United Therapeutics Corp (UTHR) 2025 Q2 法說會逐字稿

Good morning, and welcome to the United Therapeutics Corporation second quarter 2025 corporate update. My name is Steve, and I'll be your conference operator today.(Operator Instructions) Please note, this call is being recorded.

早安，歡迎收看聯合治療公司 2025 年第二季公司更新報告。我叫史蒂夫，今天我將擔任你們的會議接線生。 （接線生指示）請注意，此通話正在錄音。

I will now like to turn the webcast over to Dewey Steadman, Head of Investor Relations at United Therapeutics. Please go ahead.

現在，我想將網路直播交給聯合治療公司投資者關係主管杜威·斯特德曼 (Dewey Steadman)。請繼續。

Thank you, Steve, and good morning. It's my pleasure to welcome you to the United Therapeutics Corporation's second quarter 2025 Corporate Update Webcast. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements will involve risks and uncertainties that may cause actual results to differ materially.

謝謝你，史蒂夫，早安。我很高興歡迎您參加聯合治療公司 2025 年第二季公司更新網路廣播。今天的評論將包括前瞻性陳述，代表我們對未來事件的期望或信念。這些聲明將涉及風險和不確定性，可能導致實際結果大不相同。

Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties. We assume no obligation to update these forward-looking statements. Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products and these remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for our products are available on our website.

我們最新的 SEC 文件（包括 10-K 表和 10-Q 表）包含有關這些風險和不確定性的更多資訊。我們不承擔更新這些前瞻性陳述的義務。今天的發言可能會討論臨床試驗的進展和結果或我們產品的其他發展，這些發言僅用於教育投資者，並不旨在作為醫療決策的基礎或表明任何產品對於任何未經批准或研究用途都是安全有效的。我們的產品的完整處方資訊可在我們的網站上找到。

Accompanying me today on today's call are Dr. Martine Rothblatt, our Chairperson and Chief Executive Officer; Michael Benkowitz, our President and Chief Operating Officer; James Edgemond, our Chief Financial Officer and Treasurer; Dr. Leigh Peterson, our Executive Vice President of Product Development and Xenotransplantation; Pat Poisson, our Executive Vice President of Technical Operations; Gil Golden, our Dr. Gil Golden, our Executive Vice President and Chief Medical Officer; and CQ, Deng, our Senior Vice President of Biostatistics, Statistical Programming and Data Management.

今天陪同我參加電話會議的有我們的董事長兼首席執行官 Martine Rothblatt 博士、我們的總裁兼首席營運官 Michael Benkowitz、我們的首席財務官兼財務主管 James Edgemond、我們的產品開發和異種移植執行副總裁 Leigh Peterson 博士、我們的技術運營執行副總裁 Pat Poisson、我們的執行副總裁兼首席醫療官 Gil Peterson 博士、我們的技術運營執行副總裁 Pat Poisson、我們的執行副總裁兼首席醫療官 Gil PQ. Nang NQ Nang Nang Nang NGGeng、首席醫療官和首席醫療官。

Note that James Edgemond, my colleague, Harry Silvers and I will participate in a fireside chat and one-on-one meetings at the Morgan Stanley Global Healthcare Conference in New York on September 8. Along with Martine Rothblatt, Harry and I will be at the Bernstein's Second Annual Healthcare Forum in New York on September 23 for a fireside chat and one-on-one meetings.

請注意，我的同事 James Edgemond、Harry Silvers 和我將於 9 月 8 日參加在紐約舉行的摩根士丹利全球醫療保健大會的爐邊談話和一對一會議。9 月 23 日，Harry 和我將與 Martine Rothblatt 一起出席在紐約舉行的伯恩斯坦第二屆年度醫療保健論壇，進行爐邊談話和一對一會談。

Additionally, our scientific commercial and medical affairs team will present at the World Transplant Congress in San Francisco August 2 through 6. The European Respiratory Society Congress in Amsterdam on September 27 through October 1, the 18th Congress of the International Xenotransplantation Association in Geneva, September 30 to October 3, and the American College of Chest Physicians meeting CHEST 2025 in Chicago, October 19 through 22.

此外，我們的科學商業和醫療事務團隊將於 8 月 2 日至 6 日出席在舊金山舉行的世界移植大會。歐洲呼吸學會大會於 9 月 27 日至 10 月 1 日在阿姆斯特丹舉行，第 18 屆國際異種移植協會大會於 9 月 30 日至 10 月 3 日在日內瓦舉行，美國胸腔科醫師學會會議 CHEST 2025 於 10 月 19 日至 22 日在芝加哥舉行。

Now I'll turn the webcast over to Martine for an overview of our development pipeline and business activities. Martine?

現在，我將網路廣播交給 Martine，讓她概述我們的開發流程和業務活動。馬丁？

Thank you, Dewey, and good morning, everyone. We have slides available for reference, and I encourage you to review those at your leisure. Today, we're proud to report that United Therapeutics has achieved another record quarter of earnings, marking 12 consecutive quarters of double-digit year-over-year revenue growth. Our performance is a testament to our unwavering strategic approach which has allowed us to consistently drive sustainable growth while improving the lives of the patients we serve.

謝謝你，杜威，大家早安。我們有投影片可供參考，我鼓勵您在閒暇時查看這些投影片。今天，我們很自豪地報告，聯合治療公司又取得了創紀錄的季度收益，連續 12 個季度實現兩位數的同比收入增長。我們的業績證明了我們堅定不移的策略方針，這使我們能夠持續推動永續成長，同時改善我們服務的患者的生活。

Our strong foundational business is supported by our robust Tyvaso franchise, which continues to achieve record results underpinned by our first-in-class Tyvaso DPI device and enduring market fundamentals that we expect will propel future growth.

我們強大的基礎業務由強大的 Tyvaso 特許經營權提供支持，該特許經營權繼續取得創紀錄的業績，這得益於我們一流的 Tyvaso DPI 設備和持久的市場基本面，我們預計這將推動未來的成長。

Additionally, Orenitram, Remodulin and Unituxin remain integral components of our commercial portfolio and continued to deliver strong performance. our next wave of growth, which we call our innovation wave consists of our TETON studies in idiopathic pulmonary fibrosis and our ADVANCE OUTCOMES study in pulmonary arterial hypertension, which we're on the cusp of reporting results, starting with TETON 2 in September of this year.

此外，Orenitram、Remodulin 和 Unituxin 仍然是我們商業產品組合中不可或缺的組成部分，並繼續提供強勁的業績。我們的下一波成長，我們稱之為創新浪潮，包括我們對特發性肺纖維化的 TETON 研究和我們對肺動脈高壓的 ADVANCE OUTCOMES 研究，我們即將報告結果，從今年 9 月的 TETON 2 開始。

Each of these catalysts has the potential to fundamentally change our revenue profile and deliver growth well into the next decade. Our largest potential wave of growth, a revolution wave continues to make progress and we are on track to conduct the first transplant in our EXPAND - UKidney clinical study shortly.

每個催化劑都有可能從根本上改變我們的收入狀況，並在未來十年帶來良好的成長。我們最大的潛在成長浪潮，革命浪潮正在繼續取得進展，我們即將在 EXPAND - UKidney 臨床研究中進行首次移植。

Concurrently, with this first ever Phase I study and as part of our multiple shots on goal approach, we're also proud to announce that we have filed an investigational new drug application for our EXTEND study, evaluating our UThymoKidney, and we expect to file for our EXPRESS study evaluating UHeart.

同時，透過這項首次 I 期研究，作為我們多次努力實現目標的一部分，我們也自豪地宣布，我們已經為 EXTEND 研究提交了一份新藥研究申請，以評估我們的 UThymoKidney，並且我們預計將為評估 UHeart 的 EXPRESS 研究提交申請。

Additionally, last month, we announced that we enrolled and treated the first patient in our miroliverELAP study. Recently, our Investor Relations team launched a new pipeline website at pipeline.unither.com that contains detailed information and links to publications about our pipeline candidates.

此外，上個月，我們宣布已招募並治療了 miroliverELAP 研究中的第一位患者。最近，我們的投資者關係團隊在pipeline.unither.com上推出了一個新的管道網站，其中包含有關我們的管道候選人的詳細資訊和出版物連結。

I encourage you to take a look. Our ability to deliver such remarkable growth and pipeline innovation is matched only by our commitment to financial prudence the exceptional operating efficiency that we have cultivated has allowed us to generate nearly $1.5 billion in annual operating cash flow.

我鼓勵你去看一下。我們實現如此顯著的成長和管道創新的能力只有透過我們對財務審慎的承諾才能實現，我們所培養的卓越營運效率使我們能夠產生近 15 億美元的年度營運現金流。

Our disciplined approach allows us to strategically allocate capital, ensuring that United Therapeutics remains flexible, resilient and well positioned for sustained success in the years ahead. Given the strength of our commercial business, our robust balance sheet and confidence in our upcoming catalysts, we believe that the recent dislocation in our share price presents a particularly compelling investment opportunity. And as such, our Board of Directors has authorized the repurchase of up to $1 billion in our shares through March of next year.

我們嚴謹的方法使我們能夠策略性地分配資本，確保聯合治療公司在未來幾年保持靈活性、彈性並取得持續成功。鑑於我們商業業務的實力、穩健的資產負債表以及對即將到來的催化劑的信心，我們相信，近期股價的波動帶來了特別引人注目的投資機會。因此，我們的董事會已授權在明年 3 月之前回購價值高達 10 億美元的股票。

We will continue to regularly evaluate our capital needs and deploy cash for the highest and best uses even after the potential repurchase of shares as authorized by our Board, we remain well capitalized to continue advancing our commercial and development programs. As we approach these meaningful and potentially value-creating catalysts across pulmonary fibrosis and pulmonary arterial hypertension, we could not be more confident in the future of our business.

我們將繼續定期評估我們的資本需求，並將現金部署到最高和最佳用途，即使在董事會授權的潛在回購股票之後，我們仍然擁有充足的資本來繼續推進我們的商業和發展計劃。當我們在肺纖維化和肺動脈高壓領域研究這些有意義且可能創造價值的催化劑時，我們對業務的未來充滿信心。

To conclude, we expect to sustain growth in our foundational business which continues to drive significant cash flow and opportunity while also progressing our innovative small molecule pipeline and our platform of organ alternative technologies. We're excited about our current business and our growth potential, and we appreciate the feedback and support from our shareholders.

總而言之，我們預計基礎業務將保持成長，這將繼續推動大量現金流和機遇，同時也將推動我們創新的小分子管道和器官替代技術平台的發展。我們對目前的業務和成長潛力感到非常興奮，並感謝股東的回饋和支持。

We have a number of different presentations this morning with Michael Benkowitz addressing our commercial performance, Leigh Peterson outlining our TETON 2 study for which we expect to report data in September. CQ, Deng, our Chief Biostatistician to talk about the recent Insmed Phase II data and then Dr. Gil Golden, our Chief Medical Officer, who will outline the expected limited impact we believe TPIP will have on the market if it is approved. Mike?

今天早上我們進行了多場不同的演講，其中 Michael Benkowitz 介紹了我們的商業表現，Leigh Peterson 概述了我們的 TETON 2 研究，我們預計將於 9 月報告相關數據。CQ，我們的首席生物統計學家鄧將討論最近的 Insmed II 期數據，然後我們的首席醫療官 Gil Golden 博士將概述我們認為 TPIP 獲得批准後對市場產生的有限影響。麥克風？

Thank you, Martine, and good morning, everyone. Today, we are pleased to report record total revenue of $799 million, reflecting 12% growth over the second quarter of 2024. This is our 12th consecutive quarter of double-digit year-over-year total revenue growth driven by robust results across our commercial portfolio. Underpinning this performance, Tyvaso DPI achieved a record total revenue of $315 million, representing 22% growth over the second quarter of 2024. This quarter also marked a record for patient shipments for Tyvaso DPI as well as the total Tyvaso franchise.

謝謝你，馬丁，大家早安。今天，我們很高興地報告總收入達到創紀錄的 7.99 億美元，比 2024 年第二季成長了 12%。這是我們連續第 12 個季度實現兩位數的同比總收入成長，這得益於我們商業投資組合的強勁業績。在這項業績的支撐下，Tyvaso DPI 實現了創紀錄的 3.15 億美元總收入，比 2024 年第二季成長了 22%。本季度還創下了 Tyvaso DPI 以及整個 Tyvaso 特許經營店的患者出貨量記錄。

The underlying dynamics remain strong with referrals and starts each reaching record levels for Tyvaso DPI during the quarter. We also saw year-over-year double-digit revenue growth for nebulized Tyvaso, Orenitram and Unituxin. For Orenitram, this quarter represented a record in both total revenue and patient shipments.

在本季度，Tyvaso DPI 的推薦量基本上保持強勁，並開始達到創紀錄的水平。我們也看到霧化 Tyvaso、Orenitram 和 Unituxin 的營收年比實現了兩位數成長。對於 Orenitram 來說，本季的總收入和患者出貨量均創下了紀錄。

Touching briefly on Remodulin performance, we are still seeing strong demand for Remodulin, which notched a top five quarter in total patient shipments, and we are confident that parenteral prostacyclin will continue to play a meaningful role in the marketplace.

簡單介紹一下 Remodulin 的性能，我們仍然看到市場對 Remodulin 的強勁需求，其在患者總出貨量中位列前五名，我們相信腸外前列環素將繼續在市場上發揮重要作用。

We look forward to the launch of our next-generation pump RemunityPRO later this year. With the recent launch of a competing treprostinil dry powder inhaler, I'd like to address several areas of misinformation in the marketplace about Tyvaso DPI. Liquidia is attempting to differentiate their product in the areas of dosing, tolerability, particle deposition and ease of use.

我們期待今年稍後推出我們的下一代泵 RemunityPRO。隨著最近推出的競爭性曲前列尼爾乾粉吸入器，我想解決市場上有關 Tyvaso DPI 的幾個錯誤訊息。Liquidia 正試圖在劑量、耐受性、顆粒沉積和易用性方面使其產品與眾不同。

First, there is no maximum dose for Tyvaso DPI and there's no commercial available treprostinil DPI that published higher (inaudible) at higher doses than Tyvaso DPI. Recall in the brief study of Tyvaso DPI, we saw patient exposure up to 33 nebulized breadth equivalents or 176 micrograms at 51 weeks.

首先，Tyvaso DPI 沒有最大劑量，也沒有市售的曲前列尼爾 DPI 在高於 Tyvaso DPI 的劑量下具有更高的（聽不清楚）效果。回想 Tyvaso DPI 的簡短研究中，我們發現患者在 51 週時暴露量高達 33 個霧化寬度當量或 176 微克。

Next, tolerability. Clinical data for Tyvaso DPI showed the key tolerability factors like cough and throat irritation decreased meaningfully over time. Contrary to that clinical data for Liquidia's product shows that cough and throat irritation actually increase over time.

接下來是耐受性。Tyvaso DPI 的臨床數據顯示，咳嗽和喉嚨刺激等關鍵耐受性因素隨著時間的推移而顯著減少。與此相反，Liquidia 產品的臨床數據顯示，咳嗽和喉嚨刺激實際上會隨著時間的推移而增加。

Now turning to deposition and has been previously shown in peer review publications that the optimal particle size for pulmonary deposition is one to five microns, thus leading to effective delivery and absorption to more peripheral areas of the lungs. Tyvaso DPI

現在轉向沉積，先前在同行評審出版物中已經表明，肺部沉積的最佳粒徑為一到五微米，從而導致有效輸送和吸收到肺部的更多外圍區域。泰瓦索 DPI

particles at 2.6 microns are in the optimal size range to promote efficient medication delivery. This feature, coupled with our low flow and low inspiratory effort device has been shown to allow for the deep deposition of Tyvaso DPI in the lung.

2.6 微米的顆粒處於促進有效藥物傳遞的最佳尺寸範圍。事實證明，這一特點與我們的低流量和低吸氣力度裝置相結合，可以使 Tyvaso DPI 在肺部深度沉積。

Finally, there's ease of use and convenience, and we believe that Tyvaso DPI is a better all-around package for patients. Tyvaso DPI only requires one breath per cartridge 4 times a day. With administering Tyvaso DPI, patients can hold their head in a normal neutral position and Tyvaso DPI requires no daily cleaning where patients could potentially come in contact with DPI powder causing unwanted effects.

最後，還有易用性和便利性，我們相信 Tyvaso DPI 對患者來說是一個更好的全方位解決方案。Tyvaso DPI 每天只需對每個藥筒進行一次呼吸，每次 4 次。使用 Tyvaso DPI 後，患者可以將頭部保持在正常的中立位置，且 Tyvaso DPI 不需要每天清潔，因為患者可能會接觸到 DPI 粉末並產生不良影響。

As we begin our competitive journey with Tyvaso DPI we understand that physicians and patients may want to try new product offerings. However, we believe that over the long term, with Tyvaso DPI's product profile, along with the deep experience we've built in the pulmonary hypertension marketplace over the last 3 years, we are positioned for continued growth.

當我們開始與 Tyvaso DPI 的競爭之旅時，我們了解到醫生和患者可能想要嘗試新的產品。然而，我們相信，從長遠來看，憑藉 Tyvaso DPI 的產品特性，以及我們過去 3 年在肺動脈高壓市場累積的豐富經驗，我們有能力實現持續成長。

I'll now turn the call over to Leigh to discuss the TETON studies.

現在我將把電話轉給 Leigh 來討論 TETON 研究。

Thanks, Michael, and good morning, everyone. As we look ahead to the expected September data readout for our TETON 2 registration study, we wanted to spend some time today providing a brief landscape of idiopathic pulmonary fibrosis or IPF. So I'll cover the biological rationale behind treprostinil as a therapeutic approach provides details regarding our clinical trials and set the stage for interpreting the forthcoming results. .

謝謝，邁克爾，大家早安。當我們展望 TETON 2 註冊研究預計於 9 月公佈的數據時，我們今天想花一些時間簡要介紹特發性肺纖維化 (IPF)。因此，我將介紹曲前列尼爾作為一種治療方法背後的生物學原理，提供有關我們的臨床試驗的詳細信息，並為解釋即將得出的結果奠定基礎。。

So IPF is a progressive scarring disease of the lungs of unknown cause. It's most common after age 50, and it's linked to risk factors like smoking, genetics and certain environmental exposures. It affects approximately 100,000 people in the US.

因此，IPF 是一種原因不明的進行性肺部瘢痕疾病。它在 50 歲以後最為常見，並且與吸煙、遺傳和某些環境暴露等風險因素有關。它影響了美國大約10萬人。

And currently, there's only two approved therapies for IPF, nintedanib and pirfenidone. And these drugs only slow lung function decline. They're used by about 30% of the US patients largely due to their unpleasant side effects, yet together, they generate over $4 billion globally. As mentioned, these two therapies only showed a decrease in the rate of decline in FVC at 52 weeks in the registration studies.

目前，只有兩種藥物獲準用於治療特發性肺纖維化 (IPF)，即尼達尼布和吡非尼酮。而這些藥物只能減緩肺功能的衰退。大約 30% 的美國患者使用這些藥物，主要是因為它們沒有令人不快的副作用，但它們在全球範圍內的銷售額卻超過 40 億美元。如上所述，這兩種療法在註冊研究中僅顯示 52 週時 FVC 下降率下降。

The mean FVC change from baseline for nintedanib was approximately 111 milliliters from placebo and 148 milliliter for pirfenidone. However, the studies had very different placebo effects with over 200 milliliters of FVC loss in nintedanib study and more than 300 milliliters for pirfenidone, demonstrating the wide variety in the placebo responses that have plagued development efforts in IPS.

尼達尼布組與安慰劑組相比，FVC 平均變化量約為 111 毫升，吡非尼酮組與基線相比，FVC 平均變化量約為 148 毫升。然而，這些研究的安慰劑效應卻大相徑庭，尼達尼布研究中的 FVC 損失超過 200 毫升，而吡非尼酮研究中的 FVC 損失超過 300 毫升，這表明安慰劑反應的多樣性一直困擾著 IPS 的開發工作。

Many investors and even physician experts in the space believe that treprostinil is just a vasodilator. And that's likely because treprostinil has become it's much more than a vasodilator. It's likely because treprostinil has become widely used in pulmonary hypertension but it also has activity on the IP, EP2, DP1 and PPAR receptors, collectively inhibiting fibroblast proliferation and migration, fibroblast to myofibroblast differentiation extracellular matrix deposition and inflammation, all of which contribute to fibrosis.

許多投資者甚至該領域的醫學專家都認為曲前列尼爾只是一種血管擴張劑。這可能是因為曲前列尼爾的作用不再只是血管擴張劑。這可能是因為曲前列尼爾已廣泛用於治療肺動脈高壓，但它也對 IP、EP2、DP1 和 PPAR 受體有活性，共同抑製成纖維細胞增殖和遷移、成纖維細胞向肌成纖維細胞分化、細胞外基質沉積和炎症，所有這些都會導致纖維化。

These findings are supported by a post hoc analysis from our INCREASE study, where a subset of pulmonary hypertension patients with IPF treated with Tyvaso showed an improved FVC and reduced exacerbations of underlying lung disease. This, along with treprostinil's antifibrotic properties makes us optimistic that Tyvaso may benefit IPF patients by improving lung function through multiple pathways beyond those typically associated with pulmonary hypertension.

這些結果得到了我們 INCREASE 研究的事後分析的支持，該分析顯示，一組患有特發性肺纖維化的肺動脈高壓患者接受 Tyvaso 治療後，FVC 有所改善，潛在肺部疾病的惡化有所減少。這一點，加上曲前列尼爾的抗纖維化特性，讓我們樂觀地認為，泰瓦索可能透過多種途徑改善肺功能，從而使特發性肺纖維化 (IPF) 患者受益，這些途徑不僅包括通常與肺動脈高壓相關的途徑。

The TETON program is made up of 3 studies. TETON 1 is a 598 patient study of nebulized Tyvaso and IPS for participants in the US and Canada. TETON 2 is a 597 patient study identical to TETON 1 but evaluating participants outside the US and Canada. The TETON PPF is a worldwide study evaluating the use of nebulized Tyvaso in PPF or progressive pulmonary fibrosis.

TETON 計畫由 3 項研究組成。TETON 1 是一項針對美國和加拿大 598 名患者進行的霧化 Tyvaso 和 IPS 研究。TETON 2 是一項針對 597 名患者的研究，與 TETON 1 相同，但評估對像是美國和加拿大以外的參與者。TETON PPF 是一項全球性研究，旨在評估霧化泰瓦索在 PPF 或進行性肺纖維化中的應用。

As we've been saying, we expect TETON 2 to report data in September, while TETON 1, which was fully enrolled in January of 2025 to report data in the first half of 2026 and our focus today is on TETON 2. So again, TETON 2 is a 597 patients, multicenter, randomized, double-blind, placebo-controlled Phase III study evaluating nebulized Tyvaso in IPF patients over 52 weeks outside the US and Canada. Full enrollment was reached in July of '24.

正如我們一直所說，我們預計 TETON 2 將在 9 月報告數據，而 TETON 1（已於 2025 年 1 月全面註冊）將在 2026 年上半年報告數據，我們今天的重點是 TETON 2。再次強調，TETON 2 是一項涉及 597 名患者的多中心、隨機、雙盲、安慰劑對照的 III 期研究，在美國和加拿大以外地區對 IPF 患者進行為期 52 週的霧化泰瓦索治療進行評估。24 年 7 月已實現全部入學。

Participants were randomized to Tyvaso or placebo starting at three breaths 4 times daily or QID, titrated as tolerated up to 12 or more breaths QID. The primary endpoint is the change in FVC at 52 weeks, and the secondary endpoints include time to clinical worsening, time to acute IPS exacerbation, overall survival percent predicted FVC, quality of life measured by the King's Brief ILD questionnaire and change in lung diffusing capacity.

參與者隨機接受泰瓦索或安慰劑治療，起始劑量為每天 4 次，每次 3 次，或 QID，根據耐受程度逐漸增加至 QID 12 次或更多次。主要終點是 52 週時的 FVC 變化，次要終點包括臨床惡化時間、急性 IPS 加重時間、總體生存百分比預測 FVC、透過 King's Brief ILD 問卷測量的生活品質和肺彌散能力的變化。

Safety is assessed via adverse events, lab, vital signs and ECGs. The inclusion criteria of note include subjects who are 40 or more years of age have a predicted FVC of 45% or more be on a stable dose of nintedanib or perfenidone, if using one, and have a diagnosis

安全性透過不良事件、實驗室、生命徵象和心電圖進行評估。值得注意的納入標準包括：年齡在 40 歲或以上、預測 FVC 為 45% 或以上、服用穩定劑量的尼達尼布或哌非尼酮（如果使用），並且診斷為

of IPF confirmed by HRCT within the last 12 months. The inclusion criteria of note include obstructive diseases, high supplemental oxygen use, use of drugs commonly used for PAH, recent IPF exacerbation, or pulmonary infections.

過去 12 個月內經 HRCT 確診的 IPF。值得注意的納入標準包括阻塞性疾病、高補充氧氣使用、使用常用於治療 PAH 的藥物、近期 IPF 加重或肺部感染。

First, the TETON 1 and 2 protocols, we reviewed the blended blinded data and adjusted the sample size, considering the SEC variability, discontinuation rate, background therapy use and regulatory feedback.

首先，對於 TETON 1 和 2 方案，我們審查了混合盲法數據並調整了樣本量，同時考慮了 SEC 變異性、停藥率、背景治療使用和監管回饋。

And in 2024, we expanded each of these studies from 396 to 576 participants to account for observed data, patient retention and better alignment with the other major IPF trials.

2024 年，我們將這些研究的參與者人數從 396 人擴大到 576 人，以考慮觀察到的數據、患者保留率以及與其他主要 IPF 試驗更好地保持一致。

At ATS this year, we presented fully enrolled baseline data for TETON 1 and TETON 2 reflecting the full populations of both studies. The baseline demographics of TETON 1 and 2 are largely similar and compared favorably with the recently reported FIBRONEER- IPF study and earlier clinical programs for nintedanib and pirfenidone. While our statistical analysis plan is very long and detailed, we've been getting some questions in 4 key areas that I'd like to address.

在今年的 ATS 上，我們展示了 TETON 1 和 TETON 2 的完整入組基線數據，反映了這兩項研究的全部人群。TETON 1 和 2 的基線人口統計數據大致相似，與最近報告的 FIBRONEER- IPF 研究以及尼達尼布和吡非尼酮的早期臨床項目相比具有優勢。雖然我們的統計分析計劃非常冗長和詳細，但我們在 4 個關鍵領域中遇到了一些問題，我想就這些問題進行解答。

First, the study is 80% powered to detect an 80-milliliter change in FVC. This compares to a 90% power to detect a 74-milliliter change in FVC for the recent FIBRONEER-IPF study. Next, deaths in the study will be penalized with an FVC value at the 2.5 percentile of observed values across arms. This is based on recent feedback from the FDA. This is more conservative than the tenth percentile value used in the FIBRONEER-IPF study.

首先，研究有 80% 的功效檢測出 FVC 的 80 毫升變化。相較之下，最近的 FIBRONEER-IPF 研究中，檢測 FVC 74 毫升變化的功率為 90%。接下來，研究中的死亡病例將以各組觀測值的 2.5% 的 FVC 值進行懲罰。這是根據 FDA 最近的回饋得出的。這比 FIBRONEER-IPF 研究中使用的第十個百分位數值更為保守。

Discontinuation for other reasons will be handled through statistical models like the mixed model repeated measures or multiple imputation.

因其他原因而中斷的情況將透過混合模型重複測量或多重插補等統計模型來處理。

Finally, we've had five data monitoring committee reviews that evaluated safety over the course of the studies and the last one occurred in February of this year which covered more than 1,100 patients between the two studies.

最後，我們進行了五次資料監測委員會審查，對研究過程中的安全性進行了評估，最後一次審查發生在今年 2 月，涵蓋了兩項研究之間的 1,100 多名患者。

To close, our expectation is that our TETON 2 study will report top line data in September of this year, as said, and TETON 1 will report top line data in the first half of 2026. And if both trials are successful, we intend to use the data from the study to support a regulatory filing with the FDA to add IPF to the labeled indications for nebulized Tyvaso and setting up a commercial launch by 2027.

最後，我們預計 TETON 2 研究將在今年 9 月報告頂線數據，而 TETON 1 將在 2026 年上半年報告頂線數據。如果兩項試驗都成功，我們打算利用研究數據向 FDA 提交監管文件，將 IPF 添加到霧化 Tyvaso 的標籤適應症中，併計劃在 2027 年之前進行商業發布。

And with that, I'll now turn the call over to CQ, to discuss TPIP.

現在，我將把電話轉給 CQ，討論 TPIP。

Thank you, Leigh. It's a pleasure to speak with you today about the questions we have concerning the TPIP Phase IIb PAH data that was recently presented. Of course, our discussions are based on publicly available information.

謝謝你，Leigh。今天我們很高興與您討論有關最近提出的 TPIP IIb 階段 PAH 資料的問題。當然，我們的討論是基於公開的資訊。

First, we believe the patient population in the recently launched Phase IIb PAH study was imbalanced between the active and the placebo groups that may have favored treatment effect, in the active group.

首先，我們認為在最近啟動的 IIb 期 PAH 研究中，活性藥物組和安慰劑組之間的患者群體不平衡，活性藥物組的治療效果可能更佳。

Second, we believe inappropriate statistical analysis was conducted in the PAH study, again favoring the active arm of the study and potentially overestimating the treatment effect.

其次，我們認為 PAH 研究中進行了不當的統計分析，再次偏向研究的活躍部分，並可能高估了治療效果。

And finally, we did not see compelling data in the Phase IIa PAH, PH-ILD study that give us confidence TPIP can be successful in Phase III PH-ILD study.

最後，我們沒有在 IIa 期 PAH、PH-ILD 研究中看到令人信服的數據，這些數據讓我們相信 TPIP 能夠在 III 期 PH-ILD 研究中取得成功。

We think the study population in the Phase IIb PAH study was imbalanced and not reflective of PAH patients who present today that are more heavily pretreated and less symptomatic then when we first developed nebulized Tyvaso. The combined baseline 6 minute walking distance in Phase IIb study was meaningfully lower and at least 45 meters lower relative to the recent clinical studies in PAH, potentially favoring treatment effect.

我們認為 IIb 期 PAH 研究的受試者群體不平衡，不能反映當今 PAH 患者的情況，這些患者與我們首次開發霧化 Tyvaso 時相比，接受了更充分的預先治療，並且症狀較少。IIb 期研究中綜合基線 6 分鐘步行距離明顯較低，與近期 PAH 臨床研究相比至少低 45 米，可能有利於治療效果。

Most, if not all, recent PAH studies conducted this decade have had baseline 6 minute walking distance of 400 meters or more, reflecting improvements in the standard of care of this patient population globally.

本十年進行的大多數（如果不是全部）PAH 研究都將基線 6 分鐘步行距離設為 400 公尺或以上，這反映了全球範圍內該患者群體護理標準的提高。

Further, there was an imbalance between the two arms of the study with baseline 6 minute walking distance. The 23-meter difference in baseline 6-minute walking distance between the active and placebo arms is more than 3 times that of previous well controlled the studies in PAH. Of course, this favors the treatment arm of the study, potentially leading to great treatment effect.

此外，研究的兩個部分在基線 6 分鐘步行距離方面存在不平衡。治療組和安慰劑組之間的基線 6 分鐘步行距離相差 23 米，是先前在 PAH 中控制良好的研究中結果的 3 倍多。當然，這對研究的治療部門有利，可能帶來很好的治療效果。

Moving to study discontinuation we also saw a large imbalance that could favor the active arm with 10% of active participants discontinued study versus low discontinuations in the control group. The high discontinuation level imbalance, especially relative to the control group could influence how missing values should be imputed.

在研究中止方面，我們也看到了很大的不平衡，這可能有利於活躍組，10％的活躍參與者中止了研究，而對照組中止研究的比例較低。較高的中斷水準不平衡（尤其是相對於對照組而言）可能會影響如何估算缺失值。

Moving to strategic analysis the change from baseline to week 16 data is not symmetric and it's skewed to opposite directions. In the TPIP Group, the mean value was approximately 20% higher than the median, suggesting that the data was right skewed or positively skewed. In the placebo group, the mean was 40% lower than the median, suggesting that the data was less skewed or negatively skewed.

轉向策略分析，從基線到第 16 週資料的變化並不對稱，並且偏向相反的方向。在 TPIP 組中，平均值比中位數高出約 20%，這表示資料右偏或正偏。在安慰劑組中，平均值比中位數低 40％，這表明數據偏斜較小或呈負偏斜。

The nonparametric method is used to report this data. In the case in this case, red in color and the (inaudible) estimate relied on the data to be symmetric or at least skewed towards the same direction. However, the right skewed data in the active arm and the left skewed data in the control arm, it's likely causing the overestimation of the treatment effect by (technical difficulty) estimate or making the (inaudible) estimate of the location shift in medians not interpretable.

使用非參數方法來報告該數據。在這種情況下，顏色為紅色，並且（聽不清楚）估計依賴於數據對稱或至少向同一方向傾斜。然而，活動組的數據右偏，對照組的數據左偏，很可能會導致對治療效果的估計過高（技術難度），或使得中位數位置偏移的估計（聽不清楚）無法解釋。

Finally, there were eight subjects or 12% with missing data at week 16 in the active group and 0 in the control group, the severe imbalance in dropout rate suggests the data is not missing at random. The multiple imputation method relies on the data actually being missing as random, which is not the case here.

最後，在第 16 週時，治療組有 8 名受試者（12%）數據缺失，而對照組中有 0 名受試者數據缺失，脫落率的嚴重不平衡表明數據並非隨機缺失。多重插補法依賴實際缺失的資料是隨機的，但這裡的情況並非如此。

As such, we think these analysis may have overestimated the treatment effect of TPIP in PAH. Beyond the consent with the recent Phase IIb PAH data, we continue to question earlier Phase IIa PH-ILD data. And it may not be an indicate of potential Phase III success in this indication. First, the study was extremely small in sample size with a 3:1 randomization ratio.

因此，我們認為這些分析可能高估了 TPIP 對 PAH 的治療效果。除了同意最近的 IIb 期 PAH 數據之外，我們還繼續質疑早期的 IIa 期 PH-ILD 數據。這可能並不代表該適應症的 III 期臨床研究會成功。首先，研究的樣本數極小，隨機化比例為 3:1。

There were only 10 patients in the placebo arm. So it's difficult to draw any efficacy conclusion from the study. In addition, though based on 6 minute walking distance we're securing and the 6 minute walking distance results were not statistically significant.

安慰劑組只有 10 名患者。因此很難從該研究中得出任何功效結論。此外，雖然我們以 6 分鐘步行距離為依據，但 6 分鐘步行距離的結果在統計上並不顯著。

Further, the ILD is subtype to result in the PH-ILD study were not balanced between arms, for example, only 2 CPFE patients were randomized into the study, but were all randomized to placebo group on a 3:1 to placebo randomization ratio. CPFE is known to be a category in which inhaled treprostinil is less effective.

此外，ILD 的亞型導致 PH-ILD 研究的各組之間不平衡，例如，只有 2 名 CPFE 患者隨機進入研究，但全部以 3:1 的安慰劑隨機化比例隨機分配到安慰劑組。CPFE 被認為是吸入曲前列尼爾效果較差的一類藥物。

Finally, the first data is the PH-ILD uncovers additional imbalance between arms, as five subjects or 17% of active subjects had a decent gap compared to only 1 subject or 10% of subjects in control group. Dyspnea is not a prostacyclin class adverse event and we saw more dyspnea in the control group than the active group INCREASE study.

最後，第一個數據是 PH-ILD 揭示了各組之間的額外不平衡，因為五名受試者或 17% 的活躍受試者與對照組中只有 1 名受試者或 10% 的受試者相比存在相當大的差距。呼吸困難不是前列環素類藥物的不良事件，我們發現對照組的呼吸困難比活性組 INCREASE 研究更嚴重。

As you can tell, we think that investors have overreacted to the TPIP Phase IIb PAH data, the baseline imbalance skewed data in the opposite direction and aggressive statistical analysis based on the missing and the random assumption may all contribute to the potential overestimation of the treatment effect, and we have no convincing data in PH-ILD.

正如您所看到的，我們認為投資者對 TPIP IIb 期 PAH 數據反應過度，基線不平衡使數據向相反方向傾斜，以及基於缺失和隨機假設的激進統計分析都可能導致對治療效果的潛在高估，並且我們在 PH-ILD 方面沒有令人信服的數據。

I will now hand the call to Gil Golden, our Chief Medical Officer to outline the expected indicative impact, we believe TPIP have on the market if it's approved.

我現在將電話交給我們的首席醫療官吉爾·戈爾登 (Gil Golden)，概述我們認為如果 TPIP 獲得批准，它將對市場產生的預期指標性影響。

Thank you, CQ, We believe that investors have overreacted to TPIP data and misunderstand the opportunity or lack thereof in the marketplace. Specifically, we do not see a near-term path to market in IPF. Long-term safety has not been proven, a potential launch, even if it happens, is many years away. And our business profile will look very different if and when TPIP reaches the market.

謝謝，CQ，我們認為投資者對 TPIP 數據反應過度，誤解了市場上的機會或缺乏機會。具體來說，我們看不到 IPF 近期進入市場的途徑。長期安全性尚未得到證實，即使有可能發射，也需要很多年的時間。一旦TPIP進入市場，我們的業務狀況將會有很大不同。

So first, TPIP lacks a clear path to approval in IPF before 2034, if Tyvaso gains approval in 2027 due to orphan drug exclusivity. Further, as an ester prodrug, TPIP would need to show clear clinical superiority over Tyvaso or a meaningful improvement in patient care and less frequent dosing may not qualify. The slide lists an example for LUMRYZ from Avadel that was the only recent declaration of meaningful improvement in patient care by FDA that was on the same dosage form.

首先，如果 Tyvaso 因孤兒藥專營權而在 2027 年獲得批准，那麼 TPIP 在 2034 年之前缺乏在 IPF 獲得批准的明確途徑。此外，作為一種酯類前驅藥物，TPIP 需要顯示比 Tyvaso 明顯的臨床優勢或在患者護理方面有顯著改善，而較低頻率的給藥可能不符合要求。幻燈片中列舉了 Avadel 公司的 LUMRYZ 的一個例子，這是 FDA 最近宣布的唯一一種在相同劑型上對患者護理有顯著改善的藥物。

Next, long-term safety data for a liposomal prodrug and pulmonary hypertension is lacking with the longest studies covering only 16 weeks, for progressive diseases like PAH, PH-ILD and IPF, robust long-term data is essential. Recent experience with sotatercept, for example, shows that even after FDA approval.

其次，脂質體前藥和肺動脈高壓的長期安全性數據缺乏，最長的研究僅涵蓋 16 週，對於 PAH、PH-ILD 和 IPF 等進行性疾病，可靠的長期數據至關重要。例如，最近對索他西普的使用經驗表明，即使經過 FDA 批准。

Unexpected safety issues can arise over time, highlighting the need for caution. So if TPIP were to pass through all these remaining hurdles at still the end of the decade or even the next decade before the product will reach the market. Recent Phase III studies in PAH have taken an average of three years to complete with clinical outcome studies taking even longer to complete.

隨著時間的推移，可能會出現意想不到的安全問題，凸顯了謹慎的必要性。因此，如果TPIP能夠克服所有這些剩餘的障礙，那麼到本世紀末甚至下一個十年，產品才能進入市場。近期 PAH 的 III 期研究平均需要三年時間才能完成，而臨床結果研究則需要更長的時間才能完成。

So if everything works perfectly, we could see a product on the market in late 2029 or 2030. Looking ahead to 2030 then, the market landscape will likely shift significantly. If the true if the ADVANCE OUTCOMES study succeeds next year, ralinepag may become the first true once-daily oral prostacyclin for PAH potentially reducing the need for inhaled therapies like TPIP. We're also working on our own once-daily inhaled prostacyclin, which is on a similar development time line as TPIP and could serve both PAH and PH-ILD.

因此，如果一切順利的話，我們可能會在 2029 年底或 2030 年看到產品上市。展望2030年，市場格局可能會發生重大變化。如果 ADVANCE OUTCOMES 研究明年取得成功，ralinepag 可能成為第一個真正用於治療 PAH 的每日一次口服前列環素，從而有可能減少對 TPIP 等吸入療法的需求。我們也正在研發自己的每日一次吸入式前列環素，其開發時間與 TPIP 相似，可以同時治療 PAH 和 PH-ILD。

Additionally, in line with our approved and improved strategy, we are developing new Tyvaso devices and combinations to enhance convenience for patients. And lastly, by 2030, our organ development programs could begin generating revenue, making competition from small molecule drugs relatively minor compared to our broader long-term opportunities.

此外，根據我們批准和改進的策略，我們正在開發新的 Tyvaso 設備和組合，以提高患者的便利性。最後，到 2030 年，我們的器官開發計畫可以開始產生收入，與我們更廣泛的長期機會相比，小分子藥物的競爭相對較小。

So to close, with no near-term path to market and IPF, unproven safety and many, many years before reaching the market, we have little reason to be concerned about our prospects in the face of TPIP.

總而言之，由於短期內沒有進入市場和特發性骨髓纖維化（IPF）的途徑，其安全性尚未得到證實，而且要經過許多年才能進入市場，因此我們沒有理由擔心我們在 TPIP 面前的前景。

And with that, I'd like to turn the call back to Martine to start our Q&A session. Martine?

現在，我想將電話轉回給 Martine，開始我們的問答環節。馬丁？

Thank you, Gil. Operator, you can open up the phones for Q&A?

謝謝你，吉爾。接線員，您可以打開電話問答嗎？

(Operator Instructions)

（操作員指示）

Olivia Brayer from Cantor Fitzgerald.

來自 Cantor Fitzgerald 的 Olivia Brayer。

Yes, can you guys hear me?

是的，你們聽得到我說話嗎？

Yes, please go ahead.

是的，請繼續。

Okay. Perfect. Sorry about that. Any comments on what you're seeing in terms of Yutrepia uptake in those PAH and ILD so far? I mean it looks like you're not really seeing any impact on DPI, but appreciate anything you can tell us.

好的。完美的。很抱歉。到目前為止，您對 Yutrepia 在 PAH 和 ILD 中的應用程式有何評論？我的意思是，看起來您並沒有真正看到對 DPI 的任何影響，但還是感謝您能告訴我們任何資訊。

And any color on why ex US nebulized Tyvaso was down sequentially, whether that had more to do with ordering patterns or any sort of demand trend that you're seeing? And then I've got one follow-up question on TETON, if you don't mind. .

能否解釋為什麼美國以外地區的泰瓦索霧化劑銷售量會持續下降，這是否與訂購模式或您所看到的任何需求趨勢有關？如果您不介意的話，我還有一個關於 TETON 的後續問題。。

Olivia, there's no more there's so many people in the queue. There's not going to be time for a follow-up question, sorry. The marketing question, Michael will handle.

奧莉維亞，沒有了，排隊的人太多了。抱歉，沒有時間回答後續問題。行銷問題由邁克爾來處理。

Sure. Thanks for the question, Olivia. Based on the visibility we have into what's going on, which admittedly is not perfect we're things are going about as we expected in terms of the launch. I mean we finished Q2 really strong in terms of shipments and orders in June. July, based on what we're seeing so far looks really good.

當然。謝謝你的提問，奧莉維亞。根據我們對正在發生的事情的了解，雖然這並不完美，但就發布而言，事情進展正如我們預期的那樣。我的意思是，就 6 月的出貨量和訂單量而言，我們第二季的表現非常強勁。從我們目前看到的情況來看，七月看起來非常好。

So really, from our standpoint, no surprises in terms of what we're seeing in terms of the launch. As I said in my opening remarks, we know that docs are curious people. There's a new kid on the block, a new product and some other want to try it out.

因此，從我們的角度來看，對於這次發表會的結果，我們確實沒有什麼意外。正如我在開場白中所說，我們知道醫生都是好奇的人。這裡有新來者、新產品，還有一些人想試試看。

And seeing what it could potentially do for patients. I think particularly in light of some of claims that Liquidia is making about their product. And so we're seeing a little bit of that. But as I said, to really kind of, to wrap up my opening remarks, I think we're really confident that with Tyvaso's Tyvaso DPI's product profile, plus the associated support that we provide to physician offices and patients along with the really deep experience.

並觀察它對患者可能產生什麼作用。我認為，特別是考慮到 Liquidia 對其產品提出的一些主張。所以我們看到了一點這樣的情況。但正如我所說的，為了總結我的開場白，我認為我們非常有信心，憑藉 Tyvaso 的 Tyvaso DPI 產品概況，加上我們為醫生辦公室和患者提供的相關支持以及真正豐富的經驗。

I mean there really more than 10,000 patients have used DPI, you've got almost 3,000 prescribers for Tyvaso DPI. So we think over the long term, that's going to support continued growth of Tyvaso DPI well into the future.

我的意思是，實際上有超過 10,000 名患者使用過 DPI，而 Tyvaso DPI 的處方醫生則有近 3,000 人。因此，我們認為從長遠來看，這將支持 Tyvaso DPI 未來的持續成長。

Joseph Thome with TD Cowen.

TD Cowen 的 Joseph Thome。

Congrats on the progress. Leigh called out the variability seen in FVC decline in placebo arms of IPF studies. Is there a way in the TETON trial that you attempted to standardize this? Or is there a way to make this predictable? And when we think about any considerations in clinical practice between your US and ex US experience, what should we think about going to the first data in September and translatability into the US trial in the first half of next year? .

恭喜你取得進展。Leigh 指出，在 IPF 研究中，安慰劑組 FVC 下降的情況存在差異。在 TETON 試驗中，您是否嘗試過以某種方式對其進行標準化？或者有沒有什麼方法可以讓它變得可預測？當我們考慮您在美國和美國以外地區臨床實踐中的經驗時，我們應該如何考慮 9 月的第一批數據以及明年上半年美國試驗的可轉化性？。

Thank you, Joe. Questions relating to TETON will be answered by Dr. Peterson.

謝謝喬。關於TETON的問題將由彼得森博士解答。

Thanks, Martine. Yes. So again, as you noticed, there's very wide variability in FVC measures, and this is this really shows in the placebo arms especially of the 2 approved drugs.

謝謝，馬丁。是的。所以，正如您所注意到的，FVC 測量值存在很大的可變性，這在安慰劑組中得到了充分體現，尤其是對兩種已批准的藥物。

What we've done to really narrow that is we have a central readers of our FVC results. And we've also made very huge attempts at each at the site level in order for training and for on the procedures and to make sure that people are doing everything consistently with regard to the pulmonary function testing. And so that's really been at the top of our list as far as management of these studies. And so hopefully, we will see that we have less variability which will show better true results.

為了真正縮小範圍，我們所做的就是為我們的 FVC 結果設立一個中心讀者。我們還在每個站點層面做出了巨大的努力，以進行培訓和改進程序，並確保人們在肺功能測試方面始終如一地做每件事。因此，就這些研究的管理而言，這確實是我們最重視的。因此，我們希望看到更少的變異，從而顯示出更好的真實結果。

Jessica Fye from JPMorgan.

摩根大通的傑西卡費伊 (Jessica Fye)。

Another one for Dr. Peterson, which is really a question that we hear from investors and that is how to read across from the compelling increased IPF subgroup where the patients saw improvement in FVC, but they also all had pulmonary hypertension. And so the question is, how do we read that across to an IPF population where presumably the majority of folks are not going to have pulmonary hypertension. Can you address that kind of question on the read across, and if I can ask one more, it would be just whether you can touch on the circumstances under which you would deploy a share repo authorization? .

另一個問題是問彼得森博士的，這實際上是我們從投資者那裡聽到的一個問題，那就是如何從引人注目的 IPF 亞組增加中解讀出來，在這個亞組中，患者的 FVC 有所改善，但他們也都患有肺動脈高壓。所以問題是，我們如何向 IPF 族群傳達這個訊息，因為據推測大多數人不會患有肺動脈高壓。您能否在閱讀過程中回答此類問題？如果我可以再問一個問題，您是否可以談談在什麼情況下您會部署股票回購授權？。

Dr. Peterson, it's another TETON question for you.

彼得森博士，這是您要問的另一個 TETON 問題。

Yes, sure. Yes. So for I mean, as I discussed in the in my script, earlier, treprostinil has very multiple mechanisms of action. It works through multiple receptors. And so an increase of course, we've already seen, I mean, Tyvaso had already been approved for PAH. And we believe and some nonclinical studies support that, that really is for PAH in main mechanism, as I also discussed, is through maybe a vasodilation function.

是的，當然。是的。所以我的意思是，正如我之前在腳本中討論的那樣，曲前列尼爾具有多種作用機制。它透過多種受體起作用。當然，我們已經看到了成長，我的意思是，Tyvaso 已經被批准用於治療 PAH。我們相信，並且一些非臨床研究也支持這一點，這確實是 PAH 的主要機制，正如我所討論的，可能是透過血管舒張功能。

And that tends at least the nonclinical studies have shown that really is works working through the IP receptor to do that. But on top of it, there's other receptors, EP2 receptor, DP1, PPAR receptors they have additional functions that they basically as I went through, they can inhibit fibroblast activity and extracellular matrix deposition and really work on the fibrosis end of the disease.

並且至少非臨床研究表明它確實是透過 IP 受體起作用的。但除此之外，還有其他受體，EP2 受體、DP1、PPAR 受體，它們具有額外的功能，基本上正如我所經歷的，它們可以抑製成纖維細胞活性和細胞外基質沉積，並真正作用於疾病的纖維化末端。

And so while treprostinil does work on IP, working through these other receptors we believe that it can work on fibrosis, which means it would be effective in IPF and PPF. So again, multiple mechanisms of action would lead to efficacy in multiple indications.

因此，雖然曲前列尼爾確實對 IP 起作用，但我們相信透過這些其他受體，它可以對纖維化起作用，這意味著它對 IPF 和 PPF 有效。因此，多種作用機制將對多種適應症產生療效。

Superb answer Dr. Peterson. James Edgemond, could you kindly address Jess's question regarding the buyback.

彼得森博士的回答非常精彩。詹姆斯·埃奇蒙德，您能否回答傑西關於回購的問題。

Yes. Thanks, Martine. And Jess, thanks for the question. We did announce this morning that our Board of Directors authorized a share repurchase of up to $1 billion of our shares, and we plan to implement this Board of Director authorization expeditiously.

是的。謝謝，馬丁。傑西，謝謝你的提問。我們今天早上確實宣布，我們的董事會授權回購價值高達 10 億美元的股票，我們計劃迅速實施董事會的授權。

As a little bit of background, maybe as to why now, it really is given the continued strength of our commercial business, our robust balance sheet, our confidence in our upcoming catalysts and our belief in our share price potential, we and the Board of Directors concluded that now was the right time to authorize the share repurchase. .

作為一點背景介紹，也許至於為什麼現在，確實是考慮到我們商業業務的持續強勁、我們穩健的資產負債表、我們對即將到來的催化劑的信心以及我們對股價潛力的信念，我們和董事會得出結論，現在是授權股票回購的正確時機。。

And like many shareholders we've met with, we believe the return of capital represents confidence in our near-term as well as long- term business prospects and we share the view of many shareholders that our stock is an excellent investment opportunity. So Jess, thanks for the question and Martine, back to you.

就像我們遇到的許多股東一樣，我們相信資本回報代表著對我們的短期和長期業務前景的信心，我們和許多股東一樣認為我們的股票是一個絕佳的投資機會。所以，傑西，謝謝你的提問，馬丁，回到你的問題。

Thank you so much for that great response. James.

非常感謝您的正面回覆。詹姆斯。

Roger Song from Jefferies.

傑富瑞 (Jefferies) 的羅傑宋 (Roger Song)。

Great. Congrats for the progress, also a question related to TETON. So given the increased subgroup data and then the powering assumption, 80% detect the 80 milliliter difference, so what will be considered clinically for FVC results from that trial and then what will be the home-run scenario from that trial? And then also a follow-up on the Jessica's question earlier. So do you have a sense or any top level comment on how many patients from the TETON is actually having the pulmonary hypertension with IPF versus a pure IPF. .

偉大的。祝賀取得進展，還有一個與 TETON 相關的問題。因此，考慮到增加的亞組數據和功效假設，80% 檢測到 80 毫升的差異，那麼該試驗的 FVC 結果在臨床上將被視為什麼，然後該試驗的本壘打場景將是什麼？然後也要跟進傑西卡之前提出的問題。那麼，您是否了解或有任何高層評論，關於 TETON 患者中究竟有多少人實際上患有 IPF 伴隨肺動脈高壓，或者有多少人患有單純的 IPF。。

Thank you, Roger, for that concatenated question. It's all basically in the domain of biostatistics. So I'll ask Dr. Deng to kindly answer that question.

羅傑，謝謝你提出這個連貫的問題。這一切基本上都屬於生物統計學領域。因此我請鄧博士來回答這個問題。

Since the TETON study, we are testing the antifibrotic effect not the vasodilate effect, let's say, we designed our studies that to enroll the patient similar to other IPF studies, not try to design the study similar to previous PH-ILD studies. So we actually did not perform hemodynamic measure to actually determine if the subject that had a pulmonary hypertension or not.

自 TETON 研究以來，我們正在測試抗纖維化作用而不是血管擴張作用，可以說，我們設計的研究是為了招募與其他 IPF 研究類似的患者，而不是嘗試設計與先前的 PH-ILD 研究類似的研究。因此，我們實際上並沒有進行血流動力學測量來真正確定受試者是否患有肺動脈高壓。

Andreas Argyrides from Oppenheimer.

奧本海默的 Andreas Argyrides。

Congrats on the quarter and all the positive updates. I appreciate the additional color here. I wanted to ask about ralinepag, with the PAH space with the PAH space moving towards more convenient dosing, can you share your thoughts more on the ralinepag opportunity with once-daily oral dosing and the powering assumptions from the ADVANCE OUTCOMES study? .

恭喜本季取得的所有積極進展。我很欣賞這裡的額外色彩。我想問一下 ralinepag 的情況，隨著 PAH 領域朝著更方便的給藥方式發展，您能否分享更多關於 ralinepag 每日一次口服給藥的機會以及 ADVANCE OUTCOMES 研究的支持假設的看法？。

And then just a quick question for Dr. Peterson. You mentioned the refined imputation for TETON 2, can you expand on how that method aligns with FDA expectations and whether this adds confidence in the strength of the upcoming readout?

然後我想問彼得森醫生一個簡單的問題。您提到了 TETON 2 的精細插補，您能否詳細說明該方法如何與 FDA 的預期相符，以及這是否增加了對即將發布的讀數強度的信心？

All right, Andreas, thanks for the kudos on the quarter. And both of those questions are really within Dr. Peterson's domain. So Dr. Peterson, could you address them?

好的，安德烈亞斯，感謝您對本季的讚揚。這兩個問題其實都屬於彼得森博士的研究範圍。那麼彼得森博士，您能解答一下這些問題嗎？

Yes. So I guess so the powering I'm not sure that I got all of the questions, but the powering for ralinepag is powered at 80% to detect a treatment difference the 0.65 hazard ratio. So that's for a clinical worsening event and we're on target to achieve the number of clinical worsening events to be able to see a difference and to detect a treatment difference by the end of the year. And so I think that was your question about the powering and then you had a TETON question, and I didn't quite get all of that. I'm sorry.

是的。因此我猜，我不確定我是否得到了所有問題的答案，但 ralinepag 的功效為 80%，可以檢測到治療差異，風險比為 0.65。這就是臨床惡化事件，我們的目標是在年底前達到一定數量的臨床惡化事件，以便能夠看到差異並檢測出治療差異。所以我認為這是你關於供電的問題，然後你有一個關於 TETON 的問題，而我沒有完全明白。對不起。

Andreas, can you repeat your TETON question? Okay. Well, I'm sure IR can follow up with him. Operator, can you answer the next question?

安德烈亞斯，你能重複一下你的 TETON 問題嗎？好的。嗯，我相信 IR 可以跟進他的情況。接線生，您能回答下一個問題嗎？

Ash Verma from UBS.

瑞銀的 Ash Verma。

So I wanted to ask about the design of TETON studies, specifically about the potential amputation of measurement for discontinuation further protocol. So in this case, based on your protocol, would these be reported as a missing or a 0 or excluded from the analysis. So that's one.

所以我想問一下 TETON 研究的設計，特別是關於停止進一步研究方案的潛在測量截斷。因此在這種情況下，根據您的協議，這些會被報告為缺失或 0 或從分析中排除。這就是其中之一。

And then secondly, to the extent like there is Tyvaso-induced cough in the study, wouldn't that mean functional unblinding if patients are only seeing that in the Tyvaso arm?

其次，就研究中 Tyvaso 引起的咳嗽而言，如果患者僅在 Tyvaso 組中看到這種咳嗽，這是否意味著功能性揭盲？

Okay. Thank you Ash for that question. I'd like to ask CQ, if he could answer the first part of the question, CQ,, if you got it all. And then Dr. Peterson to answer the second part of the question on the unblinding. .

好的。感謝 Ash 提出這個問題。我想問 CQ，他是否可以回答問題的第一部分，CQ，如果你明白了一切。然後彼得森博士回答有關揭盲問題的第二部分。。

I addressed that potential unblinding due to cough the event. Actually, based on the previous study, even the patients who are randomized to the placebo group, they will also experience some cough event. So it's not, just the once you see there's a cough event you can guess that the subject will be in the active arm. So you probably see a little more cough in the active group than placebo group, but placebo patients also experience cough events. So we don't think that unblinding potential unblinding is the issue there.

我解決了由於咳嗽事件可能導致的揭盲問題。事實上，根據先前的研究，即使是隨機分配到安慰劑組的患者，也會出現一些咳嗽事件。所以事實並非如此，只要您看到出現咳嗽事件，您就可以猜測該物件將處於活動臂中。因此，您可能會發現活性組的咳嗽比安慰劑組多一點，但安慰劑組患者也會出現咳嗽事件。因此，我們認為揭盲的潛在揭盲並不是問題所在。

Thank you, CQ, Dr. Peterson, since CQ, answered kind of the second question. Do you want to comment on the first question?

謝謝 CQ，Peterson 博士，因為 CQ 回答了第二個問題。您想對第一個問題發表評論嗎？

Yes. So we talked quite a bit about the death how they'll be penalized with FVC value at 2.5 percentile observed values and then discontinuations for other reasons will be handled through statistical models like the mixed model repeated measures or multiple imputation.

是的。因此，我們討論了很多關於死亡的問題，他們將如何受到 FVC 值 2.5 百分位觀察值的懲罰，然後由於其他原因而停藥將通過統計模型（如混合模型重複測量或多重插補）來處理。

And yes, and I agree with what CQ, said, I mean we it's just like any study where there's a known AE that can be associated with the treatment. But very often, there's a similar AE that's seen with the placebo and we I mean, we generally are we definitely are surprised at the end of the day, sometimes we see things, we think, oh, yes, maybe that's on active because of cough, it's definitely not. So I would say there's no risk and especially in the study of cough because people cough a lot just by inhaling placebo. So no worries there.

是的，我同意 CQ 所說的，我的意思是，這就像任何研究一樣，其中存在與治療相關的已知 AE。但很多時候，會出現與安慰劑類似的不良反應，我的意思是，我們通常會在一天結束時感到驚訝，有時我們會看到一些東西，我們會想，哦，是的，也許那是因為咳嗽而起作用，但絕對不是。所以我想說沒有風險，特別是在咳嗽研究中，因為人們光是吸入安慰劑就會咳嗽得很厲害。所以不用擔心。

Perfect, Dr. Peterson. Thank you so much.

非常好，彼得森博士。太感謝了。

Jason Gerberry from Bank of America.

美國銀行的 Jason Gerberry。

Mine is also just on IPF and I guess the physician KOL seemed to think that the nerandomilast data at ATS were pretty underwhelming, just the neutral benefit on exacerbation as a secondary endpoint and the lack of a p-value in the monotherapy subgroup. So I'm just kind of curious how important is it in your view to show a meaningful improvement on the exacerbation as well as sort of established with stats a benefit maybe in a pooled manner in the monotherapy subgroup.

我的研究也只是關於 IPF，我猜醫生 KOL 似乎認為 ATS 的 nerandomilast 數據相當令人失望，只是對病情惡化的中性益處作為次要終點，並且單一療法亞組缺乏 p 值。所以我只是有點好奇，在您看來，在單一療法亞組中以匯總的方式顯示出對惡化的有意義的改善以及通過統計數據證實的益處有多重要。

Thank you so much for the question. And Dr. Peterson, I think would be the best person to answer it.

非常感謝您的提問。我認為彼得森博士是回答這個問題的最佳人選。

Okay. Yes. So I mean, yes, there was definitely a positive study for the FIBRONEER-IPF and PPF. But and they've met their endpoints. They had 90% power to detect a 74-milliliter change in FVC. We're 80% powered to detect 80-milliliter change.

好的。是的。所以我的意思是，是的，對 FIBRONEER-IPF 和 PPF 肯定有積極的研究。但他們已經達到終點了。他們有 90% 的能力檢測出 FVC 的 74 毫升變化。我們有 80% 的能力來檢測 80 毫升的變化。

But we obviously, we look forward to seeing events or seeing results where there's Ideally, we would see that our Tyvaso is disease- modifying and that patients don't decline. However, we may see a slight decline or more decline. But we fully anticipate having a clinically meaningful effect which would be greater than an 80-milliliter change in FVC. So again, but blinded, we will know in September.

但我們顯然期待看到事件或看到結果，理想情況下，我們會看到我們的 Tyvaso 能夠改變病情，並且患者不會病情惡化。然而，我們可能會看到小幅下降或更多的下降。但我們完全預期會產生具有臨床意義的效果，其影響將大於 FVC 80 毫升的變化。所以，再說一次，但我們會在九月知道答案。

Well, thank you so much, Dr. Peterson. That's an excellent answer.

好吧，非常感謝您，彼得森博士。這是一個很好的答案。

Terence Flynn from Morgan Stanley.

摩根士丹利的 Terence Flynn。

Great. I'll stick to one. Just on TETON, when you look at background therapy from the INCREASE study, it looked like there was maybe a difference in terms of patients that were on background TKI versus those that were on no background TKI. And so maybe you could just talk through that dynamic? And then as we think about the Phase III, the mix there and how that might impact the overall treatment effect that you're expecting to see?

偉大的。我會堅持一個。僅在 TETON 上，當您查看 INCREASE 研究中的背景療法時，似乎接受背景 TKI 治療的患者與未接受背景 TKI 治療的患者之間可能存在差異。那麼也許您可以談談這種動態？然後，當我們考慮第三階段時，那裡的組合以及它將如何影響您期望看到的整體治療效果？

Thank you, Terence. Dr. Peterson, you'd be the best person.

謝謝你，特倫斯。彼得森博士，您是最適合的人選。

Yes. So we I mean, definitely versus INCREASE we see more background therapy use. And both TETON 1 and TETON 2 as shown on one of the slides that I went through today. TETON 1 and TETON 2 have 77% background therapy use and 75%. So it's more I mean, it can just like any again, any study when you have effective background therapy, then it can mute your efficacy of your our investigational drug. But again, we're right in there FIBRONEER-IPF also had 78% use of background therapy. And there's a lot of room for improvement.

是的。因此，我的意思是，我們肯定會看到更多背景療法的使用。我今天看過的一張幻燈片上顯示了 TETON 1 和 TETON 2。TETON 1 和 TETON 2 的背景治療使用率為 77%，而 TETON 2 為 75%。所以我的意思是，它可以像任何其他研究一樣，當您有有效的背景療法時，它可以減弱我們研究藥物的功效。但是，我們再次發現，FIBRONEER-IPF 也使用了 78% 的背景療法。但仍有很大的進步空間。

I mean, I also showed the slide that the patients even on their active background therapies have a significant decline in FVC. So there's a lot of room for improvement, and this is exactly what we expected as far as the use of background therapy. So again, stay tuned in September, but that doesn't it's not a concern.

我的意思是，我還在幻燈片中展示了即使接受積極的背景治療，患者的 FVC 也會顯著下降。因此還有很大的改進空間，這正是我們對背景療法的使用所期望的。所以，再次強調，請繼續關註九月的情況，但這並不意味著什麼。

Dr. Peter said, thank you so much. And just because you've been on the phone so much answering these questions, I do want to take your form for a moment to make sure these questioners understand your expertise that you were the lead author on the New England Journal of Medicine publication on our INCREASE study, in addition to being the lead author of our physiological reviews, publication on xenotransplantation. So folks on the phone, you're privileged really to hear from such an expert sources, Dr. Peterson.

彼得醫生說，非常感謝。因為你經常透過電話回答這些問題，所以我想稍微了解一下你的情況，以確保提問者了解你的專業知識，你不僅是《新英格蘭醫學雜誌》上有關 INCREASE 研究的出版物的主要作者，也是我們生理評論、異種移植出版物的主要作者。所以電話裡的各位朋友，你們很榮幸能夠聽到彼得森博士這樣一位專家的演講。

Martine, there's no more questions in the queue, but I do have Andreas' follow-up question, and he was asking, can you expand on how the FVC imputation method in TETON aligns with FDA expectations and whether this adds confidence in the strength of the upcoming readout. So it relates to the recent change in how we handle deaths in that study.

Martine，隊列中沒有其他問題了，但我有 Andreas 的後續問題，他問，你能否詳細說明一下 TETON 中的 FVC 估算方法如何與 FDA 的預期保持一致，以及這是否增加了對即將發布的讀數強度的信心。因此，這與我們在該研究中處理死亡問題的方式的最新變化有關。

Sure. Well, since we have the New England Journal Medicine lead author in this field down the line, we'll ask Dr. Peterson to answer.

當然。好吧，既然我們有《新英格蘭醫學雜誌》這個領域的主要作者，我們將請彼得森博士來回答。

Yes. And I must correct. I'm not lead, but I'm one of them, for that one. But thank you, Martine.

是的。我必須糾正。我不是領導，但就這一點而言，我是其中之一。但謝謝你，馬丁。

But I think you are the boss of the lead.

但我認為你是領導的上司。

What was the question? Yes. So we have our statistical analysis plan is very lengthy and very long. And all of that is submitted to FDA for their feedback. And so and often they and they have and given us feedback. Again, we've talked extensively about the death penalty with them. This is what this is the current feedback as just a few weeks ago. So that's already set. And then CQ, and his group have been in conversations with FDA about, as was true for increase, the same for these studies where what specific statistical models should be used and how to impute the measures. Again, the mixed model repeated measures or multiple imputations.

問題是什麼？是的。所以我們的統計分析計畫非常冗長。所有這些都已提交給 FDA 徵求他們的反饋。所以他們經常給我們回饋。我們再次與他們廣泛討論了死刑問題。這就是幾週前的當前回饋。那就已經設定好了。然後，CQ 和他的團隊一直在與 FDA 進行對話，就像增加一樣，對於這些研究，應該使用什麼特定的統計模型以及如何估算這些指標。再次，混合模型重複測量或多重估算。

Perfect. Thank you so much, Dr. Peterson. Thank you, folks on the call. Operator, you can wrap up the call now.

完美的。非常感謝您，彼得森博士。謝謝各位來電。接線員，您現在可以結束通話了。

Thank you for participating in today's United Therapeutics Corporation earnings webcast. A rebroadcast of this webcast will be available for replay for one week by visiting the Events and Presentations section of the United Therapeutics Investor Relations website at ir.unither.com. Thank you.

感謝您參加今天的聯合治療公司收益網路廣播。本次網路直播的重播將持續一周，您可以透過造訪 United Therapeutics 投資者關係網站 ir.unither.com 的「活動及示範」區塊進行重播。謝謝。