Lexicon Pharmaceuticals Inc (LXRX) 2025 Q1 法說會逐字稿

Welcome to the Lexicon Pharmaceuticals First Quarter 2025 Financial Results Conference Call. (Operator Instructions) As a reminder, this call is being recorded today, May 13, 2025.

歡迎參加 Lexicon Pharmaceuticals 2025 年第一季財務業績電話會議。（操作員指示）提醒一下，本次通話於今天（2025 年 5 月 13 日）進行錄音。

I will now turn the call over to Lisa DeFrancesco, SVP Investor Relations and Corporate Communications for Lexicon. Please go ahead, Lisa.

現在我將電話轉給 Lexicon 投資人關係和企業傳播資深副總裁 Lisa DeFrancesco。請繼續，麗莎。

Thank you, Shannon. Good afternoon, and welcome to the Lexicon Pharmaceuticals First Quarter 2025 Financial Results Conference Call. Joining me today are Dr. Mike Exton, Lexicon's Chief Executive Officer and Director; and Scott Coiante, Senior Vice President and Chief Financial Officer. Dr. Craig Granowitz, Senior Vice President and Chief Medical Officer, will join us for Q&A.

謝謝你，香農。下午好，歡迎參加 Lexicon Pharmaceuticals 2025 年第一季財務業績電話會議。今天與我一起出席的還有 Lexicon 執行長兼董事 Mike Exton 博士和高級副總裁兼財務長 Scott Coiante。高級副總裁兼首席醫療官 Craig Granowitz 博士將與我們一起進行問答。

Earlier this afternoon, Lexicon issued a press release announcing our financial results for the first quarter of 2025, which is available on our website at www.lexpharma.com and through our SEC filings. A webcast of this call, along with the slide presentation is also available on our website. During this call, we will review the information provided in the release, provide a corporate update, and then use the remainder of our time to answer your questions.

今天下午早些時候，Lexicon 發布了一份新聞稿，宣布了我們 2025 年第一季的財務業績，您可以在我們的網站 www.lexpharma.com 和 SEC 文件上查閱。本次電話會議的網路直播以及幻燈片簡報也可在我們的網站上找到。在此次通話中，我們將審查新聞稿中提供的信息，提供公司最新動態，然後利用剩餘時間回答您的問題。

Before we begin, let me remind you that we will be making forward-looking statements, including statements related to the safety, efficacy, clinical development, regulatory status, and therapeutic and commercial potential of pilavapadin, LX9851, sotagliflozin, and our other drug programs, as well as our business generally. These statements may include characterizations and projections related to the clinical development, regulatory status, and market opportunity for our drug programs and the commercial performance of INPEFA for heart failure.

在我們開始之前，請允許我提醒您，我們將做出前瞻性陳述，包括與 pilavapadin、LX9851、sotagliflozin 和我們的其他藥物項目的安全性、有效性、臨床開發、監管狀態以及治療和商業潛力以及我們的業務總體相關的陳述。這些聲明可能包括與我們的藥物計畫的臨床開發、監管狀況和市場機會以及 INPEFA 治療心臟衰竭的商業表現相關的特徵和預測。

This call may also contain forward-looking statements related to our growth, and future operating results, discovery and development of our drug candidates, strategic alliances, and intellectual property as well as other matters that are not historical facts or information. Various risks may cause our actual results to differ materially from those expressed or implied in such forward-looking statements, and we refer you to our most recent annual report on Form 10-K and other SEC filings for detailed information describing such risks.

本次電話會議也可能包含與我們的成長、未來營運績效、候選藥物的發現和開發、策略聯盟和智慧財產權以及其他非歷史事實或資訊有關的前瞻性陳述。各種風險可能導致我們的實際結果與此類前瞻性陳述中表達或暗示的結果有重大差異，我們建議您參閱我們最新的 10-K 表格年度報告和其他 SEC 文件，以獲取描述此類風險的詳細資訊。

I would now like to turn the call over to Mike Exton. Mike?

現在我想把電話轉給麥克·艾克斯頓。麥克風？

Good day, everyone. Thanks for joining us. As those of you following Lexicon know, the first quarter of 2025 was a busy and productive one for us.

大家好。感謝您的加入。關注 Lexicon 的朋友都知道，2025 年第一季對我們來說是忙碌而富有成效的一年。

Starting with our most recent announcement. At the end of March, we announced an exclusive license agreement with Novo Nordisk for LX9851, our first-in-class oral non-incretin candidate for obesity and other metabolic conditions. Now this agreement grants Novo an exclusive worldwide license to develop, manufacture, and commercialize 9851 in all indications.

從我們最近的公告開始。三月底，我們宣布與諾和諾德公司就 LX9851 達成獨家許可協議，LX9851 是我們用於治療肥胖症和其他代謝疾病的首創口服非腸促胰島素候選藥物。現在，該協議授予諾和諾德公司在全球範圍內開發、生產和商業化 9851 的所有適應症的獨家許可。

Under the terms, Lexicon was eligible to receive upfront and near-term milestone payments of up to $75 million, of which $45 million was received in April and up to $1 billion in aggregate upfront and development, regulatory and sales milestone payments as well as tiered royalties on future net sales of 9851.

根據條款，Lexicon 有資格獲得高達 7500 萬美元的預付款和近期里程碑付款，其中 4500 萬美元已於 4 月份收到，此外還有總計高達 10 億美元的預付款和開發、監管和銷售里程碑付款以及 9851 未來淨銷售額的分級特許權使用費。

Lexicon will be responsible for completing agreed-upon investigational new drug application enabling activities for 9851 and providing clinical supply to Novo Nordisk at an agreed-upon transfer price for a limited time period, while Novo will be responsible for filing the IND and conducting all further development, manufacturing and commercialization of LX9851.

Lexicon 將負責完成商定的 9851 新藥研究申請授權活動，並在限定的時間內以商定的轉讓價格向 Novo Nordisk 提供臨床供應，而 Novo 將負責提交 IND 並進行 LX9851 的所有進一步開發、製造和商業化。

Now we couldn't be more pleased with this collaboration. Novo Nordisk's experience and global capabilities in obesity make them an ideal partner to maximize the value of LX9851. This truly is a validation of the science and the potential of this novel asset. We're gratified that we have continued to make great progress in our partnering strategy to find the highest quality partners that augment our capabilities and realize the full value of our assets.

我們對這次合作感到非常高興。諾和諾德在肥胖症領域的經驗和全球能力使其成為最大化 LX9851 價值的理想合作夥伴。這確實驗證了這項新資產的科學性和潛力。我們感到欣慰的是，我們在合作策略方面不斷取得巨大進展，找到了最優質的合作夥伴，增強了我們的能力，並實現了我們資產的全部價值。

Now the other major development in the first quarter was the top-line readout of our PROGRESS Phase 2b study of pilavapadin, which is our oral non-opioid drug candidate for DPNP. We're pleased to have identified a well-tolerated dose that has repeatedly showing clear evidence of effect to take forward in Phase 3 studies. Once we have the full data package later in Q2, we look forward to engaging the FDA on the Phase 3 design using 10 milligrams of pilavapadin.

現在，第一季的另一個重大進展是我們對 pilavapadin 的 PROGRESS 2b 期研究的頂線讀數，pilavapadin 是我們用於 DPNP 的口服非阿片類藥物候選藥物。我們很高興找到了一種耐受性良好的劑量，並且已反覆顯示出明顯的效果證據，可以在第三階段研究中繼續推進。一旦我們在第二季度稍後獲得完整的數據包，我們期待與 FDA 合作進行使用 10 毫克 pilavapadin 的 3 期設計。

And finally, we completely revised our cost structure to reflect our pivot to an R&D-focused company by reducing our operating costs and utilizing the upfront payment from the Novo Nordisk agreement to reduce our debt while ensuring we have the cash runway to meet our objectives and support continued development of our R&D programs.

最後，我們徹底修改了成本結構，以反映我們向以研發為重點的公司轉型，透過降低營運成本並利用 Novo Nordisk 協議的預付款來減少債務，同時確保我們有足夠的現金來滿足我們的目標並支持我們研發項目的持續發展。

So all in all, we ended the first quarter in a very strong position. We have a clear path forward for pilavapadin in DPNP, having cleared the hurdle of identifying the appropriate dose for Phase 3. We improved our balance sheet and are on a strong financial footing for the milestones ahead.

總而言之，我們以非常強勁的地位結束了第一季。我們已經為 DPNP 中的 pilavapadin 制定了明確的前進方向，並且已經掃清了確定第 3 階段適當劑量的障礙。我們改善了資產負債表，為未來的里程碑奠定了堅實的財務基礎。

So I'd like to dive a little bit deeper now into our DPNP program and primarily reiterate two key points here. First and importantly, across both the RELIEF and PROGRESS studies, we've now demonstrated 3x that the 10-milligram dose shows early and sustained separation versus placebo.

因此，我現在想更深入地探討我們的 DPNP 計劃，並主要重申兩個關鍵點。首先，也是最重要的一點，在 RELIEF 和 PROGRESS 研究中，我們已經證明 3 倍劑量的 10 毫克藥物與安慰劑相比，表現出早期和持續的分離。

And second, while absence of a day 1 loading dose improved the tolerability of all pilavapadin arms in PROGRESS, that 10-milligram dosing schedule was particularly well-tolerated, showing placebo-like completion rates.

其次，雖然沒有第一天的負荷劑量改善了 PROGRESS 中所有 pilavapadin 組的耐受性，但 10 毫克的給藥方案耐受性特別好，顯示出類似安慰劑的完成率。

Collectively, in our view, these data derisk our advancement into Phase 3 with a 10-milligram dose and give us great confidence in the potential of pilavapadin to be the first novel oral non-opioid DPNP medication in more than two decades.

總的來說，我們認為這些數據降低了我們以 10 毫克劑量進入第 3 階段的風險，並讓我們對 pilavapadin 成為二十多年來第一個新型口服非阿片類 DPNP 藥物的潛力充滿信心。

I can't emphasize enough the opportunity for innovation in this market. As I talk with patients, caregivers and payers, it's absolutely clear that there's a tremendous need for new non-opioid treatment options for neuropathic pain.

我再怎麼強調這個市場的創新機會也不為過。當我與患者、照護者和付款人交談時，我很清楚，對神經性疼痛的新型非鴉片類治療方案有著巨大的需求。

DPNP is a relatively common complication of diabetes, impacting one in every four people with diabetes. Today, there are approximately 9 million people in the US with DPNP, and that number is expected to grow to 13 million by 2035.

DPNP 是糖尿病的一種相對常見的併發症，每四個糖尿病患者中就有一個患有該疾病。目前，美國約有 900 萬人擁有 DPNP，預計到 2035 年將成長到 1,300 萬人。

This is a chronic and progressive pain disorder that severely impairs people's quality of life. Not only is it painful, but it's unrelenting and burdensome to patients and can lead to other complications like a loss of sensation, falls, fractures, even limb amputation. And so the message from all stakeholders is loud and clear. The community needs new and better medications to manage DPNP.

這是一種慢性、進行性疼痛疾病，嚴重損害人們的生活品質。它不僅帶來疼痛，對患者來說也是持續不斷的負擔，並可能導致其他併發症，如感覺喪失、跌倒、骨折，甚至截肢。因此，所有利害關係人所發出的訊息都是響亮而明確的。社會需要新的、更好的藥物來治療 DPNP。

For 70% of people with DPNP, currently available treatment options don't provide adequate relief. 60% have tried multiple therapies, either by switching or by adding on to their treatment regimen. But people with DPNP often feel like they're stuck in a cycle of trial and failure with different treatments.

對於 70% 的 DPNP 患者，目前可用的治療方案無法提供足夠的緩解。 60% 的患者嘗試了多種療法，無論是透過更換或增加治療方案。但患有 DPNP 的人常常覺得自己陷入了嘗試不同治療方法但又失敗的循環中。

But the need for new non-opioid treatments for pain is also underscored by recent proposed legislation such as the Alternatives to PAIN Act that's being proposed supporting greater access to non-opioid therapies. We're committed to advancing our pilavapadin development program as quickly as possible with the aim of providing a novel oral treatment that can improve the lives of people with DPNP.

但是，最近提出的立法也強調了對新的非鴉片類疼痛治療方法的需求，例如《疼痛替代療法法案》，該法案旨在支持更多地獲得非鴉片類藥物治療。我們致力於盡快推進我們的 pilavapadin 開發計劃，旨在提供一種可以改善 DPNP 患者生活的新型口服治療方法。

So we look forward to providing further updates as the year progresses, including full data from the PROGRESS study at an upcoming medical meeting. We're targeting a Phase 3 study initiation for pilavapadin in DPNP later this year following our end of Phase 2 review meeting with the FDA.

因此，我們期待在未來的一年中提供進一步的更新，包括即將舉行的醫學會議上提供的 PROGRESS 研究的完整數據。我們計劃在今年稍後與 FDA 結束第 2 階段審查會議後，啟動 DPNP 中 pilavapadin 的第 3 階段研究。

Moving on now to sotagliflozin. We remain on track with enrollment in our global pivotal SONATA-HCM study of sotagliflozin in hypertrophic cardiomyopathy or HCM. HCM represents an area of significant opportunity and need where we feel sota has the potential to offer a differentiated treatment option.

現在繼續討論索格列淨。我們仍在按計畫進行全球關鍵性 SONATA-HCM 研究，研究索格列淨治療肥厚型心肌病變 (HCM) 的療效。HCM 代表著一個充滿重大機會和需求的領域，我們認為 sota 有潛力提供差異化的治療選擇。

Now in the US, there are just over 1 million people with HCM. And of those, approximately 1/3 have nonobstructive HCM, which the heart muscle is thicken but doesn't block flow, whereas 2/3 are diagnosed with obstructive HCM, which the thickening of the heart muscle wall blocks or reduces blood flow from the heart.

目前，美國有 100 多萬 HCM 患者。其中，約有 1/3 的患者患有非阻塞性 HCM，即心肌增厚但不會阻礙血流，而 2/3 的患者被診斷為阻塞性 HCM，即心肌壁增厚會阻礙或減少心臟的血流。

An important characteristic of HCM that may not be fully appreciated is that as a chronic progressive disease, HCM can deteriorate over time, leading to other complications including heart failure. Indeed, 43% of people with HCM also have progressive heart failure.

HCM 的一個重要特徵可能尚未被充分認識，那就是作為一種慢性進行性疾病，HCM 會隨著時間的推移而惡化，導致包括心臟衰竭在內的其他併發症。事實上，43% 的 HCM 患者也會出現進行性心臟衰竭。

Now we have great confidence in sota as an option for HCM. As you're all aware, there have been a number of innovations that target the sarcomere being developed for this disease, one of which is approved for the treatment of obstructive HCM.

現在我們對 Sota 作為 HCM 的選擇非常有信心。眾所周知，目前已有許多針對這種疾病的肌節的創新療法正在研發中，其中一種已被批准用於治療阻塞性肥大性心肌病變 (HCM)。

Nevertheless, despite significant investment and increasing awareness in HCM, these novel agents have only penetrated about 1% of the market. So we believe the potential approval of sota would significantly expand the population treated with novel agents.

然而，儘管在 HCM 方面投入了大量資金並且人們的認識不斷提高，這些新型藥物僅滲透了約 1% 的市場。因此，我們相信 SOTA 的潛在批准將大大擴大接受新型藥物治療的人群。

Our confidence derives from a number of sota's features. First of all, besides its approval in the US for heart failure, there are important data that give us confidence that sota will be effective in both obstructive and nonobstructive HCM. Namely, we've observed significant benefit of sotagliflozin in heart failure and MACE in patients with left ventricular hypertrophy with normal blood pressure.

我們的信心源自於 sota 的諸多特質。首先，除了在美國獲準用於治療心臟衰竭外，還有重要的數據讓我們相信 SOTA 對阻塞性和非阻塞性 HCM 均有效。也就是說，我們觀察到索格列淨對血壓正常的左心室肥大患者的心臟衰竭和 MACE 有顯著的益處。

Furthermore, mechanistically, sota appears to reduce cardiac work and improve cardiac metabolism. Importantly, we would expect no REMS for sota in HCM, consistent with our heart failure label, which would provide access to a broad prescriber base.

此外，從機制上看，sota 似乎可以減少心臟工作量並改善心臟代謝。重要的是，我們預計 HCM 中的 sota 不會出現 REMS，這與我們的心臟衰竭標籤一致，這將提供廣泛的處方基礎。

And finally, we can have confidence that to date in clinical trials and post-marketing experience, sota has not been associated with an increased risk of atrial fibrillation. Therefore, we expect sota has the potential to become a disruptor in this space and become widely used in the market across the spectrum of disease.

最後，我們可以確信，迄今為止，在臨床試驗和上市後經驗中，Sota 並未與心房顫動風險的增加有關。因此，我們預期 sota 有潛力成為該領域的顛覆者，並在各種疾病的市場上廣泛應用。

The next slide provides an overview of our global Phase 3 SONATA study of sota in HCM. SONATA is enrolling at full speed with EU and LATAM sites either already online or imminent. Now we expect that all of the Phase 3 sites will be up and running by the third quarter of this year. So we're pleased with that progress.

下一張投影片概述了我們對 HCM 中的 sota 進行的全球第 3 階段 SONATA 研究。SONATA 正在全速招生，歐盟和拉丁美洲的網站已經上線或即將上線。現在我們預計第三階段的所有站點將在今年第三季投入運作。所以我們對這項進展感到滿意。

SONATA is the only ongoing study evaluating a treatment in both obstructive and nonobstructive HCM. We feel that there's potential for this study to support an sNDA with a broad label. Once the SONATA study is complete and we have that data in hand, we will also have an opportunity to revisit the totality of the sotagliflozin potential opportunity across indications in the US, where we continue to build differentiating evidence that the mechanism of dual inhibition of SGLT1/2 does have different outcomes in MACE events, including MI and stroke as most recently published in the Lancet.

SONATA 是唯一一項正在進行的評估阻塞性和非阻塞性 HCM 治療方法的研究。我們認為這項研究有可能支持具有廣泛標籤的 sNDA。一旦 SONATA 研究完成並且我們掌握了數據，我們還將有機會重新審視索他格列淨在美國各個適應症中的全部潛在機會，我們將繼續構建差異化證據，證明 SGLT1/2 雙重抑制機制在 MACE 事件（包括心肌梗塞和中風）中確實有不同的結果，正如最近在《柳葉刀》上發表的那樣。

Now touching briefly on business development. As I mentioned at the top of our call, we're very pleased with our recently announced collaboration with Novo Nordisk for LX9851, which both strengthens our financial position and provides LX9851 the best possible chance of success by benefiting from the expertise, resources, and capability of Novo Nordisk, an established leader in the obesity market.

現在簡單談談業務發展。正如我在電話會議開始時提到的，我們對最近宣布的與諾和諾德在 LX9851 方面的合作感到非常高興，這不僅增強了我們的財務狀況，而且通過受益於肥胖市場領先者諾和諾德的專業知識、資源和能力，為 LX9851 提供了最大的成功機會。

As the obesity treatment landscape continues to grow and evolve, we expect to see an opportunity for next-gen treatments to build on the success of the earlier incretin-based therapies.

隨著肥胖治療領域的不斷發展和演變，我們期望看到下一代治療方法有機會在早期基於腸促胰島素的療法的成功基礎上再接再厲。

Based on 9851's unique mechanism, oral administration, preclinical findings to date, and possibility for both monotherapy and combination applications, we feel LX9851 has the opportunity to occupy a unique space in the treatment landscape for obesity and metabolic conditions. And we look forward to working with Novo to maximize the potential of this innovative medicine.

基於 9851 的獨特機制、口服給藥、迄今為止的臨床前發現以及單一療法和聯合應用的可能性，我們認為 LX9851 有機會在肥胖和代謝疾病治療領域佔據獨特的空間。我們期待與諾和諾德合作，最大限度地發揮這種創新藥物的潛力。

So zooming out to look at business development more broadly. Our innovative and flexible partnership approach is unlocking long-term value for Lexicon. Viatris has been a committed and collaborative partner for sota outside of the US and Europe, and is extending the geographical reach for sota across cardiometabolic and other indications.

因此，我們需要從更廣闊的視角來看待業務發展。我們創新且靈活的合作方式正在為 Lexicon 釋放長期價值。Viatris 一直是 sota 在美國和歐洲以外的忠實合作夥伴，並正在擴大 sota 在心臟代謝和其他適應症領域的地理覆蓋範圍。

This agreement included a $25 million upfront payment and potential milestone payments of up to almost $200 million. This collaboration leverages Viatris' global scales and capabilities, allowing us to reach more patients worldwide.

該協議包括 2500 萬美元的預付款和高達近 2 億美元的潛在里程碑付款。此次合作利用了 Viatris 的全球規模和能力，使我們能夠接觸到全球更多的患者。

Viatris recently announced it's been preparing regulatory approval applications for sota in a number of ex-US markets. Filings in the UAE and Saudi Arabia have been submitted, and the filing in Canada is expected to be submitted shortly. So as you can see, we've been working closely with Viatris and making significant progress together.

Viatris 最近宣布，它正在為多個美國以外市場的 SOTA 準備監管批准申請。阿聯酋和沙烏地阿拉伯的申請已經提交，預計很快將提交加拿大的申請。正如您所看到的，我們一直與 Viatris 密切合作並共同取得了重大進展。

Now as I just noted, our partnership with Novo has the potential to generate significant value for LX9851 in obesity and for Lexicon as a partner. And as we look to our future partnerships, we're heavily focused on pilavapadin, where our aim is to unlock value globally across multiple indications with a partner that has complementary capabilities, therapeutic area expertise, and a global commercial footprint to help fully realize pilavapadin's pipeline and appeal potential.

正如我剛才提到的，我們與 Novo 的合作有可能為 LX9851 在肥胖症治療領域以及作為合作夥伴的 Lexicon 創造巨大的價值。當我們展望未來的合作夥伴關係時，我們將重點放在 pilavapadin，我們的目標是與具有互補能力、治療領域專業知識和全球商業足蹟的合作夥伴一起在多種適應症中釋放全球價值，以幫助充分實現 pilavapadin 的管道和吸引力潛力。

With our significant clinical expertise in the space, we have flexibility in the types of partners that would be a great fit for this asset. We've been having a significant amount of interest and dialogue with these potential partners.

憑藉我們在該領域豐富的臨床專業知識，我們可以靈活地選擇最適合該資產的合作夥伴類型。我們與這些潛在合作夥伴一直保持著濃厚的興趣並進行了對話。

And with that, I'd like to now turn it over to Scott to walk you through our financial results for the quarter ended March 31, 2025.

現在，我想把時間交給史考特，讓他向大家介紹我們截至 2025 年 3 月 31 日的季度財務表現。

Thank you, Mike. For the first quarter of 2025 (technical difficulty) from sales of INPEFA compared to $1.1 million for the first quarter of 2024. Research and development expenses for the first quarter of 2025 increased to $15.3 million from $14.4 million for the same period in 2024, and primarily reflect expenses associated with our late-stage development programs, including the SONATA Phase 3 study for HCM and our PROGRESS Phase 2b study of pilavapadin in DPNP.

謝謝你，麥克。2025 年第一季（技術難度）INPEFA 的銷售額為 110 萬美元，而 2024 年第一季為 110 萬美元。2025 年第一季的研發費用從 2024 年同期的 1440 萬美元增至 1530 萬美元，主要反映與我們的後期開發計劃相關的費用，包括針對 HCM 的 SONATA 第 3 階段研究和我們在 DPNP 中對 pilavapadin 的 PROGRESS 第 2b 階段研究。

Selling, general and administrative expenses for the first quarter of 2025 decreased to $11.6 million compared to $32.1 million for the first quarter of 2024, primarily due to the efforts of our strategic repositioning in late 2024 and the reduced marketing efforts for INPEFA.

2025 年第一季的銷售、一般和行政費用從 2024 年第一季的 3,210 萬美元下降至 1,160 萬美元，這主要歸因於我們在 2024 年底進行策略重新定位的努力以及對 INPEFA 的營銷力度的減少。

Net loss for the first quarter of 2025 was $25.3 million or $0.07 per share as compared to a net loss of $48.4 million or $0.20 per share for the same period in 2024.

2025 年第一季淨虧損為 2,530 萬美元，即每股 0.07 美元，而 2024 年同期淨虧損為 4,840 萬美元，即每股 0.20 美元。

We ended the first quarter with $194.8 million in cash and short-term investments as compared to $238 million of cash and short-term investments as of December 31, 2024.

我們第一季末的現金和短期投資為 1.948 億美元，而截至 2024 年 12 月 31 日的現金和短期投資為 2.38 億美元。

I'd like to take a minute to note a few items. The first quarter is typically the quarter with the greatest use of cash and included in the cash used for Q1 2025 was approximately $7.5 million in severance payments related to our restructuring, which were accrued in Q4 2024. We expect the use of cash to be less in the subsequent quarters of this year.

我想花一點時間來記錄一些事項。第一季通常是現金使用最多的季度，2025 年第一季使用的現金中包括與我們的重組相關的約 750 萬美元的遣散費，這些遣散費已於 2024 年第四季度累計。我們預計今年後續幾季的現金使用量將會減少。

Revenue associated with the $45 million upfront payment from Novo has been deferred and will be recognized over the estimated completion period of our obligations under the exclusive licensing agreement. We anticipate stable US INPEFA revenues this year despite limited promotional activity.

與 Novo 支付的 4500 萬美元預付款相關的收入已被遞延，並將在我們根據獨家許可協議承擔的義務預計完成期間確認。儘管促銷活動有限，我們預計今年美國 INPEFA 收入將保持穩定。

And we are also reiterating our previously provided operating expense guidance and expect total operating expenses to be between $135 million and $145 million for 2025 with R&D expected between $100 million and $105 million and SG&A expected between $35 million and $40 million.

我們也重申了先前提供的營運費用指導，預計 2025 年總營運費用將在 1.35 億美元至 1.45 億美元之間，其中研發費用預計在 1 億美元至 1.05 億美元之間，銷售、一般及行政費用預計在 3500 萬美元至 4000 萬美元之間。

We also expect lower interest expense for the remainder of the year as a result of our partial debt repayment in April. We are confident that we are capitalized to meet our objectives to support our Phase 3 readiness for DPNP, our ongoing Phase 3 trial in HCM, and all IND-enabling activities related to 9851.

由於我們在四月償還了部分債務，我們也預計今年剩餘時間的利息支出將會降低。我們有信心，我們有足夠的資金來實現我們的目標，以支持我們為 DPNP 做好第 3 階段的準備、我們正在 HCM 進行的第 3 階段試驗以及與 9851 相關的所有 IND 支持活動。

I'd now like to turn it back to Mike for closing remarks.

現在我想請麥克做最後發言。

Yes. Thanks a lot, Scott. So in summary, with the significant amount of progress we've made so far this year, we're incredibly well-positioned with a number of pipeline-in-a-pill assets that we can continue to explore ways to leverage and add value for Lexicon with potential for new indications, new partnerships, and late-stage regulatory developments.

是的。非常感謝，斯科特。總而言之，憑藉我們今年迄今為止的重大進展，我們擁有一系列非常有利的藥丸資產，我們可以繼續探索利用這些資產並為 Lexicon 增加價值的方法，並有可能獲得新的適應症、新的合作夥伴關係和後期監管發展。

Our goal is to advance these additional programs on our own or in the case of pilavapadin, in partnership with a committed collaborator with therapeutic expertise and global scale. And we have demonstrated our ability to find the right high-quality partners for our assets where appropriate.

我們的目標是自行推進這些附加項目，或者就 pilavapadin 而言，與具有治療專業知識和全球規模的忠誠合作夥伴合作推進這些附加項目。我們已經證明我們有能力在適當的情況下為我們的資產找到合適的高品質合作夥伴。

Earlier in the year, we introduced Lead to Succeed. And I think it's important that we continue to discuss this as an important pillar of our strategy as we think about the opportunities that we have in our pipeline. In particular, I feel it's important that we focus on areas where we believe we have the greatest chance of success, where we can be first or only in large markets with significant unmet need and where we have the internal clinical and medical experience necessary to be successful. We'll continue to apply this lens to our future opportunities as we develop our path forward.

今年早些時候，我們推出了「引領成功」計畫。我認為，當我們思考我們所擁有的機會時，繼續討論這一點作為我們策略的重要支柱非常重要。特別是，我認為我們必須專注於我們認為最有可能成功的領域，我們可以在那些具有巨大未滿足需求的大型市場中率先或唯一佔據主導地位的領域，以及我們擁有成功所必需的內部臨床和醫療經驗的領域。在我們開拓前進的道路上，我們將繼續運用這個視角來看待未來的機會。

Now importantly, we've got a number of very important and impactful catalysts as we look towards the remainder of this year. For pilavapadin in DPNP, we anticipate sharing full PROGRESS data in Q3, along with an end of Phase 2 meeting. We're also preparing to present data at upcoming medical meetings and partnership discussions are ongoing.

現在重要的是，展望今年剩餘時間，我們已經獲得了許多非常重要且有影響力的催化劑。對於 DPNP 中的 pilavapadin，我們預計將在第三季分享完整的 PROGRESS 數據，同時結束第二階段會議。我們也準備在即將召開的醫學會議上展示數據，並且合作討論正在進行中。

For LX9851 in obesity and weight management, we'll collaborate with Novo Nordisk on IND-enabling activities, and Novo will be responsible for the IND submission. For sotagliflozin in HCM, we're actively enrolling our SONATA-HCM study with all Phase 3 study sites expected to be operational by Q3.

對於肥胖和體重管理中的 LX9851，我們將與 Novo Nordisk 合作進行 IND 支持活動，Novo 將負責 IND 提交。對於 HCM 中的索他格列淨，我們正在積極進行 SONATA-HCM 研究，預計所有 3 期研究地點將在第三季投入運作。

Viatris continues to advance regulatory submissions for sotagliflozin in heart failure outside of the US and Europe, with the UAE and Saudi Arabia complete and Canada anticipated shortly.

Viatris 繼續在美國和歐洲以外地區推進索格列淨用於治療心臟衰竭的監管申請，其中阿聯酋和沙烏地阿拉伯的申請已完成，加拿大的申請也即將提交。

As we discussed last quarter, we see opportunities to differentiate sota as a mechanism and believe that the recent MACE data potentially supports expanding the use of this medicine into adjacent indications. We plan to engage in a regulatory process regarding this data later this year.

正如我們上個季度所討論的那樣，我們看到了將 sota 區分為一種機制的機會，並相信最近的 MACE 數據可能支持將這種藥物的使用擴展到相鄰的適應症。我們計劃在今年稍後啟動有關這些數據的監管流程。

Finally, regarding Zynquista for type 1 diabetes with CKD. While we're not currently actively investing in this program, it's important that we continue to move forward with the end of review process in support of the significant number of patients that continue to actively and strongly advocate for approval of this drug, underscoring the need in T1D. To that end, we held an end of review meeting with the FDA in Q2, and we expect to continue discussions with the FDA.

最後，關於 Zynquista 治療患有 CKD 的第 1 型糖尿病。雖然我們目前沒有積極投資這個項目，但重要的是我們要繼續推進審查程序的結束，以支持大量繼續積極和強烈主張批准這種藥物的患者，強調 T1D 的必要性。為此，我們在第二季與 FDA 舉行了審查結束會議，我們希望繼續與 FDA 進行討論。

We remain enthusiastic as we look to the potential updates in the remainder of this year, and we look forward to keeping you all informed of progress across all of these programs in the coming months.

我們仍然對今年剩餘時間可能出現的更新充滿熱情，並期待在未來幾個月內向大家通報所有這些計劃的進展。

With that, Craig, you can join us, and we'll have time to take everyone's questions. So over to you, operator.

克雷格，這樣你就可以加入我們了，我們將有時間回答大家的問題。那麼交給你了，接線生。

(Operator Instructions) Andrew Tsai, Jefferies.

（操作員指示） Andrew Tsai，傑富瑞。

First is on the pain program. I know the base case is going to be running two pivotal Phase 3 studies. Can you talk about the intended trial designs, whether they're identical? And could it actually make sense to do three studies instead with the third one serving as a backup?

首先是疼痛計劃。我知道基本情況是進行兩個關鍵的第三階段研究。您能談談預期的試驗設計嗎？它們是否相同？那麼，進行三項研究並以第三項研究作為備份是否真的有意義呢？

Andrew, it's Craig Granowitz. Thank you for your question. Our plan is still, as we've previously communicated, to run two parallel trials with very similar design. One would most likely be US only and the other would be a worldwide trial, including US and non-US sites.

安德魯，我是克雷格‧格拉諾維茲。感謝您的提問。正如我們之前所傳達的，我們的計劃仍然是進行兩項設計非常相似的平行試驗。其中一個很可能僅在美國進行，另一個可能是全球試驗，包括美國和非美國站點。

There's been nothing, since our last update, that would change our plans in that regard. As a reminder, the sites would be roughly about 300 or 350 patients per arm, two-arm trials of a 10-milligram dose flat from the outset versus placebo and run in parallel in patients with moderate to severe pain with a subset of that group stratified for an underlying DPNP medication.

自上次更新以來，沒有任何事情可以改變我們在這方面的計劃。提醒一下，每個試驗點大約有 300 或 350 名患者，雙組試驗從一開始就採用 10 毫克劑量與安慰劑進行比較，並在中度至重度疼痛患者中同時進行，其中該組的一個子集根據基礎 DPNP 藥物進行分層​​。

With respect to the third trial, we don't believe -- as Mike mentioned during the prepared remarks, we believe that we have a robust clinical signal in these trials that is observable and reproducible, and rapidly separating from placebo in each case with the 10-milligram dose arm.

關於第三次試驗，我們不相信——正如麥克在準備好的發言中提到的那樣，我們相信我們在這些試驗中有一個強有力的臨床信號，它是可觀察和可重複的，並且在每種情況下都與 10 毫克劑量組的安慰劑迅速分離。

And also, as a reminder, the reduction of pain score from patient baseline is approaching 1.5- to 2-point drop from baseline, which is what the patients would experience. So with all of that and a drug that we feel confident that's once daily has placebo-like completion rates and no identified yet drug-drug interactions or other safety concerns of significance, we feel quite confident in this program. Depending upon what we hear from the FDA, that would obviously be subject to change, but that is certainly our intention going into the end of Phase 2 meeting.

另外，需要提醒的是，患者疼痛評分相對於基線的降低接近 1.5 到 2 分，這是患者會經歷的。因此，考慮到所有這些，以及我們相信每天服用一次的藥物具有類似安慰劑的完成率，並且尚未發現藥物相互作用或其他重大安全問題，我們對該計劃非常有信心。根據我們從 FDA 聽到的消息，這顯然可能會發生變化，但這肯定是我們在第二階段會議結束時的意圖。

And assuming the end of Phase 2 does go well and you start the Phase 3s in, let's just say, Q4, when would the pain data sets be? And then as those Phase 3s are studying, what other peripheral studies do you think you need to accomplish or finish to ensure you can file an NDA right after the Phase 3 data?

假設第 2 階段結束進展順利，並且您開始第 3 階段，那麼假設 Q4，疼痛資料集會在何時出現？那麼，在研究這些第 3 階段的研究時，您認為還需要完成哪些其他外圍研究，以確保您可以在第 3 階段資料之後立即提交 NDA？

Yes. Great questions, Andrew. I think as all drugs that are centrally acting in this category, we need to look at addiction liability. We believe and hope that those would be animal model studies only because we have no indication. We've seen no rebound or other unusual liking behavior with the use of pilavapadin. That would be a critical study. There are some additional metabolism studies that we're looking at.

是的。很好的問題，安德魯。我認為，對於所有在這一類別中起主要作用的藥物，我們需要考慮成癮性。我們相信並希望那些只是動物模型研究，因為我們沒有跡象表明。我們沒有看到使用 pilavapadin 後出現反彈或其他異常的喜好行為。這將是一項重要的研究。我們正在研究一些額外的代謝研究。

As a reminder, this drug is renally cleared, and we're looking to validate the clearance and the level of renal impairment that we can include in the trials. Those studies, we think, will be important. And then obviously, there are long-term [KORK] studies and a few other preclinical trials.

提醒一下，這種藥物是透過腎臟清除的，我們正在尋求驗證其清除率以及可以納入試驗的腎功能損害程度。我們認為這些研究非常重要。顯然，還有長期的 [KORK] 研究和一些其他臨床前試驗。

We feel quite confident that we have a robust manufacturing process that we're ready to go right into Phase 3 and precommercial scale manufacturing with a process that is robust, and I don't think we'll be cost prohibitive in that regard.

我們非常有信心，我們擁有強大的製造流程，我們已準備好進入第 3 階段和預商業規模製造，我認為在這方面我們的成本不會過高。

So I think there's always more things to do. I'm sure that FDA might have some suggestions for us in addition. But based on our interactions with the FDA, we believe that those are going to be the major components of things we need to look at.

所以我認為總是有更多的事情要做。我相信 FDA 可能也會給我們一些建議。但根據我們與 FDA 的互動，我們認為這些將是我們需要關注的主要內容。

Roanna Ruiz, Leerink Partners.

Roanna Ruiz，Leerink Partners。

So a couple for me. I'll start with 9851. How are the IND-enabling studies progressing? And could you talk a bit about any remaining gating factors for this stage of development and eventually entering the clinic? And I was also curious how closely involved is Novo with your work in development here for this asset at this stage?

對我來說這是一對。我先從 9851 開始。IND 支持研究進展如何？您能否談談這一發展階段以及最終進入臨床階段的其他限制因素？我還很好奇，Novo 目前與您在此階段的資產開發工作有多密切的聯繫？

Yes. Thanks for the question, Roanna. Actually, the IND-enabling studies are going splendidly. They're all on track for finishing this year. And the relationship with Novo is very strong. They're very engaged in the data, and we're actually giving them direct line to the outputs of that data. So they're very collaborative and engaged as we go through this process, and are very pleased with the progress so far. And so as we have outlined, we expect that that will all conclude this year and then the information will be over to Novo to submit the IND.

是的。謝謝你的提問，Roanna。事實上，IND 支持研究進展非常順利。他們都有望今年完成學業。並且與 Novo 的關係非常牢固。他們非常關注數據，我們實際上為他們提供了直接獲取數據輸出的管道。因此，在我們進行這一過程時，他們非常合作和投入，並且對迄今為止的進展感到非常滿意。正如我們所概述的，我們預計這一切都將在今年完成，然後資訊將交給 Novo 提交 IND。

And one more follow-up for me. I noticed we've had a couple of updates in the HCM space from other companies, including the failed ODYSSEY trial for mavacamten in nonobstructive HCM. I was curious if that updates sort of refine some of your thinking around sota's potential going after nonobstructive HCM. Would you actually consider upsizing the SONATA trial or making any modifications based on what you're seeing in the field?

我還有一件事要跟進。我注意到我們在 HCM 領域收到了來自其他公司的一些更新，包括針對非阻塞性 HCM 的 mavacamten 的 ODYSSEY 試驗失敗。我很好奇，這些更新是否會在某種程度上完善您對 sota 追求非阻塞性 HCM 的潛力的一些想法。您是否真的會考慮擴大 SONATA 試驗的規模或根據您在現場看到的情況做出任何修改？

Yes. Look, it's really been an amazing quarter for HCM. There's been a lot of information, a lot of updates and a lot of interest. And I think what a number of the outputs that we've seen from ODYSSEY and others just reinforces our belief in sota.

是的。看，對於 HCM 來說，這確實是一個令人驚嘆的季度。有大量的資訊、大量的更新和大量的關注。我認為我們從 ODYSSEY 和其他公司看到的大量輸出強化了我們對 sota 的信念。

As we outlined in the prepared remarks, there's a number of pieces of evidence that we collected both preclinically and -- in clinical and preclinical studies that give us confidence in the efficacy of sotagliflozin in nonobstructive HCM. And we're actually powered to see an effect in both nonobstructive and obstructive as it is. So we don't think that it's necessary to increase to any degree the sample sizes that we see in SONATA and are confidently moving forward with that.

正如我們在準備好的評論中所概述的那樣，我們在臨床前和臨床及臨床前研究中收集了大量證據，這些證據讓我們對索格列淨在非阻塞性 HCM 中的療效充滿信心。事實上，我們有能力看到非阻塞性和阻塞性的效果。因此，我們認為沒有必要增加 SONATA 中的樣本量，並且我們有信心繼續進行這項工作。

So Craig, do you have any thoughts or?

那麼 Craig，你有什麼想法嗎？

Yes. No, well said, Mike. Roanna, I think the other important development really is the opportunity now to rapidly enroll the trial. So as BMS mentioned, there is no further work that they're doing on ODYSSEY. So the long-term extension trial is, my understanding, not taking place. And as Cytokinetics mentioned, they have now fully enrolled in ACACIA. So there are no other large trials that are running currently right now actively enrolling patients.

是的。不，說得好，麥克。Roanna，我認為另一個重要的進展實際上是現在有機會快速參與試驗。正如 BMS 所提到的，他們沒有在 ODYSSEY 上進行進一步的工作。因此，據我了解，長期延長試驗不會進行。正如 Cytokinetics 所提到的，他們現在已經完全加入 ACACIA。因此，目前沒有其他正在進行的大型試驗來積極招募患者。

And I think between the ease of our protocol for sites to complete, and as a reminder, we allow the use of CMIs or not CMIs, we have an ejection fraction down to 50%. We include both obstructive and nonobstructive patients. The burden on the sites is relatively limited in terms of the number of echoes, which is a rate-limiting step, I think, for some other companies just in terms of the capacity to do all those echoes. The lack of the need for doing the peak VO2 measurements or other difficult to execute physiologic tests, the feedback we've had from really all sites, whether we've talked to sites in Europe, the US or Latin America is that this is a trial that people are excited to participate in both patients and the study sites themselves.

我認為，考慮到我們的協議對於網站完成的便利性，以及提醒一下，我們允許使用 CMI 或不使用 CMI，我們的射血分數會下降到 50%。我們包括阻塞性患者和非阻塞性患者。就迴聲數量而言，站點的負擔相對有限，我認為，對於其他一些公司來說，這是一個限速步驟，僅就處理所有這些迴聲的能力而言。由於無需進行峰值攝氧量測量或其他難以執行的生理測試，我們從所有站點得到的反饋（無論我們與歐洲、美國還是拉丁美洲的站點進行過交流）是，這是一項人們很高興參與的試驗，無論是患者還是研究站點本身。

Yasmeen Rahimi, Piper Sandler.

亞斯明·拉希米、派珀·桑德勒。

I guess the first question, after -- obviously, as you guys have been engaging with the agency on pilavapadin end of Phase 2 meetings and in preparation for Phase 3. Do you think getting the minutes in the line -- in the sign-off on the Phase 3, is that a gating factor for the strategic discussions you're having in parallel? Or is it just both are kind of concurrently ongoing is not necessary for other to occur? That's maybe the first one, Mike.

我想第一個問題是——顯然，在第二階段會議結束後，你們一直在與該機構進行接觸，為第三階段做準備。您是否認為，在第三階段的簽字儀式上獲得會議記錄是您同時進行的策略討論的一個限制因素？還是只是兩者同時發生，不需要其他事情發生？這可能是第一個，麥克。

Thanks, Yas. It doesn't seem to be a gating factor at the moment. That's not the conversations that we're having. We -- as we sort of await the full data set and all of the full analysis, we will continue to have those discussions with the strategics, and that will be the sort of natural course of the engagement going forward. So no, we don't see at this stage the FDA end of Phase 2 meeting being a gating factor.

謝謝，Yas。目前這似乎不是一個限制因素。這不是我們正在進行的對話。我們——在等待完整的數據集和所有完整的分析的同時，我們將繼續與戰略部門進行討論，這將是未來合作的自然進程。所以，不，我們目前並不認為 FDA 結束第二階段會議是限制因素。

And maybe the second question is, obviously, top-line data was very helpful and thoughtful, but I think you guys have said, we will -- and I think even in the press release today, you're planning to share more data at medical meetings. Could you help us understand the type of data that we could see? What are some of the key additional analyses that you hope to present and maybe the significance of it? And then I have a third last question.

也許第二個問題是，顯然，頂線數據非常有幫助和深思熟慮，但我認為你們已經說過，我們會的——而且我認為即使在今天的新聞稿中，你們也計劃在醫學會議上分享更多數據。您能幫助我們了解我們可以看到哪些類型的資料嗎？您希望提出哪些關鍵的附加分析以及意義是什麼？我還有倒數第三個問題。

Yes, Yas, it's Craig Granowitz. Thanks for your question. What we intend to show later on in the year will be additional detail on the secondary analyses, which would be the qualitative aspects related to the quality and types of pain and functionality, which were a series of secondary endpoints.

是的，Yas，我是 Craig Granowitz。謝謝你的提問。我們計劃在今年稍後展示有關次要分析的更多細節，這些分析將是與疼痛和功能的品質和類型相關的定性方面，它們是一系列次要終點。

I also think we might be able to place into better context the 20-milligram dose arm with exposure and some other pharmacokinetic and other data to place that in additional context of why that arm performed the way that it performed. So I think this data will be very helpful for both the medical community and the investor community to provide additional context of our confidence in the trial and the results that we've seen.

我還認為，我們也許能夠將 20 毫克劑量組的暴露情況和其他一些藥物動力學及其他數據放在更好的背景下，以便進一步解釋為什麼該組的表現如此出色。因此，我認為這些數據對於醫學界和投資者界都非常有幫助，可以為我們對試驗和所看到的結果的信心提供額外的背景資訊。

And then a last question on the SONATA study, sort of consistent with Roanna's question that she asked around non-obstructive study of recently ODYSSEY failing. I think it was clear that the commentary at least peripherally have been just saying non-obstructive is a very distinct population different from obstructive. So I think it has raised sort of the bar for a lot of investors of thinking about how do companies create a homogeneous population. Obviously, we haven't seen the data. But could you maybe talk about as you guys designed SONATA in terms of inclusion, exclusion, what was built in to create maybe a more homogeneous population within the nonobstructive specifically? To the extent you can comment on that would be helpful.

然後是關於 SONATA 研究的最後一個問題，與 Roanna 提出的有關最近 ODYSSEY 失敗的非阻塞性研究的問題一致。我認為很明顯，評論至少從表面上看只是說非阻塞性人群與阻塞性人群有著非常明顯的不同。所以我認為這提高了許多投資者思考公司如何創造同質人口的標準。顯然，我們還沒有看到數據。但是，您能否談談，在設計 SONATA 時，在包容性和排斥性方面，具體是如何構建的，以便在非阻塞環境中創造更同質的人口？如果您能對此發表評論，那將會很有幫助。

Yes. Thanks, again, Yas, great question. The major criteria we have for the trial is symptomatic disease. And I think that is really reflective of the diastolic dysfunction that is sine qua non of HCM. And it's funny, I think we've had this conversation in other calls previously about people feeling more confident, at least from the investor community of the activity of sotagliflozin in the nonobstructive group as opposed to the obstructive. We believe that nonobstructive is really -- is a great surrogate and is a subset of HFpEF, and we feel very confident in our HFpEF results in that the high degree of efficacy that we see both in heart failure reduction and MACE reduction in those with HFpEF.

是的。再次感謝你，Yas，這個問題問得好。我們進行試驗的主要標準是有症狀的疾病。我認為這確實反映了 HCM 的必要條件——舒張功能障礙。有趣的是，我認為我們之前在其他電話會議上討論過這個問題，人們感覺更有信心，至少從投資者群體的角度來看，他們對非阻塞組而非阻塞組的索他格列淨的活性更有信心。我們相信非阻塞性心臟衰竭確實是一種很好的替代品，也是 HFpEF 的一個子集，我們對我們的 HFpEF 結果非常有信心，因為我們在 HFpEF 患者的心臟衰竭減少和 MACE 減少方面都看到了很高的療效。

I think that on top of the data that we've demonstrated in terms of that left ventricular hypertrophy group with normal blood pressure, which is a real surrogate for HCM, and again, that 50% reduction in both MACE and heart failure is really encouraging to us.

我認為，除了我們已經證明的血壓正常的左心室肥大組的數據之外，這是 HCM 的真正替代品，而且 MACE 和心臟衰竭減少 50% 對我們來說確實令人鼓舞。

And as a reminder, one of the reasons why we tried to highlight the MACE data that was recently published in the Lancet is that patients with HCM remain at significant elevated risk of MI and stroke. So I think having that additional benefit in a group of heart failure patients is all continue to be supportive, particularly in the nonobstructive group.

提醒一下，我們試圖強調最近在《刺胳針》上發表的 MACE 數據的原因之一是，患有 HCM 的患者仍然面臨顯著較高的 MI 和中風風險。因此，我認為，對於心臟衰竭患者來說，這種額外的益處將繼續起到支持作用，尤其是在非阻塞性心臟衰竭患者群體中。

Yes. And it's important for us, Yas, as we think across the breadth of the HCM market that the nonobstructive HCM, as we know, it's about 1/3 of all HCM patients which at the moment, as you know, doesn't have an indicated -- the CMIs haven't shown robust efficacy there. And so it's all aligning with our approach of a broad potential application for a broad prescriber base and broad applicability across the patient population as well. So we actually have a lot of data now that gives us great confidence in nonobstructive HCM. And the SONATA trial was built to capitalize on both opportunities.

是的。對我們來說，Yas，重要的是，我們認為在整個 HCM 市場中，非阻塞性​​ HCM 約佔所有 HCM 患者的 1/3，目前，如您所知，沒有指徵 — — CMI 尚未顯示出強大的療效。因此，這一切都符合我們的方法，即為廣大處方者提供廣泛的應用潛力，並在整個患者群體中廣泛適用。因此，我們現在實際上擁有大量數據，這些數據讓我們對非阻塞性 HCM 充滿信心。SONATA 試驗就是為了利用這兩個機會。

Yigal Nochomovitz, Citigroup.

花旗集團的 Yigal Nochomovitz。

A few more on the design of SONATA. I think you mentioned, Craig, that it's powered for both obstructive and nonobstructive. I'm just curious, are those coprimary endpoints? What is the exact detail around how that measurement is structured in the protocol?

還有一些關於 SONATA 的設計。克雷格，我想你提到過，它既能為阻塞式供電，又能為非阻塞式供電。我只是好奇，這些是共同主要終點嗎？關於該測量在協議中的結構，具體細節是什麼？

And then with regard to the relative proportions of obstructive and nonobstructive, you just mentioned it was 1/3, 2/3. How is that playing out in terms of the enrollment? Is it balanced and is it adhering to those ratios? Or you're trying to go for more of a 50/50?

然後關於阻塞性和非阻塞性的相對比例，您剛才提到是 1/3、2/3。從招生情況來看，情況如何？它是否平衡並且符合這些比例？還是您想追求 50/50 的比例？

Yes. Great question, Yigal. Similar to what we did in the SCORED trial and SOLOIST trial, the study is powered for the overall endpoint. And that in the case of the preserved ejection fraction, reduced ejection fraction, it really is the issue of consistency across results. So FDA has not asked for, in a sense, two independently powered arms.

是的。伊加爾，問得好。與我們在 SCORED 試驗和 SOLOIST 試驗中所做的類似，該研究以總體終點為目標。在射血分數保留和射血分數降低的情況下，這實際上是結果一致性的問題。因此，從某種意義上來說，FDA 並沒有要求安裝兩個獨立供電的臂。

And if I gave that a misimpression in one of my answers, I apologize for any misunderstanding on that. So the study is powered on the base of 500 patients with a difference in KCCQ compared to placebo. And really, what FDA would be looking for similar to what we showed in SCORED and SOLOIST is that there would be consistency, but not necessarily formally powered for each one of the two subgroups. So I think that really is the critical design element.

如果我的回答給您留下了錯誤的印象，我對此造成的任何誤解深表歉意。因此，該研究以 500 名使用 KCCQ 和安慰劑的患者為基礎。實際上，FDA 所尋求的與我們在 SCORED 和 SOLOIST 中所展示的類似，是存在一致性，但不一定對兩個子組中的每一個都有正式的效力。所以我認為這確實是關鍵的設計元素。

The trial is designed as a stratified with a one-to-one enrollment of obstructive and nonobstructive. And right now, we don't really have enough patients in the study for me to say whether we're going to have more or less difficulty enrolling one or other of those two groups.

本試驗採用分層設計，阻塞性和非阻塞性患者以一對一的比例入組。目前，我們研究中的患者數量還不夠多，因此我無法判斷在招募這兩組中的其中一組患者時，我們是否會遇到更多或更少的困難。

And as Mike had mentioned, a vast majority of the patients right now are not being treated. And again, we're looking for just patients with symptomatic disease, whether or not they're on a CMI. So we think that there are certainly adequate patient number. And again, we are -- the study includes patients with an ejection fraction down to 50%, which is one that the currently approved agent is not indicated to treat. So we think we have a number of opportunities to enroll patients, especially with no competing trials right now and the drug really not being available outside the United States.

正如麥克所提到的，目前絕大多數患者都沒有得到治療。再次強調，我們尋找的是有症狀的患者，無論他們是否正在接受 CMI 治療。所以我們認為患者數量肯定是足夠的。再次強調，這項研究包括射血分數下降至 50% 的患者，而目前核准的藥物不適用於治療此類患者。因此，我們認為我們有很多機會招募患者，特別是目前沒有競爭性試驗，而且這種藥物在美國以外還買不到。

And then on the choice of the endpoint, specifically KCCQ CSS, I'm just wondering, you mentioned peak VO2 is cumbersome and complicated endpoint. Was that the reason you picked KCCQ? Or was it also because since you're doing HCM and nonobstructive that it's just the easier endpoint to deal with given the broader population as opposed to what we saw this morning with MAPLE-HCM, where they did peak VO2, but that was only obstructive?

然後關於終點的選擇，特別是 KCCQ CSS，我只是想知道，您提到峰值 VO2 是一個繁瑣而複雜的終點。這就是您選擇 KCCQ 的原因嗎？或者也是因為，現在您正在進行 HCM 和非阻塞性研究，那麼考慮到更廣泛的人群，這只是更容易處理的終點，而不是像我們今天早上在 MAPLE-HCM 中看到的那樣，他們確實達到了峰值 VO2，但那隻是阻塞性的？

Yes. No, great question, as always, Yigal. The advantage with sota is we have outcomes. So we have heart failure outcomes in 12,000 patients, and we have an FDA approval for outcomes, and we've demonstrated reductions in MACE as well as heart failure events.

是的。不，一如既往，伊加爾，這個問題問得真好。sota 的優勢在於我們有結果。因此，我們對 12,000 名患者進行了心臟衰竭治療，並獲得了 FDA 批准，我們已經證明 MACE 和心臟衰竭事件有所減少。

I think one of the issues with the newer class of agents is they don't have the experience to have anything with outcome. So what they're really looking for as a surrogate for outcome besides functionality is that they're looking for some sort of metabolic parameter. And I think that is going to be really one of the long-term questions is, are they modifying the disease in any way? We know we modify the disease. We prevent heart failure events and cardiovascular death, and we reduce stroke and MI in -- overlapping in similar groups of patients.

我認為新代理商存在的一個問題是他們缺乏成果的經驗。因此，除了功能之外，他們真正尋找的結果替代品是某種代謝參數。我認為這確實是一個長期問題：他們是否以某種方式改變了這種疾病？我們知道我們可以改變這種疾病。我們預防心臟衰竭事件和心血管死亡，並減少相似患者群體中重疊的中風和心肌梗塞。

So from that standpoint, the FDA didn't ask for any additional endpoints, and we really wanted to run a pragmatic study. We wanted to have it as open and inclusive as possible to give us the broadest possible label, just like what we did with SCORED and SOLOIST is we have a very broad label that provides the maximum opportunity for labeling and for patient inclusion in the criteria. And we took that same mindset and approach to how we structured SONATA with a lot of input from the medical community and agreement from the FDA.

因此從這個角度來看，FDA 並沒有要求任何額外的終點，我們確實想進行一項務實的研究。我們希望它盡可能開放和包容，以便為我們提供盡可能廣泛的標籤，就像我們對 SCORED 和 SOLOIST 所做的那樣，我們有一個非常廣泛的標籤，為標籤和將患者納入標準提供了最大的機會。我們在建構 SONATA 時也採用了同樣的思維方式和方法，並聽取了醫學界的大量意見並獲得 FDA 的同意。

And just to pile on, on top of that, really coming from a patient's perspective, a patient with HCM, not too dissimilar from a patient with heart failure, quite frankly, the primary issue or the primary want, the primary need that they have is for symptomatic benefit. The primary thing that a patient with HCM wants to be able to do is to have the energy to walk outside, walk to the letter box, to feel better. And that's frankly what the CMIs do as well. Yes, they're indicated for symptomatic and functional benefit, but the primary reason to believe is that they make the patients feel better, at least in obstructive HCM.

除此之外，從患者的角度來看，患有 HCM 的患者與心臟衰竭的患者並沒有太大的不同，坦白說，他們的主要問題或主要願望、主要需求是獲得對症治療。HCM 患者最希望做的事就是有精力走到外面，走到信箱那裡，讓自己感覺好一點。坦白說，這也是 CMI 所做的。是的，它們確實可以緩解症狀並帶來功能益處，但主要原因是它們可以讓患者感覺更好，至少對於阻塞性 HCM 患者來說是如此。

And so you combine the pragmatism of the trial with developing something for what patients actually need. And in fact, we've seen the benefit in KCCQ already in diastolic dysfunction. It not only gives us confidence in the outcome that we're going to produce, but confidence in that should the trial be positive, it's something that patients really, really want.

因此，您將試驗的實用性與開發患者實際需要的東西結合起來。事實上，我們已經看到了 KCCQ 在治療舒張功能障礙方面的益處。它不僅讓我們對即將產生的結果充滿信心，而且讓我們相信，如果試驗結果是正面的，那麼這就是患者真正想要的。

Yes. I mean just to make it really pragmatic, Yigal, I mean, having the primary as KCCQ and the secondary as New York Heart, at the end of the day, as Mike said, people want functionality. I think it's very hard to explain to a patient you can achieve 15 meters more in a six-minute walk test. I think that's pretty hard to try to wrap your head around as a patient and a provider, but to say it's very likely that you'll be able to do your activities of daily living with an improvement. For patients, again, we're focused on symptomatic patients. That, I think, is meaningful. And that's really why the CMIs have been approved is for symptom benefit.

是的。我的意思是，只是為了讓它真正實用，伊加爾，我的意思是，將 KCCQ 作為主要機構，將紐約中心作為次要機構，最終，正如邁克所說，人們想要功能性。我認為向患者解釋在六分鐘步行測試中可以多走 15 公尺是非常困難的。我認為作為一名患者和提供者，很難理解這一點，但可以肯定的是，透過治療，您將能夠更好地進行日常生活活動。對於患者，我們再次關注有症狀的患者。我認為這很有意義。這就是 CMI 獲得批准的真正原因，是為了緩解症狀。

Joe Pantginis, H.C. Wainwright.

喬潘特吉尼斯、H.C. 溫賴特。

This is Lander on for Joe. So just to follow up with the pain program and regarding additional progress data anticipated soon. Do you expect pilavapadin to have a differential effect in the stratification analysis based on background therapy? And if so, would these observations change the design of the upcoming registrational Phase 3 studies?

我是 Lander，負責 Joe 的後續工作。我只是想跟進疼痛治療計劃，並很快帶來更多進展數據。您是否預期 pilavapadin 在基於背景治療的分層分析中會產生差異效應？如果是這樣，這些觀察結果會改變即將進行的註冊第 3 階段研究的設計嗎？

So I think what we can say and I think we've already communicated is we see a benefit whether or not the patient is on an underlying DPNP medication. Again, the sample sizes -- and I think we've had some of these conversations, so I apologize if I'm being redundant, but there were only 30% or 50% of 100 patients in each one of the trials. So I wouldn't want to over-interpret the data of whether it's better with or without an underlying DPNP medication. And as a reminder, about 90% of the patients were on gabapentin. So that is the most widely used agent.

因此我認為我們可以說並且我認為我們已經傳達的是，無論患者是否正在服用基礎 DPNP 藥物，我們都看到了益處。再次，樣本量——我想我們已經進行過一些這樣的對話，所以如果我說得重複，我深表歉意，但每次試驗中只有 100 名患者中的 30% 或 50%。所以我不想過度解讀數據，不知道有或沒有潛在的 DPNP 藥物是否會更好。提醒一下，大約 90% 的患者服用加巴噴丁。所以這是最廣泛使用的代理。

I think what we've already published on and we presented previously on PROGRESS as well as RELIEF is that we're seeing a benefit regardless of whether they're on an underlying DPNP medication, which is not surprising because they have different mechanisms of action, and it's not surprising you will get additive benefit whether or not they're on a DPNP medication.

我認為我們已經發表過並且之前在 PROGRESS 和 RELIEF 上介紹過的內容是，無論患者是否使用基礎 DPNP 藥物，我們都看到了益處，這並不奇怪，因為他們具有不同的作用機制，而且無論患者是否使用 DPNP 藥物，您都會獲得附加益處，這並不奇怪。

I would now like to turn the call back over to Mike Exton for closing remarks.

現在我想將電話轉回給麥克·埃克斯頓，請他做最後發言。

Well, thanks very much, and thanks for the question, guys. Always very engaging. So that wraps up our Q1 earnings call. It's been a busy and productive quarter for us and a lot more to do in quarter 2 and throughout the year. We've got a lot of important catalysts coming up for the rest of the year and look forward to updating you as the year progresses. So thanks very much for your time, and we'll speak to you soon.

好吧，非常感謝，也感謝大家提出這個問題。總是非常吸引人。這就是我們第一季財報電話會議的結束。對我們來說，這是一個忙碌而富有成效的季度，第二季度和全年還有很多工作要做。我們在今年剩餘的時間裡有很多重要的催化劑，並期待在今年進展中向您更新最新情況。非常感謝您抽出時間，我們很快就會與您聯繫。

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

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。