Ironwood Pharmaceuticals Inc (IRWD) 2024 Q1 法說會逐字稿

Thank you for standing by. My name is Kath, and I will be your conference operator today. At this time, I would like to welcome everyone to the Ironwood Pharmaceuticals first-quarter 2024 investor update call. (Operator Instructions)

謝謝你的支持。我叫凱絲，今天我將擔任你們的會議操作員。此時此刻，我歡迎大家參加 Ironwood Pharmaceuticals 2024 年第一季投資者更新電話會議。（操作員說明）

I would now like to turn the call over to Matt Roache, Director of Investor Relations. Please go ahead.

我現在想將電話轉給投資者關係總監 Matt Roache。請繼續。

Thank you, Kath. Good morning, and thanks for joining us for our first-quarter 2024 investor update. Our press release issued this morning can be found on our website.

謝謝你，凱絲。早安，感謝您接受我們的 2024 年第一季投資者更新。我們今天早上發布的新聞稿可以在我們的網站上找到。

Today's call and accompanying slides include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements involve risks and uncertainties that may cause actual results to differ materially. A discussion of these statements and risk factors is available on the current Safe Harbor statement slide as well as under the heading Risk Factors in our annual report on Form 10-K for the year ended December 31, 2023, and in our subsequent SEC filings. All forward-looking statements speak as of the date of this presentation, and we undertake no obligation to update such statements.

今天的電話會議和隨附的幻燈片包含 1995 年《私人證券訴訟改革法案》含義內的前瞻性陳述。此類陳述涉及風險和不確定性，可能導致實際結果有重大差異。有關這些聲明和風險因素的討論可在當前的安全港聲明幻燈片以及我們截至 2023 年 12 月 31 日的 10-K 表格年度報告以及我們隨後提交給 SEC 的文件中的風險因素標題下找到。所有前瞻性陳述均截至本簡報發布之日，我們不承擔更新此類陳述的義務。

Also included are non-GAAP financial measures which should be considered only as a supplement to, not a substitute for or superior to GAAP measures. To the extent applicable, please refer to the tables at the end of our press release for reconciliations of these measures to the most directly comparable GAAP measures.

還包括非 GAAP 財務指標，這些指標僅應被視為 GAAP 指標的補充，而不是替代或優於 GAAP 指標。在適用的範圍內，請參閱我們新聞稿末尾的表格，以了解這些指標與最直接可比較的公認會計準則指標的對帳情況。

During today's call, Tom McCourt, our Chief Executive Officer, will begin with a brief overview; Mike Shetzline, our Chief Medical Officer, will discuss our pipeline; and Sravan Emany, our Chief Financial Officer, will provide a commercial update and review our financial results and guidance. Today's webcast includes slides. So for those of you dialing in, please go to the Events section of our website to access the accompanying slide separately.

在今天的電話會議上，我們的執行長湯姆·麥考特 (Tom McCourt) 將首先進行簡要概述；我們的首席醫療官 Mike Shetzline 將討論我們的產品線；我們的財務長 Sravan Emany 將提供商業更新並審查我們的財務表現和指導。今天的網路廣播包括幻燈片。因此，對於撥打電話的人，請前往我們網站的「活動」部分，並單獨訪問隨附的幻燈片。

With that, I'll turn the call over to Tom.

這樣，我就把電話轉給湯姆。

Thanks, Matt. Good morning, everyone, and thanks for joining us. We are pleased to be here to discuss our significant advancements that we've made across our portfolio so far this year and our mission to become the leading GI healthcare company. I always like to start with the three strategic priorities which are: maximize LINZESS, advance our GI pipeline, and deliver sustained profits and cash flow.

謝謝，馬特。大家早安，感謝您加入我們。我們很高興能在這裡討論今年迄今為止我們在產品組合中取得的重大進步，以及我們成為領先的胃腸道醫療保健公司的使命。我總是喜歡從三個策略重點開始：最大化 LINZESS、推進我們的 GI 管道以及提供持續的利潤和現金流。

In the first quarter of 2024, LINZESS maintained its strong demand momentum with prescription volume increasing 10% year over year, supported by a robust new-to-brand prescription growth of 18% versus the prior year, marking the fifth consecutive quarter of double-digit new-to-brand growth.

2024 年第一季度，LINZESS 保持強勁的需求勢頭，處方量同比增長 10%，新品牌處方量較上一年強勁增長 18%，這標誌著林澤連續第五個季度實現雙倍增長。成長數字。

As you may have seen in our press release this morning, based on information provided by AbbVie, we recorded an adjustment to the first quarter collaborative arrangement revenue as a result of a gross-to-net change in estimate for LINZESS related to the year ended December 31, '23, which led to our revised full-year '24 outlook. Sravan will provide more detail on the impact of this one-time adjustment later on the call.

正如您今天早上在我們的新聞稿中看到的那樣，根據艾伯維(AbbVie) 提供的信息，我們記錄了對第一季度合作安排收入的調整，這是由於LINZESS 與截至年底相關的估計的總淨額變動所致2023 年 12 月 31 日，我們修訂了 24 年全年展望。斯拉萬稍後將在電話會議上提供有關此一次性調整影響的更多細節。

Moving to our pipeline. We made important progress across our development programs in the quarter. Most notably, we believe we have transformed our company with a positive topline results in February from the Phase III STARS trial, evaluating the efficacy and safety of apraglutide in patients with short bowel syndrome with intestinal failure. These positive Phase III results demonstrate the potential of apraglutide as the first and only weekly GLP-2 therapy for the treatment of adults with short bowel syndrome who are dependent on parenteral support, if approved.

轉向我們的管道。本季我們的開發計劃取得了重要進展。最值得注意的是，我們相信我們已經透過2 月份III 期STARS 試驗的積極頂線結果改變了我們的公司，該試驗評估了阿普拉魯肽對患有腸衰竭的短腸綜合徵患者的有效性和安全性。這些積極的 III 期結果表明，如果獲得批准，阿普拉魯肽有可能成為第一個也是唯一一個每週一次的 GLP-2 療法，用於治療依賴腸外支持的成人短腸綜合徵。

Following the topline results shared in late February, we have continued to analyze a robust data set of the STARS Phase III, and new data was submitted as a late breaking abstract and selected for an oral presentation at the upcoming Digestive Disease Meeting. These data further strengthen the clinical profile of apraglutide, which we're eager to share with the broader GI medical and scientific community.

繼 2 月底分享的主要結果之後，我們繼續分析 STARS III 期的強大數據集，新數據作為最新摘要提交，並選擇在即將舉行的消化疾病會議上進行口頭報告。這些數據進一步強化了阿普拉魯肽的臨床概況，我們渴望與更廣泛的胃腸道醫學和科學界分享。

Based on the combination of demonstrated efficacy, tolerability, and once weekly dosing, we are confident that apraglutide has a high probability of approval. We believe these three distinguishing factors will drive uptake, compliance, and improvement in quality of life for patients, reinforcing our belief that apraglutide has the potential to achieve $1 billion in peak net sales.

基於已證實的療效、耐受性和每週一次給藥的結合，我們相信阿普拉魯肽獲得批准的可能性很高。我們相信這三個顯著因素將推動患者的使用、依從性和生活品質的改善，從而增強我們對阿普拉魯肽有潛力實現 10 億美元峰值淨銷售額的信念。

We are now focused on ensuring a successful path forward to commercialization, an area where we have significant expertise and a track record of success. We are working swiftly and plan to file the NDA as soon as possible with a label focused on adult SBS patients who are dependent on parenteral support and continue to expect a commercial launch in 2025.

我們現在專注於確保商業化的成功之路，我們在這一領域擁有豐富的專業知識和成功的記錄。我們正在迅速開展工作，並計劃盡快提交新藥申請 (NDA)，其標籤重點關注依賴腸外支持的成年 SBS 患者，並預計在 2025 年繼續上市。

We estimate that there's approximately 17,000 adult patients across the United States and Europe, who suffer from short bowl syndrome with intestinal failure, with a significant portion of these patients still untreated by GLP-2s. We have the commercial infrastructure already in place and expect only incremental investments needed to launch apraglutide successfully.

我們估計，美國和歐洲大約有 17,000 名成年患者患有伴有腸衰竭的短碗綜合徵，其中很大一部分患者仍未接受 GLP-2 治療。我們已經擁有商業基礎設施，預計只需增量投資即可成功推出阿普拉魯肽。

We are well on our way with the launch planning and believe we are equipped to commercialize apraglutide, if approved, with a strong sales presence already established in the offices of GI specialists across the United States. We are confident the positive results from the STARS trial coupled with our proven track record of effective commercial execution position us uniquely in the market. We're excited to leverage our expertise to maximize the potential for apraglutide and drive meaningful impactful outcomes for patients with short bowel syndrome who are dependent on parenteral support.

我們的上市計劃進展順利，相信如果獲得批准，我們有能力將阿普拉魯肽商業化，並且已經在美國各地的地理標誌專家辦公室建立了強大的銷售網絡。我們相信 STARS 試驗的積極結果，加上我們在有效商業執行方面的良好記錄，使我們在市場上處於獨特地位。我們很高興能夠利用我們的專業知識最大限度地發揮阿普拉魯肽的潛力，並為依賴腸外支持的短腸綜合徵患者帶來有意義的影響結果。

So to wrap up, we are poised for future growth for the following reasons: First, LINZESS continues to deliver robust demand growth and is driving meaningful cash flows for Ironwood, which we expect to continue until generic entry in 2029. Second, we believe we have transformed our company with a positive Phase III results from the STARS trial, which reinforce our conviction in apraglutide's high probability of approval and long-term revenue and profit growth potential.

總而言之，我們為未來的成長做好了準備，原因如下：首先，LINZESS 繼續帶來強勁的需求成長，並為Ironwood 帶來有意義的現金流，我們預計這種情況將持續到2029 年仿製藥上市。其次，我們相信我們已經透過 STARS 試驗的第三階段積極結果實現了公司轉型，這增強了我們對阿普拉魯肽獲得批准的高機率以及長期收入和利潤成長潛力的信心。

Finally, we're excited to see the Phase II topline results from CMP-104 later this year. We believe CMP-104 has the potential to be a disease-modifying therapy for the treatment of primary biliary cholangitis.

最後，我們很高興在今年稍後看到 CMP-104 的 II 期頂線結果。我們相信 CMP-104 有潛力成為治療原發性膽汁性膽管炎的疾病緩解療法。

With that, I'll hand it over to Mike to discuss apraglutide and our pipeline in more detail. Mike?

接下來，我將把它交給 Mike 來更詳細地討論阿普拉魯肽和我們的產品線。麥克風？

Thanks, Tom, and good morning, everyone. We're pleased with the progress we made across our pipeline programs in the first quarter.

謝謝，湯姆，大家早安。我們對第一季管道項目的進展感到滿意。

I'll begin with apraglutide for short bowel syndrome in patients dependent on parenteral support. We're very proud of the positive results from the pivotal global Phase III STARS study which is the largest ever GLP-2 trial in short bowel syndrome with intestinal failure, generating a robust data set across 68 sites and 18 countries. An important aspect of the STARS Phase III study design was the rigorous optimization of parenteral support volumes prior to treatment. That resulted in a low placebo rate which in turn generated a robust treatment effect for apraglutide in this patient population.

我將從阿普拉魯肽開始治療依賴腸外支持的患者的短腸症候群。我們對關鍵的全球III 期STARS 研究取得的積極結果感到非常自豪，該研究是有史以來最大規模的短腸綜合徵合併腸衰竭的GLP-2 試驗，在18 個國家的68 個地點生成了可靠的數據集。STARS III 期研究設計的一個重要面向是治療前嚴格優化腸外支持量。這導致安慰劑率較低，反過來又在該患者群體中產生了阿普拉魯肽的強勁治療效果。

Apraglutide is the only once weekly GLP-2 to meet its primary endpoint of relative change from baseline in actual weekly parenteral sport volume at week 24 with a 2 times treatment effect relative to placebo, driven by both stoma and colon in continuity populations. As a clinician myself, I'm thrilled about apraglutide's strong profile, including the convenience of once weekly administration and its potential to benefit a patient community in need of new treatment options.

阿普拉魯肽是唯一每週一次的GLP-2，其主要終點是第24 週時實際每週腸外運動量相對於基線的相對變化，相對於安慰劑，治療效果是安慰劑的2 倍，這是由連續性群體中的造口和結腸驅動的。作為一名臨床醫生，我對阿普拉魯肽的強大優勢感到興奮，包括每週一次給藥的便利性及其造福需要新治療方案的患者群體的潛力。

Summarized on slide 9, I'm excited by the demonstrated efficacy in the primary endpoint in both stoma and colon in continuity patient populations at 24 weeks. With further analysis of the data, we're also excited by the rapid onset of treatment effect observed at week 8 and onward throughout the study. The fact that some patients in both stoma and colon in continuity populations reached enteral autonomy or a complete weaning off of parenteral support and the low prevalence of reported injection site reactions and abdominal distension, which are in line with placebo.

在投影片 9 中進行了總結，我對 24 週連續患者群體中造口和結腸的主要終點所顯示的功效感到興奮。透過對數據的進一步分析，我們也對在整個研究過程中第 8 週及之後觀察到的治療效果的快速起效感到興奮。事實上，連續人群中造口和結腸中的一些患者達到了腸內自主或完全脫離腸外支持，並且報告的注射部位反應和腹脹的發生率較低，這與安慰劑一致。

Overall, we believe apraglutide's differentiated profile, including its demonstrated efficacy and tolerability and convenience of once weekly dosing support our belief in apraglutide's high probability of approval and potential to improve the standard of care for patients with short bowel syndrome who are dependent on parenteral support.

總體而言，我們相信阿普拉魯肽的差異化特徵，包括其已證實的療效、耐受性以及每週一次給藥的便利性，支持我們相信阿普拉魯肽獲得批准的可能性很高，並且有可能改善依賴腸外支持的短腸綜合徵患者的護理標準。

We're very much looking forward to the upcoming DDW meeting and presenting data, which we believe further supports and enhances the clinical profile of apraglutide. We also look forward to continuing to evaluate the robust data set from the largest ever GLP-2 study in short bowel syndrome with intestinal failure, and plan to disclose further findings at additional meetings later this year.

我們非常期待即將舉行的 DDW 會議並展示數據，我們相信這將進一步支持和增強阿普拉魯肽的臨床概況。我們也期待繼續評估有史以來最大規模的短腸症候群合併腸衰竭 GLP-2 研究的可靠數據集，並計劃在今年稍後的其他會議上披露進一步的研究結果。

In addition to the positive Phase III results from apraglutide in short bowel syndrome with intestinal failure, we also announced positive results from our exploratory STARGAZE trial of apraglutide in patients with steroid refractory gastrointestinal acute graft-versus-host disease. The primary objective of the trial was to evaluate the safety and tolerability of once weekly apraglutide in steroid refractory acute GVHD patients treated with standard of care.

除了阿普拉魯肽治療短腸症候群伴隨腸衰竭的III 期陽性結果外，我們還宣布了阿普拉魯肽在類固醇難治性胃腸道急性移植物抗宿主病患者中的探索性STARGAZE試驗的陽性結果。該試驗的主要目的是評估每週一次的阿普拉魯肽在接受標準護理治療的類固醇難治性急性 GVHD 患者中的安全性和耐受性。

Results up to day 91 showed that apraglutide in acute GVHD was well tolerated with an acceptable safety profile, the study's primary objective. In addition to evaluating safety, secondary endpoints assessed efficacy via lower GI and all organ responses. The majority of patients responded to treatment by day 28 and day 56, all lower GI responders at day 28 maintained their response through day 56 and 91.

截至第 91 天的結果表明，阿普拉魯肽在急性 GVHD 中的耐受性良好，具有可接受的安全性，這是該研究的主要目標。除了評估安全性外，次要終點還透過較低的胃腸道反應和所有器官反應來評估療效。大多數患者在第 28 天和第 56 天對治療有反應，所有較低胃腸道反應者在第 28 天都保持其反應直至第 56 天和第 91 天。

We're encouraged by the data on safety, tolerability, and maintenance of response and expect to present additional data at a future medical congress. The STARGAZE study will continue through its two-year endpoint when apraglutide will be evaluated for safety and efficacy.

我們對安全性、耐受性和反應維持方面的數據感到鼓舞，並期望在未來的醫學大會上提供更多數據。STARGAZE 研究將持續到兩年終點，屆時將評估阿普拉魯肽的安全性和有效性。

Moving to CNP-104 on slide 10. In the first quarter, COUR completed patient enrollment for the Phase II proof-of-concept study in patients with PBC and are on track to report topline results in the third quarter of this year. The CNP-104 Phase II study is a 42-patient, placebo-controlled study evaluating the safety, tolerability, pharmacodynamics, and efficacy of CNP-104 in patients with PBC who are unresponsive to UDCA and/or Ocaliva. Top prime results will be based on data through day 120 of treatment.

前往投影片 10 上的 CNP-104。第一季度，COUR 完成了針對 PBC 患者的 II 期概念驗證研究的患者入組，並預計在今年第三季度報告主要結果。CNP-104 II 期研究是一項 42 名患者參與的安慰劑對照研究，評估 CNP-104 對 UDCA 和/或 Ocaliva 無反應的 PBC 患者的安全性、耐受性、藥效學和療效。最佳主要結果將基於治療第 120 天的數據。

The strong immunology underpinning the CNP program is focused on targeting the specific PDC-E2 antigen and responsible for the T cell driven pathology of PBC. Last year, we saw early data showing favorable PDC-E2 specific T cell responses in patients treated with CNP-104. In the topline results anticipated in the third quarter, we're looking for a demonstrated T cell response, which we believe is a leading indicator of clinical benefit.

支持 CNP 計畫的強大免疫學重點是針對特定的 PDC-E2 抗原，並負責 T 細胞驅動的 PBC 病理學。去年，我們看到早期數據顯示接受 CNP-104 治療的患者俱有良好的 PDC-E2 特異性 T 細胞反應。在第三季預期的主要結果中，我們正在尋找已證實的 T 細胞反應，我們認為這是臨床效益的領先指標。

The study will also evaluate several markers of liver function, a positive signal on liver function markers in addition to the T cell response could further support the potential for CNP-104. We believe CNP-104 has the potential to be the first disease modifying therapy for patients suffering with PBC as there are no therapies on the market today that address the root cause of the T cell-driven immune destruction of the liver bile ducts.

該研究還將評估幾種肝功能標記物，除了 T 細胞反應之外，肝功能標記的陽性訊號可以進一步支持 CNP-104 的潛力。我們相信 CNP-104 有潛力成為針對 PBC 患者的第一種疾病修飾療法，因為目前市面上沒有任何療法可以解決 T 細胞驅動的肝膽管免疫破壞的根本原因。

With that, I'll turn it over to Sravan.

這樣，我就把它交給 Sravan。

Thanks, Mike, and good morning, everyone. I'll begin on slide 12. As Tom mentioned earlier, LINZESS carried the positive demand momentum into the first quarter. This is now the 12th year on market for LINZESS. And as you can see, prescription demand remains remarkably strong. LINZESS volume rose 10% year-over-year in the first quarter, while new-to-brand prescriptions increased 18% compared with the first quarter of 2023, reinforcing that patients and healthcare professionals continue to choose LINZESS.

謝謝麥克，大家早安。我將從幻燈片 12 開始。正如 Tom 之前提到的，LINZESS 將積極的需求動能帶入了第一季。今年是 LINZESS 上市的第 12 年。正如您所看到的，處方藥需求仍然非常強勁。第一季 LINZESS 銷售量年增 10%，而新品牌處方量較 2023 年第一季度增長 18%，這強化了患者和醫療保健專業人員繼續選擇 LINZESS。

We believe the strong demand momentum and success of LINZESS will continue as a result of high treatment satisfaction with both patients and healthcare professionals, combined with increased utility from the pediatric syndication, class-leading formulary access, guideline recommendations, focused commercial execution, and new patient start acceleration.

我們相信，由於患者和醫療保健專業人員對治療的高度滿意，再加上兒科聯合組織的效用不斷增加、一流的處方集獲取、指南建議、專注的商業執行和新產品，LINZESS 的強勁需求勢頭和成功將持續下去。

I'd like to take a moment to provide additional details on the LINZESS gross-to-net change in estimate that was reflected in the first quarter of 2024 on slide 13. In the first quarter, AbbVie reported US net sales of $257 million, an increase of 3% year over year. Based on information subsequently provided by AbbVie, Ironwood estimates a $60 million adjustment to LINZESS US net sales, representing the difference between AbbVie's gross-to-net estimates made in 2023 and actual subsequent payments made.

我想花點時間提供有關幻燈片 13 中 2024 年第一季反映的 LINZESS 總淨值變化的更多詳細資訊。艾伯維第一季美國淨銷售額為2.57億美元，年增3%。根據艾伯維隨後提供的信息，Ironwood 預計 LINZESS 美國淨銷售額將調整 6000 萬美元，這代表了艾伯維 2023 年毛淨額預估與後續實際付款之間的差異。

As a result of this change in estimate, Ironwood recorded a $30 million reduction to collaborative arrangements revenue. With this adjustment, total Ironwood revenue in the first quarter was approximately $75 million, down 28% year over year.

由於這項預估變化，Ironwood 的合作安排收入減少了 3,000 萬美元。經過此次調整，Ironwood 第一季總營收約 7,500 萬美元，較去年同期下降 28%。

Turning to our first-quarter financial performance on slide 14. Q1 LINZESS US net sales, as reported by AbbVie, were $257 million, an increase of 3% year over year. LINZESS' commercial margin, excluding the gross-to-net change in estimate, was 71% in the first quarter of 2024 compared to 73% in the first quarter of 2023.

轉向投影片 14 上我們第一季的財務表現。根據艾伯維 (AbbVie) 報告，LINZESS 美國第一季淨銷售額為 2.57 億美元，較去年同期成長 3%。不包括估計的毛淨變化，LINZESS 2024 年第一季的商業利潤率為 71%，而 2023 年第一季為 73%。

As I noted a few moments ago, Ironwood revenue was $75 million, driven primarily by US LINZESS collaboration revenue of $72 million. Revenues in Q1 were lower year over year primarily due to the $30 million change in estimate recorded to collaborative arrangements revenue.

正如我剛才指出的，Ironwood 收入為 7500 萬美元，主要由美國 LINZESS 合作收入 7200 萬美元推動。第一季的營收年減，主要是由於合作安排收入的預估發生了 3,000 萬美元的變化。

As a result, GAAP net loss was $4 million, and adjusted EBITDA was $13 million. In the first quarter, Ironwood generated approximately $45 million in cash flow from operations, and ended the quarter with $122 million in cash and cash equivalents. After repaying $25 million of the outstanding principal balance on our revolving credit facility in cash.

結果，GAAP 淨虧損為 400 萬美元，調整後 EBITDA 為 1,300 萬美元。第一季度，Ironwood 的營運現金流量約為 4,500 萬美元，季度末現金及現金等價物為 1.22 億美元。以現金償還我們循環信貸額度的 2,500 萬美元未償本金餘額後。

As of the end of March, the outstanding drawn balance on the revolver was $275 million. In the near term, we continue to expect to settle our 2024 convertible notes that mature on June 15, through a combination of cash on hand and undrawn revolver capacity.

截至 3 月底，左輪手槍的未清支取餘額為 2.75 億美元。短期內，我們繼續預計透過手頭現金和未提取的循環能力的結合來結算將於 6 月 15 日到期的 2024 年可轉換票據。

Regarding capital allocation. We are in a fortunate position with meaningful cash flow generation for LINZESS, which we believe will be sufficient to fund all ongoing operations, and we do not anticipate the need to access the capital markets for incremental funding to support the potential apraglutide launch and further progress our development programs.

關於資本配置。我們很幸運，能夠為LINZESS 產生有意義的現金流，我們相信這將足以為所有正在進行的業務提供資金，並且我們預計不需要進入資本市場獲取增量資金來支持潛在的阿普拉魯肽上市並進一步進展我們的發展計劃。

Next, I'll review our updated 2024 guidance on slide 15. As a result of LINZESS' gross-to-net change in estimate in the first quarter for full-year 2024, we now expect LINZESS US net sales decline in the mid-single digits percent, Ironwood revenue of between $405 million and $425 million, and adjusted EBITDA of greater than $120 million.

接下來，我將回顧投影片 15 上更新的 2024 年指南。由於 LINZESS 對 2024 年全年第一季毛淨額預測的變化，我們現在預計 LINZESS 美國淨銷售額將出現中個位數百分比下降，Ironwood 收入在 4.05 億美元至 4.25 億美元之間，調整後的EBITDA 超過1.2 億美元。

To wrap up, we made significant advancements across our portfolio in the first quarter. We look forward to sharing additional detail from the apraglutide STARS Phase III study at Digestive Disease Week later this month, which we believe will further enhance its clinical profile of apraglutide. With the positive STARS data readout, we believe we are well on our way to diversifying our portfolio and extending our growth horizon beyond LINZESS.

總而言之，我們的投資組合在第一季取得了重大進展。我們期待在本月稍後的消化疾病週上分享阿普拉魯肽 STARS III 期研究的更多細節，我們相信這將進一步增強阿普拉魯肽的臨床概況。憑藉積極的 STARS 數據讀數，我們相信我們正在努力實現投資組合多元化，並將我們的成長視野擴展到 LINZESS 之外。

Looking ahead, we are focused on moving quickly to get apraglutide approved and to patients with SBS who are dependent on parenteral support as soon as possible and executing across our strategic priorities by advancing our other GI pipeline assets, driving robust LINZESS demand growth, and delivering sustained profits and cash flow. I want to close by thanking all of our employees, patients, caregivers, and advocates for their shared dedication to advancing and supporting therapies for GI diseases.

展望未來，我們的重點是快速行動，讓阿普拉魯肽獲得批准，並儘快為依賴腸外支持的SBS 患者提供服務，並透過推進我們的其他胃腸道管道資產、推動LINZESS 需求的強勁增長和交付來執行我們的策略重點。最後，我要感謝我們所有的員工、病人、照護人員和倡議者，感謝他們共同致力於推動和支持胃腸道疾病的治療。

Operator, you may now open up the line for questions.

接線員，現在可以撥打電話提問。

Thank you. We will now begin the question-and-answer session. (Operator Instructions) David Amsellem, Piper Sandler.

謝謝。我們現在開始問答環節。（操作說明）David Amsellem、Piper Sandler。

So a couple of questions here. I know you've got the data coming at DDW. But I just wanted to get some additional color on what you mean about efficacy across both stoma and colon-in-continuity patients. And I guess what I'm getting at is just within the CIC subgroup, is their statistical separation? I know what you had shown at 48 weeks, but is there statistical separation, say, at earlier time points, say, 24 weeks or 12 weeks?

這裡有幾個問題。我知道 DDW 已經收到了數據。但我只是想進一步了解您對造口和結腸連續患者的療效的含義。我想我所得到的只是在 CIC 子組內，他們的統計分離嗎？我知道你在 48 週時顯示的內容，但是是否有統計分離，例如，在更早的時間點，例如 24 週或 12 週？

So just help us understand that. And if you can't answer it, that's fine, but I thought I'd ask the question anyway. And then secondly, on 104, what do you have to see in order to move forward? Help us understand how you're thinking about the bar for continued advancement. I'll leave it there.

所以請幫助我們理解這一點。如果你不能回答，那也沒關係，但我想我還是會問這個問題。其次，在104上，你必須看到什麼才能繼續前進？幫助我們了解您如何看待持續進步的標準。我會把它留在那裡。

So we're very excited about the data from apraglutide. And a lot has been discussed around CIC versus stoma. It's just critical to remember that the primary endpoint included both stoma and colon-in-continuity patients. So we clearly think we have a high probability of approval for the whole population, stoma and CIC, based on the fact that colon-in-continuity patients contributed to the primary endpoint. That was quite distinct from what happened with the regulatory precedent that GATTEX set, where they really didn't see a meaningful contribution for the colon i--continuity patients.

因此，我們對阿普拉魯肽的數據感到非常興奮。關於 CIC 與造口的討論已經很多。重要的是要記住，主要終點包括造口和結腸連續患者。因此，我們清楚地認為，基於結腸連續性患者對主要終點做出貢獻的事實，我們有很高的機率批准整個人群、造口和 CIC。這與 GATTEX 設定的監管先例截然不同，他們確實沒有看到對結腸 i-連續性患者有任何有意義的貢獻。

So we continue to believe that the potency of the asset is well established now with this Phase III data and that that has given us the opportunity for once-weekly therapy. And what you'll see at DDW is a further rollout of the colon-in-continuity specific data which certainly gives us even more confidence in the efficacy in colon-in-continuity patients. And we certainly fully support the submission we're going to do for the whole population and have a high probability of success for approval in colon-in-continuity and stoma patients.

因此，我們仍然相信，根據 III 期數據，該資產的效力現已得到充分證實，這為我們提供了每週一次治療的機會。您將在 DDW 上看到的是結腸連續性特定數據的進一步推出，這無疑讓我們對結腸連續性患者的療效更有信心。我們當然完全支持我們將為整個人群所做的提交，並且在結腸連續性和造口患者中獲得批准的可能性很高。

In addition, there will be a fair amount of tolerability data which will further support the differentiation of apraglutide from other GLP-2 therapies in the class. We've really learned a lot from the pivotal trial data in terms of the safety and tolerability. And you'll see details on events and numbers at DDW, which really support a very safe and well-tolerated profile. And in principle, most all events were actually in line with placebo. So we think it's a very good profile for commercial success.

此外，還將有大量的耐受性數據，這將進一步支持阿普拉魯肽與其他同類 GLP-2 療法的差異。我們確實從安全性和耐受性方面的關鍵試驗數據中學到了很多。您將在 DDW 上看到有關事件和數字的詳細信息，這確實支援非常安全且耐受性良好的配置文件。原則上，大多數事件實際上都與安慰劑相符。所以我們認為這是商業成功的一個非常好的形象。

And the next question you asked was on CNP, okay? What we plan -- what we hope to see in CNP as we discussed the real strength of the CMC program is the science behind the immunology and what we know about the pathology of PBC. It's a PDC-E2-driven disease. And we can test the T cells that destroy the bile ducts with PDC-E2 to determine if treatment with CNP-104 modulates or reprograms those T cells.

你問的下一個問題是關於 CNP 的，好嗎？當我們討論 CMC 計畫的真正優勢時，我們計劃在 CNP 中看到的是免疫學背後的科學以及我們對 PBC 病理學的了解。這是一種 PDC-E2 驅動的疾病。我們可以測試用 PDC-E2 破壞膽管的 T 細胞，以確定 CNP-104 治療是否會調節或重新編程這些 T 細胞。

So we're really looking for a demonstrated T cell effect that shows that those T cells are no longer pathologic, no longer prone to destroying bile ducts. And in combination with that, we're looking for a meaningful clinical outcome, and that's why we have a number of liver function assessments in the trial as well. And this 120-day assessment gives the opportunity to look at that demonstrated T cell response and the potential opportunity to improve liver function assessment.

因此，我們真正在尋找已證實的 T 細胞效應，顯示這些 T 細胞不再是病理性的，不再容易破壞膽管。與此結合，我們正在尋找有意義的臨床結果，這就是我們在試驗中進行大量肝功能評估的原因。這個 120 天的評估讓我們有機會觀察已證實的 T 細胞反應以及改善肝功能評估的潛在機會。

Chase Knickerbocker, Craig-Hallum.

蔡斯·尼克博克、克雷格·哈勒姆。

Maybe just digging in a little bit on the gross-to-net adjustment from last year. Can you just talk to us about kind of what that was specifically as far as probably by payer channel or just however you think it's best to break that down just a little bit more detail around exactly what that $60 million adjustment was that was not accounted for by AbbVie?

也許只是稍微研究去年的毛淨調整。您能否與我們談談具體的支付管道具體情況，或者您認為最好將其分解為更多細節，以了解 6000 萬美元的調整到底是什麼沒有考慮在內艾伯維？

I'd say that -- I'm taking it zooming out first. I would say the fluctuations in gross to net relating to shift in channel mix are common and they're normal occurrence within this industry, as you know. It's something that happens on a periodic basis for us, really isn't this material.

我想說的是——我先把它縮小。我想說，與通路組合轉變相關的毛淨值波動很常見，而且如您所知，這在這個行業內是正常現象。這對我們來說是定期發生的事情，實際上不是這種材料。

I think the change in estimate for us was based on information that AbbVie provided subsequent to their reporting. And it was the difference between the gross-to-net during the year and the actual invoices they got. And it was primarily associated with government and contractual rebates. I think that's the color probably can give you in terms of where we were.

我認為我們估計的變化是基於艾伯維在報告後提供的資訊。這是當年的毛淨額與他們收到的實際發票之間的差額。它主要與政府和合約回扣有關。我認為這種顏色可能可以告訴你我們所處的位置。

Got it. That's helpful. Maybe one for Mike. Can you just talk around kind of next steps with the APRA NDA? Certainly looking forward to the data, just maybe specifically on the filing. Have you had your Type B meeting or is that scheduled for soon? And then kind of talk a little about what's left to be done with all the data work that you've been doing in the background to prepare the submission.

知道了。這很有幫助。也許是給麥克的。您能談談 APRA NDA 的後續步驟嗎？當然期待數據，也許只是特別關注備案。您是否曾經舉行過 B 類會議或即將舉行？然後稍微談談您在後台為準備提交所做的所有資料工作還需要做什麼。

Yeah. Sure. That's good question. And clearly, that's our key priority. Our number one, two, and three priorities is the APRA submission. So it's all hands on deck as for that. We clearly continue to look at the data. That's what resulted in the DDW oral abstract acceptance. So we're very excited about that. That's going to support, obviously, getting the data out. But also all that data is part and parcel to the submission and aligns with everything we're trying to do to get the submission in and on track.

是的。當然。這是個好問題。顯然，這是我們的首要任務。我們的第一、第二和第三優先事項是向 APRA 提交。因此，大家都在全力以赴。我們顯然會繼續關注數據。這就是 DDW 口頭摘要被接受的原因。所以我們對此感到非常興奮。顯然，這將支援獲取數據。而且所有這些數據都是提交內容的重要組成部分，並且與我們為使提交內容步入正軌而努力所做的一切保持一致。

So we're currently not planning the pre-NDA meeting, which we'll do as well. And we're really looking forward to moving that submission forward as expeditiously as possible. We're still targeting a potential launch in 2025. And as we get more granular on the submission timelines, we'll certainly make that available.

因此，我們目前沒有計劃 NDA 前會議，但我們也會這樣做。我們非常期待盡快提交該提交。我們的目標仍然是在 2025 年發布。隨著我們對提交時間表的了解更加細化，我們肯定會提供該時間表。

Okay. And then just last for me on CNP-104. Just to confirm for investors, when we get that data in 3Q, that will be both T cell response, and we will also be able to see that liver function data. Is that right, Mike?

好的。然後就在 CNP-104 上為我做最後一個。只是為了向投資者確認，當我們在第三季度獲得數據時，這將是 T 細胞反應，我們也將能夠看到肝功能數據。是這樣嗎，麥克？

Yeah. We plan to talk about the T cell, the demonstrated T cell effects, to obviously prove the point of the program which is the reprogramming and the immunology around the PDC-E2 specific antigens. So we plan to share that as well as liver function outcome as well. Remember, it's a 120-day study. It's a Phase II study. It's the first in-human study for CNP-104, and so that is a sort of early timeframe.

是的。我們計劃談論 T 細胞，即已證實的 T 細胞效應，以明確證明該程序的要點，即圍繞 PDC-E2 特異性抗原進行重編程和免疫學。因此，我們計劃也分享這項結果以及肝功能結果。請記住，這是一項為期 120 天的研究。這是一項二期研究。這是 CNP-104 的首次人體研究，所以這是一個早期的時間框架。

You may know that things like obeticholic acid and CymaBay and those products went out to a year. But we clearly think based on the science and the technology and why we did the deal that we have an opportunity to see a real early clinical endpoint in those liver function assessments.

你可能知道像奧貝膽酸和 CymaBay 這樣的產品已經過期一年了。但我們清楚地認為，基於科學和技術以及我們為何進行這項交易，我們有機會在這些肝功能評估中看到真正的早期臨床終點。

Great. And then just last Sravan, I'll come back to you. Just on guidance. I mean, looking at it, it certainly seems really the only material changes to your guys' expectations was this $30 million adjustment. Is that fair to say as far as the Medicaid changes on the rebate cap this year, everything else is the same as far as your expectation goes on your revenue expectations in 2024 from LINZESS.

偉大的。然後就在最後一個斯拉萬，我會回到你身邊。只是指導而已。我的意思是，從這個角度來看，對你們的期望來說，唯一實質的改變似乎就是這 3000 萬美元的調整。公平地說，只要醫療補助今年的回扣上限發生變化，只要您對 LINZESS 2024 年收入的預期，其他一切都是一樣的。

Yeah. So I would say that our guidance now is reflective of the one-time adjustment. As you can see, based on AbbVie's reporting, I think we would have been -- the performance of the brand continues to be really strong with double-digit demand growth. The pricing headwinds that we would have faced or we anticipated having a high single-digit price erosion and low single-digit revenue growth were kind of there outside of the one-time out of period adjustment.

是的。所以我想說，我們現在的指導反映了一次性調整。正如您所看到的，根據艾伯維的報告，我認為我們會——該品牌的表現繼續非常強勁，需求增長兩位數。我們可能會面臨的定價逆風，或者我們預期會出現高個位數的價格侵蝕和低個位數的收入成長，這些都是在一次性超期調整之外的情況。

I think the only other comment that I would make on this is, as you can see, the demand is really remarkable with regard to what kind of growth we're seeing in year 11, year 12 for the brand, which we obviously want to continue to nurture. And what we do know is there's really kind of three things that are driving that. Certainly, the high treatment satisfaction, no question. But I think the other piece is payer access, which is part of the marketing mix.

我想對此我要發表的唯一評論是，正如您所看到的，對於我們在第 11 年、第 12 年看到的品牌增長的需求確實非常顯著，我們顯然希望繼續培育。我們所知道的是，確實有三件事在推動這一趨勢。當然，高治療滿意度是毫無疑問的。但我認為另一部分是付款人訪問，這是行銷組合的一部分。

Now what we will be doing moving forward, is really working with our partner to continue to evolve that marketing mix, so we can really optimize the value that LINZESS can create. So we have been doing this from day one as we've evolved the marketing mix, we've reduced the investment and increase the profit of the brand. As we move forward, I think we're seeing very durable growth in brand demand and what we really want to focus on now is what is the right appropriate marketing mix and investment to continue to drive profits to the bottom line.

現在，我們將繼續與我們的合作夥伴合作，繼續發展行銷組合，以便我們能夠真正優化 LINZESS 可以創造的價值。因此，我們從第一天起就一直這樣做，隨著我們不斷發展行銷組合，我們減少了投資並增加了品牌的利潤。隨著我們的前進，我認為我們看到品牌需求非常持久的成長，我們現在真正想要關注的是什麼是正確的行銷組合和投資，以繼續將利潤推向底線。

Amy Li, Jefferies.

艾米李，傑弗里斯。

On apraglutide, what is your current internal estimate on durability of treatment? And will we get any data at DDW to support potential differentiation on this organics? Additionally, can you give us any updates on how you're thinking about the addressable market for APRA post the ICD-10 codes being put in place late last year? And how many of these patients do you have access to with your current sales force?

對於阿普拉魯肽，您目前對治療持久性的內部估計是多少？我們能否在 DDW 獲得任何數據來支持這種有機物的潛在差異化？此外，您能否向我們介紹一下去年年底實施 ICD-10 代碼後您對 APRA 潛在市場的看法？您目前的銷售團隊可以接觸到多少這樣的患者？

Mike, why don't you start with the first one? I'll answer the second one.

麥克，你為什麼不從第一個開始呢？我來回答第二個。

In terms of durability, I suspect you mean more longer term. Clearly, as the only once-weekly available therapy, we certainly think that Phase III data supports the weekly administration and sort of the pharmacokinetics and pharmacodynamics really lend itself to that once-weekly dosing. So the data speaks for itself in that regard. It's a once-weekly therapy. I think in terms of longer term, right, the actual ideal goal for most patients is enteral autonomy, where they could come off all parenteral support.

就耐用性而言，我懷疑你的意思是更長期。顯然，作為唯一每週一次的可用療法，我們當然認為 III 期數據支持每週一次給藥，而藥物動力學和藥效學確實適合每週一次給藥。因此，在這方面，數據是不言而喻的。這是每週一次的療法。我認為從長遠來看，大多數患者的實際理想目標是腸內自主，他們可以擺脫所有腸外支持。

In that setting, they often would need continued GLP-2 therapy to maintain that intestinal growth. Then from that going forward, it will be up to them, obviously, and they're position a caretaker to understand how that long-term plays out. But the reality is in patients with short bowel who have limited bowel epithelium, they benefit from continued therapy from the GLP-2 because as we've seen with other GLP-2 therapies, when you come off it, used to often revert back to a need for parenteral support.

在這種情況下，他們通常需要持續的 GLP-2 治療來維持腸道生長。從那時起，顯然，這將取決於他們，他們將擔任看守以了解長期的發展。但現實情況是，對於腸上皮細胞有限的短腸患者，他們會受益於GLP-2 的持續治療，因為正如我們在其他GLP-2 療法中看到的那樣，當您停止使用它時，通常會恢復到原來的狀態。

And then on the question about the ICD-10 codes and our overall sales force, just taking a step back again, our level of access to the major GI practices across the United States is probably unparalleled from our perspective. We've got over 90 sales reps calling on these practices and leading clinicians. Specifically with the ICD-10 codes, we're really excited about this development, honestly, Amy Li.

然後，關於 ICD-10 代碼和我們整體銷售團隊的問題，再退一步，從我們的角度來看，我們對美國主要地理標誌實踐的了解程度可能是無與倫比的。我們有 90 多名銷售代表拜訪這些診所和領先的臨床醫生。特別是對於 ICD-10 代碼，我們對這一發展感到非常興奮，說實話，Amy Li。

I think the big thing for us is that these ICD-10 codes are starting to shed real light on how many patients are actually are. I think you've heard a little bit on some of the things you've hosted yourself about differences in what the estimates are. I think there have been 7,000 or so patients that have been identified already to date through the ICD-10 codes in just a few months. It just reinforces our estimates as more data comes to light about how many patients there are.

我認為對我們來說最重要的是這些 ICD-10 代碼開始真正揭示到底有多少患者。我想您已經在自己主持的一些活動中聽說過一些關於估算值差異的情況。我認為迄今為止，在短短幾個月內已經透過 ICD-10 代碼識別了大約 7,000 名患者。隨著更多數據顯示有多少患者，這只會加強我們的估計。

And then I think given our presence across the United States, I think our ability to capture share with our best-in-class product with our -- as an overall profile with apraglutide having once weekly administration, demonstrated real efficacy across the both stoma and CIC patient populations. And then now, as you'll see in a few weeks, the safety and tolerability data of being equivalent to placebo. I think that is -- I think our ability to penetrate that and capture share to be a billion-dollar brand is in sight. We feel confident about it.

然後，我認為考慮到我們在美國各地的業務，我認為我們有能力透過我們的同類最佳產品獲得市場份額——作為阿普拉魯肽每週一次給藥的整體概況，證明了對造口和造口的真正功效。現在，幾週後您將看到與安慰劑相當的安全性和耐受性數據。我認為，我們有能力滲透到這一領域並佔領市場份額，成為價值十億美元的品牌。我們對此充滿信心。

Jason Butler, Citizens JMP.

Jason Butler，公民 JMP。

First one is for APRA. Can you maybe talk about the work you're doing pre-commercial to build awareness of the brand and beyond just obviously presentation of data? What work you're going to do this year to prepare the market for the drug? And then just secondly, on LINZESS, can you maybe speak to the contribution of the pediatric market to growth this quarter and looking forward into 2024? Thanks.

第一個是針對 APRA 的。您能否談談您在商業前所做的工作，以建立品牌知名度，而不僅僅是明顯的數據呈現？今年您將做哪些工作來為該藥物的市場做好準備？其次，關於 LINZESS，您能否談談兒科市場對本季成長的貢獻以及對 2024 年的展望？謝謝。

Yeah. So Tom, why don't you handle the first one and then maybe I'll take the second part of the question, if that works.

是的。那麼湯姆，你為什麼不處理第一部分，然後也許我會回答問題的第二部分，如果可行的話。

I mean, remind me, the first question was --

我的意思是，提醒我，第一個問題是--

The brand awareness, the activity.

品牌知名度、活動。

Sure. So as far as the prelaunch activities, we are just in the midst of launching a disease education program targeted primarily on the GI community which will probably stretch into a digital platform for patients and for patients to seek better understanding and options. So this is really about increasing the awareness of who these patients are, how debilitating this disease is and the need for more effective therapy. And through that exercise, a big objective here as far as overall impact on performance is identifying available patients within these large GI practices as well as the academic centers of excellence.

當然。就啟動前活動而言，我們正在啟動一項主要針對胃腸道社區的疾病教育計劃，該計劃可能會延伸到一個數位平台，供患者以及患者尋求更好的理解和選擇。因此，這實際上是為了提高人們對這些患者是誰、這種疾病的嚴重程度以及對更有效治療的需求的認識。透過這項工作，就對績效的整體影響而言，這裡的一個重要目標是在這些大型胃腸病診所以及卓越的學術中心中確定可用的患者。

We've been very, very encouraged by the feedback that we're getting from the key opinion leaders in the center of excellence as far as the response rate and the acceptance of apraglutide in the clinical trials and they're all looking forward to working in a very collaborative way, not just as far as educating people, but also how do we really work with the patients to help them through the process to get better care. So we're -- I think we're very well positioned to prepare our go-to-market strategy. And of course, that work has been ongoing, and we're just in the early stages of implementing the disease awareness program. Do you want to take the LINZESS question?

我們從卓越中心的關鍵意見領袖那裡得到的關於臨床試驗中阿普拉魯肽的反應率和接受度的反饋讓我們深受鼓舞，他們都期待著合作以一種非常協作的方式，不僅是教育人們，而且是我們如何真正與患者合作，幫助他們完成整個過程，獲得更好的照護。因此，我認為我們已經做好了準備我們的上市策略的準備。當然，這項工作一直在進行中，我們正處於實施疾病意識計畫的早期階段。您想回答 LINZESS 問題嗎？

Yeah. I'll happy do that. So Jason, good morning. So I think on your question about the pediatric launch and its progress, I think we are clearly, I think, overall, I think since the launch has started, we're really positive about pediatric indication. We're still early in the launch, frankly. But to date, we're really encouraged by the strong new-to-brand prescription volume growth.

是的。我很樂意這樣做。傑森，早上好。因此，我認為，關於您關於兒科產品上市及其進展的問題，我認為我們顯然，我認為，總體而言，我認為自從啟動以來，我們對兒科適應症非常積極。坦白說，我們還處於發布初期。但迄今為止，新品牌處方量的強勁成長確實令我們感到鼓舞。

I think Tom mentioned earlier on the call that 18% new-to-brand growth that specifically a large portion of that growth on a year-over-year basis is in the 72-microgram dose, which is the approved dose for the 6- to 17-year-old patient group. So it's embedded in those numbers. And I think it's part of what's sustaining our long-term growth here for LINZESS as we're in year 12.

我認為湯姆早些時候在電話會議上提到，新品牌增長了 18%，特別是同比增長的很大一部分來自 72 微克劑量，這是 6- 的批准劑量。所以它嵌入在這些數字中。我認為這是維持 LINZESS 長期成長的一部分，因為我們已經進入第 12 年了。

Mohit Bansal, Wells Fargo.

莫希特·班薩爾，富國銀行。

Great. Thank you very much for taking my question. I have a couple of questions. So one on the guidance again, thanks for clarification. But one thing I wanted to ask was that typically, this happens because your -- you had a particular mix in the, Mike, for government versus commercial and that mix change subsequently because you don't know it until you get the receipts and all. Are you expecting similar mix, which like the updated mix for 2024 as well? I'm asking because by our math, the impact that you are modeling is a little bit more than $60 million. So that's the first question.

偉大的。非常感謝您回答我的問題。我有一些問題。所以再次指導一下，感謝您的澄清。但我想問的一件事是，通常會發生這種情況，因為麥克，你在政府與商業方面有一個特定的組合，而這種組合隨後發生變化，因為你不知道，直到你收到收據和所有資訊。您是否期待類似的組合，就像 2024 年更新的組合一樣？我這麼問是因為根據我們的計算，您所建模的影響略高於 6000 萬美元。這是第一個問題。

And the second question is on ALP with CNP-104. So if I look at drugs like Seladelpar, there was an impact on ALP by month one and then at month three, it was more like stabilized, after that, it was not an incremental impact. So isn't 120-day enough to see benefit? I appreciate the mechanisms are different. So how should we think about benefit on endpoints like ALP there. Thank you.

第二個問題是關於 CNP-104 的 ALP。因此，如果我觀察像 Seladelpar 這樣的藥物，第一個月就會對 ALP 產生影響，然後在第三個月，它更像是穩定的，之後就不再是漸進式影響了。那麼 120 天還不足以看到效益嗎？我很欣賞這些機制是不同的。那我們應該如何考慮 ALP 等端點的好處。謝謝。

Mike, why don't you go first and then I'll answer the guidance question.

麥克，你先走吧，然後我來回答指導問題。

Yes. Thanks. It's a good question because, as you know, the regulatory like precedent is around alk phos that's clearly how obeticholic acid got approved and what CymaBay's gone through right now. So it clearly is an approved path for accelerated approval, which is not full approval. You may know CymaBay's actually added pruritus in that to sort of help balance that need. Alk phos is a very nonspecific sort of effect on liver function in a lot of ways because it really speaks to how the bile is moving through the liver. So it's very important to understand that if you give something like obeticholic acid, which is a bio acid mimetic, it actually increases bile flow.

是的。謝謝。這是一個很好的問題，因為如您所知，類似監管的先例是圍繞 alk phos 的，這顯然是奧貝膽酸如何獲得批准以及 CymaBay 目前經歷的事情。所以這顯然是一個加速批准的批准路徑，而不是完全批准。您可能知道 CymaBay 實際上添加了瘙癢症，以幫助平衡這種需求。Alk phos 在許多方面對肝功能都有一種非常非特異性的影響，因為它確實說明了膽汁如何通過肝臟。因此，了解這一點非常重要：如果您服用奧貝膽酸（一種生物酸模擬物）之類的藥物，它實際上會增加膽汁流量。

One of the early benefits you'll get from that is improved alk phos. It's also not necessarily part and parcel that that's aligning with liver function improvement. And that's why obeticholic acid had to have a post-marketing commitment to show a benefit in liver function more broadly with histology which incidentally did not meet needs at the time. So it is important to understand what alk phos is there for. And as you highlighted, our mechanism is completely different. We're actually targeting the root cause of PBC, which is the T cell-driven bile duct destruction.

您將從中獲得的早期好處之一是改進的鹼性磷酸鹽。它也不一定與肝功能的改善一致。這就是為什麼奧貝膽酸必須有一個上市後承諾，以透過組織學更廣泛地顯示對肝功能的益處，而這恰好不能滿足當時的需求。因此，了解 alk phos 的用途非常重要。正如您所強調的，我們的機製完全不同。我們實際上針對的是 PBC 的根本原因，即 T 細胞驅動的膽管破壞。

So we clearly believe that we can affect the T cells and then reprogram those T cells so they no longer attack the bile ducts, we'll see clinical improvement. And then to your point, the time line for that clinical improvement, we're going to learn. We clearly think we have an opportunity to see it early given the specificity of PDC-E2 and the specificity of this therapy. That's why we have a 120-day look, but we're certainly going to learn from that. And that's why we have this combination of need, meaning to demonstrate a T cell response and the liver function improvement. So certainly, the different mechanism is important to understand.

因此，我們清楚地相信，我們可以影響 T 細胞，然後對這些 T 細胞進行重新編程，使它們不再攻擊膽管，我們將看到臨床改善。然後到你的觀點，即臨床改善的時間表，我們將了解。鑑於 PDC-E2 的特異性和該療法的特異性，我們顯然認為我們有機會儘早看到它。這就是為什麼我們要進行 120 天的觀察，但我們肯定會從中學到教訓。這就是為什麼我們有這種組合需求，即證明 T 細胞反應和肝功能改善。因此，理解不同的機制當然很重要。

And also, it's very important to realize that we're actually going for a very disease-modifying approach, not just moving bile flow through the liver better, which is a biomarker for potential benefit for liver disease.

而且，重要的是要認識到，我們實際上正在尋求一種非常有效的疾病緩解方法，而不僅僅是更好地移動膽汁流經肝臟，這是對肝病具有潛在益處的生物標記。

So on your guidance question, Look, I think on high level, I'd say again. One, I think from our perspective, and it's -- the guidance we gave for 2024 accounts or the mix we anticipate in 2024, it's our 2024 guidance. We expect to still see high single-digit prescription demand growth, and I think the decline is as stated, based on our overall annual guidance. This is a onetime adjustment. We've been pretty good as a brand over the last several years and anticipating with our estimates as with respect to what that mix is in a channel.

因此，關於您的指導問題，我想再說一次。第一，我認為從我們的角度來看，我們為 2024 年帳戶或我們預計 2024 年的組合提供的指導，這是我們的 2024 年指導。我們預計處方藥需求仍將出現個位數的高成長，而且我認為根據我們的整體年度指導，下降幅度如上所述。這是一次性調整。在過去的幾年裡，我們作為一個品牌表現得相當不錯，並且根據我們對通路中的組合的估計進行了預測。

Channel mix is pretty fluid and predicting LINZESS net sales can move in a positive or in a negative directions has always been true, but we've been pretty good about it over the years. And I think at this point, we're still expecting to deliver a mid-single-digit decline, as I said before, and that's predominantly driven by the onetime out-of-period adjustment. Outside of that, I think we would have been in line with guidance for the full year.

通路組合相當不穩定，對 LINZESS 淨銷售額可能朝正或負方向變化的預測一直都是正確的，但多年來我們一直對此非常滿意。我認為，正如我之前所說，目前我們仍預計會出現中等個位數的下降，這主要是由一次性的期外調整所推動的。除此之外，我認為我們全年的指導方針都是一致的。

Tim Chiang, Capital One.

蔣添明，第一資本。

I was just looking back at the secondary endpoints from the STARS study, do you guys plan on showing, I guess, the earlier week data from the CIC patient population at DDW, especially with the secondary endpoints that you didn't need statistical significance on.

我只是回顧了 STARS 研究的次要終點，我想你們是否計劃展示 DDW 的 CIC 患者群體的前一周數據，特別是那些不需要統計顯著性的次要終點。

Yeah, Tim. If you're referring to sort of specifically things like enteral autonomy or things you might see at 24 weeks versus the key secondaries at 48, the answers is yes. And we certainly think that data further supports our conviction of good efficacy in both stoma and CIC patient populations. So yes, we plan to see that -- to have that at DDW as well as sort of the decrease in parenteral support volume and the relative change from baseline in that capacity as well.

是的，提姆。如果您指的是一些具體的事情，例如腸內自主權或您在 24 週時可能會看到的情況與 48 週時的關鍵次要情況，那麼答案是肯定的。我們當然認為這些數據進一步支持了我們對造口和 CIC 患者群體良好療效的信念。所以，是的，我們計劃看到這一點——在 DDW 上實現這一點，以及腸外支持量的減少以及該能力相對於基線的相對變化。

The DDW have planned oral presentation. It's obviously still in development, but we have a lot done on it already, and it's very data heavy. I think you'll be very impressed with the amount of data. We're certainly clearly very excited by it because it clearly supports our conviction that the drug is approvable and works in both colon in continuity and stoma patients. So we really are looking forward to sharing that more broadly with the community.

DDW 計劃進行口頭陳述。它顯然仍在開發中，但我們已經做了很多工作，而且數據量很大。我想您會對數據量印象深刻。我們顯然對此感到非常興奮，因為它明確支持了我們的信念，即該藥物是可批准的，並且對結腸連續性和造口患者均有效。因此，我們真的很期待與社區更廣泛地分享這一點。

Mike, just one follow-up. Why is the placebo effect so high in these studies? Because I noticed on your third secondary endpoint, the placebo rate was almost 44%. Can you comment on that?

麥克，只是一個後續行動。為什麼這些研究中安慰劑效應如此高？因為我注意到你的第三個次要終點，安慰劑率幾乎是 44%。你能對此發表評論嗎？

Yeah. I mean I think the key to realize there is that the primary endpoint placebo response was 12.5%, right? And that's the key driver for the study's positivity statistically and the path to approval. So I think that's a key thing to keep aware of. The other thing to realize is the 48 week endpoints never had been tested in a GLP-2 therapy before. And there can be a tendency for placebo response to change during a clinical trial.

是的。我的意思是，我認為認識到這一點的關鍵是主要終點安慰劑反應為 12.5%，對吧？這是該研究在統計上的積極性和獲得批准的關鍵驅動力。所以我認為這是需要注意的關鍵事情。另一件需要意識到的事情是，48 週終點之前從未在 GLP-2 療法中進行過測試。在臨床試驗期間，安慰劑反應可能會改變。

And it's also important to realize that what we're actually talking about here, placebo response is different at 24 weeks on the primary endpoint, meaning it's the relative change from baseline versus the one day off, which is the third key secondary, you alluded to, that's 44%. And then in addition, we instituted a new design in this trial, which is the winning algorithm. So that's clearly played forward through the study.

同樣重要的是要認識到，我們實際上在這裡討論的是，安慰劑反應在24 週的主要終點上是不同的，這意味著它是相對於基線與休息一天的相對變化，這是您提到的第三個關鍵次要終點到，即 44%。此外，我們在這次試驗中提出了一種新的設計，這就是獲勝的演算法。因此，這項研究清楚地體現了這一點。

We're going to analyze that data real cost carefully to make sure we understand it. But there is a potential opportunity for the winning algorithm, which would be in place for both placebo and drug-treated patients could elevate the placebo response with later time points in the study. Because early in the study, it might be more volume-driven, whereas as people wean, then you may fall under the year an output threshold of 10% and you make it exposed to weaning out.

我們將仔細分析該數據的實際成本，以確保我們理解它。但獲勝的演算法有一個潛在的機會，該演算法將適用於安慰劑和藥物治療的患者，可以在研究的後期時間點提高安慰劑反應。因為在研究的早期，它可能更多是由數量驅動的，而當人們斷奶時，你可能會低於當年 10% 的產出閾值，並且你會面臨斷奶的風險。

We're still looking into that, but that's clearly one thing on the list to figure out if that's what made the 48 week endpoint, we'll see the response so high. And one final point to realize even though the placebo response was high at the third key endpoint on the CIC population, APRA was still numerically superior. So when we get to this sort of aspect of approvability, that fact that APRA still did numerically better will be a positive in terms of not looking at it like we're worse than placebo or things like that. That's not the case.

我們仍在研究這一點，但這顯然是清單上的一件事，要弄清楚這是否是 48 週終點的原因，我們會看到如此高的反應。最後要認識到的一點是，儘管安慰劑在 CIC 族群的第三個關鍵終點上的反應很高，但 APRA 在數字上仍然具有優勢。因此，當我們談到這種可批准性方面時，APRA 在數字上仍然表現更好這一事實將是一個積極的因素，因為我們不會認為我們比安慰劑或類似的東西更差。事實並非如此。

And then given the things we talked about on the primary and the first key secondary being positive in the whole population, we clearly think that bodes well for a high probability of success for approval for both populations.

然後考慮到我們討論的主要問題和第一個關鍵次要問題在整個人群中都是積極的，我們顯然認為這預示著這兩個人群獲得批准的可能性很高。

And maybe just one last follow-up, Mike. Are some of these items, do you think that you could get them on the label? Because I think those would be important, especially in the colon-in-continuity patient population.

也許這只是最後一個後續行動，麥克。您認為其中一些物品可以在標籤上找到嗎？因為我認為這些很重要，特別是對於結腸連續性患者族群。

Yeah. I think we're going to work to get everything in the label we can. We certainly think the drug works very well in both patient populations. One of the reasons we included those additional secondaries was for exactly that reason. However, that challenge is higher now, obviously, because they didn't meet statistical significance. But as I mentioned, both are numerically better. So we certainly have a strong confidence for approvability.

是的。我認為我們將盡力將所有內容都包含在標籤中。我們當然認為該藥物對兩種患者群體都非常有效。我們加入這些額外的次級的原因之一正是出於這個原因。然而，顯然，現在的挑戰更大了，因為它們沒有達到統計顯著性。但正如我所提到的，兩者在數字上都更好。所以我們對獲得批准當然有很強的信心。

Ladies and gentlemen, that concludes our Q&A session and today's call. Thank you all for joining. You may now disconnect.

女士們先生們，我們的問答環節和今天的電話會議到此結束。感謝大家的加入。您現在可以斷開連線。