Ironwood Pharmaceuticals Inc (IRWD) 2023 Q1 法說會逐字稿

Good day, and welcome to the Ironwood Pharmaceuticals Q1 2023 Investor Update Conference Call. Today's call is being recorded. (Operator Instructions)

美好的一天，歡迎來到 Ironwood Pharmaceuticals 2023 年第一季度投資者更新電話會議。今天的通話正在錄音中。 （操作員說明）

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

我現在將把電話轉給投資者關係總監 Matt Roache。請繼續。

Thank you, Angela. Good morning, and thanks for joining us for our first quarter 2023 investor update. Our press release issued this morning can be found on our website. Today's call and accompanying slides include forward-looking statements. Such statements involve risks and uncertainties that may cause actual results to differ materially.

謝謝你，安吉拉。早上好，感謝您加入我們的 2023 年第一季度投資者更新。我們今天上午發布的新聞稿可以在我們的網站上找到。今天的電話會議和隨附的幻燈片包含前瞻性陳述。此類陳述涉及可能導致實際結果大不相同的風險和不確定性。

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, 2022, and in our future SEC filings. All forward-looking statements speak as of the date of this presentation and we undertake no obligation to update such statements. Also included are non-GAAP financial measures, which should be considered only as a supplement to and 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.

當前的安全港聲明幻燈片以及我們截至 2022 年 12 月 31 日的 10-K 表格年度報告中的風險因素標題下以及我們未來提交給美國證券交易委員會的文件中都提供了對這些聲明和風險因素的討論。所有前瞻性陳述均截至本演示文稿發布之日，我們不承擔更新此類陳述的義務。還包括非 GAAP 財務措施，這些措施應僅被視為對 GAAP 措施的補充，而不是替代或優於 GAAP 措施。在適用的範圍內，請參閱我們新聞稿末尾的表格，了解這些措施與最直接可比的 GAAP 措施的調節情況。

During today's call, Tom McCourt, our CEO, will review our strategic priorities and provide an update on the commercial performance of LINZESS. Mike Shetzline, our Chief Medical Officer, will discuss our pipeline and Sravan Emany, our Chief Financial Officer, will review our financial results and guidance. Today's webcast includes slides. So for those of you dialing in, please go to the event's section of our website to access the accompanying slide separately.

在今天的電話會議上，我們的首席執行官 Tom McCourt 將審查我們的戰略重點，並提供有關 LINZESS 商業業績的最新信息。我們的首席醫療官 Mike Shetzline 將討論我們的管道，我們的首席財務官 Sravan Emany 將審查我們的財務業績和指導。今天的網絡廣播包括幻燈片。因此，對於撥入的那些人，請轉到我們網站的活動部分，單獨訪問隨附的幻燈片。

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

有了這個，我會把電話轉給湯姆。

Thanks, Matt. Good morning, everyone and thanks for joining us today. I'm delighted to announce our first quarter results this morning. We are off to a terrific start to the year as demonstrated by continued strong LINZESS demand growth, progress of our clinical studies and another quarter of delivering robust profits and cash flow. At Ironwood, we remain committed to advancing the treatment of GI diseases and redefining standard of care for GI patients.

謝謝，馬特。大家早上好，感謝今天加入我們。我很高興今天早上宣布我們的第一季度業績。 LINZESS 需求持續強勁增長、臨床研究取得進展以及另一個季度實現強勁利潤和現金流就證明了我們今年開局良好。在 Ironwood，我們始終致力於推進胃腸道疾病的治療並重新定義胃腸道患者的護理標準。

I believe the progress we've made across the organization in the first quarter demonstrate the steps that we're taking to become the leading GI Healthcare Company in the U.S. Let's begin on Slide 6 with our strategic priorities. Our strategy starts with maximizing LINZESS. LINZESS continues to experience remarkable prescription demand growth and widespread adoption amongst healthcare practitioners as a leading branded prescription treatment for adults with IBS-C and chronic idiopathic constipation.

我相信我們在第一季度在整個組織中取得的進展展示了我們為成為美國領先的 GI 醫療保健公司而採取的步驟。讓我們從幻燈片 6 開始我們的戰略重點。我們的戰略從最大化 LINZESS 開始。 LINZESS 作為治療 IBS-C 和慢性特發性便秘成人的領先品牌處方藥，繼續經歷顯著的處方需求增長和醫療保健從業者的廣泛採用。

In the first quarter, LINZESS U.S. net sales growth increased 8% year-over-year. Prescription demand growth increased over 10% as compared to the first quarter of 2022, demonstrating that the momentum of the brand remains strong. We believe there's still a significant opportunity to reach appropriate new patients and drive additional prescription demand growth, including a potential midyear indication for linaclotide in functional constipation for patients 6 to 17 years of age, if approved.

第一季度，LINZESS 美國淨銷售額同比增長 8%。與 2022 年第一季度相比，處方藥需求增長超過 10%，表明該品牌的勢頭依然強勁。我們認為，如果獲得批准，仍然有很大的機會接觸到合適的新患者並推動額外的處方需求增長，包括 6 至 17 歲患者功能性便秘患者利那洛肽的潛在年中適應症。

Next, we are focused on continuing to strengthen and progress our innovative GI portfolio starting with CNP-104, a potentially disease-modifying treatment for primary biliary cholangitis. The clinical study is ongoing and we continue to expect early data assessing the T-cell response in the second half of the year from the patients enrolled in the studies, which will inform the timing of top line data.

接下來，我們專注於繼續加強和推進我們創新的 GI 產品組合，從 CNP-104 開始，這是一種潛在的原發性膽汁性膽管炎疾病緩解療法。臨床研究正在進行中，我們繼續期待今年下半年來自參與研究的患者評估 T 細胞反應的早期數據，這將告知頂線數據的時間。

Second, IW-3300. We are continuing the proof-of-concept study in patients with interstitial cystitis and bladder pain syndrome. Finally, we continue to actively evaluate opportunities to strengthen our portfolio. And we see several attractive opportunities in the market that we believe are accessible and could benefit from Ironwood's expertise and capabilities in GI.

二、IW-3300。我們正在繼續對間質性膀胱炎和膀胱疼痛綜合徵患者進行概念驗證研究。最後，我們繼續積極評估機會以加強我們的產品組合。我們在市場上看到了幾個有吸引力的機會，我們認為這些機會是可以訪問的，並且可以從 Ironwood 在 GI 方面的專業知識和能力中受益。

Our third strategic priority is delivering sustained profits and generate cash flow. We delivered GAAP net income and adjusted EBITDA of $46 million and $60 million respectively and ended the first quarter with $740 million in cash and cash equivalents on the balance sheet. With our unique profile as a profitable GI-focused biopharma company with a strong and growing cash balance, we believe we're well positioned to maximize LINZESS growth and continue to build an innovative GI portfolio to create the next growth horizon for the company.

我們的第三個戰略重點是提供持續的利潤和產生現金流。我們實現了 GAAP 淨收入和調整後 EBITDA 分別為 4600 萬美元和 6000 萬美元，第一季度末資產負債表上的現金和現金等價物為 7.4 億美元。憑藉我們作為一家盈利的以 GI 為重點的生物製藥公司的獨特形象，擁有強勁且不斷增長的現金餘額，我們相信我們有能力最大限度地提高 LINZESS 的增長，並繼續建立創新的 GI 產品組合，為公司創造下一個增長前景。

Now let's turn to the performance of LINZESS on Slide 7. As you can see on the left side of Slide 7, LINZESS performed exceptionally well in the first quarter. As I mentioned a few moments ago, LINZESS prescription demand increased 10% year-over-year and net sales increased 8% year-over-year and generated $250 million in the quarter. Over the first quarter, the adult IBS-C and chronic constipation prescription market experienced strong growth with LINZESS experiencing an all-time high in new to brand patient volume to strengthen its position in the market as the #1 prescribed brand for adults with IBS-C and chronic constipation.

現在讓我們來看看LINZESS在Slide 7上的表現。正如你在Slide 7的左側看到的，LINZESS在第一季度的表現非常出色。正如我剛才提到的，LINZESS 處方藥需求同比增長 10%，淨銷售額同比增長 8%，本季度產生了 2.5 億美元。第一季度，成人 IBS-C 和慢性便秘處方藥市場經歷了強勁增長，LINZESS 的新品牌患者數量創歷史新高，鞏固了其作為 IBS 成人處方藥第一品牌的市場地位- C、慢性便秘。

Most importantly, we are proud to have had treated more than 4.5 million unique patients since the launch of the brand over 10 years ago. The growing number of patients that are actively seeking care and have been treated with LINZESS is evidence of the high treatment satisfaction expressed by both clinicians and patients.

最重要的是，自該品牌 10 多年前推出以來，我們已經治療了超過 450 萬名獨特的患者，我們為此感到自豪。積極尋求護理並接受 LINZESS 治療的患者數量不斷增加，證明了臨床醫生和患者對治療的高度滿意度。

We believe these market dynamics, combined with class-leading formulary access, the clinical guideline recommendations from both GI societies and the strong commercial execution is driving the demand momentum that we continue to see. And we expect this momentum to be augmented midyear should FDA approve the pediatric functional constipation indication, reinforcing the growth potential for the brand.

我們相信，這些市場動態，加上一流的處方准入、來自兩個 GI 協會的臨床指南建議和強大的商業執行正在推動我們繼續看到的需求勢頭。如果 FDA 批准兒科功能性便秘適應症，我們預計這種勢頭將在年中增強，從而增強該品牌的增長潛力。

Looking ahead, we're excited about the continued growth of LINZESS, the advancement of our clinical program and our stronger financial position as we advance Ironwood's leadership in GI. In a few days, we'll be presenting 5 abstracts at the Digestive Disease Week meeting or DDW, including an oral presentation.

展望未來，我們對 LINZESS 的持續增長、我們臨床項目的進步以及我們在推進 Ironwood 在 GI 領域的領導地位時更強大的財務狀況感到興奮。幾天后，我們將在消化疾病週會議或 DDW 上展示 5 篇摘要，包括口頭展示。

These abstracts will highlight new data that reinforce the potential of linaclotide to treat functional constipation in children and adolescents. We look forward to DDW, where each year, we have an important presence demonstrating our commitment to advancing GI therapies, including expanding the clinical utility of linaclotide.

這些摘要將突出強調利那洛肽治療兒童和青少年功能性便秘潛力的新數據。我們期待著 DDW，每年我們都有重要的存在表明我們致力於推進 GI 治療，包括擴大利那洛肽的臨床效用。

Before handing it over to Mike to discuss the pipeline programs, I'd like to take a moment to say a very big thank you to Jason Rickard for his leadership and events contributions to Ironwood over the last 11 years, most recently serving as our Chief Operating Officer and for helping make Ironwood the company it is today. While a change like this is not easy. As an organization committed to maximizing shareholder value, we continue to look for ways to streamline our team and align key functions and resources to meet our current and future needs and support Ironwood through its next phase of growth. I would also like to acknowledge all the Ironwood employees who have continued the momentum and strong execution against our strategic priorities as we continue to help make a remarkable impact to patients' lives. I would now like to hand the call over to Mike. Mike?

在將其交給 Mike 討論管道計劃之前，我想花點時間非常感謝 Jason Rickard 在過去 11 年中對 Ironwood 的領導和活動貢獻，最近擔任我們的首席運營官並幫助 Ironwood 成為今天的公司。雖然這樣的改變並不容易。作為一家致力於實現股東價值最大化的組織，我們將繼續尋找精簡團隊並調整關鍵職能和資源的方法，以滿足我們當前和未來的需求，並支持 Ironwood 實現下一階段的增長。我還要感謝 Ironwood 的所有員工，在我們繼續幫助對患者的生活產生顯著影響的過程中，他們繼續保持勢頭並強有力地執行我們的戰略重點。我現在想把電話轉給邁克。麥克風？

Thanks, Tom. Good morning, everyone. We continue to make progress across our 3 pipeline programs. I'll begin with our linaclotide pediatric program on Slide 9. We believe the pediatric opportunity, if approved, could expand the market potential for LINZESS as functional constipation affects roughly 6 million 6- to 17-year-old children and adolescents in the United States. If our sNDA is approved by the FDA, LINZESS would be the first and only prescription therapy to treat this patient population. And this is a population that's in need of better therapeutic options. We continue to work through the sNDA with the FDA and look forward to the June 14 PDUFA date.

謝謝，湯姆。大家，早安。我們繼續在我們的 3 個管道項目中取得進展。我將從幻燈片 9 上的利那洛肽兒科項目開始。我們相信，如果獲得批准，兒科機會可能會擴大 LINZESS 的市場潛力，因為功能性便秘影響著美國大約 600 萬 6 至 17 歲的兒童和青少年狀態。如果我們的 sNDA 獲得 FDA 批准，LINZESS 將是第一個也是唯一一個治療該患者群體的處方療法。這是一個需要更好的治療選擇的人群。我們繼續通過 sNDA 與 FDA 合作，並期待 6 月 14 日的 PDUFA 日期。

As Tom mentioned, we'll be presenting pediatric data on the efficacy and safety profile of linaclotide in treating functional constipation in this patient group at the upcoming DDW meeting.

正如 Tom 所提到的，我們將在即將召開的 DDW 會議上展示利那洛肽治療該患者組功能性便秘的療效和安全性的兒科數據。

Next is CNP-104 for the potential treatment of primary biliary cholangitis, which affects an estimated 133,000 people in the United States. The proof-of-concept study is ongoing and given the strong science underlying this therapy, we plan to assess T-cell responses in patients those with CNP-104 in the second half of '23. This will inform the timing of top line data and the potential option exercise. We expect to provide an update on the program at that time.

其次是 CNP-104，用於治療原發性膽汁性膽管炎，估計影響美國 133,000 人。概念驗證研究正在進行中，鑑於該療法背後的強大科學依據，我們計劃在 23 年下半年評估 CNP-104 患者的 T 細胞反應。這將告知頂線數據和潛在期權行使的時間。我們希望屆時提供該計劃的更新。

We're excited about CNP-104 because it is truly precision medicine and it introduces a potentially new game-changing asset for PBC patients as there are no therapies on the market today that address the root cause of this autoimmune destruction of the bile duct in PBC. With respect to IW-3300, our wholly owned Ironwood asset for the potential treatment of interstitial cystitis and bladder pain syndrome. There is a significant unmet medical need in this area as this chronic condition affects millions of Americans if there are very few treatment options currently on the market or in development. Last year, we successfully completed dosing in healthy volunteers and are currently executing the proof-of-concept Phase II study.

我們對 CNP-104 感到興奮，因為它是真正的精準醫學，它為 PBC 患者引入了一種潛在的改變遊戲規則的新資產，因為目前市場上沒有任何療法可以解決這種自身免疫性膽管破壞的根本原因中國人民銀行。關於 IW-3300，我們全資擁有的 Ironwood 資產可用於治療間質性膀胱炎和膀胱疼痛綜合徵。如果目前市場上或開發中的治療方案非常少，這種慢性病會影響數百萬美國人，因此該領域存在大量未滿足的醫療需求。去年，我們成功地完成了對健康志願者的給藥，目前正在進行概念驗證二期研究。

Interstitial cystitis and bladder pain syndrome patients are being screened, dosed and site activations are ongoing and going very well. We're excited about this program as is the first time that crosstalk hypothesis will be tested in humans, and we're proud to be at the forefront of clinical development in this area. We're looking forward to providing updates as the study continues to advance. With that, I'll turn the call over to Sravan.

正在對間質性膀胱炎和膀胱疼痛綜合徵患者進行篩查、給藥，並且正在進行現場激活，並且進展順利。我們對這個項目感到興奮，因為這是串擾假說首次在人體中進行測試，我們很自豪能夠站在該領域臨床開發的最前沿。隨著研究的繼續推進，我們期待提供更新。有了這個，我會把電話轉給 Sravan。

Thanks, Mike and good morning, everyone. It is wonderful to be in a position to discuss such great financial performance with all of you. I will begin with an update on LINZESS, which is off to an impressive start to the year. As shown on Slide 11, U.S. net sales were $250 million in the first quarter of 2023, an increase of 8% compared to the first quarter of 2022 driven by strong prescription demand growth of 10% year-over-year.

謝謝，邁克，大家早上好。很高興能夠與大家討論如此出色的財務業績。我將從 LINZESS 的更新開始，這是今年令人印象深刻的開端。如幻燈片 11 所示，在處方藥需求同比強勁增長 10% 的推動下，2023 年第一季度美國淨銷售額為 2.5 億美元，較 2022 年第一季度增長 8%。

We are excited about the strong start to the year and the continued momentum of the brand. Turning to LINZESS brand profitability. Commercial margins in the first quarter of 2023 were 73% compared to 74% in the first quarter of 2022. Moving to Ironwood revenues.

我們對今年的強勁開局和品牌的持續發展勢頭感到興奮。轉向 LINZESS 品牌盈利能力。 2023 年第一季度的商業利潤率為 73%，而 2022 年第一季度為 74%。轉向 Ironwood 收入。

In the first quarter of 2023, Ironwood revenues were $104 million, driven primarily by U.S. LINZESS collaboration revenues of $102 million. Ironwood recorded $20 million of income tax expense, the majority of which was noncash. GAAP net income was $46 million and adjusted EBITDA was $60 million in the first quarter.

2023 年第一季度，Ironwood 的收入為 1.04 億美元，主要受美國 LINZESS 合作收入 1.02 億美元的推動。 Ironwood 記錄了 2000 萬美元的所得稅支出，其中大部分是非現金支出。第一季度 GAAP 淨收入為 4600 萬美元，調整後的 EBITDA 為 6000 萬美元。

Next, cash and capital allocation. In the first quarter, we generated $80 million in cash flow from operations and ended the quarter with $740 million in cash and cash equivalents.

接下來，現金和資本配置。第一季度，我們從運營中產生了 8000 萬美元的現金流，並在本季度末擁有 7.4 億美元的現金和現金等價物。

We believe we are positioning our company for future success by maximizing LINZESS growth and actively pursuing innovative highly differentiated GI assets to strengthen our portfolio. We continue to take a balanced and disciplined approach to capital deployment and remain focused on identifying and investing in opportunities that we believe while the potential to create value for our patients and our shareholders over the long term.

我們相信，我們正在通過最大化 LINZESS 增長和積極追求創新的高度差異化 GI 資產來加強我們的產品組合，為我們公司未來的成功做好準備。我們繼續對資本部署採取平衡和有紀律的方法，並繼續專注於發現和投資我們認為有潛力為我們的患者和股東長期創造價值的機會。

Next, I'll review our 2023 guidance on Slide 12. We are encouraged by the strong start to the year and reiterate our full year 2023 guidance across all metrics. We continue to expect LINZESS U.S. net sales growth of between 3% and 5%, driven by high single-digit percent prescription demand growth. In addition, we expect to maintain our class leading payer access.

接下來，我將在幻燈片 12 上回顧我們的 2023 年指南。我們對今年的強勁開局感到鼓舞，並重申我們對所有指標的 2023 年全年指南。我們繼續預計 LINZESS 美國淨銷售額增長 3% 至 5%，受高個位數百分比處方需求增長的推動。此外，我們希望保持一流的付款人訪問權限。

We expect Ironwood revenue of between $420 million and $435 million and adjusted EBITDA of greater than $250 million, which includes increased investment to advance our pipeline programs CNP-104 and IW-3300.

我們預計 Ironwood 的收入在 4.2 億美元至 4.35 億美元之間，調整後的 EBITDA 超過 2.5 億美元，其中包括增加投資以推進我們的管道項目 CNP-104 和 IW-3300。

To wrap up, we had a strong start to the year and expect to build on the momentum with potential midyear pediatric functional constipation indication. Our first quarter results reflect continued execution against our strategic priorities. We remain -- we believe Ironwood is well positioned for continued growth and we remain focused on maximizing LINZESS, strengthening and progressing our innovative GI portfolio and delivering sustained profits and generating free cash flow. We are excited about what's ahead this year and we'll continue to keep you updated on our progress. 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 disorders.

總而言之，我們今年開局良好，並希望在年中潛在的兒科功能性便秘適應症的勢頭基礎上再接再厲。我們第一季度的業績反映了我們對戰略重點的持續執行。我們仍然——我們相信 Ironwood 處於持續增長的有利位置，我們仍然專注於最大化 LINZESS，加強和推進我們創新的 GI 產品組合，並提供持續的利潤和產生自由現金流。我們對今年的前景感到興奮，我們將繼續讓您了解我們的最新進展。最後，我要感謝我們所有的員工、患者、護理人員和倡導者，感謝他們共同致力於推進和支持胃腸道疾病的治療。

Operator, you may now open the line for questions.

接線員，您現在可以打開問題熱線。

(Operator Instructions) Your first question comes from Tim Chiang with Capital One.

（操作員說明）您的第一個問題來自 Capital One 的 Tim Chiang。

Tom, could you talk a little bit about just obviously, the demand trends for LINZESS are doing quite well. And could you just talk a little bit about how you sort of see the rest of the year playing out for LINZESS? Obviously, it looks like you're going to get a pediatric functional constipation indication. How much additional growth do you think you'll see with that indication longer?

湯姆，你能談談嗎，很明顯，LINZESS 的需求趨勢非常好。你能談談你如何看待 LINZESS 今年剩餘時間的表現嗎？很明顯，看起來你會得到小兒功能性便秘的指徵。您認為隨著該指示的延長，您會看到多少額外的增長？

Thanks, Tim. Well, I think you can hear we're quite excited about what we're seeing in the first half -- the first quarter of this year. And we're continuing to see this demand growth moving forward. I think we'll see -- we need a couple of more data points to really understand how we think we're going to land the year. So it's the reason why we're kind of staying firm on our current guidance. But I think the next month or so will give us a really good idea. As you know, this market tends to slow down a little bit in the summer and then accelerate growth in the back half of the year.

謝謝，蒂姆。嗯，我想你可以聽到我們對我們在上半年 - 今年第一季度看到的情況感到非常興奮。我們將繼續看到這種需求增長向前發展。我想我們會看到 - 我們需要更多的數據點來真正了解我們認為我們將如何登陸這一年。因此，這就是我們堅持當前指導方針的原因。但我認為下個月左右會給我們一個非常好的主意。如您所知，這個市場在夏季往往會稍微放緩，然後在下半年加速增長。

But we're not seeing that right now. I mean, we're seeing the market grow and we are growing disproportionately capturing that market. So I think we're in a very, very healthy place for the brand. It's interesting. We've seen this growth spike that seems to be coinciding with our new DTC ad as well as we made some adjustments to the physician call plan with AbbVie, which we think is helping augment some of the growth we're seeing. I think we're very optimistic about the pediatric population. As Mike said, there are 6 million to 8 million kids out there that are suffering.

但我們現在還沒有看到。我的意思是，我們看到市場在增長，而且我們正在不成比例地佔領該市場。所以我認為我們的品牌處於一個非常、非常健康的位置。這真有趣。我們已經看到這種增長高峰似乎與我們的新 DTC 廣告相吻合，我們也對 AbbVie 的醫生呼叫計劃進行了一些調整，我們認為這有助於增加我們看到的一些增長。我認為我們對兒科人群非常樂觀。正如邁克所說，那裡有 600 萬到 800 萬兒童正在受苦。

And I think the big opportunity here, Tim, is the fact that these kids are actively seeking care, which is very different than the adult population where adults will struggle and try to self-medicate. But if you have a kid that's really disabled with abdominal symptoms and constipation, you're talking to a doctor probably multiple times here, which we're going to certainly see what we can do to help. We're going to -- we're trying to be very thoughtful about how we're going to allocate the investment and we'll be running a series of pilots with our partner, AbbVie, to really assess how promotionally responsive this pediatric market is, which really will inform the investment for next year. So I don't know that we'll see a whole lot of growth coming out of this market.

蒂姆，我認為這裡的大機會是這些孩子正在積極尋求護理，這與成年人會掙扎並嘗試自我治療的成年人有很大不同。但是，如果您的孩子真的因腹部症狀和便秘而殘疾，那麼您可能會在這裡多次與醫生交談，我們肯定會看到我們可以做些什麼來提供幫助。我們將 - 我們正在努力考慮如何分配投資，我們將與我們的合作夥伴 AbbVie 一起進行一系列試點，以真正評估這個兒科市場的促銷反應是，這真的將為明年的投資提供信息。所以我不知道我們會看到這個市場出現大量增長。

I will hope we see growth, but I think the real impact will come in '24 and '25 as we invest -- focus and invest in this market. But at this point in time, Tim, we're really delighted with the performance of the drug.

我希望我們能看到增長，但我認為真正的影響將在 24 和 25 年出現，因為我們投資 - 關注並投資這個市場。但在這個時候，蒂姆，我們對這種藥物的表現非常滿意。

Okay. Great. That's helpful. And maybe just one question on CNP-104. Mike, you talked about T-cell response. What sort of threshold do you need to see in this Phase II study?

好的。偉大的。這很有幫助。也許只有一個關於 CNP-104 的問題。邁克，你談到了 T 細胞反應。在這項 II 期研究中，您需要看到什麼樣的閾值？

Yes. Thanks for the question. So as you know, this is a first-in-human study with this technology in PBC, so we're going to learn a lot. It's one of the reasons why we actually did this deal because the science is so strong and we think -- we feel we really do have an opportunity to understand how the drug may work by looking at the T-cell responses. You may also recall back in the celiac study, they had a pretty robust T-cell response, meaning the using nanoparticles with gliadin or gluten inside that reduced T-cell responses with treatment roughly like 88%. So that's was pretty robust. But the key point is not necessarily a T-cell reduction, but that it correlates with the biomarkers as well and in celiac, it actually correlated with epithelial histology improvement.

是的。謝謝你的問題。如您所知，這是在 PBC 中使用這項技術進行的首次人體研究，因此我們將學到很多東西。這是我們實際上做這筆交易的原因之一，因為科學是如此強大，我們認為 - 我們覺得我們確實有機會通過觀察 T 細胞反應來了解藥物的作用。您可能還記得在乳糜瀉研究中，它們具有非常強大的 T 細胞反應，這意味著使用內部含有麥醇溶蛋白或麩質的納米顆粒可以降低大約 88% 的 T 細胞反應。所以這是非常強大的。但關鍵點不一定是 T 細胞減少，而是它也與生物標誌物相關，在乳糜瀉中，它實際上與上皮組織學改善相關。

So we're going to look at the T-cell responses and we think we can get a really clear gauge on whether the drug is going to work by the T-cell responses. The absolute percent will remain to be seen, but we're going to have to look at the correlation with the biomarkers in terms of liver function to really understand where that's going to play out in terms of the longer-term clinical benefit, but we're really excited about the opportunity to look at the T-cell responses early to really make an early read for further investment and for the business case downstream because we think the science is so strong. There's just a great opportunity to do that.

因此，我們將研究 T 細胞反應，我們認為我們可以通過 T 細胞反應非常清楚地衡量藥物是否會起作用。絕對百分比還有待觀察，但我們將不得不在肝功能方面研究與生物標誌物的相關性，以真正了解它在長期臨床益處方面的作用，但我們我真的很高興有機會儘早查看 T 細胞反應，以便為進一步投資和下游商業案例真正儘早閱讀，因為我們認為科學是如此強大。這是一個很好的機會。

And Mike, maybe if you comment also on which biomarkers are probably most relevant and how does the FDA look at that as an endpoint as far as drugs respond.

邁克，如果你也評論哪些生物標誌物可能最相關，以及 FDA 如何將其視為藥物反應的終點。

Yes. The biomarkers are pretty fairly established because of prior regulatory engagement because of ursodeoxycholic acid and obeticholic acid. So that -- and in those programs, the agency focused on alk phos, which is not unreasonable. Alk phos is a primary indicator of cholestasis, which is delayed or stopped bile flow and that's really what these liver diseases are about the delayed or stopped bile flow. So alk phos is clearly there.

是的。由於熊去氧膽酸和奧貝膽酸的先前監管參與，生物標誌物已經相當成熟。因此——在這些項目中，該機構專注於 alk phos，這並非不合理。 Alk phos 是膽汁淤積的主要指標，膽汁流動延遲或停止，而這正是這些肝病與膽汁流動延遲或停止有關的原因。所以 alk phos 顯然在那裡。

And then we also have things in there for liver function like bilirubin and other assessments, transaminases as well. And then importantly, we have in there the biopsy too because you may recall also that obeticholic acid needed to do a biopsy type study. And that's because the agency wants to make sure the biomarkers correlate with real improved liver function and the biopsy is sort of the standard today.

然後我們還有肝功能的東西，比如膽紅素和其他評估，還有轉氨酶。然後重要的是，我們也在那裡進行了活檢，因為您可能還記得奧貝膽酸需要進行活檢類型研究。那是因為該機構希望確保生物標誌物與真正改善的肝功能相關，而活檢是當今的標準。

But that's another reason why we think we're in a great position with this technology because the way the agency uses the biopsy and the other programs is really for objective evidence that the drug is working and not necessarily biomarker-driven evidence, that's where the biopsy plays, but that's why we like the T-cells because the T-cells will be a really strong objective assessment as well. And to be able to get an early read on such a strong objective assessment that really is the underlying mechanism of how the drug works is quite strong and very powerful in drug development.

但這是我們認為我們在這項技術方面處於有利地位的另一個原因，因為該機構使用活組織檢查和其他程序的方式實際上是為了客觀證據證明該藥物正在起作用，而不一定是生物標誌物驅動的證據，這就是活檢發揮作用，但這就是我們喜歡 T 細胞的原因，因為 T 細胞也將是一個非常強大的客觀評估。並且能夠及早閱讀如此強大的客觀評估，這確實是藥物如何起作用的潛在機制，這在藥物開發中非常強大。

Your next question comes from the line of David Amsellem with Piper Sandler.

你的下一個問題來自 David Amsellem 和 Piper Sandler 的台詞。

This is Skyler on for David. Can you remind us how you're thinking about the physician target audience for the pediatric opportunity and the potential need to expand sales force head count to support this opportunity.

這是戴維的斯凱勒。您能否提醒我們您是如何考慮兒科機會的醫生目標受眾以及擴大銷售人員人數以支持這一機會的潛在需求。

Sure. As I mentioned earlier, we're going to be running a series of pilots. There won't be any -- at this point, there won't be any increase in selling effort. We're really -- the good news here is this is a fairly concentrated prescriber base, like 3,000 to 4,000 docs will generate 30% to 40% of the volume. So we can easily fold those docs into our existing call list and trade off those for kind of lower performing or lower -- less busy positions.

當然。正如我之前提到的，我們將進行一系列試點。不會有任何——在這一點上，銷售努力不會有任何增加。我們真的——這裡的好消息是這是一個相當集中的處方基礎，比如 3,000 到 4,000 個文檔將產生 30% 到 40% 的數量。因此，我們可以輕鬆地將這些文檔折疊到我們現有的呼叫列表中，並將這些文檔換成性能較低或不太忙的職位。

And we'll let the data really guide our decision on this one. So if we see some fairly significant response there, then we'll go back and take a look at do we think we need to increase our selling effort. At this point, that's not the plan. Keep in mind, we're currently calling out about 35,000 physicians who generate the majority of the business. So this isn't a significant increase in the number of targets, but it will really give us a good line of sight with regard to how hard do we think we need to push to make -- to really affect and I'll come and then we'll come back and look at not only the selling effort, but the overall promotional mix, which we continue to refine as we balance both personal promotion with direct-to-consumer advertising and our direct patient programs.

我們會讓數據真正指導我們對此的決定。因此，如果我們在那裡看到一些相當顯著的反應，那麼我們將回頭看看我們是否認為我們需要增加銷售力度。在這一點上，這不是計劃。請記住，我們目前正在召集約 35,000 名產生大部分業務的醫生。所以這並不是目標數量的顯著增加，但它確實會讓我們很好地了解我們認為我們需要付出多大的努力才能真正產生影響，我會來的然後，我們不僅會回過頭來審視銷售工作，還會審視整體促銷組合，我們會在平衡個人促銷與直接面向消費者的廣告和我們的直接患者計劃時繼續完善這一組合。

Your next question comes from the line of Boris Peaker with Cowen.

你的下一個問題來自 Boris Peaker 與 Cowen 的對話。

I guess for CNP-104, I just want to clarify for approval, ultimately, can you get an approval in this indication based on some of these biomarkers like you just talked about. Or would you have to do an actual study with a clinical outcome?

我想對於 CNP-104，我只是想澄清一下批准，最終，你能不能根據你剛才談到的這些生物標誌物中的一些來獲得這個適應症的批准。還是您必須進行具有臨床結果的實際研究？

Yes. So prior history has kind of addressed that with obeticholic acid because they got approval based on the biomarker of improvement in alk phos. That has also been historic with ursodeoxycholic acid or Urso that class of compounds. So it has been done usually in that setting has happened in the obeticholic acid case. They get a post-marketing requirement to do another study like a liver study, but they're on the market. And that's clearly because the benefit with those agents, they improve cholestasis. So patients do better and they should be on them, and they're good products, but they don't address the root cause of the disease like we do with CNP-104, and that's also evident in what a responder is for obeticholic acid because the alk phos is the biomarker, but you don't have to normalize alk phos to actually be a responder in those programs.

是的。因此，之前的歷史已經用奧貝膽酸解決了這個問題，因為他們基於 alk phos 改善的生物標誌物獲得了批准。這對於熊去氧膽酸或 Urso 這類化合物也具有歷史意義。所以它通常是在奧貝膽酸案例中發生的情況下完成的。他們得到上市後要求進行另一項研究，如肝臟研究，但他們已經上市了。這顯然是因為這些藥物的好處，它們可以改善膽汁淤積。所以患者做得更好，他們應該服用，他們是好產品，但他們沒有像我們對 CNP-104 那樣解決疾病的根本原因，這在奧貝膽酸的反應者中也很明顯因為 alk phos 是生物標誌物，但您不必將 alk phos 標準化為這些程序中的實際響應者。

You can actually get to 1.5x or 1.67x normal, which still means you have roughly 50% or 67% of your liver function potentially abnormal because your alk phos is elevated to that degree. So alk phos has been accepted by the agency for a marker for success and does usually come with post-mark agreements. And that's why we like the objectivity around the T-cell response because getting an early read on that, I think, gives us a real good insight into the opportunity more longer term.

實際上，您可以達到正常值的 1.5 倍或 1.67 倍，這仍然意味著您大約有 50% 或 67% 的肝功能可能出現異常，因為您的 alk phos 升高到了那個程度。因此，alk phos 已被該機構接受為成功的標記，並且通常帶有標記後協議。這就是為什麼我們喜歡圍繞 T 細胞反應的客觀性，因為我認為，及早閱讀它可以讓我們真正深入了解更長期的機會。

Clear, Mike. The actual responder endpoint that is to reduce alk phos to a level that's 1.5x normal.

清楚，邁克。將 alk phos 降低到正常水平的 1.5 倍的實際響應端點。

Correct. Right.

正確的。正確的。

Okay.

好的。

And for an ultimate pivotal study, could you get approved really on a placebo control? Or do you think you'd have to use an active control in this space since it's the standard of care?

對於最終的關鍵研究，您真的可以通過安慰劑對照獲得批准嗎？或者你認為你必須在這個空間使用主動控制，因為它是護理標準？

Yes. I think we'll certainly, we'll have discussions with the agency on what the Phase III design would look like. Again, we don't have any data to date to have those discussions. But as soon as we get that, we will. We do anticipate that there's an opportunity for placebo-controlled now granted Urso standard of care as well as Urso failures can take obeticholic acid.

是的。我認為我們肯定會與該機構討論 III 期設計的樣子。同樣，我們目前沒有任何數據可以進行這些討論。但是一旦我們得到它，我們就會。我們確實預計，安慰劑對照現在有機會獲得 Urso 標準護理，而且 Urso 失敗可以服用奧貝膽酸。

So we need to manage that. Obviously, we want to keep patients being treated. Currently, the study we're designing is for Urso and nonresponders. So we do have to cross that bridge when we get there. But I think that's really another unique feature of this asset because even in the setting of an Urso responder or an obeticholic acid responder, again, they still have often an abnormal alk phos and there still is benefit using this therapy.

所以我們需要管理它。顯然，我們希望讓患者繼續接受治療。目前，我們正在設計的研究是針對 Urso 和無反應者的。所以當我們到達那裡時，我們必須穿過那座橋。但我認為這確實是該資產的另一個獨特特徵，因為即使在 Urso 反應者或奧貝膽酸反應者的情況下，他們仍然經常有異常的 alk phos，並且使用這種療法仍然有好處。

So standard of care are not included, we still think we have an opportunity to show a benefit even in patients who may be a responder to the other agents being used. Does that make sense, first?

因此不包括標準護理，我們仍然認為即使在可能對所使用的其他藥物有反應的患者中，我們仍然有機會顯示出益處。首先，這有意義嗎？

Your next question comes from Jacob Hughes with Wells Fargo Securities.

你的下一個問題來自富國銀行證券公司的雅各布休斯。

A couple of questions. On the pricing headwind in the quarter, I think the implied it was down 3. Could you just talk about the dynamics you're seeing for the rest of the year because if there was any benefit because I think last year, you guys had one-time growth in that benefit in the first quarter of last year? Is that a similar dynamic?

幾個問題。關於本季度的定價逆風，我認為這意味著它下降了 3。你能談談你在今年餘下時間看到的動態嗎，因為如果有任何好處，因為我認為去年，你們有一個-去年第一季度該收益的時間增長？那是類似的動態嗎？

Yes. So thanks for the question, Jacob. I would start by saying I'm really pleased with the start to the year. 8% net sales growth as you kind of got to was driven by prescription demand of about 10% and the rest is sort of essentially a price segment. Yes, price and everything else kind of performed in line. I would say that, look, we have a pretty good set of into -- good line of sight into where our expectations are for price over the course of the year. This is not similar to last year, which had a one-time price benefit. This is really about where we ended up for the quarter -- this quarter because of contracting and what we aligned for the full year. It's a little better potentially than we anticipated. But I would say that we said low single digits in terms -- sorry, mid-single digits is sort of the full year guidance in terms of implied for price. We'll see where it comes out. But I think we're really pleased with where we are today.

是的。謝謝雅各布的提問。首先，我要說我對今年的開始感到非常滿意。 8% 的淨銷售額增長是由大約 10% 的處方需求推動的，其餘基本上是一個價格段。是的，價格和其他一切都在排隊。我想說的是，看，我們有一套很好的方法——很好地了解我們對一年中價格的預期。這與去年有一次性價格優勢的情況不同。這實際上是關於我們本季度結束的地方——這個季度是因為合同和我們全年的調整。它可能比我們預期的要好一些。但我要說的是，我們說的是低個位數——抱歉，就隱含價格而言，中個位數是全年指導。我們會看到它從哪裡出來。但我認為我們對今天的狀況非常滿意。

Okay. And then on the guidance. Okay like the first quarter is a little bit better from our demand standpoint, like the weekly scripts look about the same so far in the second quarter. Pricing is a little bit better. So is there anything you're seeing in the back after the year that's giving you some pause in terms of the guidance? I know it's only 1 quarter in the back. And then like, how much of the -- how much of the pediatric functional constipation indication. Is that in there for the second half as well?

好的。然後就指導了。好吧，從我們的需求角度來看，第一季度要好一些，就像第二季度到目前為止每週的劇本看起來差不多一樣。定價稍微好一點。那麼，你在一年後看到的任何東西讓你在指導方面有所停頓嗎？我知道後面只有 1 個季度。然後，有多少 - 有多少兒科功能性便秘適應症。下半場也有嗎？

Yes. So look, yes, so let me start by saying, look, I think we're really excited about where we are this year. And I think we want to see 1 quarter doesn't make transient. I am going to see a little bit more data before we can come back to you and give you any change in the guidance at all. But we're pleased with the momentum we have in the first quarter. And on the price piece, I was trying to just put a finer point, I'd look it fluctuate from throughout the year. First quarter was more moderate than we experienced in the course of 2022. And if this sustains itself, I think we'll be able to come back to you and give you a better sense.

是的。所以看，是的，所以讓我首先說，看，我認為我們對今年的位置感到非常興奮。而且我認為我們希望看到 1 個季度不會變得短暫。在我們返回給您並對指南進行任何更改之前，我將查看更多數據。但我們對第一季度的勢頭感到滿意。在價格方面，我只是想提出一個更好的觀點，我認為它全年都在波動。第一季度比我們在 2022 年經歷的要溫和。如果這種情況持續下去，我想我們將能夠回到你身邊，讓你有更好的感覺。

Our guidance does and has always contemplated any contribution from pediatrics. So look, I think we're really happy with where we are. I think you've heard it on the call, excitements here on LINZESS performance. And if we have something to tell you in the second quarter and then we continue to see performance like this, we may come back to you to give you an update that.

我們的指南確實並且一直在考慮兒科的任何貢獻。所以看，我認為我們對我們所處的位置非常滿意。我想你已經在電話中聽到了，LINZESS 的表現令人興奮。如果我們在第二季度有什麼要告訴你的，然後我們繼續看到這樣的表現，我們可能會回來給你更新。

Yes. I think we're cautiously optimistic and this is why we're kind of being a little careful this year with regard to the upside of the pediatrics. And this is the reason why, again, we're running these pilots to really understand how promotional response this group is. And we're -- we'll have a lot more information by the end of the third quarter with regard to what we think we're going to see because I think we'll see a quick response, one way or the other.

是的。我認為我們持謹慎樂觀的態度，這就是為什麼我們今年對兒科的優勢有點謹慎。這就是為什麼我們再次運行這些試點以真正了解這個群體的促銷反應的原因。而且我們 - 到第三季度末，我們將獲得更多關於我們認為我們將要看到的信息，因為我認為我們會以某種方式看到快速反應。

I think we'll have a pretty good line of sight. I think the one thing we've learned in this market, this category is one, the kids are actively seeking care, as I mentioned. But also these physicians end up to be quite pediatricians end up following clinical practice guidelines and standard of care. And this is one where -- this will be the only drug actually approved for functional constipation. We think that's a real asset because traditionally, pediatricians don't like prescribing drugs off-label for kids. And to have a drug that's approved for these kids, I think it could be a real advantage. But stay tuned and we'll certainly keep you updated as far as what we see in the market as we launch the new indication.

我想我們會有很好的視線。我認為我們在這個市場上學到的一件事，就是這個類別，正如我提到的，孩子們正在積極尋求照顧。但這些醫生最終也會成為兒科醫生，最終會遵循臨床實踐指南和護理標準。這就是——這將是唯一一種真正被批准用於治療功能性便秘的藥物。我們認為這是一項真正的資產，因為傳統上，兒科醫生不喜歡為孩子開標籤外的藥物。擁有一種被批准用於這些孩子的藥物，我認為這可能是一個真正的優勢。但請繼續關注，在我們推出新適應症時，我們一定會讓您了解我們在市場上看到的最新情況。

With no further questions, we will conclude today's conference. Thank you for your participation. You may now disconnect.

沒有其他問題，我們將結束今天的會議。感謝您的參與。您現在可以斷開連接。