CymaBay Therapeutics Inc (CBAY) 2023 Q2 法說會逐字稿

Good day, ladies and gentlemen, and welcome to CymaBay's Second Quarter 2023 Financial Results and Business Update Conference Call.

女士們、先生們，美好的一天，歡迎參加 CymaBay 2023 年第二季度財務業績和業務更新電話會議。

(Operator Instructions)

（操作員說明）

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.

請注意，我們將根據公司的要求對通話進行錄音。該活動還在 CymaBay 網站 www.cymabay.com 的投資者部分進行網絡直播。

Now 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've had a chance to review the press release we issued announcing our second quarter 2023 financial results and business updates. You can access that release on our website under the Investors tab.

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 年第二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。

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 Harish Shantharam, Chief Finance Officer. Following our prepared remarks, we will open the call for Q&A.

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； Harish Shantharam，首席財務官。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 time lines 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. 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.

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屬於1995 年《私人證券訴訟改革法案》所定義的前瞻性陳述。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，實際結果和結果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。

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. 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 for 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.

除非適用法律要求，否則公司不承擔因新信息、未來事件或其他原因而更新或補充任何前瞻性陳述的義務。參與者請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，以了解可能導致實際結果與前瞻性聲明中預期結果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, and good afternoon, everyone. We are confidently advancing towards what is a key and exciting milestone this fall when we expect to report top line results from response, our global Phase III registration study of seladelpar in people with primary biliary cholangitis or PBC. We anticipate releasing top line results from response by the end of September, and we'll then plan to submit for regulatory approval as soon as feasible. Our update today includes the announcement of IDEAL, an important new clinical study in the development program of seladelpar for PBC, and an overview of our pre-commercial planning activities for seladelpar.

謝謝保羅，大家下午好。今年秋天，我們充滿信心地邁向一個關鍵且令人興奮的里程碑，屆時我們預計將報告我們對 seladelpar 在原發性膽汁性膽管炎或 PBC 患者中進行的全球 III 期註冊研究的反應結果。我們預計在 9 月底之前發布回复的主要結果，然後我們將計劃盡快提交監管部門批准。我們今天的更新包括 IDEAL 的發布，這是 seladelpar 用於 PBC 的開發計劃中的一項重要的新臨床研究，以及我們對 seladelpar 的商業前規劃活動的概述。

Before we get to these updates, let me welcome our new CFO, Harish Shantharam, to this call. Harish joined us in May and brings over 20 years of experience driving 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. We are delighted to have Harish during this time of critical growth for the company as we plan for the completion of our Phase III study, regulatory filing and commercialization of seladelpar for patients with PBC. His operational leadership capabilities as well as his strong strategic finance and commercial experience will be critical as we embark on a transformation to a fully integrated commercial biotech company.

在介紹這些最新消息之前，請允許我歡迎我們的新任首席財務官 Harish Shantharam 參加本次電話會議。 Harish 於 5 月加入我們，擁有 20 多年在商業生物技術公司推動各種財務職能的經驗，特別注重製定戰略、建立財務規劃和會計業務，為公司的商業藥物上市做好準備。我們很高興在公司關鍵增長時期擁有 Harish，因為我們計劃完成 seladelpar 用於 PBC 患者的 III 期研究、監管備案和商業化。當我們開始向完全一體化的商業生物技術公司轉型時，他的運營領導能力以及豐富的戰略財務和商業經驗將至關重要。

Turning to our progress with seladelpar. We continue to execute on what we believe is currently the largest clinical development program in PBC. Between our Phase II studies, prior Phase III ENHANCE study, the ongoing Phase III RESPONSE study and the open-label ASSURE study, the development program for seladelpar is one of the most robust ever conducted in patients with PBC with over 600 participants including over 300 currently receiving treatment with Seladelpar in our ongoing studies. It is the depth of clinical data that gives us the confidence in seladelpar's potential to offer a clear differentiated second-line treatment option for patients who are either intolerant or have an inadequate response to ursodeoxycholic acid, the approved first-line agent.

談談我們在 seladelpar 方面的進展。我們繼續執行我們認為目前 PBC 最大的臨床開發項目。在我們的II 期研究、之前的III 期ENHANCE 研究、正在進行的III 期RESPONSE 研究和開放標籤ASSURE 研究之間，seladelpar 的開發計劃是有史以來針對PBC 患者開展的最穩健的計劃之一，共有600多名參與者，其中包括300 多名參與者目前在我們正在進行的研究中正在接受 Seladelpar 治療。正是臨床數據的深度讓我們相信 seladelpar 有潛力為對熊去氧膽酸（已批准的一線藥物）不耐受或反應不足的患者提供明顯差異化的二線治療選擇。

At the EASL Congress in Vienna in June, there was considerable discussion among PBC thought leaders, industry sponsors and patient advocacy groups that centered on revisiting treatment goals for PBC. We noted a consistent theme in the dialogue to consider adjusting treatment goals to include normalization of cholestatic and inflammatory markers and the need to include improving symptom burden. Earlier today, we announced the initiation of IDEAL, a study that will compare the effects of seladelpar on normalization of ALP versus placebo in patients who continue to have persistent elevations of ALP above normal, but below 1.67x the upper limit of normal.

在 6 月於維也納舉行的 EASL 大會上，PBC 思想領袖、行業贊助商和患者倡導團體之間進行了大量討論，重點是重新審視 PBC 的治療目標。我們注意到對話中的一個一致主題，即考慮調整治療目標，包括膽汁淤積和炎症標誌物的正常化以及改善症狀負擔的需要。今天早些時候，我們宣布啟動 IDEAL，這項研究將比較 seladelpar 與安慰劑對 ALP 持續高於正常水平但低於正常上限 1.67 倍的患者的 ALP 正常化的影響。

A level that has been often used as a lower cutoff in clinical trials for PBC. In several publications, this population has been identified to be at continued risk for disease progression. However, they do not meet current guidelines for recommending second-line treatment and are not typically included in clinical research. We believe that IDEAL has the potential to be transformational for this neglected population, potentially resetting expectations for second-line treatment.

該水平經常被用作 PBC 臨床試驗的下限。在一些出版物中，該人群已被確定處於疾病進展的持續風險中。然而，它們不符合當前推薦二線治療的指南，並且通常不包含在臨床研究中。我們相信 IDEAL 有潛力為這一被忽視的人群帶來變革，有可能重新設定對二線治療的期望。

We are optimistic for the potential results in IDEAL given seladelpar's previous rates of alkaline phosphatase normalization and ENHANCE, a population that had much higher levels of ALP that will be recruited to IDEAL. We are excited that this study is now actively recruiting and while it is too early for us to comment on time lines for enrollment and data, Chuck will provide more detail on this study during today's call.

考慮到 seladelpar 之前的鹼性磷酸酶正常化率和 ENHANCE（ALP 水平高得多的人群將被招募到 IDEAL），我們對 IDEAL 的潛在結果持樂觀態度。我們很高興這項研究現在正在積極招募，雖然我們對招募時間和數據發表評論還為時過早，但查克將在今天的電話會議中提供有關這項研究的更多詳細信息。

Seladelpar is the first in the delpar class of drugs that targets PPAR delta in the liver. Study results to date suggest that it has a differentiated profile for efficacy on cholestatic markers of disease including the registration endpoint of primary composite response of ALP and total bilirubin and on ALP normalization. Unique among agents approved or in development for PBC, prior studies have suggested that a key feature of seladelpar's profile might be improvement in quality of life by reducing pruritus in those patients with clinically significant itch. If seladelpar's profile is confirmed in the ongoing pivotal response study, and if the safety is consistent with that seen to date, we believe seladelpar could be an important step forward in patient care.

Seladelpar 是 delpar 類藥物中第一個針對肝臟中 PPAR δ 的藥物。迄今為止的研究結果表明，它對疾病膽汁淤積標誌物的功效具有差異化特徵，包括 ALP 和總膽紅素的主要復合反應的登記終點以及 ALP 正常化。先前的研究表明，seladelpar 的一個關鍵特徵可能是通過減少臨床上明顯瘙癢的患者的瘙癢來改善生活質量，這在已批准或正在開發的 PBC 藥物中是獨一無二的。如果 seladelpar 的概況在正在進行的關鍵反應研究中得到證實，並且如果安全性與迄今為止所見的一致，我們相信 seladelpar 可能是患者護理方面向前邁出的重要一步。

If in the future, we are able to confirm our expectation of positive results in IDEAL, this would be important to advance our aspirations to remake the landscape for treating PBC to far more than those that are treated with second-line therapy today.

如果將來我們能夠確認 IDEAL 取得積極成果的預期，這對於推進我們重塑 PBC 治療前景的願望非常重要，使其遠超目前二線治療的水平。

On the operational front, we continue to make good progress with our medical affairs organizational build, including both leaders and field members having years of experience, including in PBC. We have also been successful in assembling key talent for our commercial infrastructure, in line with our pre-commercial priorities. Lewis will provide more details later in the call.

在運營方面，我們的醫療事務組織建設繼續取得良好進展，包括在 PBC 等具有多年經驗的領導者和現場成員。我們還根據我們的商業前優先事項成功地為我們的商業基礎設施聚集了關鍵人才。劉易斯將在稍後的電話會議中提供更多細節。

Before that, let me hand the call over to Chuck, who will provide updates on our clinical progress.

在此之前，讓我將電話轉交給查克，他將提供我們臨床進展的最新信息。

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. We are now entering what is the most important stage of our Phase III RESPONSE study. Our last study visits are imminent, and we are diligently closing out activities for final database cleaning and locking followed by unblinding and analysis for top line results. In this, as in all of our development activities, we are committed to the principles of quality, data integrity and efficiency. With the team having many members with experience in pivotal studies, we are well positioned to share top line results on our key prespecified endpoints by the end of September, followed by timely in-depth communication of results at a medical conference and in a publication.

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。我們現在正進入第三階段反應研究最重要的階段。我們的最後一次研究訪問即將進行，我們正在努力結束最終數據庫清理和鎖定的活動，然後對頂線結果進行揭盲和分析。在這方面，正如我們所有的開發活動一樣，我們致力於質量、數據完整性和效率的原則。由於該團隊擁有許多在關鍵研究方面具有經驗的成員，我們完全有能力在 9 月底之前分享我們預先指定的關鍵終點的主要結果，然後在醫學會議和出版物上及時深入地交流結果。

We intend to complete and submit regulatory applications for approval as soon as feasible. The depth of the seladelpar program is further underscored by the long-term safety ASSURE study. Currently active in more than 25 countries and 115 research sites, it has over 300 patients taking seladelpar 10 milligrams. We expect ASSURE to contribute to both safety and efficacy data sets supporting our regulatory filings and will be a source of important information documenting the long-term impact of seladelpar treatment on disease and symptoms in PBC. We continue to be encouraged by patient retention in both studies and are pleased to report that the most recent quarterly review by the response DSMB directed that as before, the study can continue without any changes.

我們打算盡快完成並提交監管申請以供批准。長期安全 ASSURE 研究進一步強調了 seladelpar 計劃的深度。目前活躍於超過 25 個國家和 115 個研究中心，有超過 300 名患者服用 seladelpar 10 毫克。我們預計 ASSURE 將為支持我們的監管備案的安全性和有效性數據集做出貢獻，並將成為記錄 seladelpar 治療對 PBC 疾病和症狀的長期影響的重要信息來源。我們繼續對兩項研究中的患者保留率感到鼓舞，並很高興地報告，響應 DSMB 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。

Our confidence in the clinical profile of seladelpar stems both from the robust clinical data set we have accumulated from past trials as well as our understanding of the underlying delpar mechanism driving differentiated and clinically important profiles. Seladelpar is the first selective PPAR delta agonist or delpar to regulate critical pathways important in PBC pathology in the liver, including cholestasis and inflammation. Given that this is our last call before top line results, and there may be many who are just now trying to learn more about our program, I'd like to briefly recap seladelpar's profile from our prior studies.

我們對 seladelpar 臨床特徵的信心源於我們從過去的試驗中積累的可靠臨床數據集，以及我們對驅動差異化和臨床重要特徵的潛在 delpar 機制的理解。 Seladelpar 是第一個選擇性 PPAR δ 激動劑或 delpar，用於調節肝臟 PBC 病理學中重要的關鍵通路，包括膽汁淤積和炎症。鑑於這是我們在獲得最終結果之前的最後一次電話會議，並且可能有許多人現在正試圖了解有關我們計劃的更多信息，我想簡要回顧一下我們之前研究中的 seladelpar 的簡介。

In our open-label Phase II study, among patients taking daily oral seladelpar 10 milligrams, 67% achieved the alkaline phosphatase bilirubin composite endpoint at 12 months previously used by regulators for approval. In the ENHANCE study, the seladelpar 10 milligram arm saw over 78% achieved this endpoint at 3 months. In addition, Nearly 1 in 3 of these patients had enhanced normalized alkaline phosphatase levels after 3 months despite having, on average, pretreatment ALP levels of 2.5x the upper limit of normal.

在我們的開放標籤 II 期研究中，在每日口服 seladelpar 10 毫克的患者中，67% 的患者在 12 個月時達到了監管機構批准之前使用的鹼性磷酸酶膽紅素複合終點。在 ENHANCE 研究中，seladelpar 10 毫克組中超過 78% 的患者在 3 個月內達到了這一終點。此外，儘管治療前 ALP 水平平均為正常上限的 2.5 倍，但近三分之一的患者在 3 個月後其正常鹼性磷酸酶水平有所提高。

With respect to the key quality of life result amongst patients with prespecified baseline moderate to severe itch. Those taking seladelpar 10 milligram for 3 months had significant improvements compared to placebo in their pruritus intensity using a daily electronic diary. These results give us confidence in seladelpar's clinical profile and also set our expectations on the range of outcomes that we hope to achieve in response.

關於具有預定基線中度至重度瘙癢的患者的關鍵生活質量結果。與安慰劑相比，服用 seladelpar 10 毫克 3 個月的患者在每日電子日記中的瘙癢強度有顯著改善。這些結果讓我們對 seladelpar 的臨床概況充滿信心，也讓我們對希望實現的一系列結果設定了期望。

Perhaps the high point for me on today's call is the opportunity now to talk about IDEAL, a study that we have been working on initiating over the past few months.

也許對我來說今天電話會議的重點是現在有機會談論 IDEAL，這是我們在過去幾個月裡一直致力於啟動的一項研究。

First, let me give you some background for context. Beginning in 2020, publications from the global PBC study group have shown that patients having any elevation of alkaline phosphatase above normal are at a greater risk for disease progression than those with normal levels of ALP. Our early market research suggests that in the U.S., greater than 20,000 patients on UDCA may have a persistent ALP level between 1 and 1.67x the upper limit of normal. These patients would typically be managed by treatment with UDCA in a wait to fail paradigm in spite of evidence of the risk of their progression of disease.

首先，讓我向您介紹一些背景知識。從 2020 年開始，全球 PBC 研究小組的出版物表明，鹼性磷酸酶高於正常水平的患者比 ALP 水平正常的患者面臨更大的疾病進展風險。我們的早期市場研究表明，在美國，超過 20,000 名接受 UDCA 的患者的 ALP 水平可能持續處於正常上限的 1 至 1.67 倍之間。儘管有證據表明這些患者存在疾病進展的風險，但通常會通過等待失敗模式中的 UDCA 治療來進行管理。

To make it worse, they wouldn't be eligible for clinical studies of new second-line agents. This is where IDEAL has the potential to lead the way to gather some critical evidence that this population could benefit from additional treatment with seladelpar. Given the situation for this overlooked population, we believe that the IDEAL study is groundbreaking for patients. IDEAL is a Phase III randomized, placebo-controlled study of patients with the diagnosis of PBC, taken a stable dose of UDCA unless intolerant with ALP levels between 1 and 1.67x the upper limit of normal. It is planned to randomize 75 patients 2:1, daily oral seladelpar 10 milligrams to placebo, the treatment plan for 52 weeks. The primary endpoint will be ALP normalization at 52 weeks.

更糟糕的是，他們沒有資格參加新的二線藥物的臨床研究。 IDEAL 有潛力在這方面發揮帶頭作用，收集一些關鍵證據，證明該人群可以從 seladelpar 的額外治療中受益。考慮到這一被忽視人群的情況，我們相信 IDEAL 研究對於患者來說是開創性的。 IDEAL 是一項 III 期隨機、安慰劑對照研究，受試者為診斷為 PBC 的患者，服用穩定劑量的 UDCA，除非 ALP 水平在正常上限的 1 至 1.67 倍之間不耐受。計劃將75名患者以2:1的比例隨機分組，每日口服seladelpar 10毫克至安慰劑，治療計劃持續52週。主要終點是 52 週時 ALP 正常化。

All other eligibility criteria and many secondary and exploratory endpoints will be similar to prior studies of seladelpar, pruritus will be evaluated using a daily electronic diary. In a poster, we presented at EASL in June, we reported that approximately half of the patients screened in our prior PBC studies to seladelpar screen fail because of ALP levels that are between 1 and 1.67x upper limit of normal. The prevalence of these patients provide us considerable encouragement regarding the feasibility of enrolling the study.

所有其他資格標準以及許多次要和探索性終點將與 seladelpar 的先前研究類似，將使用每日電子日記評估瘙癢症。在我們 6 月份在 EASL 上發表的海報中，我們報告說，在我們之前的 PBC 研究中，大約一半的患者因 seladelpar 篩查而失敗，因為 ALP 水平在正常上限的 1 到 1.67 倍之間。這些患者的患病率為我們參加這項研究的可行性提供了相當大的鼓勵。

Before I turn the call over to Lewis to discuss our pre-commercial preparations for seladelpar, I'll provide a brief update on the progress in our Phase IIa, proof-of-pharmacology study for MBX-2982, as a reminder, MBX-2982, a GPR119 agonist discovered and developed by CymaBay is being investigated for its potential to prevent or minimize hypoglycemia, in patients with type 1 diabetes. The study is fully funded by the Leona M. and Harry B. Helmsley Charitable Trust with CymaBay retaining all rights to MBX-2982.

在我把電話轉給 Lewis 討論我們 seladelpar 的商業前準備工作之前，我將簡要介紹一下 MBX-2982 IIa 期藥理學驗證研究的進展情況，提醒一下，MBX- 2982 是CymaBay 發現和開發的一種GPR119激動劑，目前正在研究其預防或最大程度減少1 型糖尿病患者低血糖的潛力。該研究由 Leona M. 和 Harry B. Helmsley 慈善信託基金全額資助，CymaBay 保留 MBX-2982 的所有權利。

In addition to safety and tolerability, the primary endpoints are maximum glucagon release and glucagon area under the curve for MBX-2982 treated patients versus placebo. The study is now fully enrolled, and we expect to share data before the end of the year. Depending on the results from this study, we will determine the next steps related to the clinical and regulatory path.

除了安全性和耐受性之外，主要終點是 MBX-2982 治療患者與安慰劑相比的最大胰高血糖素釋放和曲線下胰高血糖素面積。該研究現已全部入組，我們預計在年底前分享數據。根據這項研究的結果，我們將確定與臨床和監管路徑相關的後續步驟。

With that, I will turn it over to Lewis.

這樣，我就把它交給劉易斯。

Thank you, Chuck. Over the last few months, I've continued to emphasize CymaBay's commercial vision, driven by an unwavering focus on PBC and its stakeholders, utilizing a high-touch engagement model that is supported by scientific rigor and innovation. During the first half of 2023, we have been diligently building the foundation of our commercial infrastructure. We began by developing a highly specialized distribution model designed to support the patients and their providers throughout their treatment journey.

謝謝你，查克。在過去的幾個月裡，我繼續強調 CymaBay 的商業願景，其驅動力是堅定不移地關注 PBC 及其利益相關者，並利用以科學嚴謹和創新為支持的高接觸參與模式。 2023年上半年，我們認真打好商業基礎設施基礎。我們首先開發了一種高度專業化的分銷模式，旨在為患者及其提供者在整個治療過程中提供支持。

In parallel, we established agencies of record to support seladelpar patient and HCP marketing programs as well as kicked off new programs designed to enhance CymaBay's corporate brand, media outreach and, of course, ongoing partnership with all global PVC advocacy groups. During the second quarter, we were fortunate to recruit and hire key senior commercial leaders in marketing, market access and commercial operations. Each of whom come with considerable experience and will have an essential role as we accelerate our commercial build in alignment with key corporate milestones.

與此同時，我們建立了記錄機構來支持 seladelpar 患者和 HCP 營銷計劃，並啟動了旨在增強 CymaBay 的企業品牌、媒體宣傳以及與所有全球 PVC 倡導團體的持續合作關係的新計劃。在第二季度，我們有幸招募和聘用了營銷、市場准入和商業運營方面的關鍵高級商業領導者。他們每個人都擁有豐富的經驗，並將在我們根據關鍵的公司里程碑加速商業建設的過程中發揮重要作用。

CymaBay's success in achieving our commercial vision begins with the science of seladelpar and its potential for resetting the ideal goals for PBC treatment. Our secondary research indicates that less than 40% of UDCA-treated patients are able to experience a complete response. In other words, normalization of ALP and total bilirubin. Our research suggests there is an opportunity to improve biochemical response and reduce symptoms for a significant proportion of patients not being treated with second-line treatment today. We're very excited with the initiation of the IDEAL study and its potential for expanding seladelpar's utility in this target population.

CymaBay 成功實現我們的商業願景始於 seladelpar 的科學及其重新設定 PBC 治療理想目標的潛力。我們的二次研究表明，只有不到 40% 的 UDCA 治療患者能夠獲得完全緩解。換句話說，ALP 和總膽紅素正常化。我們的研究表明，對於目前未接受二線治療的很大一部分患者來說，有機會改善生化反應並減輕症狀。我們對 IDEAL 研究的啟動及其擴大 seladelpar 在這一目標人群中的效用的潛力感到非常興奮。

I'll now hand the call over to Harish to discuss our financial results. Harish?

我現在將電話轉交給哈里什，討論我們的財務業績。哈里什？

Thank you, Lewis, and good afternoon, everyone. The second quarter was another productive one for CymaBay. As highlighted by everyone before me, we made significant progress towards meeting our key objectives for the year related to development, regulatory and pre-commercial planning.

謝謝劉易斯，大家下午好。第二季度對 CymaBay 來說又是一個富有成效的季度。正如我之前的每個人所強調的那樣，我們在實現今年與開發、監管和商業前規劃相關的關鍵目標方面取得了重大進展。

In terms of financials, we finished the quarter with a strong balance sheet with cash, cash equivalents and investments totaling $213.8 million as of June 30, 2023. In line with the prior update call, we believe that cash and investments on hand are sufficient to fund CymaBay’s operating plan through the third quarter of 2024. We recognized $31 million of collaboration revenue in the second quarter of 2023 and following completion of the initial technology transfer to Kaken associated with the license to develop and commercialize seladelpar in Japan. Of the $34.2 million upfront payment paid by Kaken $2.7 million remains deferred and will be recognized upon completion of the company's ongoing clinical data delivery and CMC development performance obligations.

在財務方面，我們在本季度結束時擁有強勁的資產負債表，截至2023 年6 月30 日，現金、現金等價物和投資總額為2.138 億美元。根據之前的更新電話，我們認為手頭的現金和投資足以資助CymaBay 的運營計劃直至2024 年第三季度。在完成向Kaken 的初步技術轉讓（與在日本開發和商業化seladelpar 的許可相關）後，我們在2023 年第二季度確認了3100 萬美元的合作收入。 Kaken 支付的 3420 萬美元預付款中，有 270 萬美元仍處於遞延狀態，並將在完成公司正在進行的臨床數據交付和 CMC 開發履約義務後予以確認。

As for our operating expenses, research and development expenses for the quarter ended June 30, 2023 and 2022 were $19.5 million and $17.9 million, respectively. Research and development expense for the quarters ended June 30, 2023, were higher than the corresponding period in '22 and were primarily driven by higher personnel costs to support our clinical studies and regulatory activities. As we continue to progress in the 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6月30日和2022年6月30日的季度的研發費用分別為1950萬美元和1790萬美元。截至 2023 年 6 月 30 日的季度的研發費用高於 22 年同期，主要是由於支持我們的臨床研究和監管活動的人員成本增加所致。隨著我們人民銀行seladelpar後期開發的不斷進展，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 June 30, 2023 and 2022 were $11.6 million and $5.9 million, respectively. General and administrative expenses for the quarters ended June 30, 2023, were higher than the corresponding period in 2022 and were primarily driven by initiation of commercial and medical affairs organization build and spend related to pre-commercial planning.

現在簡要回顧一下一般和行政費用。截至 2023 年 6 月 30 日和 2022 年 6 月 30 日的季度的這些成本分別為 1160 萬美元和 590 萬美元。截至 2023 年 6 月 30 日的季度的一般和行政費用高於 2022 年同期，主要是由於商業和醫療事務組織建設的啟動以及與商業前規劃相關的支出所致。

Overall, our net loss for each of the quarters ended March 31, 2023 (sic) [June 30, 2023] and 2022 was $0.8 million and $27.1 million or $0.01 and $0.31 per share, respectively. Net loss for the quarter ended June 30, 2023, was lower than the corresponding period in 2022 and due primarily to higher collaboration revenue, partially offset by an increase in operating expenses. 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（原文如此）[2023 年6 月30 日]和2022 年每個季度的淨虧損分別為80 萬美元和2710 萬美元，即每股0.01 美元和0.31 美元。截至 2023 年 6 月 30 日的季度淨虧損低於 2022 年同期，主要是由於協作收入增加，部分被運營費用增加所抵消。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 hand the call back to Sujal.

讓我把電話轉回給 Sujal。

Thank you, Harish. I'd like to take this opportunity to thank our team here at CymaBay for their tireless efforts, the PBC patient community and their caregivers for their dedication to our work and our investigators, thought leaders and investors for their support. It is the result of these partnerships that we have been able to come one step closer in our journey towards our goal of improving the lives of patients with PBC. We remain laser focused on this objective and look forward to sharing updates related to top line results from response before the end of September. We're now happy to take questions. Operator?

謝謝你，哈里什。我想藉此機會感謝 CymaBay 團隊的不懈努力，感謝 PBC 患者社區及其護理人員對我們工作的奉獻，感謝我們的調查人員、思想領袖和投資者的支持。正是這些合作夥伴關係的結果，使我們能夠在改善 PBC 患者生活的目標的道路上更近了一步。我們仍然高度關注這一目標，並期待在 9 月底之前分享與響應的頂線結果相關的最新信息。我們現在很樂意回答問題。操作員？

(Operator Instructions)

（操作員說明）

Our first question going to the line of Yasmeen Rahimi with Piper Sandler.

我們的第一個問題涉及亞斯明·拉希米 (Yasmeen Rahimi) 和派珀·桑德勒 (Piper Sandler) 的路線。

Thank you so much for the update and congrats on IDEAL. Two quick questions for you. The first one, I know that you guys have spoken about the IDEAL study and many calls before, but I think a lot of investors are wondering why is the time ideal now, especially as we are a couple of weeks going into the top line data? And then the second question is directed to on the commercial side, which is what percentage of the current PBC market would fall under patients that are somewhere between 1 to 1.67x, like the ideal population. And then one short mini question at the end if I may squeeze that.

非常感謝您的更新並祝賀 IDEAL。有兩個簡單的問題要問你。第一個，我知道你們之前已經談到過 IDEAL 研究和許多電話，但我認為很多投資者都想知道為什麼現在是理想的時機，特別是我們距離頂線數據還有幾週的時間？然後第二個問題涉及商業方面，即當前 PBC 市場的患者比例為 1 到 1.67 倍之間，就像理想人群一樣。最後還有一個簡短的小問題，我可以問一下嗎？

Thanks for the question, Yas. This is Sujal. I'll just start off. With respect to the timing of IDEAL, I think important for me to highlight as we have in prior calls, our experience in PBC, of course, dates back to 2015. And with the extensive work that we've conducted through Phase II development as well as our prior ENHANCE study, the timing is really predicated on an expectation around success. I think it's also important for me to highlight that it's many months in the making with respect to planning for meeting with experts, conducting market research to be very thoughtful about how we might learn from additional data sets that could really reset as we describe potential expectations around treatment and benefits for a broader treatment patient population in the setting of PBC.

謝謝你的提問，亞斯。這是蘇加爾。我就開始吧。關於IDEAL 的時間安排，我認為對我來說很重要的是，正如我們在之前的電話會議中強調的那樣，我們在PBC 的經驗當然可以追溯到2015 年。通過我們在第二階段開發中進行的廣泛工作，與我們之前的 ENHANCE 研究一樣，時機實際上是基於對成功的期望。我認為對我來說，強調這一點也很重要：與專家會面的計劃、進行市場研究的準備工作已經進行了好幾個月，以便非常深思熟慮地思考我們如何從額外的數據集中學習，這些數據集在我們描述潛在期望時可能會真正重置圍繞 PBC 背景下更廣泛的治療患者群體的治療和益處。

So much of the timing, I think, from our perspective, has to do with planning for success and really being able to deliver a data set as quickly as possible. As you might imagine, these patients that we described who have not really to date, been evaluated in the second-line setting patients that we believe remain at a higher risk of progression are patients living with the disease every day. So our attention to this population is one for which we're excited to press forward on now and excited about collecting that data set as quickly as we can to support more knowledge that we may have around these potential benefits for patients.

我認為，從我們的角度來看，大部分時間都與成功規劃以及真正能夠盡快交付數據集有關。正如您可能想像的那樣，我們所描述的這些患者迄今為止尚未真正在二線環境中進行過評估，我們認為這些患者仍處於較高的進展風險，這些患者是每天患有該疾病的患者。因此，我們對這一人群的關注是我們現在很高興能夠繼續推進的一個問題，並且很高興能夠盡快收集該數據集，以支持我們可能掌握的有關這些對患者的潛在益處的更多知識。

With respect to your second question, maybe I'll just start off and invite Lewis to provide some additional context. We continue to conduct a significant amount of market research, as you might imagine, as we particularly advanced beyond RESPONSE top line data towards regulatory submissions and then all the planning that Lewis and his entire team will continue to conduct from a commercial launch readiness perspective.

關於你的第二個問題，也許我會首先邀請劉易斯提供一些額外的背景信息。正如您可能想像的那樣，我們將繼續進行大量的市場研究，因為我們特別將 RESPONSE 頂線數據推進到監管提交，然後劉易斯和他的整個團隊將繼續從商業發布準備的角度進行所有規劃。

Early market research that we have to date suggests that of the patients, if I just look at the U.S. population that are on UDCA, post at least 12 months of treatment on UDCA, it could be a population that is almost 1/3 of those that are actually taking UDCA that could be patients that remain in this bucket between 1 and 1.67x the upper limit of normal.

我們迄今為止的早期市場研究表明，如果我只看接受 UDCA 治療的美國患者群體，在接受 UDCA 治療至少 12 個月後，該患者群體可能接近其中的 1/3實際上正在服用UDCA 的患者可能仍處於正常上限1 至1.67 倍之間。

Lewis, I don't know if you want to talk a little bit about what we're continuing to do to get a better sense of this population.

劉易斯，我不知道你是否想談談我們正在繼續做什麼，以更好地了解這一群體。

Yes. We continue to evaluate really how these patients flow through their treatment of UDCA. We -- as I mentioned in my earlier comments, about less than 40% of those patients actually experienced a complete response. So we tend to segment these patients out as, of course, as Sujal described, the 20,000 that are partial responders and then on into those patients and, of course, above 1.67x upper limit of normal, which are the incomplete responders. And of course, as we've defined the second-line market based on POISE criteria, at 1.67x upper limit of normal, that's about 25,000 to 30,000 patients.

是的。我們將繼續評估這些患者如何接受 UDCA 治療。正如我在之前的評論中提到的，我們大約只有不到 40% 的患者真正獲得了完全緩解。因此，我們傾向於將這些患者細分為，當然，正如 Sujal 所描述的，20,000 名部分緩解者，然後再細分為這些患者，當然，高於正常上限的 1.67 倍，即不完全緩解者。當然，正如我們根據 POISE 標准定義的二線市場（正常上限的 1.67 倍），大約有 25,000 至 30,000 名患者。

So we continue to look at this population. We'll continue to understand exactly how those patients really experience, not just from a standpoint of liver health but also, of course, symptom management too. We think that between both the complete responders and those that, of course, are partial responders, there are probably about 15,000 patients that continue to experience pruritus. So that's how we're looking at it now, but we'll continue to look at that data.

所以我們繼續關注這個人群。我們將繼續準確了解這些患者的真實感受，不僅從肝臟健康的角度來看，當然也從症狀管理的角度來看。我們認為，在完全緩解者和部分緩解者之間，可能有大約 15,000 名患者繼續出現瘙癢症狀。這就是我們現在看待它的方式，但我們將繼續關注這些數據。

And then just in regards to the timing of RESPONSE, I just want to make sure that everyone is clear when you're saying the data is coming by end of September, does that mean it can be any day between now and the last day of September or the option to, it will come end of September.

然後就回复時間而言，我只是想確保每個人都清楚，當您說數據將於 9 月底之前發佈時，這是否意味著它可以是從現在到最後一天之間的任何一天九月或者選擇，九月底到來。

Yes. The expectation has always been that we would release top line data before the end of Q3. I think importantly, we highlight that we want to have appropriate quality and data integrity as we close out final visits, follow-up visits, cleaning and locking the database. I think I would simply leave it as having an expectation that the top line results will come sometime in September.

是的。我們一直期望在第三季度末之前發布營收數據。我認為重要的是，我們強調，在結束最終訪問、後續訪問、清理和鎖定數據庫時，我們希望擁有適當的質量和數據完整性。我想我會簡單地保留它，因為預計頂線結果將在 9 月份的某個時候出現。

Our next question is from Steven Seedhouse with Raymond James.

我們的下一個問題來自 Steven Seedhouse 和 Raymond James。

I have 2 on IDEAL. One is just you published some -- I think data, I think, at EASL on the screen failure rates for your prior clinical studies, and it was something like 1/4 of screen failures -- 1/4 of patients screened, I believe, in fact, actually failed on the basis of having this range of ALP, like some -- over 250 patients, let's say. Does that mean -- like are these patients essentially in the care of your investigators and very easy to go back and identify and enroll this study rapidly? Or will this be sort of starting from scratch and enrolling steadily despite that dynamic?

我在 IDEAL 上有 2 個。一是你在 EASL 上發表了一些關於你之前臨床研究的篩查失敗率的數據，大約有 1/4 的篩查失敗——我相信 1/4 的患者接受了篩查事實上，在擁有這個範圍的ALP 的基礎上實際上失敗了，就像一些患者一樣——比方說，超過250 名患者。這是否意味著——這些患者基本上由您的研究人員照顧，並且很容易返回并快速識別並參加這項研究？或者，儘管存在這種動態，這是否會從頭開始並穩定招生？

And then the second question is just pruritus in this population. Do you have any data in a sense of if it's similar or less prevalent given the ALP levels than it would be in the population with over 1.67x upper limit of normal ALP?

第二個問題就是這個人群的瘙癢症。您是否有任何數據表明，在給定 ALP 水平的情況下，這種情況是否與正常 ALP 上限超過 1.67 倍的人群中的情況相似或不太普遍？

Yes. Thanks, Steve, for that question. I think you've identified a strategy that, of course, has occurred to us to go back to investigators who would want to be involved in IDEAL who've already screened patients and may know patients who would potentially qualify. So that, of course, is a lever that we will pull. I would say a couple of comments. When you say easy, of course, clinical research, it always takes attention, and it's never something that we take lightly.

是的。謝謝史蒂夫提出這個問題。我認為您已經確定了我們當然想到的策略，即回到那些想要參與 IDEAL 的研究人員那裡，他們已經篩查過患者，並且可能知道可能符合資格的患者。當然，這就是我們要拉動的槓桿。我想說幾句評論。當然，當你說臨床研究很容易時，它總是需要引起注意，而且我們從來不會掉以輕心。

I do -- I would, though, add a comment that based upon our experience, look, there's no competing trials for this population, right? This is the first example where we know where a sponsor has stepped forward and said, we want to study patients with this level of alkaline phosphatase to find out what might benefit might accrue to them. So I do think we have an opportunity to move forward very expeditiously in the study. We're not ready to communicate any time lines yet because we're basically just off the mark now, but we're pretty excited about the potential. And I must say that the feedback from our experts who we consulted when we first conceived of this idea and then developed the protocol as well as the investigators is extremely enthusiastic. So stay tuned for that.

我確實 - 不過，我會根據我們的經驗添加一條評論，看看，沒有針對這一人群的競爭性試驗，對吧？這是我們知道申辦者站出來表示的第一個例子，我們想研究具有這種鹼性磷酸酶水平的患者，以找出他們可能獲得的益處。所以我確實認為我們有機會在研究中快速推進。我們還沒有準備好傳達任何時間表，因為我們現在基本上還沒有達到目標，但我們對潛力感到非常興奮。我必須說，當我們第一次想到這個想法並製定方案時，我們諮詢了專家以及研究人員，他們的反饋非常熱情。所以請繼續關注。

In terms of pruritus, it's a hard question to answer with from a perspective of pruritus intensity that's used in the study in a clinical research setting because we don't generally collect with an electronic diary with a 24-hour recall, those values. But if you look at our poster that we presented at EASL, what you can see is you can look at medical history of pruritus, and it was very significant in this population.

就瘙癢而言，從臨床研究環境中使用的瘙癢強度的角度來看，這是一個很難回答的問題，因為我們通常不會通過具有 24 小時回憶的電子日記來收集這些值。但如果你看一下我們在 EASL 上展示的海報，你會發現你可以查看瘙癢病史，這在這個人群中非常重要。

I wouldn't want to draw a conclusion about exactly the same. One is greater, one is less just because of the limitations in the methodology that I mentioned. It's really just a patient saying yes, I've been vexed with itching before. But we do think that it's quite common. And in fact, if you look in the literature, you'll find that generally speaking, there's not a strong connection between levels of alkaline phosphatase and pruritus and in fact, published work with UDCA, which is a drug that for many patients, has a good effect on disease activity. It lowers alkaline phosphatase, it can affect bilirubin, it doesn't affect pruritus.

我不想得出完全相同的結論。一者較大，一者較小，只是因為我提到的方法論的局限性。真的只是一個病人說的，我以前也曾被瘙癢困擾過。但我們確實認為這很常見。事實上，如果你查閱文獻，你會發現一般來說，鹼性磷酸酶水平和瘙癢之間並沒有很強的聯繫，事實上，已發表的UDCA 的研究成果對許多患者來說是一種藥物，對疾病活動性有良好的作用。它會降低鹼性磷酸酶，會影響膽紅素，但不會影響瘙癢。

So while pruritus is a consequence of the disease, it doesn't travel in lockstep with the level of disease activity. So this is another interesting aspect for us as we examine seladelpar, which at least initially appears to have effects on cholestatic markers as well as pruritus.

因此，雖然瘙癢是疾病的結果，但它並不與疾病的活動水平同步傳播。因此，當我們檢查 seladelpar 時，這對我們來說是另一個有趣的方面，它至少最初似乎對膽汁淤積標誌物和瘙癢有影響。

Our next question is from Kristen Kluska with Cantor Fitzgerald.

我們的下一個問題是克里斯汀·克魯斯卡和坎托·菲茨杰拉德提出的。

I know in your prepared remarks, you talked about quality of life and symptom burden really being a major issue that physicians are looking to address these new treatments. So given the huge unmet need in addressing pruritus, can you talk about what specifically you would characterize as a win here in the upcoming readout?

我知道在您準備好的發言中，您談到生活質量和症狀負擔確實是醫生尋求解決這些新療法的一個主要問題。因此，考慮到解決瘙癢症的巨大需求尚未得到滿足，您能否談談您在即將發布的報告中具體將什麼描述為勝利？

Yes. Happy to start off and answer that question, Kristen. I think important here first to recognize that existing treatment, as Chuck mentioned, with UDCA, the only existing first-line treatment, it's never really been shown to reduce pruritus in patients with PBC. And so as one element of quality of life for patients, you've got a first-line treatment that has yet to demonstrate real benefit on improving quality of life from that perspective. The only existing second-line treatment, obeticholic acid in the U.S., of course, has been shown to cause or worsen itch.

是的。克里斯汀，很高興開始回答這個問題。我認為首先要認識到，正如 Chuck 提到的，現有的治療方法 UDCA（唯一現有的一線治療方法）從未真正被證明可以減少 PB​​C 患者的瘙癢。因此，作為患者生活質量的一個要素，您所獲得的一線治療尚未從這個角度證明對改善生活質量有真正的益處。當然，美國現有的唯一二線治療藥物奧貝膽酸已被證明會引起或加重瘙癢。

So when we look at the totality of the evidence we've generated to date with seladelpar, whether it's from our Phase II studies, looking at VAS scores on pruritus or even the scores from the 5-D itch scale and PBC-40 questionnaire, as well as, of course, the placebo-controlled benefits we saw on 10 milligram seladelpar and ENHANCE at reducing NRS even the responder rates for patients with 3 and 4 points or greater reductions in itch on seladelpar versus placebo and then marry all of that with the evidence that we shared at EASL with respect to IL-31 an inflammatory cytokine that's been associated with itch and seeing those reductions correlate with patient reported reductions in itch.

因此，當我們查看迄今為止使用 seladelpar 生成的全部證據時，無論是來自我們的 II 期研究，還是查看瘙癢的 VAS 評分，甚至是 5-D 瘙癢量表和 PBC-40 問卷的評分，當然，還有我們在10 毫克seladelpar 和ENHANCE 上看到的安慰劑對照益處，在減少NRS 方面，甚至與安慰劑相比，seladelpar 瘙癢減輕3 點和4 點或更多的患者的反應率，然後將所有這些與我們在 EASL 上分享的關於 IL-31 的證據，IL-31 是一種與瘙癢相關的炎症細胞因子，並且看到這些減少與患者報告的瘙癢減少相關。

We fundamentally believe that the benefits patients have on pruritus with seladelpar is quite real. And so we think a bit about the win. Clearly, there's an opportunity to differentiate when you don't cause or worsen itch from existing second-line treatment. But obviously, our aspiration is really suggestive of what we've seen to date with seladelpar, which is to see this improvement. And so our expectation is we'll continue to see this improvement to the degree that we see statistical significance in that measure in response in the key secondary endpoint, of course, it puts us in a much stronger position to go to regulators thinking about opportunities to get seladelpar's approval potentially for actually treating itch in PBC patients as well.

我們從根本上相信，seladelpar 對患者瘙癢的益處是非常真實的。所以我們對勝利進行了一些思考。顯然，當您不引起或加重瘙癢時，有機會與現有的二線治療區分開來。但顯然，我們的願望確實體現了我們迄今為止在 seladelpar 上看到的情況，即看到這種改進。因此，我們的期望是，我們將繼續看到這種改善，達到我們在關鍵次要終點中看到該指標的統計顯著性的程度，當然，這使我們處於更有利的地位，可以讓監管機構考慮機會以獲得 seladelpar 的批准，可能用於實際治療 PBC 患者的瘙癢。

So we think there's real opportunity based on the profile of seladelpar that exists today. If that's really confirmed in response to take a new dialogue to patients really for the first time in a treatment alternative that has an opportunity to improve quality of life.

因此，我們認為，根據 seladelpar 現有的情況，存在真正的機會。如果這一點確實得到證實，那麼我們將首次與患者進行新的對話，以有機會改善生活質量的治療替代方案。

And can you talk about what additional hiring plans you anticipate after RESPONSE?

您能談談在響應之後您預計還有哪些額外的招聘計劃嗎？

Well, I can say that to date, we've started to build out, as we mentioned in the prepared remarks, our medical affairs organization, both in-house as well as folks out in the field. I think post top line data with -- and by the way, we've also done the same with some of our key commercial hires internally. Marketing, market access, commercial operations, a host of additional folks internally here now with the company preparing ourselves, again, for a positive result and ultimately preparing for both regulatory approval and commercial launch.

嗯，我可以說，到目前為止，正如我們在準備好的發言中提到的那樣，我們已經開始建立我們的醫療事務組織，包括內部人員和現場人員。我認為發布頂線數據——順便說一句，我們也對內部的一些關鍵商業員工做了同樣的事情。營銷、市場准入、商業運營、公司內部的許多其他人員現在都在為取得積極成果做好準備，並最終為監管批准和商業發布做好準備。

Post data, you'll see us only continue to step up those specific [approvers] within medical affairs and particularly within commercial. Of course, the field force itself would come later, closer to approval from a time line perspective, but we'll have continued activity here in supportive roles within the company. Again, all geared towards helping us prepare ourselves for commercial launch if we're successful in RESPONSE as well as in regulatory submissions.

發布數據後，您會看到我們只會繼續加強醫療事務領域，特別是商業領域的那些特定[批准者]。當然，現場人員本身會稍後出現，從時間線的角度來看更接近批准，但我們將繼續在公司內以支持性角色開展活動。同樣，如果我們在 RESPONSE 和監管提交方面取得成功，所有這些都是為了幫助我們為商業發布做好準備。

Our next question is from Patrick Dolezal with LifeSci Capital.

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

So a couple more on IDEAL, if I may. Could you just speak to any potential kind of label expansion implications of this study? Or is this kind of more so a study that just might support some marketing efforts. And then as it relates to success in the primary, obviously, it's kind of alk phos focused. How are you guys thinking about variability there and I mean I'm curious if there are any patients in past studies that were like just above 1.67x upper limit of normal that may have helped inform the study design there?

如果可以的話，我還想再介紹一些關於 IDEAL 的內容。您能否談談這項研究對標籤擴展的任何潛在影響？或者說，這更像是一項可能支持某些營銷工作的研究。然後，由於它與初選的成功有關，顯然，它是一種以鹼性磷酸為重點的東西。你們如何看待那裡的變異性，我的意思是我很好奇過去的研究中是否有任何患者的值略高於正常上限的 1.67 倍，這可能有助於為那裡的研究設計提供信息？

Yes. Thank you, Patrick. I appreciate your question. I guess, ultimately, we would think that the potential for label expansion is a question down the road. But of course, it was very much central to our thinking. Initially, we worked very hard to develop a strategy for the study. We had a very concerted effort internally where we looked at the known distributions of alkaline phosphatase, not only in our screening efforts work that we've done in clinical studies, but also accessing registry data where we could look at the distribution.

是的。謝謝你，帕特里克。我很欣賞你的問題。我想，最終，我們會認為品牌擴張的潛力是未來的一個問題。但當然，它是我們思想的核心。最初，我們非常努力地制定研究策略。我們內部進行了非常協調的努力，我們研究了鹼性磷酸酶的已知分佈，不僅在我們在臨床研究中所做的篩選工作中，而且還訪問了可以查看分佈的註冊數據。

So I think what you're kind of getting at is, are there any concerns around imbalances or something that's going to lead you astray where you might have some representation of alkaline phosphatase. It's not distributed across the range that we're intending to study. And I think we got very comfortable around the design, the availability and prevalence of patients, both in screen populations and registries so that I think we're really set up for success. With respect to the label expansion question, I guess, I would just say that our first intent is really to gather the data, what's the evidence? Are we convinced that the effects that we expect to see are in fact seen.

所以我認為你想要了解的是，是否存在任何關於不平衡的擔憂，或者是否有一些因素會導致你誤入歧途，而你可能會出現一些鹼性磷酸酶的表現。它沒有分佈在我們打算研究的範圍內。我認為我們對設計、患者的可用性和患病率（無論是在篩查人群還是登記方面）都非常滿意，所以我認為我們真的已經為成功做好了準備。關於標籤擴展問題，我想，我只想說，我們的首要意圖實際上是收集數據，證據是什麼？我們是否確信我們期望看到的效果實際上已經出現了？

Then of course, we would share those results with the medical community and then we've, of course, submitted this protocol both to ethics committees and IRBs as well as to the agency. We had very little feedback from them other than just in a very supportive way. I think right now, our focus is on RESPONSE and making sure that we get the first indication lockdown, those conversations, the cadence of regulatory interactions as you might imagine, is very high at this stage. And we would address the issues around IDEAL and label expansion basically at a later point in time.

當然，我們會與醫學界分享這些結果，然後我們當然會將這份協議提交給倫理委員會和 IRB 以及該機構。除了非常支持的方式之外，我們從他們那裡得到的反饋很少。我認為現在，我們的重點是響應，並確保我們得到第一個指示鎖定，這些對話，正如你想像的那樣，監管互動的節奏在這個階段非常高。我們基本上會在稍後的時間點解決有關 IDEAL 和標籤擴展的問題。

The only other thing I'd add, Patrick, is as you know, the label based on response would be an indication for treating patients who are either intolerant or inadequate responders to UDCA. And with response serving as the initial registration study for approval and that label, the idea around IDEAL is to perhaps have a support for a broader patient population, of course, and that's part of that key consideration. And I think we're excited to have an opportunity to learn how patients in this category may benefit from seladelpar.

帕特里克，我唯一要補充的另一件事是，如您所知，基於反應的標籤將是治療對 UDCA 不耐受或反應不足的患者的適應症。當然，隨著響應作為批准和標籤的初始註冊研究，圍繞 IDEAL 的想法也許是為更廣泛的患者群體提供支持，這是關鍵考慮因素的一部分。我認為我們很高興有機會了解此類患者如何從 seladelpar 中受益。

Definitely makes sense. Appreciate the thoughts.

絕對有道理。欣賞這些想法。

Our next question is from Julian Harrison with BTIG.

我們的下一個問題來自 BTIG 的 Julian Harrison。

Really looking forward to the RESPONSE data next month. On IDEAL, I'm curious if you have any feedback yet from payers regarding what they would like to see in terms of clinical data for reimbursement in patients between 1 and 1.67x the upper limit of normal at the start of second line therapy?

真的很期待下個月的響應數據。關於 IDEAL，我很好奇付款人是否希望看到二線治療開始時正常上限 1 至 1.67 倍患者報銷的臨床數據？

It's a good question, Julian. Certainly, work that's actually in front of us. We don't yet have input yet from payers, but when we think a bit about creating the body of evidence that would support the potential benefits in the population. As Chuck mentioned, we spent a considerable time thinking about the design of IDEAL, gathering input from thought leaders in the field, HCPs and the like. And we think very carefully about how this data set may influence treatment guidelines in the future. So I think with all of that work in front of us, inclusive of getting feedback from payers, these are things that will continue to provide some updates on into the future.

這是個好問題，朱利安。當然，工作實際上擺在我們面前。我們還沒有收到付款人的意見，但是當我們考慮創建證據來支持人口的潛在利益時。正如 Chuck 提到的，我們花了相當多的時間思考 IDEAL 的設計，收集該領域思想領袖、HCP 等的意見。我們非常仔細地思考該數據集可能如何影響未來的治療指南。因此，我認為，我們面前的所有工作，包括從付款人那裡獲取反饋，這些都將繼續為未來提供一些更新。

Okay. Got it. That's helpful. And then beyond IDEAL for those with incomplete response to UDCA, but have not yet gone on to pursue second-line therapy, is there a prevailing reason why these patients are not seeking additional treatment now? And could that change at all if seladelpar is initially approved supported by RESPONSE?

好的。知道了。這很有幫助。那麼，對於那些對 UDCA 反應不完全、但尚未繼續尋求二線治療的患者來說，除了 IDEAL 之外，這些患者現在不尋求額外治療的普遍原因是否存在？如果 seladelpar 最初得到 RESPONSE 的支持，這種情況會發生改變嗎？

That's a good question. I think, again, from some of our early market research, it's very likely a variety of different reasons. You think about, first of all, the only existing treatment itself dictates to some degree which patients are willing to go on to second line or I should even say which patients HCPs believe would be good for the current second-line treatment.

這是個好問題。我再次認為，根據我們的一些早期市場研究，這很可能是多種不同的原因。首先，你想一想，現有的唯一治療方法本身在某種程度上決定了哪些患者願意接受二線治療，或者我什至應該說，HCP 認為哪些患者適合當前的二線治療。

And here, again, I think if we're successful with seladelpar based on the profile we've seen to date, meaningful response rate on the primary composite endpoint to bring patients below 1.67x the upper limit of normal, a meaningful proportion of patients actually fully normalizing alkaline phosphatase, lipid parameters, clinical symptom burden using, of course, pruritus as a key element of that improving over time.

在這裡，我再次認為，根據我們迄今為止所看到的情況，如果我們在seladelpar 上取得成功，主要復合終點的有意義的緩解率將使患者低於正常上限的1.67 倍，這是一個有意義的患者比例實際上，鹼性磷酸酶、血脂參數、臨床症狀負擔完全正常化，當然，瘙癢症是隨著時間的推移而改善的關鍵因素。

And to date, good safety across both non-cirrhotics as well as compensated cirrhotics that we've studied to date. When you think about that overall profile, we certainly believe there'll be more patients that are not yet on second-line treatment today, moving to second-line treatment. And so excited about having additional treatment alternatives for those patients that have perhaps been hesitant or perhaps haven't been considered for second line as of yet.

迄今為止，我們研究的非肝硬化患者和代償性肝硬化患者均具有良好的安全性。當你考慮到總體情況時，我們當然相信今天會有更多尚未接受二線治療的患者轉向二線治療。對於那些可能猶豫不決或尚未考慮使用二線治療的患者來說，有更多的治療替代方案令我感到非常興奮。

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 the progress. Can you talk about the rate of normalization you've seen with seladelpar in the ENHANCE trial for patients with ALP above 1.67x the upper limit of normal? And how could we potentially extrapolate that normalization rate to a population of patients with ALP between 1 and 1.67x?

祝賀取得的進展。您能談談您在 ENHANCE 試驗中使用 seladelpar 治療 ALP 高於正常值上限 1.67 倍的患者的正常化率嗎？我們如何才能將正常化率外推到 ALP 介於 1 到 1.67 倍之間的患者群體中？

Well, at least I'll highlight ENHANCE here and maybe give some additional commentary, Jay, thank you for the question. I think in ENHANCE, as you've seen with the data at 3 months, 10 milligrams, we saw about 27% of patients normalized ALP. Again, these are patients that started above 1.67x upper limit of normal, as you highlighted. The baseline, of course, in ENHANCE was around 290 units per liter across the enrolled population in each arm. So obviously, striking when you compare that to 0 patients out of roughly 55 in placebo that normalized at 3 months.

好吧，至少我會在這裡強調“增強”，也許還會提供一些額外的評論，傑伊，謝謝你的問題。我認為在 ENHANCE 中，正如您在 3 個月、10 毫克的數據中看到的那樣，我們看到大約 27% 的患者 ALP 正常化。同樣，正如您所強調的，這些患者的起始水平高於正常上限的 1.67 倍。當然，ENHANCE 中各組登記人群的基線約為每升 290 單位。顯然，當你將這一結果與服用安慰劑的大約 55 名患者中的 0 名在 3 個月時恢復正常進行比較時，結果是驚人的。

I think a bit difficult for us to extrapolate here for this population. Of course, the baseline that ultimately becomes enrolled in IDEAL will be 1 parameter that has influence. But I'd take you back to data we've shared and is in our published literature, around the percent reductions we see in alkaline phosphatase from baseline. That's, I think, largely the guide as we think about the potential to bring patients that are at these lower levels of alk phos fully into the normal range.

我認為我們很難推斷出這個人群的情況。當然，最終加入 IDEAL 的基線將是有影響的參數之一。但我想帶您回顧一下我們共享的數據以及我們已發表的文獻中的數據，這些數據涉及我們看到的鹼性磷酸酶相對於基線的減少百分比。我認為，這在很大程度上是我們考慮將處於較低水平的烷磷酸的患者完全恢復到正常範圍的潛力的指南。

And remember, these are patients were enrolling who despite being on UDCA for at least 12 months are at these levels above normal and below 1.67x the upper limit of normal. So with what we've seen with seladelpar versus placebo, I think we'd expect to continue to see these 45% reductions potentially in this patient population because it's not a measure that's been dependent on baseline ALP. And I think that will ultimately dictate what we see in terms of the data set out of IDEAL.

請記住，這些患者儘管服用 UDCA 至少 12 個月，但其水平仍高於正常水平且低於正常上限的 1.67 倍。因此，根據我們在 seladelpar 與安慰劑對比中所觀察到的情況，我認為我們預計該患者群體中可能會繼續看到 45% 的下降，因為這不是一個依賴於基線 ALP 的衡量標準。我認為這最終將決定我們在 IDEAL 數據集上看到的內容。

Yes. Just -- this is Chuck, Jay. Thanks for the question. Maybe I'll just add just a fact is that if you take 1.67x upper limit of normal, which is in our reference range is right around 196 units per liter and take a 45% reduction that's below the upper limit of normal. That's actually 0.9x the upper limit of normal. Not to say that you would -- of course, you wouldn't expect -- that's an at 45% as an average and the baselines are going to be on average, you're going to get some distribution if patients are to drop out, of course, they're imputed nonresponders. But it just kind of sets you -- I guess, it's encouraging to know that at the top end of the range, if you get the average response, you're actually normalized.

是的。只是——這是查克，傑伊。謝謝你的提問。也許我只想補充一個事實，如果您採用正常上限的 1.67 倍（在我們的參考範圍內，大約為每升 196 個單位），則減少 45%，低於正常上限。這實際上是正常上限的 0.9 倍。並不是說你會——當然，你不會期望——平均為 45%，並且基線將是平均的，如果患者退出，你將得到一些分佈當然，他們被認為是無反應者。但這只是讓你感到鼓舞——我想，知道在範圍的頂端，如果你得到平均的反應，你實際上已經正常化了，這是令人鼓舞的。

Okay. Great. That's super helpful. And I had a couple of follow-ups, if I could. Do you know if the patients who are currently between 1 and 1.67x upper limit of normal are receiving off-label treatment with OCA based on your market research? And if so, what the sort of response would be?

好的。偉大的。這非常有幫助。如果可以的話，我進行了一些後續行動。根據您的市場研究，您是否知道目前處於正常上限 1 至 1.67 倍之間的患者是否正在接受 OCA 的超說明書治療？如果是這樣，會是什麼樣的反應？

Yes. It's another good question, Jay. We don't really believe these patients are. In fact, off-label therapy, particularly in the U.S. is not what we believe a very significant proportion of patients. And so I think fundamentally, these are patients that are just left on UDCA as the best alternative and wherever their ALP lands, they are maintained at those levels effectively. So this is what's exciting about an opportunity perhaps to demonstrate some additional benefit for this patient population.

是的。這是另一個好問題，傑伊。我們真的不相信這些病人是這樣的。事實上，我們認為接受超適應症治療的患者比例並不高，特別是在美國。因此，我認為從根本上來說，這些患者只是將 UDCA 作為最佳替代方案，無論他們的 ALP 到達何處，他們都會有效地維持在這些水平。因此，這就是一個令人興奮的機會，也許可以向該患者群體展示一些額外的好處。

Okay. Great. And if I could sneak in one more question. Can you just talk about what percent of patients in RESPONSE have rolled over into the ASSURE study?

好的。偉大的。如果我可以再問一個問題。您能否談談 RESPONSE 中的患者有多少百分比轉入 ASSURE 研究？

Yes. We haven't provided specific numbers there, Jay. But historically, we've seen across our prior studies when we've had long-term extensions ongoing significant proportion of patients actually roll into the long-term extension over 90% historically. So as we've mentioned, ASSURE now has over 300 patients, many of which came from prior studies, but of course, many of which now, as RESPONSE is nearing completion, have, in fact, rolled over into RESPONSE. So it's a high number, just based on the patient experience from our clinical studies to date.

是的。傑伊，我們還沒有提供具體數字。但從歷史上看，我們在之前的研究中發現，當我們進行長期延期時，歷史上超過 90% 的患者實際上會進入長期延期。正如我們所提到的，ASSURE 現在有超過 300 名患者，其中許多來自之前的研究，但當然，隨著 RESPONSE 接近完成，其中許多現在實際上已經轉入 RESPONSE 中。因此，根據我們迄今為止的臨床研究的患者經驗，這個數字很高。

Our next question is from Andy Hsieh with William Blair.

我們的下一個問題來自安迪謝和威廉布萊爾。

So just couple of quick ones. For the IDEAL study, any plans regarding longer-term follow-up? Or basically, these patients will eventually be rolled over to ASSURE as well?

所以只有幾個快速的。對於IDEAL研究，有長期隨訪的計劃嗎？或者基本上，這些患者最終也會轉入 ASSURE？

Yes. So currently, we haven't put in place an opportunity for those patients to roll over into ASSURE. But we're at the beginning of the study, I guess we wouldn't necessarily roll that out. Another option would be to open up an extension of IDEAL. And then depending on things how play out, they could potentially even transition into commercial. So we'll have to see. We're just at the start now. It's a good question, but I just don't have an answer for you yet.

是的。因此，目前我們還沒有為這些患者提供轉入 ASSURE 的機會。但我們正處於研究的開始階段，我想我們不一定會推出它。另一種選擇是開放 IDEAL 的擴展。然後根據事情的發展情況，它們甚至有可能轉變為商業化。所以我們得看看。我們現在才剛剛開始。這是個好問題，但我還沒有給你答案。

Got it. That's fair. And since we are on the theme of expansion opportunities, just curious about your thoughts on potentially combination therapies going forward, maybe perhaps like a triplet with 5 rates. Happy to hear your thoughts there.

知道了。這還算公平。由於我們的主題是擴張機會，只是想知道您對未來潛在的聯合療法的想法，也許就像有 5 個比率的三聯療法。很高興聽到你的想法。

Yes. I think there are a number of pads forward as we think about broader treatment for the treatment landscape in PBC. Of course, there will be some patients even after UDCA, and if we're successful, seladelpar say as a second-line agent that may require a third agent who have ultimately a highly elevated alk phos. So we haven't yet committed Andy, to any specific studies or strategies there, but I can tell you we've got a team that continues to think thoughtfully about additional life cycle management as we think about success, hopefully, post RESPONSE.

是的。我認為，當我們考慮對 PBC 治療領域進行更廣泛的治療時，有很多進展。當然，即使在接受 UDCA 治療後，仍然會有一些患者，如果我們成功，seladelpar 表示，作為二線藥物，可能需要最終具有高度升高的烷磷酸的第三種藥物。因此，我們還沒有讓安迪參與任何具體的研究或策略，但我可以告訴你，我們有一個團隊，在我們考慮成功（希望是在響應後）時，繼續深思熟慮額外的生命週期管理。

Got it. Got it. And I just want to make sure, so for IDEAL, the requirement is basically patients would have to be on UDCA for 12 months, right? So it can't be 6 months, it can't be 3 months, have to be 12 months?

知道了。知道了。我只是想確定一下，對於 IDEAL，要求基本上是患者必須服用 UDCA 12 個月，對嗎？所以不能是6個月，不能是3個月，必須是12個月？

That's right. We're following the standard practice. We want to enroll a population that couldn't be criticized as being something that's not more traditionally a second line treatment. I would mention though, that, of course, they can be intolerant to UDCA. So if they have levels of alkaline phosphatase between 1 and 1.67x, but simply can't take UDCA, they've tried it before and not able to tolerate it, they would also be eligible.

這是正確的。我們遵循標準做法。我們希望招募一群不會被批評為不屬於傳統二線治療的人群。不過我要提一下，當然，他們可能無法容忍 UDCA。因此，如果他們的鹼性磷酸酶水平在 1 到 1.67 倍之間，但根本無法服用 UDCA，他們之前已經嘗試過但無法耐受，那麼他們也符合資格。

Our next question is from Ed Arce with H.C. Wainwright & Company.

我們的下一個問題來自 Ed Arce 和 H.C.溫賴特公司。

Great and congrats on continued progress with the study. Regarding IDEAL, I know you mentioned this on this call already. Obviously, label expansion is clearly a goal there. I wanted to ask you though, if that would be a reason to also consider further data expansion on label with your quality of life measures regarding pruritus and fatigue, 2 of which I know you've collected and generated data on new trials. Yes, and then I have a follow-up.

太棒了，祝賀你的研究不斷取得進展。關於 IDEAL，我知道您已經在這次電話會議中提到了這一點。顯然，標籤擴展顯然是那裡的一個目標。不過，我想問您，這是否是考慮進一步擴展標籤上的數據以及有關瘙癢和疲勞的生活質量測量的理由，我知道您已經收集並生成了其中的兩項新試驗數據。是的，然後我有一個後續行動。

Yes. Ed, I certainly say that's absolutely a focus of ours as well. As we continue to generate data on pruritus as well as some data that we hope to gather in RESPONSE, particularly from the PBC-40 questionnaire around fatigue. These will continue to be areas that we invest as we better understand seladelpar's effects on both of these symptoms of disease and quality of life overall.

是的。艾德，我當然說這也絕對是我們關注的焦點。隨著我們繼續生成有關瘙癢的數據以及我們希望在 RESPONSE 中收集的一些數據，特別是來自有關疲勞的 PBC-40 調查問卷的數據。隨著我們更好地了解 seladelpar 對這些疾病症狀和整體生活質量的影響，這些將繼續成為我們投資的領域。

Great. And with regard to pruritus, I wanted to ask if you had a sense from the agency including additional data, how important would it be to have the mechanistic rationale that you have now at least initially with IL-31 and having some of that rationale is part of underlying this and supporting the inclusion of some of that data on the future label.

偉大的。關於瘙癢症，我想問您是否從該機構獲得了包括額外數據在內的感覺，了解您現在至少在 IL-31 最初了解的機械原理有多重要，並且了解其中的一些原理是這是基礎的一部分，並支持在未來的標籤上包含一些數據。

Yes. Well, thank you for mentioning that. Ed, of course, we're pretty interested and very intensely thinking about IL-31 and the mechanism, which is the mechanism of cholestatic pruritus has really not been understood for decades. I wouldn't want to speak for regulators. I don't know how they think about it, are going to think about it. Hopefully, they take a scientific perspective. I think that, of course, pruritus, not only for PBC, but for many different diseases as subjective, it's nothing that you can measure, only the patient can tell you about a symptom.

是的。嗯，謝謝你提到這一點。 Ed，當然，我們對 IL-31 及其機制非常感興趣，也非常深入地思考，幾十年來，膽汁淤積性瘙癢症的機制確實未被了解。我不想代表監管機構發言。我不知道他們會怎麼想，會不會想。希望他們能採取科學的觀點。我認為，當然，瘙癢，不僅對於PBC，而且對於許多不同的主觀疾病來說，它是你無法測量的，只有患者可以告訴你症狀。

Now moving to something that could potentially be considered a biomarker is really intriguing. I think that would be something -- if I were a patient, I would be -- feel very validated. I now have something that I can line up what I'm experiencing with what's something that can be measured as a starting point. And also just to know how well people respond, pruritus is something that fluctuates quite a bit, having something you can measure, I think, is quite interesting.

現在轉向可能被視為生物標誌物的東西確實很有趣。我認為如果我是一名患者，我會感到非常有效。我現在有了一些東西，可以將我正在經歷的事情與可以作為起點進行測量的事情聯繫起來。而且只是為了知道人們的反應如何，瘙癢症的波動很大，我認為有一些可以測量的東西是非常有趣的。

At the end of the day, I really kind of coming to your question, what's the FDA going to look at? I think they're going to start with the patient-reported outcome, have we used appropriate methodology or the data robust? Do we have data that supports a sensitivity analysis that confirms not only the key measure of pruritus that we negotiated with them, but also suggest that there's additional independent ways to measure it.

歸根結底，我真的想問你的問題，FDA 會看什麼？我認為他們將從患者報告的結果開始，我們是否使用了適當的方法或可靠的數據？我們是否有支持敏感性分析的數據，該分析不僅證實了我們與他們協商的瘙癢症關鍵衡量標準，而且還表明還有其他獨立的方法來衡量它。

I think they're going to focus on that first because it's a patient-reported outcome. But having something else that's biochemically or laboratory related, I think, well, at least let the medical community have some increased confidence what regulators do, we'll just have to wait and see.

我認為他們會首先關注這一點，因為這是患者報告的結果。但我認為，如果有其他與生化或實驗室相關的東西，至少讓醫學界對監管機構的做法更有信心，我們只需要拭目以待。

Right. Great. And then one last one, if I could. For Harish, I think you had mentioned in your prepared remarks an expectation for overall OpEx to increase. I realize all of this is related to the commercial build-out and launch preparations. But is there any sense qualitatively or just subjectively to describe the degree of increase this year and into next year.

正確的。偉大的。如果可以的話，還有最後一張。對於 Harish，我認為您在準備好的發言中提到了總體運營支出增加的預期。我意識到所有這一切都與商業建設和發布準備有關。但是，從定性或主觀角度來描述今年和明年的增長程度是否有任何意義？

Ed, I would -- the only thing I would add, I think Sujal had talked about, I mean, our infrastructure we're building both in the medical side as well as in the commercial side as for bringing on are in our MSLs and then the commercial will accelerate. We've added some key commercial leaders now, which will -- and then we'll bring in more on the other side of data. And I think the main, I would say, the lift will be on the -- when we bring on the field teams, which will be mostly next year closer to approval.

Ed，我想——我唯一要補充的是，我想 Sujal 已經談到了，我的意思是，我們正在醫療方面和商業方面建設的基礎設施都在我們的 MSL 中，那麼商業化將會加速。我們現在已經增加了一些關鍵的商業領導者，然後我們將在數據的另一面引入更多。我認為，我想說，主要的提升將在於——當我們引入現場團隊時，這將在明年接近批准。

So I think the goal is to make sure where we have the best possible launch and to support and to have the resources that's required to support that. Beyond that, I'm not in a position to give any quantitative specific guidance on what the level of that spend would be, but we're making sure we're having the infrastructure that's needed to support launch.

所以我認為我們的目標是確保我們在哪裡有最好的發布並提供支持並擁有支持它所需的資源。除此之外，我無法就支出水平提供任何定量的具體指導，但我們正在確保我們擁有支持發布所需的基礎設施。

I think what's helpful there, Ed, as you think about the runway guidance of having cash that takes us at least to the end of Q3 next year, that can help you with some estimates.

我認為這有什麼幫助，艾德，當你考慮擁有現金的跑道指導時，我們至少可以到明年第三季度末，這可以幫助你做出一些估計。

Our next question is from Thomas Smith with Leerink Partners.

我們的下一個問題來自 Leerink Partners 的 Thomas Smith。

And let me add my congrats on all the progress. Just a follow-up on pruritus. I guess, based on what we've seen from the elafibranor top line, it doesn't seem like Ipsen will be able to claim an explicit benefit there. I'm just wondering, within all of your recent market research, whether you've been able to quantify a clinician prescribing preference for an agent that's explicitly labeled with that benefit, versus an agent that has data suggesting a trend toward improvement but isn't explicitly labeled, like all things being equal, have you been able to quantify the incremental benefit of having the pruritus play on the label?

讓我對所有進展表示祝賀。只是瘙癢症的後續行動。我想，根據我們從 elafibranor 頂線看到的情況，Ipsen 似乎無法在那裡聲稱獲得明確的好處。我只是想知道，在你們最近的所有市場研究中，你們是否能夠量化臨床醫生對明確標有該益處的藥物的處方偏好，以及數據表明有改善趨勢但實際上沒有的藥物的偏好。沒有明確的標籤，就像所有事情都是平等的一樣，您是否能夠量化標籤上的瘙癢症所帶來的增量好處？

We don't have a very specific increase that I can give you, but I can tell you qualitatively, there's no question there's a significant impact that we see in overall expectations for utilization based on pruritus and having the claim. I think that couple that with really the fact that patients really tell us, so succinctly how their expectations around symptom burden really aren't being addressed by the providers. And of course, providers just have not had the tools to address those.

我們沒有可以給您的非常具體的增加，但我可以定性地告訴您，毫無疑問，我們看到基於瘙癢和索賠的總體利用率預期產生了重大影響。我認為，這與患者真實告訴我們的事實相結合，簡明地說，醫療服務提供者並沒有真正解決他們對症狀負擔的期望。當然，提供商只是沒有解決這些問題的工具。

And I think that as we think about a new paradigm for treatment, not only will you have certainly providers interested and wanting to utilize seladelpar in that setting, but there are going to be patients coming in and saying, really, that they want to be able to address this issue that they've been played with throughout their -- the course of the disease. So I think what we see qualitatively is an extremely strong preference for an agent that provides that benefit.

我認為，當我們考慮一種新的治療模式時，不僅會有提供者對這種情況感興趣並希望使用 seladelpar，而且還會有患者進來並說，真的，他們想要成為能夠解決他們在整個疾病過程中一直面臨的這個問題。因此，我認為我們從定性上看到的是，人們對能夠提供這種好處的代理人有著極其強烈的偏好。

Got it. That's helpful. And then I was just wondering if you could elaborate a little bit on some of the sort of pre-NDA preparation activities, things that you can kind of undertake now to try to help prepare for the submission and maybe try to close the gap between the time from top line data to NDA submission?

知道了。這很有幫助。然後我想知道您是否可以詳細說明一些 NDA 前的準備活動，您現在可以採取一些措施來幫助準備提交，也許可以嘗試縮小與 NDA 之間的差距。從頂線數據到 NDA 提交的時間？

It's a great question, Thomas. You can imagine that anybody in our industry and our situation who wants to be successful is doing exactly what you're alluding to. There are a lot of things that are complete in the nonclinical space. We've made a lot of progress in manufacturing. We have prior clinical studies that are completed and closed out. We have ongoing studies that are approaching completion for which we have a lot of information we can assemble into all the documentation that has to be assembled, written, QC made consistent.

這是一個很好的問題，托馬斯。你可以想像，在我們這個行業和我們所處的環境中，任何想要成功的人都在做你所提到的事情。非臨床領域有很多事情已經完成。我們在製造方面取得了很大進步。我們之前已經完成並結束了臨床研究。我們正在進行的研究即將完成，為此我們擁有大量信息，可以將其匯總到所有必須匯總、編寫、質量控制保持一致的文檔中。

All of those efforts are in place. We built our teams really around this as being the most important activity in the company. We have supported that with additional expertise, consultants and the like who have experience in this space that can set us up to succeed. So I think what you're getting at is that you do as much of the work, you prepare as much as you can in advance so that you're ready to drop the data in, so to speak. And I think that's really what everyone does in this situation.

所有這些努力都已到位。我們確實圍繞這一點建立了我們的團隊，並將其視為公司最重要的活動。我們通過額外的專業知識、顧問等在這一領域擁有豐富經驗的人來支持這一點，這可以幫助我們取得成功。所以我認為你要做的就是做盡可能多的工作，提前做好盡可能多的準備，以便你準備好投入數據，可以這麼說。我認為每個人在這種情況下都會這麼做。

Got it. That's helpful.

知道了。這很有幫助。

Our next question is from Mayank Mamtani with B. Riley Securities.

我們的下一個問題來自 B. Riley Securities 的 Mayank Mamtani。

Congrats on the progress. So great to see Harish join the team here. So maybe just on that runway comment, if I could, Harish, beyond ideal, what additional trials are sort of big in the runway guidance. I know you've talked about in the past about cirrhosis population, outcomes, obviously, I'm sure is top of mind and any crossover study to solidify pruritus label.

祝賀取得的進展。很高興看到哈里什加入這裡的團隊。因此，也許就跑道評論而言，如果我可以的話，哈里什，超出理想範圍，跑道指南中還有哪些額外的試驗是比較重要的。我知道您過去曾談論過肝硬化人群、結果，顯然，我確信這是首要考慮因素，也是任何鞏固瘙癢標籤的交叉研究。

And maybe for Chuck, you guys do get very broad spectrum, liver biochemistry going down. Any of your trials, any of your work even in IDEAL that looks at the complete biochemical response as an endpoint, which obviously also is being talked about in that ad board setting, in that the EASL group that you talked about. So would love to hear your thoughts on that. And I have a quick follow-up.

也許對於查克來說，你們確實得到了非常廣泛的肝臟生化下降。你的任何試驗，你的任何工作，甚至在 IDEAL 中，都將完整的生化反應視為終點，這顯然也在廣告板設置中進行了討論，在你談到的 EASL 小組中。所以很想听聽您對此的想法。我有一個快速的跟進。

Mayank, let me first start with the question on the R&D clinical trial expenses, right? I think you listed some of the key ones there. We spoke about ASSURE, of course, which is where we have enrolled over 300 patients. That's the long-term study that's actually currently on -- and besides that IDEAL as we talk about, this is something that will expand as we recruit patients in this study.

Mayank，我先從研發臨床試驗費用的問題開始吧？我認為您在那裡列出了一些關鍵的內容。當然，我們談到了 ASSURE，我們已經招募了 300 多名患者。這是目前正在進行的長期研究——除了我們所說的“理想”之外，隨著我​​們在這項研究中招募患者，這項研究還將擴大。

And then the other one is the outcome study that we will have -- we'll be initiating and this is part of our NDA filing. So we need to have that activated and enrolling so we will see that ramp up. So those are the 3 main ones that I would say from a clinical trial perspective that we would -- it would hit it from a spend lens and those are the main trials out there.

另一項是我們將啟動的結果研究，這是我們 NDA 備案的一部分。所以我們需要激活並註冊，這樣我們才能看到增長。因此，從臨床試驗的角度來看，我會說這三個主要的試驗——它會從支出的角度來看，這些是主要的試驗。

Chuck, I don't know if you want to add on the other part of the question?

Chuck，不知道你是否想補充一下問題的另一部分？

Yes. So thanks for the question, as you've seen the recent presentations, both from us as well as from others, normalization of biochemical parameters is a very appealing idea. The total normalization or if you wanted to call it biochemical remission, of course, is something that's talked about. But it's not actually receive the same level of validation and it's certainly not true that the regulators are there by any means.

是的。因此，感謝您提出的問題，正如您所看到的，無論是我們還是其他人最近的演示，生化參數的標準化是一個非常有吸引力的想法。當然，完全正常化或者如果你想稱之為生化緩解，這是人們談論的事情。但它實際上並沒有得到同等程度的驗證，而且監管機構無論如何也不存在。

In terms of whether the medical community will move there, I think that the concept is appealing qualitatively, but I don't think quantitatively, it's yet happened. And the issue really relates without getting too far into the weeds, these various parameters to what extent are they true independent covariants to -- or how often do they just travel together? Are you just measuring some of the same thing. What we know from the work from the global PBC study group from the U.K. PBC Group from some of the work coming out of the Italian National Registry as well as the Dutch Registry, that the key ones that there's really not much debate about our alkaline phosphatase, bilirubin is especially a powerful one.

至於醫學界是否會搬到那裡，我認為這個概念在質量上很有吸引力，但我不認為在數量上，它已經發生了。這個問題確實涉及到這些不同的參數在多大程度上是真正的獨立協變——或者它們在一起傳播的頻率是多少？您只是測量一些相同的東西嗎？我們從英國 PBC 集團的全球 PBC 研究小組的工作以及意大利國家登記處和荷蘭登記處的一些工作中了解到，關鍵的是，關於我們的鹼性磷酸酶確實沒有太多爭論，膽紅素的作用尤其強大。

And we're beginning to understand that liver injury, elevated transaminases in particular, ALT, reflects ongoing inflammation and has been linked to fibrosis, in other liver diseases like NASH, but also in PBC using histological evidence with long-term follow-up.

通過長期隨訪的組織學證據，我們開始了解肝損傷，尤其是轉氨酶升高，反映了持續的炎症，並與 NASH 等其他肝病以及 PBC 中的纖維化有關。

So those 3, we believe, have the strongest level of evidence they would get the most near-term embrace, I think, from the medical community. Clearly, ALP and bilirubin are already to a degree at least, accepted by regulators, although one still needs to look at outcome studies. We believe the data sets that we're going to produce are going to suggest that ALT is also an important parameter.

因此，我們相信，這三個人擁有最有力的證據，我認為他們將在近期得到醫學界的認可。顯然，ALP 和膽紅素至少在一定程度上已經被監管機構所接受，儘管仍需要關注結果研究。我們相信，我們將生成的數據集將表明 ALT 也是一個重要參數。

Beyond biochemical normalization, I think I would also mention that a lot of attention is moving towards noninvasive measures like liver stiffness, using fibroscan or transient elastography. I think that has a lot of merit, some of the work coming out of Christophe Corpechot as the lead is really suggesting PBC like other diseases, this is going to be an important measure in terms of serial long-term follow-up for patients, potentially in clinical research and we, by the way, include this in our long-term studies. But importantly, I think this is going to be used -- is being used, actually, I should say, in medical practice. It's being used to follow patients. Many clinicians will use it to make decisions and judgments around how patients disease are progressing, especially towards cirrhosis.

除了生化正常化之外，我想我還要提到，很多注意力正在轉向非侵入性措施，例如使用纖維掃描或瞬時彈性成像的肝硬度。我認為這有很多優點，Christophe Corpechot 作為領導者所做的一些工作確實表明 PBC 與其他疾病一樣，這將是對患者進行系列長期隨訪的一項重要措施，順便說一句，我們將其納入我們的長期研究中。但重要的是，我認為這將會被使用——實際上，我應該說，正在醫療實踐中使用。它被用來跟踪病人。許多臨床醫生將使用它來對患者疾病的進展情況（尤其是肝硬化）做出決定和判斷。

Very helpful. Appreciate the comprehensive color there. And then just on RESPONSE, as you know, after seeing another study readout, questions are asked, obviously about -- we have not seen the full data. But if you could comment on your expectation for discontinuation rate? And also on the NRS score, what placebo response you're expecting there?

很有幫助。欣賞那裡的綜合色彩。然後，正如您所知，在看到另一項研究讀數後，就回答問題提出了問題，顯然是關於——我們還沒有看到完整的數據。但您能否評論一下您對停藥率的預期？另外，在 NRS 評分上，您期望安慰劑的反應是什麼？

Thank you, Mayank. With respect to discontinuation rates, I think historically, we've seen rates that have been less than 10%. So that would continue to be our expectation with RESPONSE. Again, we anchor on very significant patient numbers from our prior experience, north of 100 patients in our 1-year Phase II study. And obviously, randomizing 265 patients into ENHANCE even though that study had been terminated early.

謝謝你，瑪雅克。關於停藥率，我認為從歷史上看，我們看到的停藥率低於 10%。因此，這將繼續是我們對 RESPONSE 的期望。再次強調，根據我們之前的經驗，我們的患者數量非常大，在我們為期 1 年的 II 期研究中，有 100 名患者。顯然，儘管該研究已提前終止，但仍將 265 名患者隨機分配至 ENHANCE 組。

So I think we continue to have the expectation that we see very similar expectations around discontinuation. With respect to NRS, again, I think all we have with respect to placebo is the data in ENHANCE itself. And so with patients that came into the study with an NRS of 4 or greater where the baseline and placebo as well as the treatment arms was 6.2. We saw this 1.5 point drop in NRS in the placebo arm, that's today our only expectation and the best data set we have, obviously, here will have more significant number of patients.

因此，我認為我們仍然期望我們對停產有非常相似的期望。再次，關於 NRS，我認為我們所掌握的關於安慰劑的數據就是 ENHANCE 本身的數據。對於參加研究的 NRS 為 4 或更高的患者來說，基線、安慰劑以及治療組均為 6.2。我們看到安慰劑組的 NRS 下降了 1.5 個百分點，這是我們今天唯一的期望，也是我們擁有的最佳數據集，顯然，這裡將有更多的患者數量。

We continue to expect to see roughly 30% of our patients coming into RESPONSE with at least an NRS of 4 or greater as well. So that's our historical experience. It's really the only data point that we have to date.

我們仍然預計大約 30% 的患者會出現緩解，且 NRS 至少為 4 或更高。這就是我們的歷史經驗。這確實是我們迄今為止唯一的數據點。

Our next question is a follow-up from Jay Olson with Oppenheimer.

我們的下一個問題是傑·奧爾森和奧本海默的後續問題。

With the increased emphasis on treating PBC early and aggressively, it seems like the IDEAL study is one step closer to first line treatment. So just wondering if you could please share your latest thoughts on the pursuit of the first-line indication for seladelpar in PBC?

隨著人們越來越重視早期和積極治療 PBC，IDEAL 研究似乎離一線治療又近了一步。所以想知道您能否分享一下您對 PBC 尋求 seladelpar 一線適應症的最新想法？

Well, thanks, Jay. I think we do kind of hold to the sentiment to treat to normal, treat earlier, treat the symptoms. Whether we would actually be frontline, I think, is a little bit further away from us. Our current focus is really trying to get the second line indication and getting data in this additional population, going for a frontline therapy has very specific implications for how one would conduct a trial. It would potentially need to be a comparator trial it might need to be an outcome trial because UDCA was approved based upon outcomes. So there's a lot of different implications.

嗯，謝謝，傑伊。我認為我們確實堅持以正常方式治療、儘早治療、治療症狀的情緒。我認為，我們是否真的會成為前線，距離我們還有些遠。我們目前的重點實際上是試圖獲得二線適應症並獲取這一額外人群的數據，一線治療對於如何進行試驗具有非常具體的影響。它可能需要是一個比較試驗，也可能需要一個結果試驗，因為 UDCA 是根據結果獲得批准的。所以有很多不同的含義。

I think seladelpar can be an enormously beneficial patient -- to patients if we confirm the profile in RESPONSE. I think it has a really bright future in terms of its positioning, it's availability. But I wouldn't want to set the expectation at least right now that we're -- that it's an easy reach to move to frontline therapy.

我認為 seladelpar 可以成為一位非常有益的患者——如果我們確認 RESPONSE 中的情況，對患者來說。我認為就其定位和可用性而言，它有著非常光明的未來。但我不想至少現在就設定這樣的期望：我們很容易就能進入一線治療。

And Mr. Shah, we have no further questions at this time. I'll turn the call back to you. You may continue with your presentation or closing remarks.

沙阿先生，我們目前沒有其他問題。我會把電話轉回給你。您可以繼續您的演講或結束語。

Thank you, operator. I'll close today with just a few thoughts. First, on IDEAL, as we've discussed today, work on the design and merits of this important study started by our teams at CymaBay many months ago. And it included gathering input from market research, thought leaders and patient advocacy groups around the world. We're excited, as we've discussed to bring this novel study to many patients with PBC who have been neglected for new treatment alternatives in many ways to date.

謝謝你，接線員。我今天將僅談幾點想法。首先，在 IDEAL 上，正如我們今天所討論的，我們對 CymaBay 團隊幾個月前開始的這項重要研究的設計和優點進行研究。它還包括收集來自世界各地的市場研究、思想領袖和患者倡導團體的意見。我們很興奮，因為我們已經討論過將這項新穎的研究帶給許多 PBC 患者，這些患者迄今為止在許多方面都被忽視了新的治療替代方案。

We look forward to the opportunity to learn from data we collect an IDEAL that we believe may have the potential to reset treatment expectations for a broader patient population that may have an opportunity to benefit from seladelpar if we're successful.

我們期待有機會從我們收集的 IDEAL 數據中學習，我們相信 IDEAL 可能有潛力為更廣泛的患者群體重新設定治療預期，如果我們成功的話，他們可能有機會從 seladelpar 中受益。

Over the coming weeks, our teams are intensely focused on final visits in RESPONSE as well as cleaning and locking the database, continuing rolling eligible patients into ASSURE and of course, conduct across many other clinical and regulatory preparatory activities. Work across all functions in the company has only been accelerating, and we're proud about the progress we're making on many fronts.

在接下來的幾週內，我們的團隊將重點關注 RESPONSE 中的最終訪問以及清理和鎖定數據庫，繼續將符合條件的患者納入 ASSURE，當然，還會開展許多其他臨床和監管準備活動。公司所有職能部門的工作都在不斷加速，我們對在許多方面取得的進展感到自豪。

Finally, we're excited about being back in front of you again before the end of September with top line results from RESPONSE. We hope this study can be a significant event for all that have been part of our journey not the least of which are the patients that may benefit from our work. We hope this may open up a new chapter in the treatment of patients with PBC, and we look forward to talking to you again soon. Thank you.

最後，我們很高興能在 9 月底之前再次與您見面，並帶來 RESPONSE 的主要結果。我們希望這項研究對於所有參與我們旅程的人來說都是一件重大事件，尤其是那些可能從我們的工作中受益的患者。我們希望這能為 PBC 患者的治療翻開新的篇章，並期待很快與您再次交談。謝謝。

And that does conclude the conference call for today. We thank you all for your participation. I kindly ask that you please disconnect your lines. Have a great day, everyone.

今天的電話會議到此結束。我們感謝大家的參與。我懇請您斷開線路。祝大家有個美好的一天。