toronto Liver Center is titled Baseline Characteristics and Risk Profiles of 1,111 Patients with Primary Biliary Cholangitis in Need of Second-line Therapy. CymaBay has acquired considerable experience, having conducted clinical research in PBC since 2015.

多倫多大學肝臟中心的 Gideon Hirschfield 教授將發表第二份臨床摘要，標題為 1,111 名需要二線治療的原發性膽汁性膽管炎患者的基線特徵和風險概況。 CymaBay自2015年起在PBC開展臨床研究，積累了豐富的經驗。

The third accepted abstract is titled Novel Pathways Implicated in the Seladelpar Mediated Reductions of Established Liver Fibrosis are identified from RNA-seq data using Plex search and 2 independent mouse pharmacology datasets. Presented by the CymaBay research team, new mechanistic preclinical findings are recorded. The full results of these abstracts and the progress they represent will be available at the Congress.

第三篇被接受的摘要標題為“使用 Plex 搜索和 2 個獨立的小鼠藥理學數據集從 RNA-seq 數據中識別了 Seladelpar 介導的肝纖維化減少中涉及的新途徑”。 CymaBay 研究團隊提出，記錄了新的機械臨床前發現。這些摘要的完整結果及其代表的進展將在大會上公佈。

At this time, I'll turn it over to Lewis.

這個時候，我會把它交給劉易斯。

Thank you, Chuck. During our last quarterly call, I shared several themes that are core components of our seladelpar go-to-market strategy. Beginning in January, we began activating numerous work streams from our commercial roadmap that will lay the groundwork for the company's overall launch readiness and set a course for flawless execution of the seladelpar PBC launch. We initiated key commercial infrastructure projects within legal, finance and human resources to support organizational readiness while beginning to evaluate logistics solutions to support our commercial supply and distribution channel strategy. Many of these projects have longer timelines with multi-stage deliverables, all to be enabled in careful alignment with key corporate milestones.

謝謝你，查克。在我們上一季度的電話會議中，我分享了幾個主題，它們是我們 seladelpar 進入市場戰略的核心組成部分。從一月份開始，我們開始啟動商業路線圖中的眾多工作流，這將為公司的整體發布準備工作奠定基礎，並為 seladelpar PBC 發布的完美執行製定路線。我們在法律、財務和人力資源方面啟動了關鍵的商業基礎設施項目，以支持組織準備工作，同時開始評估物流解決方案以支持我們的商業供應和分銷渠道戰略。其中許多項目的時間表較長，具有多階段的可交付成果，所有這些項目的啟用都需要與關鍵的公司里程碑保持一致。

Our primary market research and data analytics initiatives are ongoing and continue to inform our HCP, patient and payer strategies. We recently finalized value messaging research with key U.S. payer organizations, and we're encouraged by their response to seladelpar's target product profile, which will be further strengthened by the results from our pivotal studies and continued evidence generation.

我們的主要市場研究和數據分析計劃正在進行中，並將繼續為我們的 HCP、患者和付款人策略提供信息。我們最近與美國主要付款人組織完成了價值信息研究，我們對他們對 seladelpar 目標產品概況的反應感到鼓舞，我們的關鍵研究結果和持續的證據生成將進一步加強這一點。

Patient insights were also completed, revealing the deeper, emotional, personal and health care-related needs of people living with PBC. In addition, we interviewed 125 hepatologists and gastroenterologists on their expected attitudes, drivers and behaviors relative to future PBC patient management, which we can then use for future segmentation and targeting efforts.

患者洞察也已完成，揭示了 PBC 患者更深層次的情感、個人和醫療保健相關需求。此外，我們採訪了 125 名肝病學家和胃腸病學家，了解他們對未來 PBC 患者管理的預期態度、驅動因素和行為，然後我們可以將其用於未來的細分和針對性工作。

Finally, we're so excited to have initiated our talent search for key commercial leadership roles scheduled for hire throughout the summer months as we prepare to accelerate our launch readiness plans in the second half of 2023.

最後，我們非常高興能夠開始尋找關鍵商業領導職位的人才，計劃在整個夏季聘用，同時我們準備在 2023 年下半年加快啟動準備計劃。

I will now turn the call over to Dan.

我現在將把電話轉給丹。

Thank you, Lewis. As others on the team have highlighted, during Q1 2023, we made additional progress towards completing the patient treatment phase for the RESPONSE study. In parallel, we are preparing for a final data analysis as we focus on delivering top line results in Q3 of this year and submitting our NDA thereafter. We further strengthened our leadership team and enhanced our strategic and operational commercial launch experience by recruiting Harish Shantharam as our new CFO. Overall, our efforts to begin transforming into a fully integrated commercial biotech company are underway as we work to execute on select strategic and operational commercial readiness initiatives to prepare for potential future launch of seladelpar in PBC.

謝謝你，劉易斯。正如團隊其他人強調的那樣，2023 年第一季度，我們在完成 RESPONSE 研究的患者治療階段方面取得了更多進展。與此同時，我們正在準備最終的數據分析，因為我們的重點是在今年第三季度交付頂線結果，並隨後提交我們的 NDA。通過聘請 Harish Shantharam 擔任我們的新首席財務官，我們進一步加強了我們的領導團隊，並增強了我們的戰略和運營商業發布經驗。總體而言，我們正在努力開始轉型為一家完全一體化的商業生物技術公司，同時我們正在努力執行選定的戰略和運營商業準備計劃，為未來可能在 PBC 推出 seladelpar 做好準備。

From a financial perspective, we finished the quarter with a strong balance sheet with cash, cash equivalents and investments totaling $236.4 million as of March 31, 2023. As a reminder, from our year-end call, in Q1 2023, we enhanced our cash position following the receipt of a $34.2 million upfront license payment from our Kaken collaboration and from the completion of $92.4 million public equity offering. Overall, we believe that our cash and investments on hand as of March 31, 2023, will be sufficient to fund our current operating plan through the third quarter of 2024.

從財務角度來看，我們在本季度結束時擁有強勁的資產負債表，截至 2023 年 3 月 31 日，現金、現金等價物和投資總額為 2.364 億美元。謹提醒您，在 2023 年第一季度的年終電話會議上，我們增加了現金在收到 Kaken 合作提供的 3420 萬美元預付款許可以及完成 9240 萬美元公開股權發行後，該公司獲得了該職位。總體而言，我們相信截至 2023 年 3 月 31 日我們手頭的現金和投資將足以為我們當前的運營計劃提供資金直至 2024 年第三季度。

I will now turn to a review of our first quarter operating results. Firstly, while the company received a $34.2 million upfront payment from Kaken, all revenue associated with our collaboration was deferred as of March 31, 2023, pending completion of contractually required tech transfer activities and satisfaction of other future performance obligations associated with the agreement.

我現在將回顧我們第一季度的經營業績。首先，雖然該公司從 Kaken 收到了 3420 萬美元的預付款，但截至 2023 年 3 月 31 日，與我們合作相關的所有收入均被推遲，等待完成合同要求的技術轉讓活動並履行與協議相關的其他未來履約義務。

As for our operating expenses, research and development expenses for the quarter ended March 31, 2023, and 2022 were $18.5 million and $18.4 million, respectively. Research and development expenses for quarter ended March 31, 2023, were in line compared to corresponding periods in 2022, primarily due to the offsetting impact of lower clinical and CMC costs following enrollment completion of RESPONSE in mid-2022, offset by higher employee compensation as we continue to hire additional personnel to support our clinical studies and other development activities. As we continue to progress late-stage development of seladelpar in PBC, we expect our overall research and development expenses to increase in the future.

至於我們的運營費用，截至2023年3月31日和2022年3月31日的季度的研發費用分別為1850萬美元和1840萬美元。截至 2023 年 3 月 31 日的季度研發費用與 2022 年同期持平，主要是由於 2022 年中期 RESPONSE 入組完成後臨床和 CMC 成本降低的抵消影響，但被較高的員工薪酬所抵消我們繼續僱用更多人員來支持我們的臨床研究和其他開發活動。隨著我們在人民銀行繼續推進 seladelpar 的後期開發，我們預計未來整體研發費用將會增加。

Turning briefly now to a review of general and administrative expenses. These costs for the quarters ended March 31, 2023, and 2022 were $8.3 million and $6.1 million, respectively. General and administrative expenses for the quarter ended March 31, 2023, were higher than the corresponding period in 2022 as we continue to add administrative personnel and expand our infrastructure in support of our corporate growth.

現在簡要回顧一下一般和行政費用。截至 2023 年 3 月 31 日和 2022 年 3 月 31 日的季度的這些成本分別為 830 萬美元和 610 萬美元。截至 2023 年 3 月 31 日的季度的一般和管理費用高於 2022 年同期，因為我們繼續增加管理人員並擴大基礎設施以支持公司發展。

Overall, our net loss for each of the quarters ended March 31, 2023, and 2022 was $28.8 million and $27.8 million or $0.29 and $0.32 per share, respectively. Net loss for the quarter ended March 31, 2023, was higher than the corresponding period in 2022, due primarily to an increase in general and administrative expenses, partially offset by an increase in interest income earned on our cash equivalents and investments. Overall, we expect operating expenses to increase in the future as we continue to execute our development and pre-commercialization plans for seladelpar in PBC.

總體而言，截至 2023 年 3 月 31 日和 2022 年每個季度的淨虧損分別為 2880 萬美元和 2780 萬美元，即每股 0.29 美元和 0.32 美元。截至 2023 年 3 月 31 日的季度淨虧損高於 2022 年同期，這主要是由於一般和管理費用的增加，但部分被現金等價物和投資賺取的利息收入的增加所抵消。總體而言，隨著我們繼續在中國人民銀行執行 seladelpar 的開發和預商業化計劃，我們預計未來運營費用將會增加。

Let me now hand the call back to Sujal.

現在讓我將電話轉回給 Sujal。

Thank you, Dan. While we are thrilled with the progress we have made thus far in the year, we are even more excited about the milestones ahead of us in the coming months. Our team remains laser-focused on delivering seladelpar to patients with PBC, an objective that includes a deeper dive into the unique characteristics of the delpar mechanism, the impact seladelpar may have on both reducing the risk of disease progression and improving quality of life, and raising awareness of how we plan to lead a new frontier in treatment goals. We look forward to sharing more updates with you all at upcoming medical meetings and, of course, when we aim to share top line results from RESPONSE at the end of the third quarter.

謝謝你，丹。雖然我們對今年迄今為止所取得的進展感到興奮，但我們對未來幾個月即將實現的里程碑感到更加興奮。我們的團隊仍然專注於為 PBC 患者提供 seladelpar，這一目標包括更深入地研究 delpar 機制的獨特特徵、seladelpar 對降低疾病進展風險和改善生活質量可能產生的影響，以及提高人們對我們計劃如何引領治療目標新領域的認識。我們期待在即將召開的醫療會議上與大家分享更多最新消息，當然，我們的目標是在第三季度末分享 RESPONSE 的頂線結果。

We're now happy to take questions. Operator?

我們現在很樂意回答問題。操作員？

(Operator Instructions) Today's first question comes from Yasmeen Rahimi with Piper Sandler.

（操作員說明）今天的第一個問題來自 Yasmeen Rahimi 和 Piper Sandler。

We are very excited about the upcoming data readout in the third quarter. Two quick questions for you. The first one is, at what junction should we expect to learn about additional studies that you would be conducting with seladelpar in regards to expansion of the PBC opportunity? I know in the past, you have spoken about studies on -- for patients who -- working towards normalization of alkaline phosphate. So any commentary there?

我們對第三季度即將公佈的數據感到非常興奮。有兩個簡單的問題要問你。第一個是，我們應該在什麼時候了解您將與 seladelpar 進行的有關擴大 PBC 機會的其他研究？我知道過去您曾談到過針對患者的研究，致力於使鹼性磷酸鹽正常化。那麼有什麼評論嗎？

And then second question is, is it premature for us to expect any color in regards to post-marketing commitments and requirements at the time when you report out top line data in the third quarter or whether that will be more likely after the approval? Appreciate color on both of the questions.

第二個問題是，當您報告第三季度的頂線數據時，我們期望有關上市後承諾和要求的任何顏色是否為時過早，或者在批准後是否更有可能？欣賞這兩個問題的顏色。

Appreciate the question, Yasmeen. So I'll provide some context. I think first, as we've been describing over the course of our development path with seladelpar in PBC since 2015, we continue to remain committed not just to the current ongoing Phase III study, RESPONSE, and the long-term study, ASSURE, but we continue to be very committed around thinking about really advancing treatment guidelines, really trying to advance the treatment paradigm for patients with PBC. So we're certainly committed to thinking through additional clinical studies, datasets that we think can advance care for patients with PBC and better elucidate where seladelpar may continue to have advantages across disease spectrum for patients.

感謝這個問題，亞斯明。所以我將提供一些背景信息。我認為首先，正如我們自 2015 年以來在 PBC 與 seladelpar 的發展道路過程中所描述的那樣，我們不僅繼續致力於當前正在進行的 III 期研究 RESPONSE 以及長期研究 ASSURE，但我們仍然致力於思考真正推進治療指南，真正努力推進 PBC 患者的治療模式。因此，我們當然致力於思考更多的臨床研究和數據集，我們認為這些研究和數據集可以促進對 PBC 患者的護理，並更好地闡明 seladelpar 可能在哪些領域繼續為患者提供跨疾病譜的優勢。

But I think as we've done historically, what we'd like to do is commit to the first steps in getting those studies started. And then we'll share details around the construct of those studies and the objectives of those studies as we begin. So we look forward throughout the course of this year to sharing more updates with you around additional clinical trials as we continue to think about seladelpar across patients.

但我認為，正如我們歷史上所做的那樣，我們想做的是致力於開始這些研究的第一步。然後我們將在開始時分享有關這些研究的構建和這些研究的目標的詳細信息。因此，我們期待在今年全年與您分享有關其他臨床試驗的更多最新信息，同時我們將繼續考慮針對患者的 seladelpar。

With respect to post-marketing commitments, obviously, the approval pathway in PBC, as you've highlighted, and I think as most know on this call, is accelerated Subpart H conditional approval. We will have a commitment for a post-marketing study.

關於上市後承諾，顯然，正如您所強調的那樣，PBC 的批准途徑是加速 H 子部分有條件批准，而且我認為大多數人都知道這次電話會議。我們將承諾進行上市後研究。

I can tell you that we've had dialogue with regulators over the course of several years and are approaching our commitment to this in somewhat of a novel way given the inherent challenges that exist in running long-term placebo-controlled studies for patients with a rare disease such as PBC. We already have some feedback and key feedback back from regulators. And again, here, I think not just similar for what I just described in your first question. As we make steps forward to committing to that work, we'll share much more of these updates with you in the coming months.

我可以告訴你，我們已經與監管機構進行了幾年的對話，並且考慮到對患有以下疾病的患者進行長期安慰劑對照研究中存在的固有挑戰，我們正在以某種新穎的方式實現我們對此的承諾。罕見疾病，如原發性膽汁性膽管炎（PBC）。我們已經從監管機構收到了一些反饋和關鍵反饋。再說一次，我認為這與我剛才在你的第一個問題中描述的情況不只是相似。隨著我們進一步致力於這項工作，我們將在未來幾個月內與您分享更多此類更新。

The commitment around the post-marketing study pathway, of course, is one in which we have to have that study initiated and, in fact, make some progress in that study as we look to file for regulatory approval. And so it's very much in the near term for us. And I'd say stay tuned in the coming months. We'll have much more to share on both of these areas.

當然，圍繞上市後研究途徑的承諾是我們必須啟動這項研究，事實上，在我們尋求監管批准時，我們必須在該研究中取得一些進展。所以這對我們來說是短期內的事情。我想說在接下來的幾個月裡請繼續關注。我們將在這兩個領域分享更多內容。

The next question comes from Steve Seedhouse with Raymond James.

下一個問題來自 Steve Seedhouse 和 Raymond James。

I had 2, actually. I'll just ask them together because the first one is pretty quick. Just first on pruritus improvement. Could some of the mechanistic work you've been doing, including the presentation at EASL potentially explain, just mechanistically why PPAR delta specifically seems to improve pruritus so much more relative to pan-PPARs or fibrates?

事實上我有2個。我會一起問他們，因為第一個問題很快。首先是改善瘙癢。您一直在做的一些機制工作，包括在 EASL 上的演講，能否從機制上解釋為什麼 PPAR δ 似乎比泛 PPAR 或貝特類藥物更能明顯改善瘙癢？

And then second, on the ENHANCE publication, one of the details is that, that paper sort of confirmed or reiterated was about half of the patients screened for the study were screen failures, and the majority of those were based on alk phos less than 1.67. So it seems to suggest it would be a big demand in theory from those patients that are above upper limit of normal, but below that threshold. And I'm wondering if that's the correct interpretation of that and if you think that there's substantial upside from that sort of middle ground biochemical group of patients ultimately when you get to market.

其次，在 ENHANCE 出版物上，其中一個細節是，該論文確認或重申了該研究篩選的患者中約有一半篩選失敗，其中大多數是基於 alk phos 低於 1.67 。因此，這似乎表明，理論上，那些高於正常上限但低於該閾值的患者會有很大的需求。我想知道這是否是正確的解釋，以及您是否認為當您進入市場時，這種中間生化患者群體最終會帶來巨大的好處。

Yes. Steve, thank you for that question. This is Chuck. We certainly remain quite interested and committed to understanding the mechanism for pruritus improvement that we've seen first in our 52-week open-label study and then as reported in ENHANCE, after 3 months of treatment in a placebo-controlled fashion with the electronic diary. And of course, we're seeking to confirm that in the RESPONSE study with the key secondary endpoint in patients with clinically significant itch at 6 months.

是的。史蒂夫，謝謝你提出這個問題。這是查克。我們當然仍然非常感興趣並致力於了解瘙癢改善的機制，我們首先在為期 52 週的開放標籤研究中看到了這一機制，然後按照 ENHANCE 中的報告，經過 3 個月的安慰劑對照方式的電子治療日記。當然，我們正在尋求在 RESPONSE 研究中確認這一點，關鍵的次要終點是 6 個月時出現臨床明顯瘙癢的患者。

I think you're tracking down the right idea here. We're fully committed to trying to explain some of the mechanistic features of the delpar and how that's distinguished from other available agents that are used -- either approved or used off-label.

我認為你在這裡找到了正確的想法。我們完全致力於解釋 delpar 的一些機械特徵，以及它與其他已使用的藥物（無論是批准的還是標籤外使用的）的區別。

And as you kind of alluded to, really not able to say much more about that at this point, really quite eager to be able to share additional details once the EASL embargo is lifted. And we just have a long-term commitment, not only to improving liver disease, but also the symptoms and really sharing the mechanistic aspects of the delpar mechanism.

正如您所提到的，目前確實無法對此透露更多信息，但我真的非常渴望在 EASL 禁令解除後能夠分享更多細節。我們只是有一個長期的承諾，不僅要改善肝病，還要改善症狀，並真正分享 delpar 機制的機制方面。

And Steve, I'll answer the second question. As Chuck had mentioned in some of the prepared remarks, one of the other abstracts that will be presented at EASL by Professor Gideon Hirschfield, in fact, does carry much of detail around baseline characteristics and risk profiles for all the patients that we've screened across studies, and that's over 1,000 patients at this point. And you're correct, roughly half patients -- half the patients have screen fail for those that have been trying to be targeted with alk phos levels above 1.67x the upper limit of normal. And it is true, a vast majority of those, in fact, are because their alk phos is somewhere between upper limit of normal and 1.67. This is one of those precursors, in fact, and much of the work that we're doing as we better understand the potential benefits those patients may in fact have.

史蒂夫，我來回答第二個問題。正如 Chuck 在一些準備好的發言中提到的那樣，Gideon Hirschfield 教授將在 EASL 上發表的其他摘要之一實際上包含了有關我們篩選的所有患者的基線特徵和風險概況的大量詳細信息跨研究，目前已有 1,000 多名患者。你是對的，大約有一半的患者——對於那些一直試圖以高於正常上限 1.67 倍的 alk phos 水平為目標的患者來說，一半的患者篩查失敗。事實上，其中絕大多數是因為它們的 alk phos 值介於正常上限和 1.67 之間。事實上，這是這些先兆之一，也是我們正在做的大部分工作，因為我們更好地了解了這些患者實際上可能獲得的潛在益處。

And there's much more work in the published domain now work from the Global PBC Study Group as well as others really pointing towards the potential benefits of normalization around alkaline phosphatase specifically over the course of disease progression in PBC. And so we're really trying to follow that work and recognize the potential benefits of seladelpar in this broader group of patient populations that we've not really historically studied in clinical trials, be it CymaBay or other sponsors, in fact, as well.

現在，全球 PBC 研究組以及其他人在已發表的領域開展了更多工作，真正指出了鹼性磷酸酶正常化的潛在益處，特別是在 PBC 疾病進展過程中。因此，我們確實在努力跟踪這項工作，並認識到 seladelpar 在這一更廣泛的患者群體中的潛在益處，事實上，無論是 CymaBay 還是其他贊助商，我們在臨床試驗中都沒有真正研究過這些患者群體。

And so we think there's a significant opportunity here. We think there are many more patients, of course, that may potentially benefit from biochemical normalization and, of course, from reduction in symptom burden. And these are some of the things that, again, you'll see us talk much more about in the coming months.

所以我們認為這裡有一個重要的機會。當然，我們認為還有更多的患者可能會受益於生化正常化，當然還有症狀負擔的減輕。在接下來的幾個月裡，您將再次看到我們更多地談論這些事情。

The next question comes from Kristen Kluska with Cantor Fitzgerald.

下一個問題來自克里斯汀·克魯斯卡和坎托·菲茨杰拉德。

Looking forward to some of these upcoming data that you're going to share. So in the past year, and it sounds like heading into these upcoming data, you've done a lot more work relative to understanding the mechanism, going deep into some of the different pathways that are impacted. So I wanted to ask you, how you're thinking about comorbidities in this patient population? And any autoimmunity linked to other indications that are going to further help you to understand the mechanism? And again, while I recognize PBC is the laser focus, just future directions, what that can tell you?

期待您即將分享的一些即將發布的數據。因此，在過去的一年中，聽起來像是在研究這些即將發布的數據，您在理解該機制方面做了更多的工作，深入研究了一些受影響的不同途徑。所以我想問您，您如何看待這些患者群體中的合併症？任何與其他跡象相關的自身免疫將進一步幫助您了解該機制？再說一次，雖然我認識到 PBC 是激光焦點，只是未來的方向，但這能告訴你什麼？

Yes. Thank you, Kristen. I think with respect to comorbidities related to autoimmunity, remember that PBC is an organ restricted autoimmune disease, which is predominantly described by a dominant autoantigen related to the PDC-E2, basically, the mitochondrial antibody. Related comorbidities in terms of autoimmunity like Sjögren's disease and others really don't have that commonality with respect to the autoantigen. So from that particular perspective, I'm not sure whether there's going to be some low-hanging fruit there.

是的。謝謝你，克里斯汀。我認為，關於與自身免疫相關的合併症，請記住，PBC 是一種器官限制性自身免疫性疾病，主要由與 PDC-E2 相關的顯性自身抗原（基本上是線粒體抗體）來描述。自身免疫方面的相關合併症，如乾燥病和其他疾病，與自身抗原相比確實沒有這種共性。因此，從這個特定的角度來看，我不確定是否會有一些唾手可得的成果。

There are, of course, AIH, autoimmune hepatitis, PBC overlap, which is a disease which does carry in common PBC. And that could be an area that would be something of future interest.

當然還有AIH、自身免疫性肝炎、PBC重疊，這是一種常見PBC中攜帶的疾病。這可能是未來人們感興趣的領域。

But in terms of other comorbidities, remember that more than half of the patients with PBC have dyslipidemia, strong elevations, and we found in a recent abstract that we presented that in our studies, more than half of them have elevations in total cholesterol and in LDL-cholesterol. About 1/3 of them are on lipid-lowering therapy, many on statins. And we found that so far, seladelpar have lowered both total cholesterol -- LDL-cholesterol and triglycerides to a reasonable effect, and they did that in the presence of background lipid therapy as well. So that's an area that we continue to have a look at an additional benefit in the patient population with this common comorbidity.

但就其他合併症而言，請記住，超過一半的 PBC 患者患有血脂異常和嚴重升高，我們在最近的一份摘要中發現，在我們的研究中，超過一半的患者總膽固醇和膽固醇升高低密度脂蛋白膽固醇。其中約 1/3 正在接受降脂治療，其中許多人正在服用他汀類藥物。我們發現，到目前為止，seladelpar 已將總膽固醇（低密度脂蛋白膽固醇）和甘油三酯降低到合理的效果，並且在背景脂質治療的情況下也做到了這一點。因此，我們將繼續研究這一領域對患有這種常見合併症的患者群體的額外益處。

And then looking at the Global PBC Study Group 10-year anniversary conference agenda, it was -- very much it appears to be written and suggesting about how the landscape is going to change and how that could include new therapies such as yourself. So just wondering, since it was such an intimate group of thought leaders, if there's anything that came out of the meeting that was either a surprise to you or something that you walked away with that will be a bigger focus heading into these data or anything in general that you want to share that you felt was important.

然後看看全球 PBC 研究小組 10 週年紀念會議議程，它似乎是在寫的，並建議景觀將如何變化，以及如何包括像您這樣的新療法。所以我想知道，既然這是一個由思想領袖組成的親密小組，會議中是否有任何東西讓你感到驚訝，或者你離開時會得到什麼，這將成為這些數據或任何東西的更大焦點一般來說，您想分享您認為重要的事情。

Appreciate it. Thanks for the question, Kristen. It was actually a tremendous event. There's much work that's been going on in PBC, of course, pioneered a number of years ago when obeticholic acid was the first drug approved in 20 years since ursodeoxycholic acid. And I'd simply tell you that the energy surrounding those thought leaders in the field, the patient advocacy groups that were in attendance and participating, regulators as well as sponsors, there was really a palpable sense that there is much more to come in this field.

欣賞它。謝謝你的提問，克里斯汀。這實際上是一個巨大的事件。當然，PBC 領域正在進行大量工作，這些工作是多年前開創的，當時奧貝膽酸是繼熊去氧膽酸之後 20 年來第一個獲得批准的藥物。我只想告訴你們，圍繞著該領域的思想領袖、出席和參與的患者倡導團體、監管機構和讚助商的能量，確實有一種明顯的感覺，即這個領域還有更多的事情要做。場地。

From our perspective, when we think about seladelpar and the profile we've seen to date, the profile we hope to confirm in response in our ongoing clinical studies, we see real opportunities, as we've mentioned, to treat patients to normalization. That was one of the key themes, of course, during the 2-day set of meetings as well, normalization of alkaline phosphatase, cholestatic markers of disease progression as well as inflammatory markers of disease like ALT, AST. There was a tremendous amount of discussion around these as being really future treatment goals for patients. Those are some of the things that we think are likely to expand the broader addressable patient population potentially significantly. And I think there's a lot of excitement and enthusiasm among all of us focused in the PBC space with respect to these discussions that are ongoing.

從我們的角度來看，當我們考慮 seladelpar 和我們迄今為止所看到的概況時，我們希望在我們正在進行的臨床研究中確認的概況，我們看到了真正的機會，正如我們所提到的，治療患者正常化。當然，在為期 2 天的會議中，鹼性磷酸酶、疾病進展的膽汁淤積標誌物以及疾病的炎症標誌物（如 ALT、AST）的正常化也是關鍵主題之一。圍繞這些作為患者未來真正的治療目標進行了大量的討論。我們認為這些事情可能會顯著擴大更廣泛的可尋址患者群體。我認為，我們所有關注 PBC 領域的人都對正在進行的這些討論充滿了興奮和熱情。

There were certainly much more discussion around relieving symptom burden for patients and improving quality of life. Again, when you don't have treatment alternatives that actually have efficacy and benefit in these areas, it's hard to have the discussion with patients.

關於減輕患者症狀負擔和提高生活質量當然有更多的討論。同樣，當您沒有在這些領域確實有效和有益的治療替代方案時，就很難與患者進行討論。

It's hard to have the discussions with researchers in the field around what you might be able to do and why there should be continued focus in this area. We see that changing now. And some of the data that we've shared and published on with seladelpar, reductions in pruritus, some improvements in fatigue, if you look at our liver international paper, this was another key theme during the 2 days, I would say. And these go -- again, beyond just pruritus, of course, which is a plaguing clinical symptom of the disease, but also into fatigue and really just continuing to get a better sense of treating the patient as a whole and improving not just liver health and longevity of patients, but actually improving quality of life for those patients all at the same time. So just really great themes as we think about where seladelpar might be able to help advance care for patients if we're successful.

很難與該領域的研究人員討論您可以做什麼以及為什麼應該繼續關注該領域。我們現在看到這種情況發生了變化。我們與 seladelpar 共享和發布的一些數據，瘙癢減輕，疲勞有所改善，如果您查看我們的肝臟國際論文，我想說，這是這兩天的另一個關鍵主題。當然，這些不僅僅是瘙癢，這是一種令人困擾的疾病臨床症狀，而且還會導致疲勞，實際上只是繼續更好地治療整個患者，不僅改善肝臟健康和患者的壽命，但實際上同時提高了這些患者的生活質量。因此，當我們思考如果我們成功的話 seladelpar 可能能夠在哪些方面幫助改善患者護理時，這真是偉大的主題。

And then the last thing I'll mention relative to the meeting, of course, a lot of talk around leveraging real low data sets in demonstrating a potential long-term benefit with treatment alternatives in the setting of PBC. And so we're grateful to have the relationships we've had with the group overall. We've been working in PBC, as you know, as we've articulated since 2015, really just a group of folks that we've developed great relationships with, and we'll continue to work closely with really globally as we continue our efforts.

當然，我要提到的關於會議的最後一件事，是關於利用真實的低數據集來展示 PBC 背景下治療替代方案的潛在長期益處的大量討論。因此，我們很高興與整個團隊建立了良好的關係。如您所知，我們一直在 PBC 工作，正如我們自 2015 年以來所闡述的那樣，實際上我們只是與一群人建立了良好的關係，隨著我們繼續我們的業務，我們將繼續在全球範圍內與他們密切合作。努力。

Our next question comes from Patrick Dolezal with LifeSci Capital.

我們的下一個問題來自 LifeSci Capital 的 Patrick Dolezal。

So with competitor data on the horizon, perhaps you could provide some thoughts surrounding the importance of not just improving pruritus and alk phos, but even transaminase levels within the context of PBC.

因此，隨著競爭對手數據的出現，也許您可以提供一些關於不僅改善瘙癢和鹼性磷酸酶，甚至在 PBC 背景下改善轉氨酶水平的重要性的想法。

And then on the pruritus endpoint, I know RESPONSE is looking at this metric at 6 months. Curious what the calculus was there in determining the 6 versus 12-month time point?

然後，關於瘙癢終點，我知道 RESPONSE 會在 6 個月時查看該指標。好奇確定 6 個月與 12 個月時間點的計算原理是什麼？

Yes. Thank you for that. So with respect to other markers that are important in terms of disease stage and risk for progression, I think the delpar mechanism really lends us out to the potential to harness its effects on inflammation. And associated with inflammation is liver injury and its relationship to fibrosis and outcomes.

是的。謝謝你。因此，就疾病階段和進展風險而言重要的其他標記物，我認為 delpar 機制確實使我們有可能利用其對炎症的影響。與炎症相關的是肝損傷及其與纖維化和結果的關係。

There is a paper harkening back to 2010, which was a biopsy follow-up study that related the levels of ALT for the risk of histological progression. The study showed that, in fact, elevated ALT is a risk factor. And so we remain interested in the fact that the delpar mechanism, seladelpar, led to significant reductions in ALT in both our open-label study and its extension to 2 years as well as in the ENHANCE study. For example, in the 2-year extension study, we saw decreases of ALT of up to 40%. And in the ENHANCE study, of those patients who had elevated ALT at baseline, which is somewhat over half, half of those patients have normalized their ALT in a short 3 months.

有一篇論文可以追溯到 2010 年，這是一項活檢隨訪研究，將 ALT 水平與組織學進展風險聯繫起來。研究表明，事實上，ALT 升高是一個危險因素。因此，我們仍然對這一事實感興趣：在我們的開放標籤研究及其延長至 2 年以及 ENHANCE 研究中，delpar 機制 seladelpar 導致 ALT 顯著降低。例如，在為期 2 年的擴展研究中，我們發現 ALT 下降幅度高達 40%。在 ENHANCE 研究中，在基線時 ALT 升高的患者中（略多於一半），其中一半患者的 ALT 在短短 3 個月內恢復正常。

So to kind of wrap it up, we think that liver injury, which is a consequence of inflammation, the cholestasis, the biliary injury, is related to fibrosis. And we're hopeful to see that the effects of seladelpar on reduction of liver injury will translate in the future into outcomes.

總而言之，我們認為肝損傷是炎症、膽汁淤積、膽道損傷的結果，與纖維化有關。我們希望看到 seladelpar 對減少肝損傷的作用將在未來轉化為結果。

And then, Patrick, I'll take the second question. You asked a little bit about the decision to have the pruritus endpoint in RESPONSE at 6 months versus baseline. That was actually the original prespecified time point for that endpoint. In ENHANCE as well, of course, we modified that statistical analysis plan before that study was unblinded since we didn't have many patients out to 6 months when that study was stopped prematurely.

然後，帕特里克，我將回答第二個問題。您詢問了一些關於在 6 個月時將瘙癢終點與基線進行比較的決定。這實際上是該終點的原始預定時間點。當然，在 ENHANCE 中，我們也在該研究非盲化之前修改了統計分析計劃，因為在該研究提前停止時，我們沒有多少患者能夠接受 6 個月的治療。

When we think and look at our long-term data out to 1 year and even 2 years from Phase II, if you look at the Liver International Paper and the journal of Hepatology paper of our Phase II study, and even as you look at the data around pruritus reduction in ENHANCE, of course, again, out to 3 months for most patients, but continued and sustained out to 6 months, we think 6 months is a really strong time point for demonstrating not just the potential benefit, but sustained effects of that benefit. And again, we see that consistently sustained out to our 6-month time point in prior clinical studies.

當我們思考並查看 II 期研究的 1 年甚至 2 年的長期數據時，如果您查看《Liver International Paper》和《Hepatology》雜誌上我們 II 期研究的論文，甚至當您查看ENHANCE 中關於瘙癢減輕的數據，當然，對於大多數患者而言，持續時間長達 3 個月，但持續並持續至 6 個月，我們認為 6 個月是一個非常有力的時間點，不僅可以證明潛在益處，還可以證明持續效果的好處。我們再次看到，在之前的臨床研究中，這種情況一直持續到 6 個月的時間點。

I will highlight that, again, the measure itself is taken at 6 months as a 7-day average in the 7 days leading up to that 6-month endpoint versus the baseline reading, which is taken as a series of readings in the run-in period before those patients get seladelpar. So again, it's a time point in which we believe that seladelpar has the potential to show the benefit as well as the sustainability of that benefit based on what we've seen historically.

我要再次強調的是，該測量本身是在 6 個月時採取的，作為 6 個月終點之前 7 天的平均值，與基線讀數相比，基線讀數是運行中的一系列讀數-在這些患者接受 seladelpar 之前的一段時間內。再次強調，在這個時間點上，我們相信 seladelpar 有潛力根據我們的歷史經驗展示其效益以及該效益的可持續性。

The next question comes from Julian Harrison with BTIG.

下一個問題來自 BTIG 的 Julian Harrison。

Congrats on the progress. Assuming a successful result from RESPONSE, can you remind us of the timeline to NDA submission? What will be the gating factors there?

祝賀取得的進展。假設 RESPONSE 取得成功，您能否提醒我們提交 NDA 的時間表？那裡的門控因素是什麼？

Yes. Certainly, Julian. Our objective, of course, is to file as quickly as feasible post the top line data readout. I think at the end of the day, our goal is to get seladelpar, if we're successful, in RESPONSE, and confident around regulatory submission, our goal is to get seladelpar in the hands of patients as quickly as possible. So I think you'll look to see us provide a little bit more clarity around specific timelines once that data readout comes out. But overall, again, the urgency is clear. We've continued processes and commitments here along the way. Even as the clinical studies are ongoing, we do have intentions of having rolling work and rolling submission ongoing as we think about the path first to NDA filing and then filing in Europe. So you're going to see us provide a little bit more specificity as we get to top line data. But fundamentally, the urgency is there. And our procedures and processes internally, resource focus is all geared towards this, if successful in RESPONSE.

是的。當然，朱利安。當然，我們的目標是在頂線數據讀出後儘快歸檔。我認為歸根結底，我們的目標是獲得 seladelpar，如果我們在響應方面取得成功，並且對監管提交充滿信心，我們的目標是盡快將 seladelpar 送到患者手中。因此，我認為一旦數據讀出，您會看到我們在具體時間表上提供更清晰的信息。但總體而言，緊迫性是顯而易見的。一路走來，我們一直在繼續流程和承諾。即使臨床研究正在進行中，我們也確實有意進行滾動工作和滾動提交，因為我們正在考慮首先提交新藥申請，然後在歐洲提交的路徑。因此，當我們獲取頂線數據時，您會看到我們提供了更多的特異性。但從根本上來說，緊迫性是存在的。如果響應成功，我們內部的程序和流程、資源重點都將朝著這個方向發展。

The next question comes from Andy Hsieh with William Blair.

下一個問題來自安迪·謝和威廉·布萊爾。

Harish, congratulations on your new role and look forward to working with you. The EASL abstracts that you talked about is very intriguing. So maybe one question, but a 2-parter for Chuck and Lewis, respectively. In terms of the IL-31, right, called the itch cytokine, I would say, I was just curious, in your view, generally speaking, is that context-dependent? It depends on which cell type that's producing that or you can actually characterize on a global basis based on serum level?

Harish，祝賀您擔任新職務，並期待與您合作。您談到的 EASL 摘要非常有趣。所以也許是一個問題，但分別是查克和劉易斯的兩人問題。就 IL-31 而言，對，稱為瘙癢細胞因子，我想說，我只是很好奇，在您看來，一般來說，這是否依賴於環境？這取決於產生這種物質的細胞類型，或者您實際上可以根據血清水平在全球基礎上進行表徵？

And the second part is basically on IL-31 testing. I'm just curious if that's something that is a part of a normal panel. Or as you think about tracking this cytokine going forward, they'll have to be included and kind of developed independently?

第二部分主要是IL-31測試。我只是好奇這是否是普通面板的一部分。或者當您考慮未來追踪這種細胞因子時，它們必須被包括在內並獨立開發？

Yes. Thank you. Thank you so much, Andy, for that question. I think if you look to the literature, you'll find that IL-31 has been implicated in itch in a variety of different disease settings, whether it be dermatological or uremic or even if you look at the recent paper potentially in cholestatic disease as well.

是的。謝謝。非常感謝安迪提出這個問題。我想如果你查閱文獻，你會發現 IL-31 與多種不同疾病中的瘙癢有關，無論是皮膚病還是尿毒症，或者即使你看看最近一篇可能與膽汁淤積性疾病相關的論文：出色地。

With respect to the cell type origin, I'm not in a position really to comment on that yet just because of the embargo. We might have more to say on that in June. I would just say stay tuned. It's an interesting and an important question that you've identified. So thank you for that.

關於細胞類型的起源，由於禁運，我還無法真正對此發表評論。六月我們可能會對此有更多話要說。我只想說敬請期待。您已經發現這是一個有趣且重要的問題。非常感謝你的幫忙。

In terms of IL-31 being part of the normal panel, know that it's a highly specialized cytokine that's measured, although there are vendors who offer ability to measure that. I think our view is that its relief is first documented and reported by the patient. It's a symptom, not a sign. But having some type of biomarker associated with it would represent in advance, and it's something that we're, of course, keenly aware of.

就 IL-31 作為正常組的一部分而言，要知道它是一種被測量的高度專業化的細胞因子，儘管有些供應商提供測量它的能力。我認為我們的觀點是，它的緩解首先是由患者記錄和報告的。這是一個症狀，而不是一個徵兆。但是，某種類型的生物標誌物與之相關就代表了提前，這當然是我們敏銳地意識到的。

The next question comes from Ed Arce with H.C. Wainwright.

下一個問題來自 Ed Arce 和 H.C.溫賴特。

This is Thomas Yip asking a couple of questions for Ed. So perhaps first question, assuming positive headline readout from RESPONSE study, how -- specifically on the composite endpoint, how do you envision cellular proposition against, I believe, both either on the pruritus measurement and also in the ALT normalization as well?

我是 Thomas Yip，向 Ed 問了幾個問題。因此，也許第一個問題，假設從響應研究中獲得積極的標題讀數，特別是在復合終點上，您如何設想細胞主張反對，我相信，無論是在瘙癢測量還是在 ALT 正常化方面？

Yes, appreciate the question, Thomas. I think, of course, if we see the response that we've seen so far from our clinical studies, we think seladelpar's profile demonstrates a greater percent reduction in alkaline phosphatase, a greater proportion of patients meeting the composite primary endpoint, and as you mentioned, also a greater proportion of patients normalizing. Of course, with all the caveats that there's inherent challenges in comparing across studies as opposed to head-to-head, I think the positioning, clearly, we think, is one in which it offers patients -- more patients potentially the ability to get not just a goal, but to actual alkaline phosphatase normalization. Again, one of the areas in which I think the entire field will continue to advance in terms of an actual treatment goal for patients, and that has the ability to potentially position seladelpar as a preferred second-line treatment, and of course, as we've mentioned, a potential to be used in a broader patient population than we might have otherwise originally thought of for second-line setting.

是的，感謝這個問題，托馬斯。當然，我認為，如果我們看到迄今為止從臨床研究中看到的反應，我們認為 seladelpar 的概況表明鹼性磷酸酶降低的百分比更大，達到復合主要終點的患者比例更大，並且正如您所見提到的，還有更大比例的患者恢復正常。當然，儘管需要注意的是，不同研究之間的比較而不是面對面的比較存在固有的挑戰，但我認為，我們認為，這種定位顯然是為患者提供的——更多的患者有可能獲得不僅僅是一個目標，而是實際的鹼性磷酸酶正常化。再次強調，我認為整個領域將在患者的實際治療目標方面繼續前進，並且有能力將 seladelpar 定位為首選的二線治療，當然，隨著我們的已經提到過，它有可能用於更廣泛的患者群體，比我們最初設想的二線治療可能要廣泛。

The pruritus impact, clearly, again, as we've mentioned, is really a game changer because today, there are no treatments that have shown real significant benefit on reducing pruritus. First-line treatment with ursodeoxycholic acid, although it's never been shown to cause or worsen itch, it's never been demonstrated to relieve itch either. And so I think this goes without saying that the data that we've generated to date is significant. Having the ability to reconfirm in response to the benefit that we saw in ENHANCE statistically significant for patients with moderate to severe itch, significant proportion of patients seeing a 4-point or greater reduction in the NRS score versus placebo, this is data that we think is quite compelling. And we think the overall story relative to the improvement in overall symptoms for patients is clearly one of those that's positioned seladelpar well, again, assuming that we're successful as we move forward.

顯然，正如我們所提到的，瘙癢的影響確實是一個遊戲規則的改變者，因為今天，還沒有任何治療方法能夠顯示出對減少瘙癢真正顯著的益處。熊去氧膽酸作為一線治療，雖然從未被證明會引起或加重瘙癢，但也從未被證明可以緩解瘙癢。因此，我認為不言而喻，我們迄今為止生成的數據非常重要。能夠再次確認我們在 ENHANCE 中看到的益處對於中度至重度瘙癢患者俱有統計顯著性，與安慰劑相比，很大一部分患者的 NRS 評分降低了 4 分或更多，這是我們認為的數據是相當引人注目的。我們認為，與患者整體症狀改善相關的總體故事顯然是 seladelpar 定位良好的故事之一，假設我們在前進過程中取得了成功。

Yes. And then perhaps how do you look at both, as I mentioned, pruritus and ALT normalization? Are both measurements of seladelpar against other candidates data in clinic, for example, any other PBC candidates as well?

是的。然後，也許您如何看待我提到的瘙癢症和 ALT 正常化？ seladelpar 的兩項測量是否與臨床中其他候選數據（例如任何其他 PBC 候選數據）進行比較？

I think, Thomas, that's a bit harder of a question to answer to date because we just haven't seen as much data from other agents being developed. Obviously, as we've mentioned a number of times, we've had significant experience in PBC with rich datasets to date. And so I think harder to answer that question today. But obviously, in the coming months, we'll have a much better idea around the impacts of other agents on alk phos and even on pruritus. It's much more to digest relative to seladelpar given our experience, but harder, I think, to compare to others where there's not yet been significant data demonstrating those effects to date.

托馬斯，我認為這個問題迄今為止有點難以回答，因為我們還沒有看到來自其他正在開發的代理的大量數據。顯然，正如我們多次提到的，我們在 PBC 方面擁有豐富的經驗，迄今為止擁有豐富的數據集。所以我認為今天更難回答這個問題。但顯然，在接下來的幾個月裡，我們將對其他藥物對鹼性磷甚至瘙癢的影響有更好的了解。考慮到我們的經驗，相對於 seladelpar 來說，它更需要消化，但我認為，與迄今為止尚未有重要數據證明這些影響的其他人進行比較更困難。

Got it. And perhaps one more question from us, this one is commercial. So with your partnership in Japan, how should we look at other markets, both big and small assets, U.S., ex-U.S., et cetera?

知道了。也許我們還有一個問題，這個問題是商業性的。那麼，通過你們在日本的合作夥伴關係，我們應該如何看待其他市場，無論是大資產還是小資產，美國、美國以外的市場等等？

Yes. It's another good question. We continue to evaluate opportunities either to bring seladelpar ourselves in other geographies or to do so with third-party partners. I would simply tell you that we have ongoing dialogue constantly. And as we get to the other side of Phase III data, I think we're going to have some decision points to make thereafter.

是的。這是另一個好問題。我們將繼續評估將 seladelpar 引入其他地區或與第三方合作夥伴合作的機會。我只想告訴你，我們一直在進行持續的對話。當我們獲得第三階段數據的另一面時，我認為此後我們將做出一些決策點。

We're not in any sort of specific urgency where company is well capitalized today. We think RESPONSE is a study that will allow us to at least submit for regulatory approval both in the U.S. as well as in Europe, in the U.K. and with the MHRA as well as with EMA. So I think fundamentally, we're going to continue to progress through the conduct of our clinical studies and make the decisions that we think are best in terms of us being able to get seladelpar in the hands of patients broadly.

由於公司目前資本充足，所以我們沒有任何具體的緊迫性。我們認為 RESPONSE 是一項研究，它將使我們至少能夠提交美國、歐洲、英國以及 MHRA 和 EMA 的監管批准。因此，我認為從根本上講，我們將通過臨床研究繼續取得進展，並做出我們認為最好的決定，以便我們能夠將 seladelpar 廣泛地送到患者手中。

Our next question is from Jay Olson with Oppenheimer.

我們的下一個問題來自傑·奧爾森和奧本海默。

Congrats on all the progress, including the addition of Harish to your team. Can you talk about any physician feedback that you've received following publication of the Phase III ENHANCE results in Hepatology?

祝賀所有的進展，包括 Harish 加入您的團隊。您能否談談在《肝病學》雜誌上發表 III 期 ENHANCE 結果後收到的任何醫生反饋？

Yes. Thank you, Jay. Yes. So I think in general, it's been quite gratifying. There's been a lot of uptake. In fact, I have an application that looks at the number of citations, and it's already jumping up far higher than anything I've seen before. So I think there's a level of interest. I think a large part of that is driven by the fact that it's very closely related and designed to RESPONSE, albeit at a shorter time frame and the fact that it's placebo-controlled with a statistical methodology that looked first at the composite for registration and looking at normalization and, finally, looking at pruritus. That's something that's not been done before. We've combined both placebo-controlled with those 3 particular endpoints. I think it's something that's garnered a lot of interest.

是的。謝謝你，傑伊。是的。所以我認為總的來說，這是相當令人滿意的。已經有很多人接受了。事實上，我有一個查看引用數量的應用程序，它已經比我以前見過的任何東西都高得多。所以我認為有一定程度的興趣。我認為這很大程度上是由以下事實驅動的：它非常密切相關並且旨在響應，儘管時間範圍較短，而且它是通過統計方法進行安慰劑控制的，該方法首先查看複合材料進行註冊並查看正常化，最後觀察瘙癢。這是以前沒有做過的事情。我們將安慰劑對照與這 3 個特定終點結合起來。我認為這是引起人們廣泛興趣的事情。

Of course, in addition to that, if you look into the article, you see that we also had a subset analysis looking at cirrhotic patients. We had a number of supportive analysis looking at other measures of itch. We looked at ALT in addition to other liver biochemistry, which was also very supportive in terms of the profile we've seen thus far. And then, of course, the overall safety profile is something that I think is something that's got a lot of attention. People are really looking for an agent that can be used in this population with a safe profile, including across the different stages of disease.

當然，除此之外，如果你仔細閱讀這篇文章，你會發現我們還針對肝硬化患者進行了子集分析。我們對其他瘙癢指標進行了許多支持性分析。除了其他肝臟生化指標外，我們還觀察了 ALT，這對我們迄今為止所看到的情況也非常支持。當然，我認為整體安全狀況受到了廣泛關注。人們確實在尋找一種可以在該人群中安全使用的藥物，包括在疾病的不同階段。

Great. That's super helpful. And then can you talk about any read across or points of differentiation for seladelpar you'll be expecting when the elafibranor Phase III elated study top line?

偉大的。這非常有幫助。然後您能談談當 elafibranor III 期相關研究頂線時您對 seladelpar 的任何解讀或差異點嗎？

I think I would focus on what we know about seladelpar and the delpar mechanism. We think that, that mechanism is unique because PPAR delta activation has found to be important in hepatocytes, cholangiocytes, Kupffer cells/macrophages and in stellate cells. And so if you look at both the clinical profile, clinical markers, improvement in bile acid homeostasis, markers of cholestasis itself, whether it be alkaline phosphatase, GGT or bilirubin, improvements in markers of inflammation and liver injury, ALT, I think that's something mechanism really does quite well at. We have not yet had an opportunity in PBC to look directly at fibrosis, but we did so in NASH as well as in preclinical models. So we think there's a rationale there. And we're looking to confirm that both with liver stiffness measurements in RESPONSE, but probably more appropriately in the long-term ASSURE study where impacts on liver stiffness through effects on underlying fibrosis are probably easier to detect over the long term.

我想我會重點討論我們對 seladelpar 和 delpar 機制的了解。我們認為，該機制是獨特的，因為已發現 PPAR δ 激活在肝細胞、膽管細胞、庫普弗細胞/巨噬細胞和星狀細胞中很重要。因此，如果你同時觀察臨床特徵、臨床標誌物、膽汁酸穩態的改善、膽汁淤積本身的標誌物，無論是鹼性磷酸酶、GGT 還是膽紅素、炎症和肝損傷標誌物的改善、ALT，我認為這是一些東西機制確實做得很好。我們還沒有機會在 PBC 中直接觀察纖維化，但我們在 NASH 以及臨床前模型中做到了這一點。所以我們認為這是有道理的。我們希望通過 RESPONSE 中的肝臟硬度測量來確認這一點，但在長期 ASSURE 研究中可能更合適，從長遠來看，通過對潛在纖維化的影響對肝臟硬度的影響可能更容易檢測到。

The next question comes from Mayank Mamtani with B. Riley.

下一個問題來自 Mayank Mamtani 和 B. Riley。

Congrats on the progress. So just maybe piggybacking on the prior comments, Chuck, you had on the impressive fibrosis improvement you had in Phase II NASH and the cirrhotic patients in the past you treated. Curious how you're handling a small cohort of patients, which have liver biopsy in RESPONSE? And also, if you could remind us where you are with the hepatic impairment study. I know it's more of a check the box for NDA submission, but would be good to hear if there's anything new that you've learned from that. And then I have a couple of quick follow-ups.

祝賀取得的進展。因此，查克，也許是藉用了之前的評論，您在 NASH 和您過去治療過的肝硬化患者的 II 期纖維化方面取得了令人印象深刻的改善。好奇您如何處理一小群進行肝活檢以緩解症狀的患者？另外，您能否提醒我們您的肝損傷研究進展如何？我知道這更像是勾選提交 NDA 的複選框，但很高興聽到您從中學到了什麼新東西。然後我進行了一些快速跟進。

Yes. Well, thank you for the question. Yes, I'm pretty excited about the opportunity to examine biopsy in this population. It's not something that's normally done in PBC patients. It's not the standard of care. So we put together what we think is going to be a very exciting scientifically-driven program to evaluate both baseline and intervention effects on liver histology in the setting of PBC. Not a lot yet to share about that, but it's our intention to really have a very significant and thorough evaluation. Of course, that will be submitted to the FDA, but we also plan to publish the findings there. So it's something I would just say stay tuned. It's good receiving a lot of energy from the team here.

是的。嗯，謝謝你的提問。是的，我對有機會在這個人群中進行活檢感到非常興奮。這不是 PBC 患者通常會做的事情。這不是護理標準。因此，我們整合了我們認為將是一個非常令人興奮的科學驅動計劃，以評估 PBC 背景下肝臟組織學的基線和乾預效果。目前還沒有太多可以分享的內容，但我們的目的是真正進行一次非常重要和徹底的評估。當然，這將提交給 FDA，但我們也計劃在那裡發布研究結果。所以我想說的是，請繼續關注。很高興從這裡的團隊中獲得大量能量。

In terms of hepatic impairment and studies in cirrhotic patients, just first say that we do have already completed traditional hepatic impairment study, which recruits patients with either Child-Pugh A, B or C compared to normals regardless of the ideology of the impairment. So that's been completed and submitted to FDA.

在肝損傷和肝硬化患者的研究方面，首先要說的是，我們確實已經完成了傳統的肝損傷研究，該研究招募與正常人相比處於Child-Pugh A、B或C水平的患者，無論肝損傷的意識形態如何。現在已經完成並提交給 FDA。

In addition, we're conducting this study in patients where PBC is the cause of the impairment. That includes patients with A, with portal hypertension B and C. That study is ongoing. I can say that I think we're pleased that it's proceeding well. We expect it to be able to support the submission. It's predominantly a study that, first of all, establishes the relationship of dose to exposure and to identify whether there's any dose adjustment needed with more severe liver disease or stage.

此外，我們正在對 PBC 造成損傷的患者進行這項研究。其中包括 A 型門靜脈高壓症 B 型門靜脈高壓症患者和 C 型門靜脈高壓症患者。該研究正在進行中。我可以說，我認為我們很高興事情進展順利。我們希望它能夠支持提交的內容。它主要是一項研究，首先確定劑量與暴露的關係，並確定是否需要針對更嚴重的肝病或階段進行劑量調整。

And then secondly, we're also looking at treatment response, although over a short duration. So we expect to be able to share those results when the study is completed.

其次，我們也在研究治療反應，儘管持續時間很短。因此，我們希望在研究完成後能夠分享這些結果。

Got it. And maybe just a quick follow-up on the discussion around the alk phos. Increased discussion of using complete biochemical response as an endpoint. I was trying to do some internal modeling work of, for example, how seladelpar monotherapy stacks up again, say, using combination of sequencing approaches of FXR, PPAR. Has that been done internally? And do you have a view on that endpoint, complete biochemical response, which includes not just alk phos, but also other transaminase and biochemical markers?

知道了。也許只是對有關 alk phos 討論的快速跟進。增加了使用完整生化反應作為終點的討論。我試圖做一些內部建模工作，例如，seladelpar 單一療法如何再次疊加，例如使用 FXR、PPAR 測序方法的組合。這是內部完成的嗎？您對終點（完整的生化反應）有何看法，其中不僅包括烷磷酸，還包括其他轉氨酶和生化標記物？

Yes. Well, thank you for that question. Of course, normalizing liver biochemistry is, of course, a goal that we feel is increasingly considering. The only study that's been published that looked at that carefully was, of course, the BEZURSO study, it was published in the New England Journal in 2018. That study was challenging. Not -- it was a well-conducted study -- well conceived and well conducted. But the eligibility criteria were relatively lower than it's been seen with other studies. For example, employees or, for example, in ENHANCE or RESPONSE or even what's posted on clinicaltrials.gov for ALT. So consequently, it's a little bit easier to achieve biochemical normalization in that setting. Some parameters are easier to normalize than others, I would say.

是的。嗯，謝謝你提出這個問題。當然，肝臟生物化學正常化是我們越來越多考慮的一個目標。當然，唯一發表的仔細研究的研究是 BEZURSO 研究，它於 2018 年發表在《新英格蘭雜誌》上。這項研究具有挑戰性。不是——這是一項進行良好的研究——構思良好、實施良好。但資格標準相對低於其他研究。例如，員工，或者，例如，ENHANCE 或 RESPONSE 中的內容，甚至是在 ClinicalTrials.gov 上發布的 ALT 內容。因此，在這種情況下更容易實現生化正常化。我想說，有些參數比其他參數更容易標準化。

With respect to the triple therapy and how that might play into normalization, if you look at the (inaudible) paper, which I think you're probably familiar with, this is a study that has a very select population, patients who failed dual therapy or second-line therapy with either OCA or with a fibrate and then go on to receive triple therapy. In that particular case, I think it was interesting in patients who failed a dual therapy on OCA, but then added (inaudible) fibrate on average, they had about a 42% reduction in alk phos, indicating that the fibrate mechanism had potential additional significant reductions. If you look at the inverse group, those patients on a fibrate who failed second-line therapy, and you add OCA, you only get an 11% reduction.

關於三聯療法及其如何影響正常化，如果你看一下（聽不清）論文，我想你可能很熟悉，這是一項針對特定人群的研究，即雙聯療法失敗的患者或 OCA 或貝特類二線治療，然後繼續接受三聯治療。在這種特殊情況下，我認為對於 OCA 雙重治療失敗的患者來說很有趣，但隨後平均添加（聽不清）貝特類藥物，他們的 alk phos 減少了約 42%，這表明貝特類機制具有潛在的額外顯著效果減少。如果你觀察相反的組，即那些使用貝特類藥物但二線治療失敗的患者，如果你添加 OCA，你只會得到 11% 的減少。

It says to me, and I think it's really consistent with what we've seen in ENHANCE or the open-label Phase II, and hopefully, we'll see in RESPONSE, is that those kinds of mechanisms, the delpar mechanism and potentially even fibrates, seem to have more of an alk phos lowering effect than an FXR agonist. So it really raises the question in a future state where you have multiple approved drugs, what would you start with? Could you start with a drug that has greater effect and then add one, if needed, that's the lesser or the reverse? I think it really suggests to us a drug that could improve liver biochemistry, improve symptoms would be the first agent you would reach to look for. And then, yes, of course, if there's something left that the patient needs, then you might look for, for example, for an FXR agonist.

它對我說，我認為這與我們在 ENHANCE 或開放標籤第二階段中看到的情況確實一致，希望我們會在 RESPONSE 中看到，這些機制，delpar 機制，甚至可能貝特類藥物似乎比 FXR 激動劑具有更強的降低鹼性磷的作用。因此，這確實提出了一個問題，在未來的州，如果你有多種批准的藥物，你會從什麼開始？您能否從一種效果較大的藥物開始，然後在需要時添加一種效果較小或相反的藥物？我認為這確實向我們暗示了一種可以改善肝臟生化、改善症狀的藥物將是您要尋找的第一個藥物。然後，是的，當然，如果患者還需要一些東西，那麼您可能會尋找例如 FXR 激動劑。

Yes. That makes sense. And my final question on the strategy to get pruritus on the label beyond the RESPONSE study. I was curious, generally, mechanisms like the IBAT inhibitors that do target itch as the primary condition do have a crossover design. Are you also thinking of doing an additional study like that? Or do you think the effort that you have currently is sufficient to make sure pruritus is going to be on the label?

是的。這就說得通了。我的最後一個問題是關於在反應研究之外將瘙癢症標記在標籤上的策略。我很好奇，一般來說，像 IBAT 抑製劑這樣以瘙癢為主要症狀的機制確實有交叉設計。您是否也考慮進行類似的額外研究？或者您認為您目前所做的努力足以確保瘙癢症會出現在標籤上嗎？

Thanks for that question, of course. Our study design was based upon close conversations with regulators, including with the FDA, both in advance of ENHANCE and for RESPONSE, where we discussed our desire for indication as well as the endpoint and the method of measuring the endpoint and the statistical methodology to be used.

當然，謝謝你提出這個問題。我們的研究設計基於與監管機構（包括 FDA）的密切對話，在 ENHANCE 和 RESPONSE 之前，我們討論了我們對適應症的期望以及終點和測量終點的方法以及要採用的統計方法。用過的。

I think from our perspective, the study design is you could call nested design, where, first of all, we look at composite endpoint and normalization. These are factors that are related to outcomes. And as well because it's a rare disease, and of course, it's difficult to mount large studies, it makes sense to add in pruritus since it's a common feature. 70% of patients have a history, and in our studies, 30% or more have moderate-to-severe itch at baseline. And so in that case, looking for a secondary endpoint where we get the symptom relief makes a lot of sense.

我認為從我們的角度來看，研究設計可以稱為嵌套設計，首先，我們著眼於復合終點和標準化。這些是與結果相關的因素。而且因為它是一種罕見的疾病，當然，很難進行大規模研究，所以添加瘙癢症是有意義的，因為它是一個常見的特徵。 70% 的患者有病史，在我們的研究中，30% 或更多的患者在基線時有中度至重度瘙癢。因此，在這種情況下，尋找緩解症狀的次要終點就很有意義。

And then finally, with respect to other agents that might be used to treat cholestatic pruritus, our feeling is, once again, if you have an agent that has improved biochemistry that's related to -- as risk factors for prognostic outcomes as well as improved symptoms, that makes the most sense for the patient, makes the most sense for the physician. And I think that gives us the best opportunity for a patient to get what they need in a single agent.

最後，關於可能用於治療膽汁淤積性瘙癢的其他藥物，我們的感覺是，如果您有一種藥物可以改善與預後結果以及改善症狀相關的生化指標，這對患者來說最有意義，對醫生來說也最有意義。我認為這為我們提供了最好的機會，使患者能夠通過單一藥物獲得他們所需的東西。

At this time, we are showing no further questioners in the queue. And this concludes our question-and-answer session. I would now like to turn the conference back over to Sujal Shah for any closing remarks.

目前，我們在隊列中沒有顯示更多提問者。我們的問答環節到此結束。現在我想將會議轉回給蘇加爾·沙阿（Sujal Shah）發表閉幕詞。

Thank you all once again for joining us today. As we've mentioned a few times, it's been a fast start to the year with much more ahead of us in the coming months. We look forward to sharing data at EASL at the end of June, top line data from RESPONSE in the third quarter and additional clinical and regulatory updates with you throughout the year. Thank you.

再次感謝大家今天加入我們。正如我們多次提到的，今年的開局很快，接下來的幾個月還有更多的事情等著我們。我們期待在 6 月底與您分享 EASL 的數據、第三季度來自 RESPONSE 的頂線數據以及全年與您分享的其他臨床和監管更新。謝謝。

The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.

會議現已結束。感謝您參加今天的演示，您現在可以斷開連接了。