Intercept Pharmaceuticals Inc (ICPT) 2022 Q4 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Intercept Pharmaceuticals Fourth Quarter and Full Year 2022 Earnings Conference Call. (Operator Instructions) I would now like to hand the conference over to your speaker today, Nareg Sagherian, Executive Director, Investor Relations. Please go ahead.

美好的一天，謝謝你的支持。歡迎參加 Intercept Pharmaceuticals 第四季度和 2022 年全年收益電話會議。 （操作員說明）我現在想將會議交給您今天的發言人，投資者關係執行董事 Nareg Sagherian。請繼續。

Thank you. Good morning, and thank you for joining us on today's call. This morning, we issued a press release announcing our fourth quarter and full year 2022 results, which is available on our website at intercept pharma.com. Before we begin our discussion, I'd like you to note that during our call, we will be making forward-looking statements, including statements regarding our approved product and clinical development program, certain regulatory matters and our strategy, prospects, financial guidance and future commercial and financial performance. Listeners are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this call, and we undertake no obligation to update such statements, except as required by law.

謝謝。早上好，感謝您參加今天的電話會議。今天上午，我們發布了一份新聞稿，宣布了我們第四季度和 2022 年全年的業績，可在我們的網站 intercept pharma.com 上查閱。在我們開始討論之前，我希望您注意，在我們的電話會議期間，我們將做出前瞻性陳述，包括關於我們批准的產品和臨床開發計劃、某些監管事項以及我們的戰略、前景、財務指導和未來的商業和財務表現。告誡聽眾不要過分依賴這些前瞻性陳述，這些陳述僅在本次電話會議之日發表，我們不承擔更新此類陳述的義務，除非法律要求。

These forward-looking statements are based on estimates and assumptions that, although believed to be reasonable, are inherently uncertain and subject to a number of risks and uncertainties, some, but not necessarily all of the risk factor that could cause our actual results to differ materially from our historical results or those anticipated or predicted by our forward-looking statements are discussed in this morning's press release and in our periodic public filings with the SEC.

這些前瞻性陳述基於估計和假設，這些估計和假設雖然被認為是合理的，但本質上是不確定的，並受到許多風險和不確定性的影響，一些但不一定是所有可能導致我們的實際結果不同的風險因素今天上午的新聞稿和我們定期向美國證券交易委員會提交的公開文件中討論了我們的歷史結果或我們的前瞻性陳述所預期或預測的結果的實質性內容。

Today's call will begin with prepared remarks from our President and CEO, Jerry Durso, our Chief Commercial Officer, Linda Richardson, President of Research and Development and Chief Medical Officer, Dr. Michelle Berry; and Chief Financial Officer, Andrew Saik. We will then open the call for questions. Let me now turn the call over to our CEO, Jerry Durso.

今天的電話會議將從我們的總裁兼首席執行官 Jerry Durso、我們的首席商務官 Linda Richardson、研發總裁兼首席醫療官 Michelle Berry 博士準備好的講話開始；首席財務官 Andrew Saik。然後我們將打開問題電話。現在讓我把電話轉給我們的首席執行官 Jerry Durso。

Thanks, Nareg. Good morning, everyone. Thank you for joining us on our fourth quarter and full year conference call. Intercept made significant progress across the business in 2022, and I'm proud to highlight our achievements today. Looking at our performance in PBC. We again delivered double-digit sales growth for Ocaliva and ended 2022 with total U.S. net sales of $285.7 million.

謝謝，納雷格。大家，早安。感謝您加入我們的第四季度和全年電話會議。 Intercept 在 2022 年的整個業務中取得了重大進展，我很自豪地強調我們今天取得的成就。看看我們在 PBC 的表現。我們再次為 Ocaliva 實現了兩位數的銷售增長，到 2022 年底美國淨銷售額為 2.857 億美元。

This was 10% growth over 2021. And Importantly, in the fourth quarter of 2022, Ocaliva generated $77.2 million in U.S. net sales, which is 13% growth over the prior year quarter. We now look to 2023 as the year to continue driving growth, and we're more confident than ever in the longevity of our PBC business. We know there remains a significant number of people living with PBC who can benefit from adding Ocaliva as a second-line therapy. We added more certainty in the runway of our life cycle with the resolution of our patent infringement case for Ocaliva and that was scheduled for trial in the U.S. District Court on February 27 of this year.

這比 2021 年增長了 10%。重要的是，在 2022 年第四季度，Ocaliva 在美國的淨銷售額為 7720 萬美元，比去年同期增長了 13%。我們現在將 2023 年視為繼續推動增長的一年，我們比以往任何時候都對 PBC 業務的長壽更有信心。我們知道仍有相當數量的 PBC 患者可以從將 Ocaliva 作為二線療法中獲益。通過解決我們的 Ocaliva 專利侵權案，我們在生命週期的跑道上增加了更多確定性，該案定於今年 2 月 27 日在美國地方法院開庭審理。

The settlements protect Ocaliva market exclusivity into the 2030s and reinforce the long-term opportunity we have in PBC. In addition, we continue to progress our next-generation PBC therapy, the fixed-dose combination of OCA and bezafibrate which is another component of our long-term strategy. We look forward to sharing data on our next-generation medicine later this year and are excited about its potential. Turning now to NASH. At the end of the fourth quarter, we've resubmitted our NDA for OCA in precirrhotic liver fibrosis due to NASH.

和解協議保護了 Ocaliva 市場在 2030 年代的獨家經營權，並加強了我們在 PBC 的長期機會。此外，我們繼續推進我們的下一代 PBC 療法，即 OCA 和苯扎貝特的固定劑量組合，這是我們長期戰略的另一個組成部分。我們期待在今年晚些時候分享我們下一代藥物的數據，並對它的潛力感到興奮。現在轉向 NASH。在第四季度末，我們重新提交了用於 NASH 引起的肝硬化前肝纖維化的 OCA 的 NDA 。

Following FDA's acceptance in January, the agency has signed a PDUFA target action date of June 22. Reaching this point is the result of hard work and dedication from patients, physicians, study personnel and our team here at Intercept and is a major milestone for the NASH community. OCA has demonstrated a strongly confirmed antifibrotic effect in our rigorous NASH program, but we believe it has the potential to become an impactful therapy. We're now working through the regulatory review process and are advancing our launch readiness planning while taking a measured approach to investment as we progress through the upcoming milestones.

在 FDA 一月份接受之後，該機構簽署了 PDUFA 目標行動日期 6 月 22 日。達到這一點是患者、醫生、研究人員和我們在 Intercept 的團隊辛勤工作和奉獻的結果，是 Intercept 的一個重要里程碑納什社區。 OCA 已在我們嚴格的 NASH 計劃中展示出強有力的抗纖維化作用，但我們相信它有可能成為一種有影響力的療法。我們現在正在完成監管審查流程，並推進我們的啟動準備計劃，同時在我們通過即將到來的里程碑時採取審慎的投資方法。

We also made strides in our pipeline program with our next-generation FXR agonist INT-787. In November, we announced the lead indication for this investigational therapy, severe alcohol-associated hepatitis and initiated our Phase II Fresh trial. Michelle will elaborate on this later in the call. Notably, the progress we made last year was complemented by the transformation of our capital structure. As a result of this work, we finished the year with nearly $500 million of cash on hand. 2023 will be a pivotal year for Intercept, and we're operating from a position of strength.

我們還通過下一代 FXR 激動劑 INT-787 在我們的管道計劃中取得了長足進步。 11 月，我們宣布了該研究療法的主要適應症，即嚴重酒精相關性肝炎，並啟動了我們的 II 期新鮮試驗。米歇爾稍後將在電話中詳細說明這一點。值得注意的是，我們去年取得的進展得到了資本結構轉型的補充。由於這項工作，我們在這一年結束時手頭有近 5 億美元的現金。 2023 年將是 Intercept 的關鍵一年，我們的運營處於有利地位。

Our balance sheet and foundational PBC business provide us with the financial flexibility and the strategic optionality to drive growth while positioning ourselves for success in NASH. This year, I look forward to working alongside the team as we build on the momentum of last year's performance and grow our commercial PBC business. As we work through the regulatory review of OCA while preparing for a commercial launch in NASH, and as we progress our pipeline opportunities while continuing to innovate on behalf of people living with liver diseases. I look forward to sharing updates on our progression of these priorities throughout the year ahead. With that, I'll now turn the call over to Linda.

我們的資產負債表和基礎 PBC 業務為我們提供了財務靈活性和戰略選擇，以推動增長，同時為我們在 NASH 中取得成功做好準備。今年，我期待與團隊一起工作，在去年業績的基礎上再接再厲，發展我們的商業 PBC 業務。當我們通過 OCA 的監管審查，同時準備在 NASH 中進行商業發佈時，當我們在推進管道機會的同時繼續代表肝病患者進行創新時。我期待著在未來一年分享我們在這些優先事項方面的最新進展。有了這個，我現在將電話轉給琳達。

Thanks, Jerry. And good morning, everyone. I'm pleased to share performance highlights for 2022. It was another strong year for our foundational Ocaliva business, underscoring the strength of Ocaliva's market position as the only second-line agent approved for use in PBC. We achieved double-digit growth for both the fourth quarter and the full year compared to the same time frame as last year. Our performance in PBC was driven by a strong return to growth in the second half of 2022, with a few notable contributing factors.

謝謝，傑里。大家早上好。我很高興分享 2022 年的業績亮點。對於我們的基礎 Ocaliva 業務來說，這是又一個強勁的一年，凸顯了 Ocaliva 作為唯一獲准在 PBC 中使用的二線藥物的市場地位的實力。與去年同期相比，我們在第四季度和全年都實現了兩位數的增長。我們在中國人民銀行的表現受到 2022 年下半年強勁恢復增長的推動，其中有幾個顯著的促成因素。

First, our new-to-brand prescriptions grew nearly 30% during the second half of 2022 as reported by IQVIA's NPA audit. We believe this would be the trend as we passed the 1-year mark post label change in June of 2022. While over 95% of our business is driven by existing patients, it's good to see solid growth in new patients receiving Ocaliva and speaks to the ongoing need for second-line therapy for many patients with PBC. Second, as a result of our ongoing efforts to reach new prescribers, we continue to see an increase in first-time Ocaliva writers.

首先，根據 IQVIA 的 NPA 審計報告，我們的新品牌處方藥在 2022 年下半年增長了近 30%。我們相信這將是趨勢，因為我們在 2022 年 6 月通過了 1 年標記後標籤更改。雖然我們 95% 以上的業務是由現有患者推動的，但很高興看到接受 Ocaliva 的新患者穩步增長並與許多 PBC 患者對二線治療的持續需求。其次，由於我們不斷努力接觸新的處方者，我們繼續看到首次使用 Ocaliva 的人有所增加。

More specifically, saw a 42% increase in new writers in the second half of 2022 versus 2021, a dynamic we see is very positive and important. Third, our continued investment in patient support services through our award-winning hub and our specialty pharmacy network has resulted in an 8-day improvement in specialty pharmacy time to fill. We want to ensure that appropriate eligible patients can quickly start treatment with Ocaliva. Simplifying the facilitating processes here help sustain existing patients and initiate new ones.

更具體地說，與 2021 年相比，2022 年下半年的新作家增加了 42%，我們認為這種動態非常積極和重要。第三，我們通過屢獲殊榮的中心和專業藥房網絡對患者支持服務進行持續投資，使專業藥房的補貨時間縮短了 8 天。我們希望確保符合條件的合適患者能夠快速開始使用 Ocaliva 進行治療。在這裡簡化促進過程有助於維持現有患者並啟動新患者。

Strong customer engagement and communication of the benefits of Ocaliva remain a focus for our commercial team. In this field at major conferences and with patients. Last fall, we kicked off our new HCP and patient marketing campaigns each with updated messaging designed to drive urgency and demonstrate the need to go beyond ALP management in fully addressing PBC treatment. We recently began to proactively provide to HCPs, the gastroenterology publication that presented in greater detail, some of our strong real-world evidence regarding improved outcomes for patients taking Ocaliva.

強大的客戶參與和 Ocaliva 好處的溝通仍然是我們商業團隊的重點。在這一領域的主要會議上和與患者一起。去年秋天，我們啟動了新的 HCP 和患者營銷活動，每個活動都更新了消息，旨在推動緊迫感並證明需要超越 ALP 管理來全面解決 PBC 治療問題。我們最近開始主動向 HCPs 提供更詳細的胃腸病學出版物，以及我們關於服用 Ocaliva 的患者改善預後的一些強有力的現實證據。

We anticipate additional publications and presentations of new real-world evidence later this year. Prescribers recognize the significance of real-world outcomes data when treating PBC. In market research studies, we have seen a significant increase in projected Ocaliva market share once HEPS and GIs were presented with the results from the real-world evidence studies.

我們預計今年晚些時候會有更多的出版物和新的真實世界證據的介紹。開處方者在治療 PBC 時認識到真實世界結果數據的重要性。在市場研究中，我們發現一旦 HEPS 和 GIs 獲得真實世界證據研究的結果，預計 Ocaliva 的市場份額將顯著增加。

Turning now to NASH. We are engaging with all key stakeholders as we prepare to execute against our go-to-market commercial strategy. We continue to meet with payers to refine our thinking as we prepare for a potential launch in NASH. We are focused on understanding their needs and concerns, which has allowed us to gain valuable insight into our pricing, reimbursement and overall access strategy.

現在轉向 NASH。在我們準備執行我們的上市商業戰略時，我們正在與所有主要利益相關者進行接觸。在我們為 NASH 的潛在發布做準備時，我們將繼續與付款人會面以完善我們的想法。我們專注於了解他們的需求和擔憂，這使我們能夠深入了解我們的定價、報銷和整體訪問策略。

Market research with health care professionals shows that reversal of fibrosis stopping further progression of fibrosis and the prevention of cirrhosis will be the 3 key drivers of prescribing for NASH patients with advanced fibrosis without cirrhosis. We believe that the strong and confirmed antifibrotic effects of OCA shown in our REGENERATE trial address all these areas of concern with a unique differentiating mechanism of action. Importantly, our well-established U.S. field presence and broad geographic footprint provide Intercept with a competitive advantage.

與醫療保健專業人員進行的市場研究表明，逆轉纖維化阻止纖維化的進一步發展和預防肝硬化將是為非肝硬化晚期纖維化 NASH 患者開處方的 3 個關鍵驅動因素。我們相信，在我們的 REGENERATE 試驗中顯示的 OCA 強大且已證實的抗纖維化作用通過獨特的差異化作用機制解決了所有這些關注領域。重要的是，我們完善的美國現場業務和廣泛的地理足跡為 Intercept 提供了競爭優勢。

Based on our analysis, nearly 3 and 4 of the highest potential prescribers for NASH already are within our existing PBC customer base, where we've been building relationships for the past 6 years. This overlap will enable us to easily flex to NASH disease awareness messages and then OCA specific ones while also covering our current PBC targets. In the meantime, our disease awareness activities continue. Our unbranded website hosts our NASH Tipping Point campaign, educating providers on the significant risk associated with advanced fibrosis due to NASH. We will continue our presence at key congresses while also initiating disease awareness programs.

根據我們的分析，近 3 和 4 個最有潛力的 NASH 處方者已經在我們現有的 PBC 客戶群中，我們在過去 6 年中一直在與這些客戶群建立關係。這種重疊將使我們能夠輕鬆地適應 NASH 疾病意識信息，然後是 OCA 特定信息，同時還涵蓋我們當前的 PBC 目標。與此同時，我們的疾病宣傳活動仍在繼續。我們的無品牌網站舉辦我們的 NASH 引爆點活動，教育提供者了解 NASH 導致的晚期纖維化相關的重大風險。我們將繼續出席重要會議，同時啟動疾病意識計劃。

In closing, we had strong PBC performance in 2022, and remain confident in our ability to increase Ocaliva market penetration in 2023 and maintain a positive long-term outlook for our PBC franchise. The commercial team is actively and passionately preparing for our future in NASH. I'm proud of the team's performance and look forward to sharing updates on our progress throughout the year. I'll now turn the call over to Dr. Michelle Berrey.

最後，我們在 2022 年的 PBC 表現強勁，並且對我們在 2023 年提高 Ocaliva 市場滲透率的能力以及對我們的 PBC 特許經營權保持積極的長期前景充滿信心。商業團隊正在積極而熱情地為我們在 NASH 的未來做準備。我為團隊的表現感到自豪，並期待分享我們全年進展的最新情況。我現在將電話轉給 Michelle Berrey 博士。

Thank you, Linda. And good morning, everyone. In 2022, we made substantial progress in our NASH development program and building out our pipeline. Looking first at NASH. In January, the FDA accepted the resubmission of our new drug application for OCA and precirrhotic liver fibrosis due to NASH. We are thrilled to have progressed to this regulatory milestone one step closer to reaching our goal of delivering the first FDA-approved therapy for this devastating disease. There's a critical need to address liver fibrosis due to NASH before patients progressed to cirrhosis, a pivotal point in NASH disease progression associated with increased risk of both liver-specific and all-cause mortality.

謝謝你，琳達。大家早上好。 2022 年，我們在 NASH 開發計劃和管道建設方面取得了實質性進展。首先看 NASH。 1 月，FDA 接受了我們重新提交的用於 OCA 和 NASH 引起的肝硬化前肝纖維化的新藥申請。我們很高興已經取得了這一監管里程碑的進展，離我們的目標更近了一步，即為這種破壞性疾病提供第一個 FDA 批准的治療方法。在患者進展為肝硬化之前，迫切需要解決由 NASH 引起的肝纖維化，這是 NASH 疾病進展的關鍵點，與肝臟特異性死亡率和全因死亡率的風險增加有關。

Our NDA is supported by a robust body of evidence from the OCA NASH clinical development program, including 2 positive 18-month interim analysis from the pivotal Phase III REGENERATE study and a large robust safety assessment that includes the 2,477 patients from REGENERATE with nearly 1,000 subjects on study drug for at least 4 years. OCA has demonstrated a consistent antifibrotic effect across 2 studies and multiple analyses of the REGENERATE study that we shared over the course of 2022. Through 2 independent histologic methodologies, OCA demonstrated fibrosis improvement of at least one stage without worsening of any of the 3 histologic parameters that comprise the NAFLD activity score, or NAS.

我們的 NDA 得到來自 OCA NASH 臨床開發計劃的大量證據的支持，包括來自關鍵 III 期 REGENERATE 研究的 2 個積極的 18 個月中期分析和一個大型穩健的安全評估，其中包括來自 REGENERATE 的 2,477 名患者和近 1,000 名受試者服用研究藥物至少 4 年。 OCA 在 2 項研究和我們在 2022 年期間共享的 REGENERATE 研究的多項分析中證明了一致的抗纖維化作用。通過 2 種獨立的組織學方法，OCA 證明纖維化至少改善了一個階段，而 3 種組織學參數中的任何一種都沒有惡化包括 NAFLD 活動評分或 NAS。

In both methodologies, OCA 25 milligrams demonstrated double the response rate of placebo and reducing liver fibrosis stage without worsening of any of the 3 histologic components. It's important to note that this endpoint was defined as a result of direct interactions with the FDA prior to finalization of the REGENERATE statistical analysis plan. In addition to robust efficacy data, our safety database, which is the largest in the Nash field with the longest duration of patient exposure shows a well-characterized safety and tolerability profile that supports the potential chronic administration of OCA.

在這兩種方法中，25 毫克 OCA 顯示出兩倍於安慰劑的反應率，並在不惡化任何 3 種組織學成分的情況下降低肝纖維化階段。值得注意的是，該終點被定義為在 REGENERATE 統計分析計劃最終確定之前與 FDA 直接互動的結果。除了強大的療效數據外，我們的安全性數據庫是 Nash 領域最大的，患者暴露持續時間最長，顯示出良好的安全性和耐受性特徵，支持 OCA 的潛在長期給藥。

We know that fibrosis is the strongest predictor of clinical outcomes in patients with NASH and we continue to believe that OCA has the potential to become the first approved therapy in this disease. FDA indicated that it considers us a Class II resubmission and has assigned a PDUFA target action date at June 22 for the NDA. We fully anticipate an advisory committee meeting as part of this process, but we do not yet have a confirmed date. We'll share additional updates as appropriate as we advance through this review process.

我們知道纖維化是 NASH 患者臨床結果的最強預測因子，我們仍然相信 OCA 有可能成為該疾病的第一個獲批治療方法。 FDA 表示它認為我們是 II 類重新提交，並為 NDA 指定了 PDUFA 目標行動日期為 6 月 22 日。我們完全期待諮詢委員會會議作為此過程的一部分，但我們尚未確定日期。我們將在審查過程中推進時酌情分享其他更新。

Turning to PBC. We continue to prepare data from our post-marketing study, Cobalt, and supplementary real-world evidence from large data sets in the U.S., U.K. and Europe. These data will be included in a regulatory submission to FDA this year in support of fulfilling post-marketing requirements for Ocaliva and PBC. The real-world data we have generated to date demonstrates the actual long-term clinical benefits of Ocaliva. Specifically, patients taking OCA had improved transplant-free and decompensation free survival which we know to be the most important treatment goals both for individuals living with PBC and for their clinicians.

轉向中國人民銀行。我們繼續從我們的上市後研究 Cobalt 中收集數據，並從美國、英國和歐洲的大型數據集中收集真實世界的補充證據。這些數據將包含在今年提交給 FDA 的監管文件中，以支持滿足 Ocaliva 和 PBC 的上市後要求。我們迄今為止生成的真實世界數據證明了 Ocaliva 的實際長期臨床益處。具體而言，服用 OCA 的患者改善了無移植和無失代償生存期，我們知道這是 PBC 患者及其臨床醫生最重要的治療目標。

Building on our commitment to innovating in PBC, a -- we are making great progress with our fixed-dose combination of OCA and bezafibrate of PPAR agonist. One of our 2 Phase II studies is now fully enrolled, and we're accelerating recruitment of patients into a second. These Phase II studies and our pharmacokinetic analysis will inform dose selection and study design for a Phase III trial. We anticipate selecting doses for the fixed dose combination as well as sharing data from planned analyses of the large Phase I and Phase II studies later this year.

基於我們對 PBC 創新的承諾，我們在 OCA 和 PPAR 激動劑苯扎貝特的固定劑量組合方面取得了巨大進展。我們的 2 項 II 期研究中的一項現已完全註冊，我們正在加速招募患者。這些 II 期研究和我們的藥代動力學分析將為 III 期試驗的劑量選擇和研究設計提供信息。我們預計將選擇固定劑量組合的劑量，並在今年晚些時候共享大型 I 期和 II 期研究的計劃分析數據。

The OCA bezafibrate combination has synergistic mechanisms of action with the potential to further lower key biochemical measures that predict long-term outcomes in PBC and while also improving tolerability. We're excited to show the potential impact of this combination that we believe has best-in-class potential.

OCA 苯扎貝特組合具有協同作用機制，有可能進一步降低預測 PBC 長期結果的關鍵生化指標，同時提高耐受性。我們很高興展示我們認為具有一流潛力的這種組合的潛在影響。

Finally, I'm happy to provide updates on our next-generation FXR agonist INT-787, with a lead indication in severe alcohol-associated hepatitis or SAH. For background, alcohol-related liver disease as a cause of chronic liver disease is on the rise. And is currently the leading indication for liver transplant in the U.S. Despite the increasing incidence of SAH in the U.S., there are no approved therapies for people who could develop this disease. We believe there are several indications in which 787 could make a potential impact.

最後，我很高興提供有關我們下一代 FXR 激動劑 INT-787 的最新信息，該藥物具有嚴重酒精相關性肝炎或 SAH 的先導適應症。作為背景，酒精相關肝病作為慢性肝病的一個原因正在上升。目前是美國肝移植的主要適應症。儘管 SAH 在美國的發病率不斷增加，但對於可能患上這種疾病的人，尚無批准的治療方法。我們認為，有多種跡象表明 787 可能會產生潛在影響。

However, SAH provides us with a great initial opportunity for this FXR agonist with a different gut to liver ratio compared to OCA. In November, we announced initiation of our proof-of-concept Phase IIa study called FRESH, evaluating the safety, tolerability, efficacy and pharmacokinetics of INT-787, in patients with SAH. Our first fresh site was activated in December 2022, and we're continuing to add additional sites in the U.S., U.K. and France.

然而，與 OCA 相比，SAH 為我們提供了這種 FXR 激動劑的良好初始機會，該激動劑具有不同的腸肝比。 11 月，我們宣布啟動名為 FRESH 的概念驗證 IIa 期研究，評估 INT-787 在 SAH 患者中的安全性、耐受性、療效和藥代動力學。我們的第一個新網站於 2022 年 12 月啟用，我們將繼續在美國、英國和法國添加更多網站。

As of February 2023, we have completed recruitment for our Phase I study. We look forward to sharing additional updates as this program advances. At this point, I'll turn the call over to Andrew for financial updates.

截至 2023 年 2 月，我們已完成第一階段研究的招募。隨著該計劃的推進，我們期待分享更多更新。在這一點上，我會把電話轉給安德魯來了解財務更新。

Thank you, Michelle. And good morning, everyone. We have had a very strong 2022, and I look forward to sharing our results and discussing our plans for the pivotal year ahead. I encourage you to please refer to our press release for a detailed summary of our financial results for the fourth quarter and year ended December 31, 2022. For this call, I will focus on the highlights as they relate to 2022, and we'll also provide guidance for 2023.

謝謝你，米歇爾。大家早上好。我們度過了非常強勁的 2022 年，我期待著分享我們的成果並討論我們在未來關鍵一年的計劃。我鼓勵您參閱我們的新聞稿，了解我們截至 2022 年 12 月 31 日的第四季度和年度財務業績的詳細摘要。對於本次電話會議，我將重點關注與 2022 年相關的亮點，我們將還為 2023 年提供指導。

As I begin, I would like to remind everyone that as you review our fourth quarter and full year financial information, please note that the divestiture of our international business was completed on July 1, and our full year non-GAAP results include the divested business for the first half of the year. In our financial statements, the divested business has been moved to discontinued operations. Turning to the highlights for the fourth quarter and full year ended December 31, 2022. We were very pleased with the growth -- growth of Ocaliva in PBC in 2022.

首先，我想提醒大家，當您查看我們的第四季度和全年財務信息時，請注意我們的國際業務剝離已於 7 月 1 日完成，我們的全年非 GAAP 業績包括剝離的業務今年上半年。在我們的財務報表中，剝離的業務已轉移至終止經營業務。轉向截至 2022 年 12 月 31 日的第四季度和全年的亮點。我們對 2022 年 PBC 中 Ocaliva 的增長感到非常滿意。

Our fourth quarter net sales growth was 13% over the prior year quarter for Ocaliva in the U.S. For the full year, we reported worldwide Ocaliva non-GAAP adjusted net sales of $343.8 million, with $285.7 million in total U.S. net sales compared to $260.8 million in total U.S. net sales in 2021.

我們在美國的 Ocaliva 第四季度淨銷售額比去年同期增長 13%。全年，我們報告全球 Ocaliva 非 GAAP 調整後淨銷售額為 3.438 億美元，美國淨銷售額為 2.857 億美元，而美國淨銷售額為 2.608 億美元在 2021 年美國淨銷售額中。

Touching on operating expenses for 2022, selling, general and administrative expenses were $55.4 million in the fourth quarter of 2022 compared to $46.3 million in 2021. The period-over-period increase was primarily driven by investment in NASH launch preparation. SG&A expenses were $176.3 million in full year 2022, compared to $177.5 million in 2021, with a decrease in personnel-related costs, offset by an increase in NASH launch preparation. Research and development expenses decreased to $40.7 million in the fourth quarter of 2022 from $51.1 million in the prior year quarter.

談到 2022 年的運營費用，2022 年第四季度的銷售、一般和管理費用為 5540 萬美元，而 2021 年為 4630 萬美元。同比增長主要是由對 NASH 啟動準備的投資推動的。 2022 年全年的 SG&A 費用為 1.763 億美元，而 2021 年為 1.775 億美元，人員相關費用有所減少，但被 NASH 啟動準備工作的增加所抵消。研發費用從去年同期的 5110 萬美元減少到 2022 年第四季度的 4070 萬美元。

The decrease was primarily driven by lower NASH-related costs and cost sharing reimbursements R&D expense decreased to $176.6 million in 2022, down from $182.7 million in 2021. The decrease was primarily driven by lower NASH costs and cost sharing reimbursements and were partially offset by the recognition of lower R&D tax credits. In 2022, approximately 2/3 of our R&D costs were related to our NASH program spend.

減少的主要原因是與 NASH 相關的成本和成本分攤報銷減少，研發費用從 2021 年的 1.827 億美元減少到 2022 年的 1.766 億美元。減少的主要原因是 NASH 成本和成本分攤報銷減少，部分被承認較低的研發稅收抵免。 2022 年，我們大約 2/3 的研發成本與我們的 NASH 計劃支出有關。

2022 as a year of financial transformation for the company. We executed a series of strategic transactions to transform our capital structure, which included the sale of our international business and several private repurchases of senior secured convertible notes. Regarding our convertible notes as a result of the repurchases during 2022, the principal balance of the 2026 convertible secured notes was reduced by approximately 78% to $111.1 million. Moreover, the company dramatically decreased annual cash interest. For 2023, cash interest expense will be $8 million as we anticipate our 2023 notes will be redeemed in July with cash on hand.

2022年作為公司財務轉型的一年。我們執行了一系列戰略交易來轉變我們的資本結構，其中包括出售我們的國際業務和多次私人回購高級有擔保可轉換票據。關於我們因 2022 年回購而產生的可轉換票據，2026 年可轉換有擔保票據的本金餘額減少了約 78% 至 1.111 億美元。此外，該公司大幅降低了年度現金利息。到 2023 年，現金利息支出將為 800 萬美元，因為我們預計我們的 2023 年票據將在 7 月用手頭現金贖回。

At year-end, the company had $491 million in cash and cash equivalents and $336 million in outstanding debt. We ended 2022 with the financial flexibility to move our business forward regardless of the FDA decision on OCA and NASH expected later this year.

截至年底，該公司擁有 4.91 億美元的現金和現金等價物以及 3.36 億美元的未償債務。無論 FDA 預計今年晚些時候對 OCA 和 NASH 的決定如何，我們都以財務靈活性結束了 2022 年，以推動我們的業務向前發展。

Turning to our financial guidance for 2023. We are guiding to $310 million to $340 million of Ocaliva net sales which compares to $285.7 million in 2022. For 2023, non-GAAP adjusted operating expenses, we are guiding to $360 million to $390 million which compares to approximately $325 million in non-GAAP operating expenses in 2022 from our continuing business when excluding the sale of the international business.

轉向我們對 2023 年的財務指導。我們指導 Ocaliva 的淨銷售額為 3.1 億至 3.4 億美元，而 2022 年為 2.857 億美元。對於 2023 年，非 GAAP 調整後的運營費用，我們指導為 3.6 億至 3.9 億美元，相比之下在不包括出售國際業務的情況下，我們的持續業務在 2022 年產生的非 GAAP 運營費用約為 3.25 億美元。

Similar to what we've seen in prior years, we anticipate slightly lower revenue and higher cash utilization in the first quarter of 2023 relative to the rest of the year. We expect that Ocaliva first quarter sales will be impacted by the usual seasonality as patients are faced with insurance plan resets and Medicare coverage gaps at the beginning of the year. We also anticipate greater cash use in the first quarter due to activities from work related to preparing for a potential approval and launch in NASH and other annual expenses. Finally, we may choose to revise our 2023 guidance later in the year, pending potential regulatory approval for our NDA for OCA in precirrhotic liver fibrosis due to NASH.

與我們前幾年看到的情況類似，我們預計 2023 年第一季度的收入與今年剩餘時間相比將略有下降，現金利用率將略有上升。我們預計 Ocaliva 第一季度的銷售額將受到通常的季節性影響，因為患者在年初面臨保險計劃重置和 Medicare 覆蓋缺口。我們還預計，由於與準備 NASH 的潛在批准和啟動相關的工作活動以及其他年度支出，第一季度的現金使用量將增加。最後，我們可能會選擇在今年晚些時候修改我們的 2023 年指南，等待我們的 NDA 用於 NASH 引起的肝硬化前期肝纖維化的 NDA 的潛在監管批准。

In summary, we are pleased with our financial performance in 2022 and looking forward to a strong 2023. We are in solid financial position and believe that our current balance sheet and cash on hand gives us the financial flexibility to continue to grow our existing Ocaliva business support a potential launch in NASH and advance our pipeline programs. With that, I'd now like to turn it over to the operator for any questions. Operator?

總而言之，我們對 2022 年的財務表現感到滿意，並期待 2023 年的強勁表現。我們的財務狀況穩健，並相信我們目前的資產負債表和手頭現金使我們具有財務靈活性，可以繼續發展現有的 Ocaliva 業務支持 NASH 的潛在發布並推進我們的管道計劃。有了這個，我現在想把它交給接線員來解決任何問題。操作員？

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

（操作員說明）我們的第一個問題來自 Ritu Baral 與 Cowen 的對話。

Michelle has the FDA at any point, communicated to you what the topic of the AdCom could be and further any range we should be thinking of for the date of the AdCom? I guess we're all sort of coming at it, wondering given the -- since the resubmission, are you going to have things like a mid-cycle review meeting where they're going to tell you these things? Or are you flying blind, like last time?

米歇爾在任何時候都有 FDA，向您傳達了 AdCom 的主題是什麼，以及我們應該考慮的 AdCom 日期的任何範圍？我想我們都在考慮這個問題，想知道自從重新提交以來，您是否會召開中期審查會議之類的事情，他們會告訴您這些事情？或者你像上次一樣盲目飛行？

Ritu. So we do anticipate that the focus of the advisory committee meeting would be focused on overall benefit risk. We have had multiple conversations with the -- since the CRL, and we know that there are some areas of focus for them. We intend to convey those that certainly were all addressed in our NDA the specific areas that we have communicated at the AASLD presentation and again at NASH-TAG, we feel that we have addressed all the areas of concern with the confirmation of the antifibrotic benefit and the second analysis and a much more robust safety database with which we can address any of their earlier concerns specifically around the long-term safety and tolerability of the drive, given that this would be anticipated to be a chronically administered drug.

日圖。因此，我們確實預計諮詢委員會會議的重點將集中在整體利益風險上。自 CRL 以來，我們已經與 - 進行了多次對話，我們知道他們有一些重點領域。我們打算傳達那些在我們的 NDA 中肯定都解決了的具體領域，我們在 AASLD 演示和 NASH-TAG 上再次溝通，我們認為我們已經通過確認抗纖維化益處解決了所有關注的領域，並且第二個分析和一個更強大的安全數據庫，我們可以用它來解決他們早期的任何問題，特別是關於驅動器的長期安全性和耐受性，因為預計這是一種長期服用的藥物。

So it's important that we have years of therapy in order to demonstrate that safety and tolerability.

因此，重要的是我們要進行多年的治療以證明其安全性和耐受性。

I guess just one more point to add in there, Ritu, to your question, as Michelle indicated in her prepared remarks, all the prep for the AdCom is ongoing, but we don't yet have a confirmed date.

Ritu，我想在你的問題中再補充一點，正如 Michelle 在她準備好的發言中指出的那樣，AdCom 的所有準備工作都在進行中，但我們還沒有確定日期。

Our next question comes from the line of Mayank Mamtani with B. Riley Securities.

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

I have a few -- just maybe following up on the prior question. As part of your acceptance letter on the NDA filing, was it clearly communicated to you by FDA that they are planning to hold an Adcom? And I just wonder -- on the agency does -- is increasingly requiring in-person format. So how confident do you purely getting answered by the June 22 PDUFA date? And then I have a couple of follow-ups.

我有一些 - 可能只是跟進先前的問題。作為 NDA 申請接受函的一部分，FDA 是否明確告知您他們計劃舉行 Adcom？我只是想知道——該機構確實——越來越需要面對面的形式。那麼，您對在 6 月 22 日 PDUFA 日期之前得到答復有多大信心？然後我有幾個後續行動。

Yes. I guess on the AdCom itself, we have every indication that we'll have an AdCom. We can't speak to a date as there is none confirmed yet, but we are working in the context of the existing PDUFA date and typically, those come a handful of weeks prior to the PDUFA date. So we're moving forward, we'll be fully prepared. And of course, will provide any additional information as appropriate if we get it from the agency.

是的。我想在 AdCom 本身，我們有各種跡象表明我們將擁有一個 AdCom。我們無法確定日期，因為還沒有確定的日期，但我們正在現有 PDUFA 日期的背景下工作，通常，這些日期比 PDUFA 日期早幾週。所以我們正在前進，我們將做好充分準備。當然，如果我們從該機構獲得信息，我們將酌情提供任何其他信息。

Okay. And then on the apparently very strong guidance you had on PBC, seems like driven by new prescribers. Could you perhaps share what the overlap you may have with these new hepatologists that you're having prescribed OCA for PBC but also they may also care for NASH patients? Do you have that data cap?

好的。然後根據你對 PBC 的明顯非常強烈的指導，似乎是由新的處方者驅動的。您是否可以分享您與這些新的肝病學家之間的重疊之處，即您為 PBC 開了 OCA，但他們也可能照顧 NASH 患者？你有那個數據上限嗎？

Yes. So Mayank, we do, as you said, feel good about the performance on PBC, both for the quarter and the year where we saw an acceleration in the second half of the year. In the growth versus the first half and with a strong 13% growth in the fourth quarter. Clearly, this is a long-term area of focus for us. We have been working with many of the key prescribing physicians for several years now, and Linda can provide some details how we see a large part of that core audience also being really the first potential prescribers for NASH as we do the deep commercial planning in advance of the PDUFA and NASH.

是的。所以 Mayank，正如你所說，我們對 PBC 的表現感到滿意，無論是在我們看到下半年加速的季度還是年度。與上半年的增長相比，第四季度增長了 13%。顯然，這是我們長期關注的領域。多年來，我們一直在與許多主要的處方醫生合作，Linda 可以提供一些細節，因為我們提前進行了深入的商業計劃，因此我們如何看到大部分核心受眾也確實是 NASH 的第一批潛在處方者PDUFA 和 NASH。

Yes. We cover right now from our analysis Three out of 4 of the top potential NASH prescribers already exist within our PBC call list. So we're bringing in new PBC prescribers, but also have established relationships over the past 6 years and familiarity with Ocaliva in that same target audience.

是的。我們現在從我們的分析中涵蓋了四分之三的頂級潛在 NASH 處方者已經存在於我們的 PBC 呼叫列表中。因此，我們正在引進新的 PBC 處方者，但也在過去 6 年中建立了關係，並在同一目標受眾中熟悉了 Ocaliva。

So we feel comfortable that the work -- the groundwork that we've laid with PBC will translate very nicely and efficiently into a NASH potential NASH launch.

因此，我們對這項工作感到滿意——我們與 PBC 奠定的基礎將非常好、高效地轉化為 NASH 潛在的 NASH 發布。

Got it. And my final question on the FXR PPAR combination Phase I/II data that you intend to report later in the year. Could you just maybe provide some thoughts on what Phase III design you might be thinking since you are in a unique position to pursue 2 currently approved therapies in this drug class. So just -- I know it's early, but it would be great to hear your thoughts on the Phase III design.

知道了。我的最後一個問題是您打算在今年晚些時候報告的 FXR PPAR 組合 I / II 期數據。您能否提供一些關於您可能會想到的 III 期設計的想法，因為您處於一個獨特的位置，可以在該藥物類別中尋求 2 個目前批准的療法。所以 - 我知道現在還早，但很高興聽到您對 III 期設計的想法。

Michelle, do you want to take that one, please?

米歇爾，你要拿那個嗎？

Sure. Yes. Great question. We are really excited about the fixes combination of OCA plus bezafibrate. And as you state is we are in a unique position to have 2 potential therapies in PBC. I hesitate to give much detail on our plans for the Phase III until we have those conversations with with the FDA to review all the very exciting data coming out of the Phase II.

當然。是的。很好的問題。我們對 OCA 加苯扎貝特的修復組合感到非常興奮。正如您所說，我們處於獨特的位置，可以在 PBC 中擁有 2 種潛在療法。在我們與 FDA 進行對話以審查來自 II 期的所有非常令人興奮的數據之前，我不願詳細說明我們的 III 期計劃。

But we feel we have the potential here with the combination for potential best-in-class for PBC. So again, it really underscores our long-term commitment to innovation in this space.

但我們認為我們有潛力與 PBC 潛在的同類最佳組合。因此，它再次強調了我們對該領域創新的長期承諾。

(Operator Instructions) Our next question comes from the line of Yasmeen Rahimi with Piper Sandler.

（操作員說明）我們的下一個問題來自 Yasmeen Rahimi 和 Piper Sandler 的台詞。

This is Emma on for Yas. My question is what are your thoughts on the recent ICER pricing report? And with that, -- are you still thinking about differential pricing in NASH versus PBC? And what type of payer discussions have you had to support that, if any?

這是亞斯的艾瑪。我的問題是您對最近的 ICER 定價報告有何看法？有了這個，——你還在考慮 NASH 與 PBC 的差異定價嗎？如果有的話，您必須支持哪種類型的付款人討論？

Thanks, Emma. Maybe I'll give some overall view on how we're thinking about pricing and then Linda can comment on ICER. So as you would imagine, we're doing all the right work as we prepare for a launch that includes some up-to-date dialogue with our key payers, and those are ongoing. Will, of course, take a pricing decision once we have the full information, including final label. But we continue to work towards all the right steps to have optionality on pricing between Ocaliva and OCA and NASH should we choose to execute a pricing strategy that way.

謝謝，艾瑪。也許我會就我們如何考慮定價給出一些總體看法，然後琳達可以對 ICER 發表評論。因此，正如您想像的那樣，我們正在做所有正確的工作，因為我們正在準備發布，其中包括與我們的主要付款人進行的一些最新對話，而且這些對話正在進行中。當然，我們會在獲得包括最終標籤在內的完整信息後做出定價決定。但如果我們選擇以這種方式執行定價策略，我們將繼續朝著所有正確的步驟努力，以便在 Ocaliva 和 OCA 和 NASH 之間擁有定價的選擇權。

So we would anticipate a separate brand, separate NDC, the things that give us that option. And all the updated work, including those discussions with payers are going to be important inputs. We'll share more thinking about our strategy with the -- with the payer, which will, of course, be foundational for the launch as we get closer to the PDUFA date. And again, I think it's been several years. We've had dialogue with the payers going back to before the the first PDUFA date.

所以我們會期待一個單獨的品牌，單獨的 NDC，這些東西給了我們這種選擇。所有更新的工作，包括與付款人的討論，都將成為重要的投入。我們將與付款人分享更多關於我們戰略的想法，當然，隨著我們接近 PDUFA 日期，這將成為發布的基礎。再一次，我認為已經有好幾年了。在第一個 PDUFA 日期之前，我們已經與付款人進行了對話。

So we've done a lot of in-depth work. We're revising it with the current context as you would need to and then perhaps Linda, can comment on ICER.

所以我們做了很多深入的工作。我們正在根據您的需要根據當前上下文對其進行修改，然後 Linda 可以對 ICER 發表評論。

Yes, of course. Thanks for the question. Frankly, we disagree with several of the approaches that were used within the model, which generated the draft evidence report, specifically, when we look at the model, it does not define a standard that constitutes an acceptable data set and implies. It kind of applies an inconsistent approach and the exclusion of available data for different therapies. So what do I mean by that? An example is, it includes only Phase III data for OCA but put both Phase III and Phase II data in for Madrigal.

是的當然。謝謝你的問題。坦率地說，我們不同意模型中使用的幾種方法，這些方法生成了證據報告草案，具體來說，當我們查看模型時，它沒有定義構成可接受數據集的標準並暗示。它採用了一種不一致的方法，並排除了不同療法的可用數據。那我的意思是什麼？例如，它僅包含 OCA 的 III 期數據，但同時包含 Madrigal 的 III 期和 II 期數據。

And even though -- the Phase II data did not include fibrosis improvement without worsening of NASH, as a primary endpoint. And then furthermore, it does not use the updated available information for OCA. It doesn't incorporate all data that are publicly available, notably the full and robust safety data set we have for REGENERATE. We presented this at AASLD in November 22. And frankly, it doesn't present the new analyses that we shared at NASH-TAG in January 2023. So there's kind of a lack of consistency in approach that we are recognizing and we'll see how it goes from there. But we have some concerns with the model.

即使——II 期數據不包括在不惡化 NASH 的情況下改善纖維化，作為主要終點。此外，它不使用 OCA 的更新可用信息。它沒有包含所有公開可用的數據，尤其是我們為 REGENERATE 提供的完整而強大的安全數據集。我們於 11 月 22 日在 AASLD 上展示了這一點。坦率地說，它沒有展示我們在 2023 年 1 月在 NASH-TAG 上分享的新分析。因此我們認識到在方法上缺乏一致性，我們將看到它是如何從那裡去的。但我們對該模型有一些擔憂。

Our next question comes from the line of Jon Wolleben with JMP Securities.

我們的下一個問題來自 Jon Wolleben 與 JMP Securities 的對話。

Primarily wanted to ask about OpEx guidance. I'm wondering how much incremental NASH SG&A is included there? And if it's not fully included, how much more do you think would be necessary? And then I think, Andrew, you said that 2/3 of 2022 R&D was for NASH. I'm wondering if that's the same proportion you expect for 2023?

主要想詢問有關 OpEx 的指導。我想知道那裡包含多少增量 NASH SG&A？如果它沒有完全包含在內，您認為還需要多少？然後我想，安德魯，你說 2022 年研發的 2/3 用於 NASH。我想知道這是否與您預期的 2023 年比例相同？

Thanks, Jon. We are continuing to manage with, I think, the right intersection of ensuring we have the right investments as we prepare for NASH, but also paying a lot of attention to making sure that we're managing our OpEx in a responsible way, Andrew, maybe you can go into how we're thinking about the NASH investment in context of the guidance that you gave earlier.

謝謝，喬恩。我認為，我們將繼續管理正確的交叉點，確保我們在為 NASH 做準備時擁有正確的投資，同時也非常注意確保我們以負責任的方式管理我們的運營支出，Andrew，也許您可以根據您之前提供的指導，了解我們如何考慮 NASH 投資。

Yes, sure. Thanks for the question, Jon. Yes, so probably the right way to think about it and the reason I gave sort of our continuing cost from last year, our last year. Our spend was around $325 million when you don't count the international operations that we sold in July. So the way to think about it is the increase year-over-year is really 100% related to NASH launch then.

是的，當然。謝謝你的問題，喬恩。是的，這可能是正確的思考方式，也是我給出去年持續成本的原因。如果不計算我們 7 月份出售的國際業務，我們的支出約為 3.25 億美元。因此，考慮它的方式是，同比增長確實 100% 與 NASH 的推出有關。

So you've got about $50 million to $60 million that we've targeted is prelaunch NASH. And that's basically external, right? So we're looking at things like payers, we're looking at pricing. We're looking at disease education. We're not adding a lot to infrastructure in the meantime until we get to our PDUFA date. So it's all going to be external spend that we could ratchet up or ratchet down sort of as we go. With regard to R&D, yes, we're continuing to evolve our pipeline, as you know. So reverse is done, which means that our spend on NASH is going to be reduced this year relative to last year. overall R&D spend will be slightly down but materially flat, but you're going to see more like 50% NASH and 50% pipeline, if that helps.

所以你有大約 5000 萬到 6000 萬美元，我們的目標是預啟動 NASH。那基本上是外部的，對吧？所以我們正在研究付款人之類的東西，我們正在研究定價。我們正在研究疾病教育。在我們到達 PDUFA 日期之前，我們不會在此期間向基礎架構添加很多東西。因此，這一切都將是外部支出，我們可以在進行中逐步增加或減少。關於研發，是的，正如你所知，我們正在繼續發展我們的管道。所以反向完成了，這意味著我們今年在 NASH 上的支出將比去年減少。總體研發支出將略有下降，但基本持平，但如果有幫助的話，你會看到更多 50% 的 NASH 和 50% 的管道。

Very helpful.

很有幫助。

Our next question comes from the line of Joseph Stringer with Needham & Company.

我們的下一個問題來自 Needham & Company 的 Joseph Stringer。

Just wanted to get your updated thoughts on the precirrhotic NASH market segmentation. And looking ahead, if OCA approved in NASH with your desired label, what types of NASH patients do you anticipate getting on the drug for?

只是想了解您對肝硬化前 NASH 市場細分的最新想法。展望未來，如果 OCA 批准在 NASH 中使用您想要的標籤，您預計哪些類型的 NASH 患者會服用該藥？

Yes. Thanks, Joe. Maybe I can start and Linda can chip in if she wants. I think, look, when we think about how we would best position OCA. We continue to be focused on the antifibrotic effect and the more advanced patients. And so I think that theme, what you've heard from me for a while continues to be what we're getting back as we do these updated discussions with all of the stakeholders, the deep updated market research you would anticipate, we're doing as we're in this phase of preparation.

是的。謝謝，喬。也許我可以開始，如果琳達願意，她可以參與進來。我想，看，當我們考慮如何最好地定位 OCA 時。我們繼續關注抗纖維化作用和更晚期的患者。所以我認為這個主題，你一段時間以來從我這裡聽到的仍然是我們在與所有利益相關者進行這些最新討論時得到的反饋，你會期待的深入更新的市場研究，我們是做我們在這個準備階段。

So really, the advanced patient who is most likely identified through noninvasive means continues to be where we would 0 in on both -- it really is the patients that the physicians the payers and the patients themselves have the most amount of urgency towards seeking treatment. And we know from the profile of OCA, including, importantly, the the greater level of efficacy that we showed in some of the analysis that we reported out in the latter part of last year showing higher efficacy. For example, in that F3 subset goes in that same direction. We would also be focused in the initial phase on those patients that are already under care of the specialists of HEPS and GIs And as Linda said earlier in response to the 1 of the questions, we're seeing most of those physicians already today.

因此，實際上，最有可能通過非侵入性手段識別出的晚期患者仍然是我們在這兩個方面都為 0 的地方——實際上，醫生、付款人和患者本身對尋求治療的緊迫性最大。我們從 OCA 的概況中知道，包括，重要的是，我們在去年下半年報告的一些分析中顯示出更高的療效水平，顯示出更高的療效。例如，在那個 F3 子集中，它朝著相同的方向發展。在初始階段，我們還將重點關注那些已經接受 HEPS 和 GI 專家護理的患者。正如 Linda 早些時候在回答第一個問題時所說的那樣，我們今天已經看到了這些醫生中的大多數。

So we -- I think we have a good understanding of those practices and of those individual and group prescribers. So Linda, anything you want to add on.

所以我們——我認為我們對這些做法以及那些個人和團體處方者有很好的理解。琳達，任何你想補充的。

Yes. I think the combination of calling on these folks with the urgency that's been noted over and over again by physicians with the fibrotic patients, advanced patients we estimate that there are probably 20 million adult patients with NASH, but only a small percentage, roughly about 3.8 million have been actually diagnosed, right? There's nothing to use to treat them. So you see an increase in diagnosis that comes following the ability to have on-label treatment from therapies and lots of discussions.

是的。我認為呼籲這些人的緊迫性已經被醫生一遍又一遍地註意到纖維化患者、晚期患者，我們估計可能有 2000 萬成年 NASH 患者，但只有一小部分，大約 3.8百萬其實已經確診了吧？沒有什麼可以用來治療它們的。所以你會看到診斷的增加是在能夠通過治療和大量討論進行標籤治療之後出現的。

We continue to estimate that approximately 500,000 diagnosed NASH patients. These are diagnosed -- are currently under the care of a [helper GI] and have advanced fibrosis without cirrhosis. So from a launch mode, we feel that those patients reside in the offices that we'll be calling on and have the most need and we have the best data in that set.

我們繼續估計約有 500,000 名確診的 NASH 患者。這些被診斷出來——目前正在 [輔助 GI] 的照料下並且有晚期纖維化但沒有肝硬化。因此，從啟動模式來看，我們認為那些患者居住在我們將要拜訪的辦公室，並且最需要，我們擁有該組中最好的數據。

Our next question comes from the line of Brian Skorney with Baird.

我們的下一個問題來自 Brian Skorney 與 Baird 的對話。

I guess on the Ocaliva guidance for 2023 -- maybe you can just frame of how to think about getting that higher end of the guidance, it's almost 20% increase year-over-year, which is quite a bit of acceleration compared to where it's been trending for the last 2 years. So can you just characterize what you're seeing in the more -- that might get you there? And does that high end include anything for NASH?

我想關於 2023 年的 Ocaliva 指南——也許你可以構想一下如何考慮獲得指南的更高端，它同比增長了近 20%，與現在相比，這是一個相當大的加速過去 2 年一直在流行。那麼，您能否描述您在更多方面看到的內容——這可能會讓您到達那裡？那個高端包括 NASH 的任何東西嗎？

Andrew, maybe you just start on that.

安德魯，也許你剛剛開始。

Yes, sure. Thanks, Brian. Look, the guidance that we gave is kind of in the 9% to 19% range growth. We tend to try to target the center of that growth as to where our focus is internally, Again, we're continuing to put effort and energy into growing our top line and we're really comfortable with our guidance overall. What I would say is that the guidance that we gave on Ocaliva is unimpacted by NASH. In my prepared remarks, you probably noted that I mentioned that we would reserve the right to come back and reissue guidance when and if we get approval from the FDA.

是的，當然。謝謝，布萊恩。看，我們給出的指導是在 9% 到 19% 的範圍內增長。我們傾向於嘗試將增長的中心作為我們內部關注的重點，同樣，我們將繼續努力和精力增加我們的收入，我們對我們的總體指導非常滿意。我要說的是，我們對 Ocaliva 的指導不受 NASH 的影響。在我準備好的發言中，您可能注意到我提到過，如果我們獲得 FDA 的批准，我們將保留回來重新發布指南的權利。

And at that point, would we give more of a blended and that secondary guidance would include any impact from NASH on Ocaliva.

在這一點上，我們是否會給出更多的混合指導，並且次要指導將包括 NASH 對 Ocaliva 的任何影響。

Yes, Brian. The only other thing that I would add just in terms of dynamics, we talked in the second half of last year about the emerging data that we were beginning to publish from the real-world data sets on outcomes. We know that some of those publications came late in the year -- and look, all indications, that data, we're getting it out there appropriately in the context of the medical affairs and/or a commercial plan -- but that data is just starting to get into the hands of the prescribers. And we know from the recent market research that we're doing, it can be quite important to those prescribers as they think about potentially increasing their utilization of Ocaliva for the right second line patients.

是的，布萊恩。關於動態，我要補充的唯一另一件事是，我們在去年下半年談到了我們開始從真實世界的結果數據集中發布的新興數據。我們知道其中一些出版物是在今年晚些時候發布的——看，所有跡象表明，我們在醫療事務和/或商業計劃的背景下適當地發布了這些數據——但這些數據是剛剛開始進入處方者的手中。我們從最近正在進行的市場研究中了解到，這對那些考慮可能增加對合適的二線患者使用 Ocaliva 的處方者來說非常重要。

Yes. And I think the last thing to note is coming out of the second half of the year as we predicted we've seen accelerated growth. We saw this bolus of new writers, demand, et cetera. And we are layering that now, as Jerry noted, with the distribution of our real-world evidence data. And when we test that in market research and have people that are exposed to that data and say, all right. Now project or prescribing, we see a significant increase in allocation of share to Ocaliva. And as we have, and we anticipate additional presentations of new real-world evidence data.

是的。我認為最後要注意的是今年下半年，正如我們預測的那樣，我們已經看到了加速增長。我們看到了新作家的大量湧入、需求等等。正如 Jerry 指出的那樣，我們現在正在將其與我們真實世界證據數據的分佈進行分層。當我們在市場研究中對其進行測試並讓接觸該數據的人說，好吧。現在項目或處方，我們看到 Ocaliva 的份額分配顯著增加。正如我們所做的那樣，我們預計會出現更多新的真實世界證據數據。

And frankly, the publications that we will be able to disseminate, we see that awareness picking up and really reframing the way that physicians evaluate what does complete PBC management look like? And they've always said that preventing progression, maintaining the patients, those are the important things, and we've got not only 5 years of data from our POISE data on looking at stabilization of fibrosis and bilirubin, but now we have outcomes, and we're talking about lives, not labs.

坦率地說，在我們將能夠傳播的出版物中，我們看到人們的意識正在增強，並真正重新定義了醫生評估完整 PBC 管理的方式？他們總是說預防進展、維持患者健康，這些都是重要的事情，我們不僅從我們的 POISE 數據中獲得了 5 年的數據來觀察纖維化和膽紅素的穩定性，而且現在我們有了結果，我們談論的是生活，而不是實驗室。

These are actual patients that are benefiting from treatment with Ocaliva.

這些是真正受益於 Ocaliva 治療的患者。

Our next question comes from the line of Thomas Smith with SVB Securities.

我們的下一個問題來自 Thomas Smith 與 SVB Securities 的對話。

This Mike on for Tom. Can you provide some additional color on where you are with the PBC regulatory discussion? And what, if any, are the remaining gating factors for submission? And then just as a quick follow-up, when in 2023 specifically are you targeting for submission?

這個 Mike 代替了 Tom。您能否就 PBC 監管討論的進展情況提供一些額外的顏色？如果有的話，剩下的提交門控因素是什麼？然後作為快速跟進，您具體打算在 2023 年什麼時候提交？

Michelle, can you take that, please?

米歇爾，你能接受嗎？

Yes. Happy -- thanks for the question. So we have been in discussion with the agency about the content of our planned supplemental NDA which, as we've discussed, would include the Cobalt results, which we top lined last year as well as an external control. So comparing those patients from -- within the COBALT study, who were on OCA to a group of patients from external databases. We've looked at the KOMODO database as we've released as well as 2 different patient registries, the U.K. and global PBC databases.

是的。很高興——謝謝你的提問。因此，我們一直在與該機構討論我們計劃的補充 NDA 的內容，正如我們所討論的那樣，該補充協議將包括我們去年排在首位的 Cobalt 結果以及外部控制。因此，將來自 COBALT 研究的那些接受 OCA 的患者與來自外部數據庫的一組患者進行比較。我們已經查看了我們發布的 KOMODO 數據庫以及 2 個不同的患者登記，英國和全球 PBC 數據庫。

So we've been in discussions with the agency about inclusion there -- we will also be planning to publish these data as we did with the gastro cover last December in releasing the real-world evidence. The most striking thing about these data sets is the consistency completely independent data sets. We're seeing a 50% to 70% reduction in debt and decompensation leading to either transplant or death. So we are really excited about those data sets this would be the first non ultra-rare condition that would include real-world evidence in a significant submission.

因此，我們一直在與該機構討論是否將其納入其中——我們也將計劃發布這些數據，就像我們去年 12 月在發布真實世界證據時對胃罩所做的那樣。這些數據集最引人注目的是完全獨立的數據集的一致性。我們看到導致移植或死亡的債務和失代償減少了 50% 到 70%。因此，我們對這些數據集感到非常興奮，這將是第一個在重要提交中包含真實世界證據的非極罕見情況。

We know there's a lot of interest here. That is our plan for the submission. We haven't yet given guidance on the exact timing of that. As you might understand, with a small group, we are working in 2 parallel pads, so on the NASH preparations and for the PBC sNDA. So we'll give more guidance as that date grows closer. Thanks for the question.

我們知道這裡有很多興趣。這是我們提交的計劃。我們尚未就具體時間提供指導。正如您可能了解的那樣，在一個小組中，我們在 2 個平行墊上工作，所以在 NASH 準備和 PBC sNDA 上。因此，隨著該日期的臨近，我們將提供更多指導。謝謝你的問題。

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

我們的下一個問題來自 RBC Capital Markets 的 Brian Abrahams。

A question on IP. Can you talk about your level of confidence in OCA's exclusivity extending to 2031, just given all the recent settlements that you've been able to do, but still maybe one filer remaining out there. And then how should we be thinking about that expiration potentially applying to OCA in the NASH setting versus just in the PBC setting.

關於IP的問題。你能談談你對 OCA 的排他性延長到 2031 年的信心程度嗎，只是考慮到你最近能夠做的所有和解，但可能仍然有一個申報人在那裡。然後我們應該如何考慮在 NASH 設置中與僅在 PBC 設置中可能適用於 OCA 的到期。

Thanks for the question, Brian. Andrew?

謝謝你的問題，布賴恩。安德魯？

Yes, sure. Thanks, Brian. Yes, so look, we're extremely happy that we were able to get such a positive settlement. Not going to litigation on the IP was a great outcome for the company and getting 70% of the value of those 2033 patents is a real win for the company. Look, we can't speak to any -- the current additional filer out there, which is Zenara Pharma. That's a separate trial. It's the same jurisdiction, the same judge, same fact set it would -- but it's out there in 2024.

是的，當然。謝謝，布萊恩。是的，所以看，我們非常高興我們能夠獲得如此積極的解決方案。不對知識產權提起訴訟對公司來說是一個很好的結果，獲得這 2033 項專利價值的 70% 對公司來說是一個真正的勝利。看，我們無法與任何人交談——目前的額外申報人是 Zenara Pharma。那是一個單獨的審判。這是相同的司法管轄區，相同的法官，相同的事實設定——但它會在 2024 年出現。

The good news for the company is that we're completely ready for trial, right, because we did all the work, we did all the prep. Zenara would have to start over from scratch. We're never going to predict an outcome, but it's the same fact set, and we're ready to enforce our IP vigorously. In terms of carry on to NASH, again, assuming that we get approval, that's the same fact set. It will -- presumably, if people file against it, it would be a completely different trial. But again, we're very comfortable with the IP. We've been through it. It's the same patents. So we would have the same level of comfort that we have with Ocaliva as we have with NASH. I don't know, Jerry, if you want to add to that?

對公司來說，好消息是我們已經完全準備好接受審判，對吧，因為我們做了所有的工作，我們做了所有的準備。 Zenara 將不得不從頭開始。我們永遠不會預測結果，但它是相同的事實集，我們已準備好大力執行我們的知識產權。就 NASH 而言，再次假設我們獲得批准，這是相同的事實集。它將——大概，如果人們提出反對，那將是一個完全不同的審判。但同樣，我們對 IP 非常滿意。我們已經經歷過了。都是一樣的專利。因此，我們對 Ocaliva 的舒適程度與對 NASH 的舒適程度相同。我不知道，傑里，你是否想補充一點？

Nope. Think you got it.

沒有。以為你明白了。

Our next question comes from the line of Michael Yee with Jefferies.

我們的下一個問題來自 Michael Yee 與 Jefferies 的對話。

(inaudible) for Mike. One question from us today. So some competitors have Phase III data coming up over the span of the next year. Could you comment to us a little bit of your view on how the competitive landscape is involved -- is evolving and how Ocaliva is positioned in this?

（聽不清）邁克。今天我們有一個問題。因此，一些競爭對手在明年的跨度內獲得了 III 期數據。您能否就競爭格局如何涉及——正在演變以及 Ocaliva 在其中的定位向我們發表一些看法？

So I assume you're talking about competitive landscape on PBC just so that I'm clear.

所以我假設你是在談論 PBC 的競爭格局，這樣我就清楚了。

Yes, PBC.

是的，中國人民銀行。

Yes. Maybe a couple of comments from me, and then Linda can get in a little deeper. I think importantly, we continue to position ourselves for a long-term effort in PBC. We have leadership there. Our goal is to maintain that leadership. And I think, as Andrew just indicated, the patent settlements give us more runway and certainty on Ocaliva. And then importantly, we have the opportunity with the next generation and the FTC coming to not only potentially provide a better therapeutic solution but also more runway because there's incremental exclusivity and IP potential on the combination.

是的。也許我的一些評論，然後 Linda 可以更深入地了解。我認為重要的是，我們繼續為 PBC 的長期努力定位自己。我們在那裡有領導。我們的目標是保持這種領先地位。我認為，正如安德魯剛才指出的那樣，專利和解讓我們在 Ocaliva 上有了更多的跑道和確定性。然後重要的是，我們有機會與下一代和 FTC 一起來，不僅可能提供更好的治療解決方案，而且還有更多的跑道，因為組合具有增量排他性和 IP 潛力。

So this is a long-term play for us now. And as we get ready for potentially some Phase III data to come and new entrants in the second-line therapy, I think we feel good about our position and the work to do ahead. Maybe Linda, you can comment on how we see that evolving.

所以這對我們來說是一個長期的遊戲。當我們準備好迎接可能出現的一些 III 期數據和二線治療的新進入者時，我認為我們對我們的地位和未來要做的工作感到滿意。也許琳達，你可以評論我們如何看待這種演變。

Yes. I mean, obviously, we're the incumbent, we are still growing. We have new data that's changing the way prescribers think about the goals. We have probably 2 more publications to come this year, reinforcing our real-world evidence. And what we're really trying to do is say it goes beyond ALP and just normalizing or lowering scores, it really is about what is the long-term impact on the patient? And we are the only people right now in the new second line, not discounting or so.

是的。我的意思是，很明顯，我們是現任者，我們仍在成長。我們的新數據正在改變開處方者對目標的看法。今年我們可能還會再發表 2 篇文章，以加強我們的真實世界證據。我們真正想做的是說它超越了 ALP 並且只是正常化或降低分數，這真的是關於對患者的長期影響是什麼？我們是目前新的二線產品中唯一的人，不打折。

But in the second-line market, we are the only ones with that data, and it is important, and we are repeating the data in multiple studies, and that gives credibility and credence to what we are able to communicate and generate. And in that commitment to this space, we will continue to move the goalpost. Again, impacts lives, not labs. We have the ability to still call on these folks if we have a future NASH launch. We're in there day in and day out. And we're also strongly engaged with patient organizations with the groups that are making guidelines, et cetera, so we feel we have a lot of game and growth as is evidenced by our accelerating growth in the second half.

但在二線市場，我們是唯一擁有這些數據的人，這很重要，我們在多項研究中重複這些數據，這為我們能夠交流和生成的內容提供了可信度和可信度。在對這個空間的承諾中，我們將繼續移動球門柱。同樣，影響生活，而不是實驗室。如果我們將來推出 NASH，我們仍然有能力拜訪這些人。我們日復一日地在那裡。我們還與製定指南的團體等患者組織密切合作，因此我們覺得我們有很多遊戲和增長，下半年我們的加速增長就證明了這一點。

Our plan is to carry that forward into the year.

我們的計劃是將其推進到今年。

Our next question comes from the line of Jay Olson with Oppenheimer.

我們的下一個問題來自 Jay Olson 和 Oppenheimer 的對話。

Congrats on the progress. I'm curious about the fresh trial for INT-787. It says on clinicaltrials.gov that patients must participate in alcohol use disorder program. So will patients be allowed to consume alcohol during the study? And if so, how do you plan to manage alcohol consumption and the potential impact that could have on the trial outcomes?

祝賀進步。我對 INT-787 的新試用感到好奇。它在 clinicaltrials.gov 上說，患者必須參加酒精使用障礙計劃。那麼患者是否可以在研究期間飲酒？如果是這樣，您打算如何管理飲酒以及可能對試驗結果產生的潛在影響？

Michelle?

米歇爾？

Yes. It's a great question. As we were designing this study, we worked with many of the centers across the U.S., U.K. and France really experts in this area. And what we have found is that it's really critical for outcomes for these patients to commit to being an outpatient program immediately after their release from the hospital.

是的。這是一個很好的問題。在設計這項研究時，我們與美國、英國和法國的許多中心合作，這些中心都是該領域的真正專家。我們發現，對於這些患者來說，在他們出院後立即承諾成為門診計劃對結果非常關鍵。

So the trial is focused on hospitalized patients, of course, but then they would continue for their follow-up in this outpatient program. We do find that patients in general don't consume alcohol within the first couple of months after release from the hospital, it's I think -- special period in that recovery, certainly after that, we do see recidivism, but we are working, again, closely with these centers who have expertise in treating these patients and in maximizing the -- their retention in the trial and making sure that -- these have lost to follow up patients because of recidivism early.

因此，當然，該試驗的重點是住院患者，但隨後他們將繼續在該門診計劃中進行隨訪。我們確實發現一般患者在出院後的頭幾個月內不會飲酒，我認為這是康復的特殊時期，當然在那之後，我們確實看到了再犯，但我們正在努力，再次，與這些中心密切合作，他們在治療這些患者方面具有專業知識，並最大限度地提高了--他們在試驗中的保留率並確保--這些中心由於早期的再犯而失去了跟進患者。

Our next question comes from the line of Salveen Richter with Goldman Sachs.

我們的下一個問題來自高盛的 Salveen Richter。

This is (inaudible) for Salveen. You referred to this briefly in the past. So how are you thinking about the product market fit for OCA given the data demonstrating greater efficacy in that 3 patients compared to F2 patients in NASH as well as given the data from emerging treatments like the ones from Medical.

這是（聽不清）Salveen 的。您過去曾簡要提到過這一點。那麼，鑑於數據顯示與 NASH 中的 F2 患者相比，這 3 名患者的療效更高，以及來自 Medical 等新興療法的數據，您如何看待適合 OCA 的產品市場。

Yes. So I can start on this and just make sure I got the question correctly. I understand the question kind of positioning given our stronger efficacy in F3s in the context of other data being out there. I mean, I think -- look, we continue to do all the deep work in market and continue to confirm the understanding that this incremental efficacy that we see in the advanced population is an important part of the overall value proposition.

是的。所以我可以從這個開始，確保我答對了問題。考慮到我們在其他數據存在的情況下在 F3s 中的更強效能，我理解這種定位問題。我的意思是，我認為——看，我們繼續在市場上做所有深入的工作，並繼續確認我們在高級人群中看到的這種增量功效是整體價值主張的重要組成部分。

We also know that, look, there are different mechanisms of action at play here between OCA where you have clearly consistent antifibrotic effect and other drugs that might be working differently. So again, I think everything we learn in an updated context, including consideration of other potential profiles that are out there confirm that the unmet need is high overall. The unmet need is most pronounced in these more advanced populations and that the well-known profile of OCA plays to that more advanced population.

我們還知道，您看，OCA 和其他可能具有不同作用的藥物之間有不同的作用機制，您具有明顯一致的抗纖維化作用。因此，我再次認為，我們在更新的環境中學到的一切，包括考慮其他潛在的概況，證實了總體上未滿足的需求很高。未滿足的需求在這些更先進的人群中最為明顯，而眾所周知的 OCA 形像對這些更先進的人群起到了作用。

Of course, there is an asymmetry of information available. So we know a lot about OCA in the context of all the safety and efficacy we've put out. The profile of other emerging therapies, as you would expect, are -- there's less information, particularly when we consider the longer-term experience that we now have with OCA. And importantly, when we think about the improved -- the benefit-risk profile of OCA that we believe we have from the first submission.

當然，可用的信息是不對稱的。因此，在我們推出的所有安全性和有效性的背景下，我們對 OCA 了解很多。正如您所期望的那樣，其他新興療法的概況是——信息較少，特別是當我們考慮我們現在對 OCA 的長期經驗時。重要的是，當我們考慮改進時——我們相信我們從第一次提交時就擁有的 OCA 的收益-風險概況。

One of the important dimensions is that longer-term safety experience where we believe we have the opportunity both in the regulatory dialogue and ultimately, hopefully, in market to talk about appropriate chronic therapy, the right guidance around what to measure and monitor over time. And again, I think it speaks well to that more advanced population. So look, the unmet need in NASH is high. I guess just the last point I would stress is -- in any chronic class, and clearly, NASH will be over time, an important chronic class of therapy, it always takes multiple drugs to address the different segments of patients that are out there, and we're working towards defining the right introductory approach and the right segments for success for OCA and for the patients who have this high level of unmet needs.

一個重要的方面是長期的安全經驗，我們相信我們有機會在監管對話中以及最終希望在市場上討論適當的慢性治療，以及關於隨著時間的推移測量和監測的正確指導。再一次，我認為這對更先進的人群來說很好。所以看，NASH 中未滿足的需求很高。我想我要強調的最後一點是——在任何慢性類別中，很明顯，NASH 將隨著時間的推移而成為一種重要的慢性治療類別，它總是需要多種藥物來解決不同的患者群體，我們正在努力為 OCA 和具有如此高水平未滿足需求的患者確定正確的介紹性方法和正確的部分。

Our next question comes from the line of Eliana Merle with UBS.

我們的下一個問題來自瑞銀集團的 Eliana Merle。

Just in terms of the NASH commercial landscape, you mentioned there's a large number of undiagnosed patients. I guess what trends have you been seen recently on the horizon as potential initial therapies approved. And on the topic of reimbursement and diagnosis, I guess, as you do your pre-commercial conversations with payers, what feedback are you getting in terms of what they will view as a NASH diagnosis and any types of potential restrictions or step-throughs from the payer conversations, just given the potential for us to be able to this class and say, potential biopsies or any other types of sectors that might be needed or adjusted by payers?

就 NASH 的商業前景而言，你提到有大量未確診的患者。我猜想隨著潛在的初始療法獲得批准，您最近看到了哪些趨勢。關於報銷和診斷的話題，我想，當你與付款人進行商業前對話時，你會得到什麼反饋，他們會認為什麼是 NASH 診斷，以及任何類型的潛在限製或步驟付款人的談話，只是考慮到我們有可能在這堂課上說，潛在的活檢或付款人可能需要或調整的任何其他類型的部門？

Yes. Maybe a couple of dynamics to have in mind, Eliana thank you for the question. As I indicated earlier, obviously, we're doing all of the in-depth work. And look, our plan would be to come back with more details on the commercial plan in a formal way when we get closer to PDUFA.

是的。也許要記住一些動態，Eliana 謝謝你提出這個問題。正如我之前指出的，顯然，我們正在做所有深入的工作。看，我們的計劃是在我們接近 PDUFA 時以正式的方式返回更多關於商業計劃的細節。

Nonetheless, I think there are a couple of key themes which continue to play out. One is that we continue to see the utilization of noninvasives overall move in the right direction, right? There's good momentum there. There is a larger utilization of the variety of different noninvasives for identifying patients. And the payers do understand this dynamic and are monitoring the progress and are looking for the right ways to identify patients consistent with what the KOLs are saying and what clinical practices, which is clearly utilizations of noninvasives.

儘管如此，我認為有幾個關鍵主題將繼續發揮作用。一是我們繼續看到無創技術的整體使用朝著正確的方向發展，對嗎？那裡的勢頭很好。各種不同的非侵入性技術在識別患者方面得到了更大的利用。付款人確實了解這種動態並正在監控進展，並正在尋找正確的方法來識別與 KOL 所說的和臨床實踐相一致的患者，這顯然是無創技術的利用。

I think with the payers, one of the themes which has been really important and productive for us is that we're talking in the early discussions with the payers about a subset of our potential indication, right? We're talking about the more advanced population. We're talking about working together to find a way to find the right patients. And one of the big payer concerns is always utilization beyond your indication.

我認為與付款人一起，對我們來說非常重要和富有成效的主題之一是我們在與付款人的早期討論中討論了我們潛在適應症的一部分，對嗎？我們談論的是更先進的人口。我們正在談論共同努力尋找找到合適患者的方法。付款人最關心的問題之一是使用率總是超出您的指示。

So it's a great starting point that we're talking about the more advanced population and actually identification of a subset of our indication. And I think that gives us a good productive discussion. Of course, as I said, this will be an ongoing dialogue with the payers, and we'll come back with more details as we get closer to finalization of the strategy. And just the last point, of course, our final decision on price, et cetera, will be taken with approval, and we would communicate that as one of the last pieces in the equation.

因此，這是一個很好的起點，我們正在談論更先進的人群並實際識別我們的適應症的一個子集。我認為這讓我們進行了富有成效的討論。當然，正如我所說，這將是與付款人的持續對話，隨著我們接近戰略的最終確定，我們會回來提供更多細節。當然，最後一點，我們對價格等的最終決定將得到批准，我們會將其作為等式中的最後一部分進行傳達。

The only thing I might add to that, Ellie, is at this point, unlike 4 or 5 years ago when we were talking about initial payer discussions, the idea and the acceptance of NIT is also broader. So that plays into people trying to get to an easier path on the expense and the time and frankly, the pain per patient of biopsy.

Ellie，我唯一要補充的是，在這一點上，與 4 或 5 年前我們談論初始付款人討論時不同，NIT 的想法和接受度也更廣泛。因此，這會影響人們試圖在費用和時間上找到更簡單的途徑，坦率地說，每個活檢患者的痛苦。

So I really feel like that is an advancement from where we were before and should help with different -- the expansion of NITs being available and access to different ways to find appropriate advanced patients really has moved significantly from our earlier work.

所以我真的覺得這是我們以前的進步，應該有助於不同的 - NIT 可用的擴展和使用不同的方法來尋找合適的晚期患者確實與我們早期的工作有了很大的不同。

Our next question comes from the line of Jeff Meacham with Bank of America.

我們的下一個問題來自美國銀行的 Jeff Meacham。

This is Susan on for Jeff. Given the company's stronger cash position, are there any interesting external business development opportunities? And if external business development isn't on the books this year, which internal programs do you expect to accelerate instead?

這是傑夫的蘇珊。鑑於公司更強的現金狀況，是否有任何有趣的外部業務發展機會？如果今年沒有外部業務發展，您希望加速哪些內部項目？

Yes. So as you can imagine, we're always looking for externally for good opportunities, but we're also making sure that we're managing the cash we have on hand appropriately given the work that we're trying to do and funding the important internal programs that we discussed some this morning, INT-787, with a lead indication ongoing.

是的。所以你可以想像，我們總是在外部尋找好的機會，但我們也確保我們正在適當地管理我們手頭的現金，因為我們正在努力做的工作和資助重要的事情我們今天早上討論的一些內部計劃，INT-787，有一個領先的跡象正在進行中。

And importantly, the long-term next-generation in PBC for the fixed-dose combination will be our primary focus. We're also looking for additional indications for both of those internal assets should it -- should it make sense. So we'll continue to evolve the pipeline in the right way while we also make sure that we're focusing our cash and on our investment on the growth drivers.

重要的是，固定劑量組合在 PBC 中的長期下一代將是我們的主要關注點。我們還在尋找這兩種內部資產的其他跡象——如果有意義的話。因此，我們將繼續以正確的方式發展管道，同時我們還要確保我們將現金和投資集中在增長動力上。

Our next question is the follow-up from Mayank Mamtani with B. Riley Securities.

我們的下一個問題是 Mayank Mamtani 與 B. Riley Securities 的後續行動。

So maybe just one more NASH NDA review question. Has there been any indication for biopsy endpoint definition changing or being mechanism specific, et cetera? Anything that to suggest that agency might be looking to go beyond the scope of their 2018 draft guidance document, Michelle.

所以也許只是一個 NASH NDA 審查問題。是否有跡象表明活檢終點定義發生變化或機制特定等？任何表明該機構可能正在尋求超出其 2018 年指導文件草案 Michelle 範圍的內容。

Michelle.

米歇爾。

Well, as Linda was speaking too, we have seen a lot of interest and some great publications now coming out on the noninvasive tests. I think it's recognized certainly by the community and by the GI division that both patients and providers would really look for an alternative to biopsy. Really the only reason foster getting a liver biopsy is to participate in clinical trials. Having said that, we have relied on histology for decades. In viral hepatitis and now in NASH, and that is our agreement with the agency that this planned interim analysis would focus on histology.

好吧，正如 Linda 所說，我們已經看到很多關於無創測試的興趣和一些很棒的出版物。我認為社區和 GI 部門肯定會認識到，患者和提供者都會真正尋找活檢的替代方法。實際上，進行肝活檢的唯一原因是參與臨床試驗。話雖如此，我們幾十年來一直依賴組織學。在病毒性肝炎和現在的 NASH 中，這是我們與該機構的協議，即計劃中的中期分析將側重於組織學。

We're confident that the histology results that we've seen now with 2 independent analyses confirm our antifibrotic benefit, and we're excited about that opportunity to discuss it with the agency at upcoming opportunities. So I think it does remain draft guidance as you point out though. So as more data are being reviewed we may see some modifications to that, but we are confident in our submission and our analyses that have been submitted with the NDA. Thanks for the question.

我們相信，我們現在通過 2 項獨立分析看到的組織學結果證實了我們的抗纖維化益處，我們很高興有機會在即將到來的機會中與該機構討論它。所以我認為它確實仍然是你指出的指導草案。因此，隨著更多數據的審查，我們可能會看到一些修改，但我們對我們提交的材料和與 NDA 一起提交的分析充滿信心。謝謝你的問題。

And now I will turn the call back over to Jerry for closing remarks. Jerry?

現在我將把電話轉回給 Jerry 以作結束語。傑瑞？

So thanks, everybody, for joining us today. Just to reiterate, I'm really extremely proud of the performance that the Intercept team delivered both in the fourth quarter and for the year of 2022. We clearly have a lot of work ahead of us, but I think the achievements that we've discussed this morning, set us up to drive continued long-term growth for Intercept. And I definitely look forward to sharing updates as we progress through what is an important and exciting year ahead. So thanks, and everybody, have a great day.

所以感謝大家今天加入我們。重申一下，我為 Intercept 團隊在第四季度和 2022 年的表現感到非常自豪。顯然我們還有很多工作要做，但我認為我們取得的成就今天早上討論過，讓我們為推動 Intercept 的持續長期增長做好準備。我非常期待在我們度過重要而激動人心的一年時分享最新消息。所以謝謝大家，祝你有美好的一天。

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

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。