Lexicon Pharmaceuticals Inc (LXRX) 2025 Q2 法說會逐字稿

Welcome to the Lexicon Pharmaceuticals second quarter 2025 financial results conference call. (Operator Instructions) As a reminder, this call is being recorded today, August 6, 2025.

歡迎參加 Lexicon Pharmaceuticals 2025 年第二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 8 月 6 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.

現在我將把電話轉給 Lexicon 投資者關係和企業傳播高級副總裁 Lisa DeFrancesco。請繼續，麗莎。

Thank you, Josh. Good morning, and welcome to our second quarter 2025 conference call.

謝謝你，喬希。早上好，歡迎參加我們的 2025 年第二季電話會議。

Joining me today are Dr. Mike Exton, Lexicon's Chief Executive Officer and Director; Dr. Craig Granowitz, Senior Vice President and Chief Medical Officer; and Scott Coiante, Senior Vice President and Chief Financial Officer. This morning, Lexicon issued a press release announcing our financial results for the second 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 a slide presentation is also available on our website. During this call, we will review the information provided in the press release, provide a corporate update and then use the remainder of our time to answer your questions.

今天與我一起出席的還有 Lexicon 執行長兼董事 Mike Exton 博士、高級副總裁兼首席醫療官 Craig Granowitz 博士以及高級副總裁兼財務長 Scott Coiante。今天上午，Lexicon 發布了一份新聞稿，宣布了我們 2025 年第二季的財務業績，您可以在我們的網站 www.lexpharma.com 和 SEC 文件上查閱。我們的網站上也提供本次電話會議的網路直播以及投影片簡報。在此次電話會議中，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 also include characterizations and projections relating 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以及我們的業務的安全性、有效性、臨床開發、監管狀態和治療和商業潛力相關的陳述。這些聲明還可能包括與我們的藥物項目的臨床開發、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 relating 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和未來營運績效、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的事項有關的前瞻性陳述。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？

Yeah. Thank you, Lisa, and good day, everyone. Thanks for joining.

是的。謝謝你，麗莎，大家好。感謝您的加入。

We're really excited to give you updates on the quarter and all of the great work going on at Lexicon. When we entered 2025, if you recall, we're still in the early days of our strategic pivot to being an R&D-focused company. And now in the second half of the year, I can say that this transformation has truly taken shape. We've made great strides against our objectives for the year across the board. We're now in a very strong position to advance our innovative portfolio of potential medicines. And I'm pleased to report that all of our lead R&D programs continue to be on track. We've made important progress against each of them in the second quarter, which I'd like to highlight briefly.

我們非常高興向您提供本季度的最新情況以及 Lexicon 正在進行的所有出色工作。如果你還記得的話，當我們進入 2025 年時，我們仍處於向以研發為重點的公司的策略轉型的早期階段。而現在已經是下半年了，我可以說這種轉變已經真正成形。我們在全面實現今年目標方面取得了巨大進步。我們現在處於非常有利的地位，可以推進我們的潛在藥物創新組合。我很高興地報告，我們所有的主要研發項目都在繼續順利進行。我們在第二節的比賽中對他們每個人都取得了重要的進展，我想簡單介紹一下。

Pilavapadin, we've completed the secondary analysis of our Phase IIb progress results following the announcement of top line data in the first quarter. We're now in the process of analyzing the totality of Phase II data, which supports the broad potential for this novel mechanism while reengaging in discussions with potential partners with this additional data in hand.

Pilavapadin，在第一季公佈頂線資料後，我們已經完成了 IIb 期進展結果的次要分析。我們目前正在分析第二階段的全部數據，這證明了這種新機制的廣泛潛力，同時我們正在利用這些額外的數據重新與潛在合作夥伴進行討論。

Secondly, LX9851, our first-in-class candidate for the treatment of obesity, is on track to complete IND-enabling studies in 2025. So we look forward to continued collaboration with our licensee, Novo Nordisk.

其次，我們治療肥胖症的首創候選藥物 LX9851 預計將在 2025 年完成 IND 支持研究。因此，我們期待與我們的授權商諾和諾德繼續合作。

For sotagliflozin, we've really hit the accelerator on our Phase III SONATA study in hypertrophic cardiomyopathy or HCM, which is the only Phase III HCM program enrolling currently, evaluating sota in both obstructive and nonobstructive subtypes of HCM. We've made excellent progress on site initiations globally, and Craig will elaborate on this shortly.

對於索他格列淨，我們確實在肥厚型心肌病變 (HCM) 的 III 期 SONATA 研究上加速了進程，這是目前唯一正在招募的 III 期 HCM 項目，評估了索他格列淨在阻塞性和非阻塞性 HCM 亞型中的作用。我們在全球站點啟動方面取得了巨大進展，Craig 將很快對此進行詳細說明。

Lastly, but importantly, we're also working closely with our licensee, Viatris, on expanding the reach of sotagliflozin in territories outside of the U.S. and EU, and we're making great progress on that front as well. So in summary, the team is hard at work, and it was an incredibly productive quarter for us that I'm very proud of.

最後，但重要的是，我們也與我們的授權人 Viatris 密切合作，擴大索格列淨在美國和歐盟以外地區的覆蓋範圍，並且我們在這方面也取得了巨大進展。總而言之，團隊正在努力工作，這對我們來說是一個非常富有成效的季度，我對此感到非常自豪。

Now before I turn the call over to Craig to talk in detail about the great progress in the pipeline, I want to take a moment to acknowledge a milestone. July marked 1 year since I joined as CEO of Lexicon. And as I reflect on all the changes that we've seen in that 12 months, I'm truly proud of the dedication and adaptability of this team. We successfully advanced multiple programs to late-stage development and beyond, and we look forward to reporting even more progress to come.

現在，在我將電話轉給克雷格詳細談論管道方面的巨大進展之前，我想花點時間來確認一個里程碑。今年七月是我擔任 Lexicon 執行長一週年。當我回顧過去 12 個月中我們看到的所有變化時，我為這個團隊的奉獻精神和適應能力感到由衷的自豪。我們成功地將多個專案推進到後期開發階段及以後，我們期待報告更多的進展。

And on that note, I'd like Craig to give a more detailed update on our pipeline programs. So over to you, Craig.

關於這一點，我希望 Craig 能夠更詳細地介紹我們的管道計劃。那麼交給你了，克雷格。

Thanks, Mike.

謝謝，麥克。

I'll start by discussing pilavapadin. First quarter, we announced top line results of our Phase IIb progress study of pilavapadin in DPNP. DPNP is a chronic and progressive pain disorder that impacts approximately 30% of people with Type 1 diabetes and up to 50% of those with Type 2 diabetes. These patients experience burning pain, loss of sensation and other side effects that can severely impact their quality of life. Importantly, in both our Phase IIb PROGRESS study and our Phase IIa RELIEF study, pilavapadin 10 milligrams delivered consistent clinically meaningful reductions in these painful symptoms. Based on these data, we have concluded the 10-milligram dosage strength warrants further evaluation and is the appropriate dose to take forward into late-stage development.

我將從討論 pilavapadin 開始。第一季度，我們公佈了 DPNP 中 pilavapadin IIb 期進展研究的頂線結果。DPNP 是一種慢性進行性疼痛障礙，影響約 30% 的第 1 型糖尿病患者和高達 50% 的第 2 型糖尿病患者。這些患者會經歷灼痛、感覺喪失和其他副作用，這些副作用會嚴重影響他們的生活品質。重要的是，在我們的 IIb 期 PROGRESS 研究和 IIa 期 RELIEF 研究中，10 毫克 pilavapadin 均能持續、有臨床意義地減輕這些疼痛症狀。根據這些數據，我們得出結論，10 毫克的劑量強度值得進一步評估，並且是進入後期開發的適當劑量。

We recently convened a scientific advisory board with expertise across clinical development, regulatory and neuropathic pain to review the full body of evidence for pilavapadin in DPNP. This esteemed group provided encouraging feedback and validated our key findings from the top line data readouts, including the following: first, the advisory board confirmed that pilavapadin demonstrates clinically meaningful efficacy. Second, they confirm the 10-milligram dose is the appropriate dose for future registrational studies. This gives us clarity on our path forward and validates the dose-finding work we've done to date.

我們最近召集了一個科學顧問委員會，其專家來自臨床開發、監管和神經性疼痛領域，以審查 pilavapadin 在 DPNP 中的全部證據。這個受人尊敬的團隊提供了令人鼓舞的回饋，並驗證了我們從頂線數據讀數中獲得的關鍵發現，包括以下內容：首先，諮詢委員會確認 pilavapadin 具有臨床上有意義的功效。其次，他們確認 10 毫克劑量是未來註冊研究的適當劑量。這讓我們明確了前進的道路，並驗證了我們迄今為止所做的劑量探索工作。

Third, the board reaffirmed the safety and tolerability profile of the 10-milligram supports advancement into late-stage development. And finally, they provided validation and valuable input into Phase III study design, including suggestions to potentially lower the placebo response rate, which we believe could reduce potential study variability. The panel support gives us tremendous confidence as we prepare for our next steps and engage with potential partners for pilavapadin. It reinforces our belief that we have a potentially transformative therapy for the millions of patients living with this debilitating condition.

第三，董事會重申了 10 毫克的安全性和耐受性，支持進入後期開發階段。最後，他們為第三階段研究設計提供了驗證和寶貴的意見，包括可能降低安慰劑反應率的建議，我們相信這可以減少潛在的研究差異。當我們為下一步行動做好準備並與 pilavapadin 的潛在合作夥伴接觸時，小組的支持給了我們極大的信心。它增強了我們的信念，我們擁有一種可能為數百萬患有這種衰弱性疾病的患者帶來變革的治療方法。

I also wanted to acknowledge that our analysis of the pilavapadin development program supports its compelling value proposition with a validated mechanism of action of AAK1, compelling clinical profile and broad potential applicability across multiple indications and demonstrates why we believe pilavapadin represents a true portfolio and a pill opportunity. Overall, beginning with efficacy, pilavapadin has demonstrated consistent and clinically meaningful pain reduction across three separate Phase II trials in neuropathic pain. While our lead indication in DPNP represents a mature clinical development program that is ready for Phase III advancement, several secondary indications such as spasticity are also Phase II ready, providing significant pipeline expansion opportunities.

我還想承認，我們對 pilavapadin 開發計劃的分析支持了其令人信服的價值主張，即 AAK1 經過驗證的作用機制、令人信服的臨床特徵和跨多種適應症的廣泛潛在適用性，並證明了為什麼我們相信 pilavapadin 代表著真正的產品組合和藥丸機會。總體而言，從療效來看，pilavapadin 在神經性疼痛的三個獨立的 II 期試驗中表現出了一致且具有臨床意義的疼痛減輕效果。雖然我們在 DPNP 中的主要適應症代表了一個成熟的臨床開發計劃，已準備好進入 III 期臨床，但痙攣等幾種次要適應症也已準備好進入 II 期臨床，這為管道擴展提供了重要的機會。

In addition, our preclinical work has been extensive. We've completed IND-enabling studies across multiple neuroscience indications, both central and peripheral, establishing a broad foundation for further clinical development beyond our current focus areas. We've accumulated data from more than 600 patients treated with pilavapadin to date, demonstrating a suitable safety and tolerability profile. This extensive safety database will be valuable as the program moves into late-stage development and regulatory discussions. Finally, pilavapadin benefits from patent protection extending through 2040 when including an anticipated 5-year patent term extension. This provides substantial commercial exclusivity to maximize the value of our investment in this area.

此外，我們的臨床前工作非常廣泛。我們已經完成了針對中樞和周邊多種神經科學適應症的 IND 支持研究，為我們當前重點領域之外的進一步臨床開發奠定了廣泛的基礎。迄今為止，我們已經累積了 600 多名接受 pilavapadin 治療的患者的數據，證明了其適當的安全性和耐受性。當該專案進入後期開發和監管討論階段時，這個廣泛的安全資料庫將非常有價值。最後，如果包括預期的 5 年專利期限延長，pilavapadin 將受益於延長至 2040 年的專利保護。這提供了實質的商業獨家權，以最大化我們在該領域的投資價值。

Moving on to sotagliflozin in HCM. There are more than 1 million people with HCM in the United States. Of those, our previous research suggests approximately one-third have nonobstructive HCM and 2/3 have obstructive HCM, in which the thickening of the heart muscle wall blocks or reduces the blood flow to the heart. However, more recent technology, including a more sensitive diagnostic and AI-assisted tools suggest that the incidence of nonobstructive HCM could be much higher, potentially 50% or greater. This chronic progressive disease that can lead to more serious complications. 43% of patients with HCM have progressive heart failure and HCM can also lead to atrial fibrillation and stroke.

繼續討論 HCM 中的索他格列淨。美國有超過 100 萬人患有 HCM。其中，我們先前的研究表明，大約三分之一患有非阻塞性 HCM，三分之二患有阻塞性 HCM，其中心肌壁增厚會阻塞或減少流向心臟的血液。然而，包括更敏感的診斷和人工智慧輔助工具在內的更新技術表明，非阻塞性​​ HCM 的發病率可能要高得多，可能達到 50% 或更高。這種慢性進行性疾病可導致更嚴重的併發症。 43% 的 HCM 患者出現進行性心臟衰竭，HCM 也會導致心房顫動和中風。

The medical community's understanding of how to diagnose and treat HCM has grown significantly in recent years as there are a number of innovations in development for HCM, including the approval of cardiac myosin inhibitors for obstructive HCM. However, despite substantial commercial investment and increased awareness of HCM, CMIs have only penetrated approximately 1% of the total HCM market. With this treatment landscape in mind, we believe sotagliflozin offers several unique advantages as a potential therapeutic option for HCM. First, it has a novel MOA as a dual mechanism SGLT1, SGLT2 inhibitor and is the only HCM agent under investigation that both -- that works both inside and outside the heart. This enables treated patients to potentially achieve symptom reduction while simultaneously targeting other outcomes such as heart failure and major adverse cardiovascular events where sotagliflozin has demonstrated benefits.

近年來，隨著 HCM 領域的多項創新發展，包括批准用於治療阻塞性 HCM 的心肌肌球蛋白抑制劑，醫學界對如何診斷和治療 HCM 的理解有了顯著提高。然而，儘管商業投資龐大且 HCM 認知度不斷提高，CMI 仍僅佔據整個 HCM 市場的約 1%。考慮到這種治療前景，我們相信索格列淨作為 HCM 的潛在治療選擇具有幾個獨特的優勢。首先，它具有作為雙重機制 SGLT1、SGLT2 抑制劑的新穎作用機制，並且是唯一一種正在研究的在心臟內外均起作用的 HCM 藥物。這使得接受治療的患者有可能減輕症狀，同時針對索格列淨已證明有益的其他結果，如心臟衰竭和主要不良心血管事件。

Second, as more data is generated, it is becoming increasingly clear that sotagliflozin is uniquely myocardially targeted. From a practical standpoint, the once-daily oral dosing profile facilitates broad clinical adoption, convenience and compliance. Importantly, this comes without the burden of a risk evaluation and mitigation strategies or REMS requirements that can complicate treatment. It is worth noting that sotagliflozin is already approved for heart failure. To date, we've observed no increased risk of atrial fibrillation, which is a critical consideration in this patient population. Looking forward, we're pursuing a broad proposed indication that encompasses both nonobstructive and obstructive HCM phenotypes. This positions sotagliflozin for potentially either use as monotherapy or in combination with other agents, providing clinicians with valuable flexibility in treatment planning.

其次，隨著更多數據的產生，索他格列淨具有獨特的心肌標靶性這一點變得越來越清楚。從實用角度來看，每日一次的口服給藥方式有利於廣泛的臨床應用、便利性和依從性。重要的是，這不需要承擔風險評估和緩解策略或 REMS 要求的負擔，而這些可能會使治療變得複雜。值得注意的是，索格列淨已被批准用於治療心臟衰竭。到目前為止，我們尚未觀察到心房顫動風險增加，這對該患者群體來說是一個關鍵的考慮因素。展望未來，我們正在尋求一種涵蓋非阻塞性和阻塞性 HCM 表型的廣泛適應症。這使得索格列淨既可以單獨使用，也可以與其他藥物合併使用，為臨床醫生在治療計劃中提供寶貴的靈活性。

We have amassed a wealth of data from studies confirming sota's mechanism of action in HCM and related conditions summarized here. Specifically, the animal models studied demonstrate sotagliflozin improves cardiac function and reduces wall thickness, left ventricular mass and fibrosis and cardiac inflammation, while the ex vivo models demonstrated the direct effects of sotagliflozin on the myocardium by reducing both stroke work and increasing metabolites associated with improved cardiac energetics. Collectively, these studies provide evidence that sota has a unique ability to work across multiple markers of the disease.

我們收集了大量研究數據，證實了 sota 在 HCM 和相關疾病中的作用機制，並在此進行了總結。具體而言，所研究的動物模型表明索格列淨可改善心臟功能並減少壁厚、左心室質量和纖維化以及心臟炎症，而離體模型則通過減少每搏功和增加與改善心臟能量相關的代謝物證明了索格列淨對心肌的直接影響。總的來說，這些研究提供的證據表明，sota 具有針對該疾病的多種標記發揮作用的獨特能力。

Now I want to spend some time talking through the clinical on the current ongoing clinical program, beginning with our own Phase III SONATA-HCM study of sotagliflozin in HCM. SONATA-HCM is a large global registration trial with a KCCQ primary endpoint designed to support a regulatory filing and broad label in HCM. SONATA-HCM is the only ongoing registrational trial currently evaluating a treatment in both obstructive and nonobstructive HCM. We have recently surpassed 100 sites initiated in 20 countries, including the US, Europe, Israel and Latin America, and we're well positioned to meet our goal of 130 sites actively enrolling patients by the end of the third quarter of 2025.

現在我想花一些時間討論目前正在進行的臨床計劃的臨床情況，首先從我們自己對 HCM 中索他格列淨進行的 III 期 SONATA-HCM 研究開始。SONATA-HCM 是一項大型全球註冊試驗，其主要終點為 KCCQ，旨在支援 HCM 的監管備案和廣泛標籤。SONATA-HCM 是目前唯一正在進行的註冊試驗，旨在評估阻塞性和非阻塞性 HCM 的治療方法。我們最近已在包括美國、歐洲、以色列和拉丁美洲在內的 20 個國家/地區建立了超過 100 個站點，並且我們已準備好實現到 2025 年第三季末有 130 個站點積極招募患者的目標。

There are two important investigator-initiated studies underway that are designed to evaluate cardiac function of sotagliflozin in HCM. The first is SOTA-P-CARDIA being conducted by Dr. Juan Badimon and colleagues at the Mount Sinai School of Medicine in New York City. This study is designed to investigate the cardiorenal mechanistic benefits of sotagliflozin in 88 nondiabetic patients with HFpEF, which, as you recall, is a subset of HCM. It is a 6-month study comparing sotagliflozin 400 milligrams and placebo on the following endpoints: change in left ventricular mass, functional performance and quality of life measurements. This study was completed in July 2025, and the investigators are currently evaluating the data.

目前有兩項重要的研究者發起的研究正在進行中，旨在評估索格列淨在 HCM 中的心臟功能。第一項是紐約市西奈山醫學院的 Juan Badimon 博士及其同事進行的 SOTA-P-CARDIA。這項研究旨在調查索格列淨對 88 名患有 HFpEF 的非糖尿病患者的心腎機制益處，您記得，HFpEF 是 HCM 的一個子集。這是一項為期 6 個月的研究，比較了 400 毫克索他格列淨和安慰劑的以下終點：左心室品質的變化、功能性能和生活品質測量。這項研究於2025年7月完成，研究人員目前正在評估數據。

The second study I wanted to highlight is SOTA-CROSS, a 12-week crossover study funded by the NIH and being conducted by Dr. Sharlene Day at the Penn School of Medicine comparing sotagliflozin and placebo on exercise capacity, physical activity and symptoms and diastolic function in patients with symptomatic nonobstructive HCM. We already have shown that sota strongly improves diastole in FpEF. SOTA-CROSS will aim to specifically ascribe such functional benefits in non-HCM as well. Together with SONATA-HCM, this study could potentially be a major therapeutic advance for a large subset of patients who have limited treatment options.

我想強調的第二項研究是 SOTA-CROSS，這是一項為期 12 週的交叉研究，由美國國立衛生研究院資助，由賓夕法尼亞大學醫學院的 Sharlene Day 博士進行，比較了索格列淨和安慰劑對有症狀的非阻塞性 HCM 患者的運動能力、體力活動和症狀以及舒張功能的影響。我們已經證明 sota 可以顯著改善 FpEF 中的舒張期。SOTA-CROSS 也將致力於將這些功能優勢具體歸因於非 HCM。與 SONATA-HCM 一起，這項研究可能為大量治療選擇有限的患者帶來重大的治療進步。

Last but not least, we remain on track to complete the IND-enabling studies this year for LX9851, our first-in-class ACSL5 inhibitor for the treatment of obesity and related metabolic disorders. LX9851's oral administration, preclinical findings to date and possibility for both monotherapy and combination applications provides a compelling profile and the potential to occupy a unique space in the treatment landscape. And we look forward to working with our partner, Novo Nordisk, to maximize the potential of this innovative investigational medicine.

最後但同樣重要的一點是，我們仍有望在今年完成 LX9851 的 IND 支持研究，LX9851 是我們用於治療肥胖症和相關代謝紊亂的首創 ACSL5 抑制劑。LX9851 的口服給藥、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提供了引人注目的特性，並有可能在治療領域佔據獨特的空間。我們期待與我們的合作夥伴諾和諾德合作，最大限度地發揮這種創新研究藥物的潛力。

With that, Scott Coiante, our CFO, will now provide a report of our financial results for the second quarter.

我們的財務長 Scott Coiante 將提供第二季財務業績報告。

Thank you, Craig, and good morning, everyone.

謝謝你，克雷格，大家早安。

For the second quarter of 2025, we reported $28.9 million in revenue compared to $1.6 million for the second quarter of 2024. Q2 2025 revenue consisted primarily of $27.5 million of licensing revenue recognized from the Novo Nordisk agreement. As a reminder, we received the upfront payment of $45 million from Novo in April, which was initially recorded as deferred revenue and is being recognized as revenue throughout the remainder of 2025 as the IND-enabling work is completed. Total revenues for the quarter also include net product revenue of $1.3 million from sales of INPEFA.

2025 年第二季度，我們的營收為 2,890 萬美元，而 2024 年第二季為 160 萬美元。2025 年第二季的收入主要包括與諾和諾德協議確認的 2,750 萬美元授權收入。提醒一下，我們在 4 月收到了 Novo 支付的 4500 萬美元預付款，這筆款項最初被記錄為遞延收入，並將在 2025 年剩餘時間內隨著 IND 支持工作的完成而被確認為收入。本季總收入還包括 INPEFA 銷售的 130 萬美元淨產品收入。

Research and development expenses for the second quarter of 2025 decreased to $15.7 million from $17.6 million in 2Q 2024, primarily reflecting lower external research expense on our PROGRESS clinical trial study, partially offset by increased investment in our SONATA Phase III clinical study in HCM. Selling, general and administrative expenses for the second quarter of 2025 decreased to $9.4 million compared to $39.2 million in 2024. The decrease reflects lower costs as a result of our strategic repositioning announced in late 2024 and the significantly reduced marketing efforts in 2025 for INPEFA.

2025 年第二季的研發費用從 2024 年第二季的 1,760 萬美元減少至 1,570 萬美元，主要反映了我們對 PROGRESS 臨床試驗研究的外部研究費用減少，但部分被我們對 HCM 的 SONATA III 期臨床研究的投資增加所抵消。2025 年第二季的銷售、一般和行政費用從 2024 年的 3,920 萬美元下降至 940 萬美元。這一下降反映了成本的降低，這是由於我們在 2024 年底宣布的策略重新定位以及 2025 年 INPEFA 的營銷力度大幅減少所致。

Net income for the second quarter of 2025 was $3.3 million or $0.01 per share as compared to a net loss of $53.4 million or $0.17 per share in the corresponding period in 2024. The net income for the quarter was primarily a result of the revenue recognized from the Novo Nordisk licensing agreement in Q2. We expect to recognize the remaining $17.5 million of licensing revenue from the Novo agreement in the second half of this year as the IND-enabling work is completed.

2025 年第二季淨收入為 330 萬美元，即每股 0.01 美元，而 2024 年同期淨虧損為 5,340 萬美元，即每股 0.17 美元。本季淨收入主要來自第二季諾和諾德授權協議確認的收入。隨著 IND 支援工作的完成，我們預計在今年下半年確認 Novo 協議剩餘的 1,750 萬美元授權收入。

We ended the second quarter with $168 million in cash, short-term investments and restricted cash as compared to $238 million as of December 31, 2024.

截至第二季末，我們擁有現金、短期投資和受限現金 1.68 億美元，而截至 2024 年 12 月 31 日為 2.38 億美元。

In summarizing our financials, I would like to note a few highlights from the quarter. We've used the $45 million upfront payment received from the Novo licensing agreement to strengthen our balance sheet by reducing our long-term debt a portion of our long-term debt. On the expense side, we've made significant progress reducing our costs and streamlining our operations. Quarter-over-quarter operating expenses decreased by $31.9 million, primarily due to the strategic repositioning as an R&D-focused company announced late in 2024.

在總結我們的財務狀況時，我想指出本季的一些亮點。我們利用從 Novo 授權協議中收到的 4,500 萬美元預付款來減少部分長期債務，從而加強我們的資產負債表。在費用方面，我們在降低成本和精簡營運方面取得了重大進展。季度環比營運費用減少了 3,190 萬美元，這主要是由於公司於 2024 年底宣布策略重新定位為以研發為重點的公司。

Reviewing our full year 2025 guidance, we're lowering our operating expense projections for the year. Total operating expenses are now expected to be in the range of $105 million to $115 million from $135 million to $145 million previously announced. R&D expenses are now projected to be in the range of $70 million to $75 million, down from a range of $100 million to $105 million, primarily as a result of the transfer of cost to Novo under our licensing agreement with them. SG&A expenses remain between $35 million and $40 million. Our R&D expense assumptions do not include costs associated with Phase III pivotal studies of pilavapadin as our goal will be to take this asset forward with a development partner.

回顧我們 2025 年全年的指導方針，我們下調了今年的營運費用預測。目前預計總營運費用將在 1.05 億美元至 1.15 億美元之間，而先前宣布的總營運費用為 1.35 億美元至 1.45 億美元。目前預計研發費用將在 7,000 萬美元至 7,500 萬美元之間，低於 1 億美元至 1.05 億美元，這主要是因為我們根據與 Novo 簽訂的許可協議將成本轉移給了 Novo。銷售、一般及行政費用 (SG&A) 維持在 3,500 萬美元至 4,000 萬美元之間。我們的研發費用假設不包括與 pilavapadin 第三階段關鍵研究相關的成本，因為我們的目標是與開發合作夥伴一起推進這項資產。

Overall, we are in a strong position with the resources we need to advance our ongoing clinical programs while maintaining a disciplined approach to capital allocation and a focus on creating value for our shareholders.

總體而言，我們擁有強大的資源來推進我們正在進行的臨床項目，同時保持嚴謹的資本配置方式並專注於為股東創造價值。

Now I'll turn the call back to Mike for closing remarks.

現在我將把電話轉回給麥克，請他作結束語。

Yes. Thanks, Scott and Craig. Now as you...

是的。謝謝，斯科特和克雷格。現在你...

Please stand by, your conference will resume momentarily.

請稍候，您的會議將立即恢復。

Apologies for that brief interruption, when I'm getting to the punchline here. But look, let me go back and say that we've got lots of exciting updates in the second half of 2025. And clearly, as we've outlined, partnering is an essential part of how we plan to advance all of our assets. And on this slide, it really highlights the partnership strategy and action. Firstly, Viatris is making great progress and has recently received its first approval of sotagliflozin in the United Arab Emirates, which was a really short turnaround time and has also filed for regulatory approval in Saudi Arabia and is expecting to file for regulatory approval in Canada, Australia and New Zealand, Mexico and a number of Southeast Asian countries before the end of this year.

當我講到妙語時，我打斷了你一下，我對此深表歉意。但是，讓我回過頭來說，我們在 2025 年下半年會有很多令人興奮的更新。顯然，正如我們所概述的，合作是我們計劃如何推進所有資產的重要組成部分。這張投影片真正突顯了合作策略和行動。首先，Viatris 正在取得巨大進展，最近在阿拉伯聯合大公國首次獲得了索格列淨的批准，這是一個非常短的周轉時間，並且還向沙烏地阿拉伯提交了監管批准申請，預計在今年年底前向加拿大、澳洲和紐西蘭、墨西哥和一些東南亞國家提交監管批准申請。

We aim to maximize the potential of LX9851 with our licensee, Novo Nordisk, a global expert in obesity and related conditions and partnership discussions are ongoing for pilavapadin, where we hope to collaborate with a high-quality partner to unlock the pipeline and appeal potential of this asset globally and across multiple indications. This flexible partnership strategy is intended to allow us to follow the science broadly, but really remain focused internally on our core cardiometabolic expertise. And so as you can see on this slide, we're exceptionally well positioned with a number of pipeline opportunities from our late-stage assets to our newest opportunities and whether organically or with a partner, we expect these programs to continue to add value and bring new innovation to patients over the longer term.

我們的目標是與我們的授權商 Novo Nordisk（肥胖症和相關疾病領域的全球專家）一起最大限度地發揮 LX9851 的潛力，並且正在就 pilavapadin 進行合作討論，我們希望與高品質的合作夥伴合作，在全球範圍內和多種適應症中釋放該資產的管道和吸引力潛力。這種靈活的合作策略旨在讓我們廣泛地遵循科學，但實際上仍然專注於我們的核心心臟代謝專業知識。因此，正如您在這張投影片上看到的，我們擁有非常有利的條件，從後期資產到最新機會，我們擁有大量的管道機會，無論是有機的還是與合作夥伴的，我們都希望這些項目能夠在長期內繼續增加價值並為患者帶來新的創新。

Now as we look further into 2025, we're excited about where Lexicon stands at this moment. Starting with pilavapadin, we're expecting full progress data to be presented in Q3. Also planning our end of Phase II meeting with timing to be dependent on our partnership discussions. Our preclinical work to broaden the value of this asset into additional indications continues. And additionally, a broad partnership for pilavapadin will allow us to become therapeutically focused on our core cardiometabolic programs and expertise.

現在，當我們進一步展望 2025 年時，我們對 Lexicon 目前所處的位置感到非常興奮。從 pilavapadin 開始，我們預計將在第三季公佈完整的進度數據。我們也計劃結束第二階段的會議，具體時間取決於我們的合作討論。我們將繼續進行臨床前工作，以擴大該資產的價值，使其適用於更多適應症。此外，與 pilavapadin 建立廣泛的合作關係將使我們能夠在治療上專注於我們的核心心臟代謝計畫和專業知識。

For sota in HCM, our SONATA study is making excellent progress. Sites in the US, EU, Israel and LatAm are currently enrolling, and we expect all Phase III sites to be running by Q3. We also expect results from certain investigator-initiated studies of sota as early as Q4 of this year, which could provide valuable additional insights to the body of data on this therapeutic candidate. For INPEFA, Viatris is continuing to handle regulatory submissions and approvals outside the US and EU. They've been really a fantastic partner, fully engaged and motivated. And we expect that these approvals will build significantly on the stabilized sales of INPEFA in the US, where my team is achieved by a strong mix of focused execution and innovation.

對於 HCM 中的 sota，我們的 SONATA 研究正在取得良好進展。美國、歐盟、以色列和拉丁美洲的站點目前正在招募，我們預計所有第三階段站點都將在第三季投入營運。我們也預計最早在今年第四季就能獲得某些由研究人員發起的 sota 研究的結果，這些結果可以為該治療候選藥物的數據主體提供有價值的額外見解。對於 INPEFA，Viatris 將繼續處理美國和歐盟以外的監管提交和批准。他們確實是個非常棒的合作夥伴，全心投入，積極主動。我們預計，這些批准將極大地促進 INPEFA 在美國的穩定銷售，我的團隊透過專注的執行和創新取得了成功。

For Zynquista, the end-of-review evaluation process is underway. As you've no doubt seen, there's been an outpouring of patient support advocating for the approval of Zynquista in Type 1 diabetes, and we're committed to pursuing all potential avenues for this program.

對 Zynquista 來說，審查結束評估過程正在進行中。正如您所看到的，大量患者強烈支持 Zynquista 用於治療第 1 型糖尿病，我們也致力於為該計劃探索所有可能的途徑。

And last but not least, LX9851, our IND-enabling studies for obesity are progressing really, really well with a target completion by the end of the year. So if you look across this pipeline, any of these programs has the potential to transform patient lives and create significant value for Lexicon. But we believe that the simultaneous advancement of all five programs makes our position very compelling as we move through 2025, where we have a significant amount of opportunities for success.

最後但同樣重要的是，LX9851，我們針對肥胖症的 IND 支持研究進展非常順利，目標是在今年年底前完成。因此，如果你縱觀整個流程，你會發現其中任何一個專案都有可能改變患者的生活並為 Lexicon 創造巨大的價值。但我們相信，所有五個項目的同時推進將使我們在 2025 年佔據非常有利的地位，屆時我們將擁有大量成功的機會。

And with that, we conclude our introductory remarks and turn it to you, operator, for some Q&A.

至此，我們的介紹就結束了，接下來請接線生進行一些問答。

(Operator Instructions)

（操作員指示）

Yasmeen Rahimi with Piper Sandler.

亞斯明‧拉希米 (Yasmeen Rahimi) 與派珀‧桑德勒 (Piper Sandler)。

Hi, This is Liam on for Yasmeen Rahimi. Great presentation this morning. We just were really impressed by the SOTA-CROSS trial that's upcoming with potential data in late 2026. So we're just wondering maybe if you can kind of walk us through, given the small sample size of the study, what are the doses being assessed and how much the inclusion/exclusion criteria resemble SONATA and kind of like in that vein, whether you expect to see like a static separation on the efficacy endpoint and also why an HCM was selected rather than an OHCM patient population?

大家好，我是 Liam，代表 Yasmeen Rahimi 報道。今天早上的演講很精彩。即將進行的 SOTA-CROSS 試驗給我們留下了深刻的印象，該試驗的潛在數據將於 2026 年底公佈。因此，我們只是想知道，考慮到研究樣本量較小，您是否可以向我們介紹一下，評估的劑量是多少，納入/排除標準與 SONATA 有多相似，以及您是否希望看到療效終點的靜態分離，以及為什麼選擇 HCM 而不是 OHCM 患者群體？

Yeah, Thank you, Liam, for the question. We're really excited about working with Dr. Day on this NIH-supported mechanistic trial. And I think the idea behind the NIH's interest in this was to continue to look at therapeutic options outside the CMIs that would be much more widely applicable and more readily implementable across the United States for this large unmet medical need. Nonobstructive HCM, I think, was also the target for the NIH grant because there are options available for obstructive. There are surgical options and now medical options, but there are no treatment options that have been approved for nonobstructive.

是的，謝謝 Liam 提出這個問題。我們非常高興能與 Day 博士合作進行這項由 NIH 支持的機械試驗。我認為 NIH 對此感興趣的想法是繼續研究 CMI 以外的治療方案，這些方案將在美國更廣泛地適用且更容易實施，以滿足這一巨大的未滿足的醫療需求。我認為，非阻塞性​​ HCM 也是 NIH 資助的目標，因為對於阻塞性 HCM 還有其他選擇。有手術治療方案，現在也有藥物治療方案，但尚無針對非阻塞性治療方案獲得批准。

Relative small size of the study belies its significant power to accomplish its goals. By having a crossover design, you use the patient as their own control in the study. And the study has a number of important -- both imaging and physiologic outcomes. The inclusion criteria is very similar to that in the SONATA-HCM trial, which is a very broad cross-section of patients without diabetes who have a nonobstructive HCM. The only difference is that in SOTA-CROSS, there's not an allowance for patients on a CMI, but in SONATA-HCM, there actually is. So SONATA-HCM is even more broadly applicable.

儘管該研究規模相對較小，但卻具有實現其目標的巨大潛力。透過交叉設計，您可以在研究中將患者作為自己的對照。這項研究有許多重要的成果──包括影像學和生理學成果。納入標準與 SONATA-HCM 試驗非常相似，該試驗納入了非常廣泛的非糖尿病非阻塞性 HCM 患者。唯一的區別是，SOTA-CROSS 不允許患者使用 CMI，但 SONATA-HCM 確實允許。因此SONATA-HCM的適用範圍更為廣泛。

We believe that if you look at all of the data together in its totality and what we've tried to do really as we think about life cycle management strategically is to look at the totality of the benefit of sotagliflozin, both mechanistically, imaging and clinically across the range of heart failure, MACE and HCM using different trials to look at different aspects. And one of the reasons we presented all three of SONATA-HCM, SOTA-CROSS and the SOTA-P-CARDIA study is that they are looking at different aspects of the physiology and clinical findings of patients with HFpEF and HCM.

我們相信，如果將所有數據放在一起進行整體分析，那麼當我們從戰略上考慮生命週期管理時，我們真正想要做的就是從機制、影像和臨床兩個方面來看待索格列淨在心臟衰竭、MACE 和 HCM 方面的整體益處，並使用不同的試驗來研究不同的方面。我們提出 SONATA-HCM、SOTA-CROSS 和 SOTA-P-CARDIA 這三項研究的原因之一是，它們分別從不同方面研究 HFpEF 和 HCM 患者的生理和臨床發現。

Thanks so much.

非常感謝。

Andrew Tsai, Jefferies.

安德魯‧蔡（Andrew Tsai），傑富瑞集團（Jefferies）。

Hi, good morning. Thanks for the updates and thank you for taking my questions. A couple of questions on pain. Recently, RFK Jr. mentioned how he wanted to promote the development of non-opioid pain drugs like Vertex's JOURNAVX. And so is there something you guys can do to take advantage of this new development? And could it, for instance, make sense to apply to the Commissioner's National Priority Voucher Program?

嗨，早安。感謝您的更新，也感謝您回答我的問題。關於疼痛的幾個問題。最近，羅伯特甘迺迪 (RFK Jr.) 提到他希望推動非鴉片類止痛藥（如 Vertex 的 JOURNAVX）的開發。那麼你們可以做些什麼來利用這項新發展呢？例如，申請專員的國家優先券計劃是否有意義？

Yeah, Thanks, Andrew. In fact, my team has been very actively engaged from a legislative perspective, particularly with the Alternatives to PAIN Act, which is the act that's supporting the use of non-opioid medications in chronic pain. And we've been really supporting the utility and the passing of that particular act. And we're seeing bipartisan support for this very important facet of the management of pain. In addition to that, like we have done with Type 1 diabetes, it's also a patient advocacy groups that are very compelled to get new treatments.

是的，謝謝，安德魯。事實上，我的團隊一直積極參與立法工作，特別是《疼痛替代法案》，該法案支持使用非鴉片類藥物治療慢性疼痛。我們一直非常支持法案的實施和通過。我們看到兩黨都支持疼痛管理這一非常重要的面向。除此之外，就像我們對第 1 型糖尿病所做的那樣，它也是一個非常渴望獲得新治療方法的患者權益團體。

And really, all of those things are just a factor for, I think, what is really a zeitgeist in the realization that particularly for chronic pain actually, even though there are new alternatives for acute pain, the real issue for non-opioid alternatives is -- lies within the realm of chronic use over many years where the addictive potential is clearly much more significant. And so we're very encouraged by the bipartisan enthusiasm in this area, and we think that as we progress pilavapadin into Phase III and then beyond, that this not only gives great support for continuing to develop pilavapadin, but importantly, once it achieves commercial reality, clearly, it provides a pathway for great access and ease of patients getting on to this non-opioid medication.

事實上，我認為，所有這些都只是時代精神的一個因素，特別是對於慢性疼痛而言，儘管現在有治療急性疼痛的新方法，但非阿片類藥物替代品的真正問題在於——在多年的慢性使用範圍內，其成癮性顯然要大得多。因此，我們對這一領域的兩黨熱情感到非常鼓舞，我們認為，隨著 pilavapadin 進入第三階段及以後的階段，這不僅為繼續開發 pilavapadin 提供了強大的支持，而且重要的是，一旦它實現商業化，顯然，它為患者獲得這種非阿片類藥物提供了一條便捷的途徑。

Right. And it sounds like you will have the FDA meeting by year-end now. And so in theory, in that meeting, to you guys, what would be the realistic "worst-case scenario" that can arise from that meeting?

正確的。聽起來你們將在年底前召開 FDA 會議。那麼從理論上講，在那次會議上，對你們來說，那次會議可能出現的現實的「最壞情況」是什麼？

Yeah, Thank you, Andrew. It's Craig. I can answer your question. I mean, it actually is validating hearing other companies talk about what their pain program Phase III approaches in DPNP are. And as you recall, we have already met with the FDA on this program. And I think their feedback is going to be very similar to what we've already heard from them, and I think what other companies have also acknowledged is that you're going to need two parallel studies in the lead indication for neuropathic pain, and it is highly unlikely that with a single indication or a single study in two indications that you could get a broad neuropathic pain indication. That was always our expectation that was affirmed by the FDA, that was affirmed in our ad board, and I think it's been affirmed by other companies that are out there.

是的，謝謝你，安德魯。我是克雷格。我可以回答你的問題。我的意思是，聽到其他公司談論他們在 DPNP 中的疼痛計劃第三階段方法實際上是值得肯定的。正如您記得的，我們已經就該計劃與 FDA 進行了會面。我認為他們的回饋與我們聽到的非常相似，而且我認為其他公司也承認，你需要對神經性疼痛的主要適應症進行兩項平行研究，而且透過單一適應症或兩種適應症的單一研究，你不可能獲得廣泛的神經性疼痛適應症。這一直是我們的期望，得到了 FDA 的肯定，得到了我們廣告看板的肯定，而且我認為其他公司也對此表示肯定。

So when you think about the timing of our program and the magnitude of our program, I think it remains pretty much unchanged to what it was. It would be two parallel trials in DPNP, potentially with different geographies or slightly different designs, but primarily the same primary endpoint of neuro pain score at week 12. And I think based on all the data we've seen across the totality of our program, we think that the size of those studies to appropriately power them is very similar to what we've already been communicating to you of 2-arm studies of roughly 600 patients each with a single active arm and a placebo control arm.

因此，當你考慮到我們計劃的時間和規模時，我認為它與原來相比幾乎沒有變化。這將是 DPNP 中的兩個平行試驗，可能來自不同的地區或設計略有不同，但主要終點是第 12 週的神經疼痛評分。我認為，根據我們在整個計畫中看到的所有數據，這些研究的規模與我們已經向您傳達的雙臂研究非常相似，每組約有 600 名患者，每個患者都有一個活性組和一個安慰劑對照組。

Thank you.

謝謝。

Thank you.

謝謝。

Caroline DePaul, Citi.

花旗銀行的卡洛琳‧德保爾 (Caroline DePaul)。

Hi, This is Caroline on for Yigal Nochomovitz. So we'd like to know what is Novo's plan for the Phase I in obesity? Are there plans to combine with GLP-1?

大家好，我是 Yigal Nochomovitz 的 Caroline。那我們想知道 Novo 對肥胖症第一階段的計畫是什麼？有與GLP-1結合的計畫嗎？

Yeah, I think in our discussions with Novo, and I really want to thank our entire team for really having a great collaboration with Novo. I think as you've heard in the marketplace, and I think you've seen from both Lilly and Novo and other companies that the market is going to be moving towards oral options and combination options. And I think the data that we've already demonstrated and presented on the use of 9851 as an oral once-daily agent or the expectation of that, both with semaglutide and other agents that are being studied in development for weight loss and the potential for triple combinations. And I think you've seen other companies talking about moving both to oral and triple combinations. I think 9851 is really rightly positioned to be a part of that set of development programs.

是的，我想在我們與 Novo 的討論中，我真的要感謝我們整個團隊與 Novo 的良好合作。我想正如您在市場上聽到的那樣，而且我認為您已經從禮來、諾和諾德以及其他公司看到，市場將轉向口服選擇和組合選擇。我認為，我們已經展示和呈現了使用 9851 作為每日一次口服藥物的數據或對此的預期，包括與司美格魯肽和其他正在研究的減肥藥物以及三聯療法的潛力。我想您已經看到其他公司正在討論轉向口服和三重療法。我認為 9851 確實非常適合成為這一系列發展計畫的一部分。

If I could just provide one comment over the top of that. We've been really blessed with both of our partners with our licensees with Viatris and Novo Nordisk, the enthusiasm and capabilities that they bring to bear for both of these assets are really stellar. And although obviously, Novo is undergoing some changes at the moment, our engagement and interaction and their enthusiasm and drive for this asset is unbridled, so to speak. It's really incredible to see the team in action. And we expect that Novo will attack the Phase I program with vigor shortly after the IND.

如果我還能對此提供一則評論的話。我們非常幸運，我們的合作夥伴和授權商是 Viatris 和 Novo Nordisk，他們對這兩項資產所展現出的熱情和能力都非常出色。儘管 Novo 目前正在經歷一些變化，但我們的參與和互動以及他們對這項資產的熱情和動力可以說是無限的。看到這支球隊的表現真是令人難以置信。我們預計 Novo 將在 IND 之後不久大力推進 I 期計劃。

Thank you.

謝謝。

Joe Pantginis, H.C. Wainwright.

喬潘特吉尼斯、H.C. 溫賴特。

Hey everybody, good morning. Thanks for taking the questions. A couple, if you don't mind. First is a housekeeping question. With regard to the OpEx guidance, does this include or not include stock-based compensation?

大家好，早安。感謝您回答這些問題。如果你不介意的話，可以考慮一對。首先是一個內部問題。關於營運支出指導，是否包含股票薪酬？

It does include stock-based compensation.

它確實包括股票薪酬。

Great. And then a couple of comments here that have been coming up about the end of Phase II meeting for pilavapadin. Just curious how you feel that, that's still on track, but more specifically, do you feel this is the ultimate rate-limiting step for your partnering plans?

偉大的。然後這裡有一些關於 pilavapadin 第二階段會議結束的評論。只是好奇您對此有何感受，這仍在軌道上，但更具體地說，您是否認為這是合作計劃的最終限速步驟？

I don't think it's a rate-limiting step, Joe. I think what has been our approach here is have the initial round of discussions with partners with the top line, helping them understand and now 2 important things have happened. We have, a, completed the secondary analyses from progress or 3 important things, I would say, completed the secondary analysis. We're bringing the totality of the Phase II program data to bear so that we understand the totality of evidence. And most importantly or perhaps most importantly, we've convened the scientific advisory board.

喬，我不認為這是限速措施。我認為我們目前的策略是與合作夥伴進行初步討論，幫助他們理解，現在已經發生了兩件重要的事情。我們已經完成了從進展進行的二次分析，或者說，我想說，完成了 3 件重要的事情的二次分析。我們正在整合第二階段計劃的全部數據，以便了解全部證據。最重要的是，或者說是最重要的，我們召集了科學顧問委員會。

And we won't sort of go into who the people were, the members of that advisory board, but I can assure you, these are the top, top people that have been involved in this space from a regulatory development and mechanistic perspective for some time. And having their endorsement of as we theorized all along straight from the top line of 10 milligrams being the appropriate dose to move forward into Phase III really gives us confidence not only internally, but to reengage in those discussions and start to progress the discussions to a more concrete basis over the coming months. I think how we approach the end of Phase II meeting will be sort of dependent on now the engagement from partners around whether they want to be a part of that, whether they want to sort of see the outcome and move forward. But we're progressing that at speed.

我們不會深入探討該顧問委員會的成員是誰，但我可以向你們保證，從監管發展和機制角度來看，這些都是參與該領域一段時間的頂尖人物。正如我們一直以來所推測的那樣，得到他們的認可，10 毫克是進入第三階段的適當劑量，這不僅在內部給了我們信心，而且讓我們重新參與這些討論，並在未來幾個月內開始將討論推進到更具體的基礎。我認為我們如何結束第二階段會議將取決於合作夥伴的參與程度，他們是否願意參與其中，是否願意看到結果並繼續前進。但我們正在快速推進這項進程。

Totally fair. And then just quickly on HCM. I don't know if Craig would want to give any color on this. I think it's been a pretty impressive ramp on the number of sites that you have. So just curious, as you're looking to really ramp up enrollment as well, are there any comments from the field with regard to views towards CMI or CMI competition for patients or what have you, even though you know you have a different profile of where sota might fit?

完全公平。然後快速介紹一下 HCM。我不知道克雷格是否願意對此發表任何評論。我認為你們的網站數量有了相當令人印象深刻的成長。所以只是好奇，由於您也希望真正增加招生人數，那麼對於 CMI 或 CMI 對患者的競爭，該領域是否有任何評論，或者您有什麼看法，即使您知道您對 sota 可能適合的位置有不同的看法？

Yeah, great question, Great question, Joe. I'll answer that sort of in 2 very different ways. The first is we have this open window of enrollment. There are no active ongoing registrational trials now in HCM. And the fact that ODYSSEY ended in a sense without a long-term extension, there's a fair runoff period in that trial from what we understand, but those patients are also available with no treatment options. So we really have a nice golden opportunity here from an enrollment standpoint as we have a lot of sites with available patients that are symptomatic, both obstructive and nonobstructive whether they're on a CMI or not, that can be included in the trial. So in that regard, I think that's been a real upside.

是的，問得好，喬，這個問題問得好。我會用兩種截然不同的方式來回答。首先，我們有一個開放的招生窗口。目前 HCM 中沒有正在進行的註冊試驗。事實上，ODYSSEY 試驗在某種意義上沒有長期延長就結束了，據我們了解，該試驗有一個相當長的結束期，但這些患者也沒有治療選擇。因此，從招募的角度來看，我們確實有一個很好的黃金機會，因為我們有很多站點，其中有症狀的患者，包括阻塞性和非阻塞性患者，無論他們是否接受 CMI，都可以納入試驗。因此從這個方面來說，我認為這確實是一個好處。

The interesting aspect actually, when you think about enrollment, and I think this is what you're seeing already with some of the companies that are marketing products in obstructive HCM is there seems to be a speed limit in the capacity of the field to start new patients on CMIs because of the echoes. And while we do not require multiple echoes during treatment, unlike the CMI studies or CMIs themselves, we do require a baseline echo. So scheduling echo is an issue for enrollment, at least in the US. So it is interesting to see that flow through from the commercial market.

實際上，當您考慮招募時，有趣的是，我認為這是您已經看到的一些銷售阻塞性 HCM 產品的公司的情況，由於迴聲，該領域開始使用 CMI 治療新患者的能力似乎存在速度限制。雖然我們在治療期間不需要多次迴聲，但與 CMI 研究或 CMI 本身不同，我們確實需要基線迴聲。因此，安排迴聲對於入學來說是一個問題，至少在美國是如此。因此，看到來自商業市場的這種流動很有趣。

In the US, I would say the very early enrollment, and again, we're just looking at blinded data, but we know whether the patients are obstructive or nonobstructive, there are more nonobstructive patients being enrolled currently in the US than obstructive, which is to be expected because one of the CMIs is already approved and on the market in the US. So there are no options available at all for the nonobstructive. So in the US, we're seeing more nonobstructive than obstructives, but we think that's going to rapidly shift ex US because the CMIs are largely not available outside the US.

在美國，我想說的是早期的招募，而且我們只是在查看盲法數據，但我們知道患者是阻塞性還是非阻塞性，目前在美國招募的非阻塞性患者比阻塞性患者多，這是可以預料的，因為其中一種 CMI 已經在美國獲得批准並上市。因此，對於非阻塞而言，根本沒有可用的選項。因此，在美國，我們看到的非阻塞性呼吸器比阻塞性呼吸器多，但我們認為這種情況將在美國以外迅速轉變，因為 CMI 在美國以外基本上無法使用。

And Joe, what I hear over the last sort of 3 to 6 months speaking with KOLs, there's a couple of things. One, they're becoming more and more aware of sota in HCM. I think that's twofold. One, we're progressing SONATA and that enrollment is going nicely. And two, there's obviously been noise in the marketplace, particularly around nonobstructive and conjecture around will aficamten be successful, but they see because of some of the other evidence that we have with SONATA that this could be a real option for nonobstructive. So they're enthused about the possibility of that.

喬，在過去的 3 到 6 個月裡，我與 KOL 交談時聽到了幾件事。首先，他們越來越意識到 HCM 中的 sota。我認為這具有雙重意義。首先，我們正在推進 SONATA，招生工作進展順利。其次，市場上顯然存在一些噪音，特別是圍繞非阻塞性噪音以及關於 aficamten 是否會成功的猜測，但他們認為，由於我們掌握的有關 SONATA 的一些其他證據表明，這可能是非阻塞性的真正選擇。因此，他們對這種可能性充滿熱情。

And then more broadly, sort of having worked in this space with Entresto and understanding that general cardiology practices across the country have HCM patients, have HFpEF patients and the potential to have one medicine that can potentially treat both very significantly without sort of fear nor favor and is really compelling beyond the academic sites into the general cardiology practices where, as you know, actually the vast majority of HCM patients are being treated.

更廣泛地說，我曾在該領域與 Entresto 合作，並了解到全國各地的綜合心臟病學診所都有 HCM 患者和 HFpEF 患者，並且有可能開發出一種藥物，可以對這兩種患者進行非常有效的治療，而不必擔心或偏袒，這種藥物非常引人注目，超越了學術領域，進入了綜合心臟病學診所，正如您所知，實際上絕大多數 HCM 患者都在絕大多數治療中接受治療。

Appreciate it. Thanks a lot.

非常感謝。多謝。

(Operator Instructions)

（操作員指示）

Mazahir Alimohamed, Leerink Partners.

Mazahir Alimohamed，Leerink 合夥人。

Yeah, hi everyone, this is Maisy on for Roanna. Just two from us. But I guess the first one is, given Vertex's recent announcement about their VX-993 and its inability to meet its primary endpoint in the Phase II, how does that, I guess, impact your confidence in the overall pain market and the ability to conduct a careful Phase III trial? And then I guess the second one, Craig, just a follow-up to what you just said. So I noticed that you mentioned that there's going to be an echo for every patient when they start the trial. Is that something that you would expect if approved as well? And to the market, would it be something that you would expect commercially that they would have an echo before being started on drug?

是的，大家好，我是 Maisy，為 Roanna 主持節目。離我們只有兩個了。但我想第一個問題是，鑑於 Vertex 最近宣布其 VX-993 無法達到第二階段的主要終點，我想這會如何影響您對整個疼痛市場的信心以及進行仔細的第三階段試驗的能力？然後我想第二個問題，克雷格，只是對你剛才所說的內容的後續。所以我注意到您提到當每個病人開始試驗時都會有迴聲。如果獲得批准，這也是您所期望的嗎？對於市場而言，您是否期望它在商業上能引起反響，然後才開始用於藥物治療？

Yeah, Great couple of questions, and please pass on our best regards to Roanna. I hope it's all going well with above. Let me take a first go with the pain question and Vertex. And obviously, we followed their earnings yesterday. I think, in fact, that gives us even greater confidence in our own program. Why is that? We've now shown 3 times in -- across Phase II programs in neuropathic pain that we can separate from placebo with the 10-milligram dose. We, I think, have always been a little bit skeptical of Nav 1.8, particularly in neuropathic pain. I think the evidence in acute pain despite 993's results yesterday in post bunionectomy not reading out positively.

是的，這幾個問題很棒，請向 Roanna 轉達我們最誠摯的問候。我希望以上一切順利。讓我先討論一下疼痛問題和 Vertex。顯然，我們昨天關注了他們的收益。我認為，事實上，這讓我們對自己的計畫更有信心。這是為什麼？我們現在已經 3 次證明，在針對神經性疼痛的 II 期項目中，我們可以透過 10 毫克劑量與安慰劑區分開來。我認為，我們一直對 Nav 1.8 持懷疑態度，特別是在神經性疼痛方面。我認為儘管昨天 993 在拇囊切除術後的結果並不樂觀，但仍有證據表明存在急性疼痛。

So it allows us confidence in our program and having a novel mechanism of action compared to the number of companies that are now pursuing Navs, which really, the evidence is mixed, one would have to say apart from acute. But certainly, in neuropathic pain, the evidence is mixed at best. And actually, it's probably pretty much not great, so to speak. And it's one of those instances where being on a novel MOA with proven efficacy, really, we think, is something that we appreciate and gives us confidence moving forward. And importantly, our partners will appreciate as we sort of go back and have this next round of discussions.

因此，與現在追求 Navs 的公司數量相比，它讓我們對我們的計劃充滿信心，並且擁有一種新穎的作用機制，事實上，除了敏銳的證據之外，人們不得不說，證據是混合的。但可以肯定的是，對於神經性疼痛而言，證據充其量只是混合的。事實上，可以說它可能不太好。我們認為，這是採用一種具有已證實療效的新型藥物作用機制 (MOA) 的一個例子，這確實值得我們讚賞，並給了我們繼續前進的信心。重要的是，當我們回去進行下一輪討論時，我們的合作夥伴會感激的。

So Craig, any other thoughts on that?

那麼 Craig，對此還有其他想法嗎？

Yeah, Mike, I think that was well said. I think just scientifically, there are a couple of important points. And again, I don't want to draw undue attention to another company's communications, but they did demonstrate or they communicated that with 993, they did get more exposure with more dose, and they had no additional efficacy. So I think that the question is there is certainly a healing on the effect of Nav 1.7 to mitigate pain. I think that's also reflective of the fact that they're looking at developing combinations of Nav 1.7 and 1.8, which presupposes that they're looking for more efficacy. So I think that's an important point.

是的，麥克，我認為說得很好。我認為從科學角度來說，有幾點很重要。再說一次，我不想過多關注其他公司的溝通，但他們確實證明或傳達了使用 993 後，他們確實通過增加劑量獲得了更多的曝光，但沒有額外的功效。所以我認為問題在於 Nav 1.7 肯定具有緩解疼痛的效果。我認為這也反映了他們正在考慮開發 Nav 1.7 和 1.8 的組合，這意味著他們正在尋求更高的效率。所以我認為這是一個重要的觀點。

And as Mike said, in neuropathic pain, the Navs have not demonstrated separation from placebo. They've demonstrated similar drops in pain score compared to pregabalin. But as we know, pregabalin doesn't always separate from placebo in the pregabalin registration trials, and that's the whole issue around placebo effect. So I think those are just a couple of additional comments. And I think it also reaffirms from a regulatory standpoint that you're going to need to do 2 separate trials in a pain indication to seek approval. And so again, I think those are some important findings that we had from what we heard the other day.

正如麥克所說，在神經性疼痛方面，Navs 並未表現出與安慰劑的差異。與普瑞巴林相比，它們的疼痛評分也有類似的下降。但如我們所知，在普瑞巴林註冊試驗中，普瑞巴林並不總是與安慰劑分開，這就是安慰劑效應的全部問題。所以我認為這些只是一些補充評論。我認為從監管角度來看，這也再次證明，你需要針對一種疼痛症狀進行兩次單獨的試驗才能獲得批准。所以，我再次認為，這些是我們前幾天聽到的一些重要發現。

Switching gears on the echo. I don't think that's going to be a major impediment. All these patients are going to be getting an echo regardless. I think a lot of the issues in HCM, frankly, are related to the echoes because of the fact that CMIs reduce ejection fraction. So I think we don't have that issue, right? We're a drug that treats heart failure, whether you have low ejection fraction heart failure or normal ejection fraction heart failure. I think part of what's going on in the HCM field has been modified by the level of the agents and the fact that the current agents that have either been approved or under study actually have a negative ionotropic effect on the heart by their very design.

切換迴聲的齒輪。我認為這不會成為一個重大障礙。無論如何，所有這些患者都將接受超音波心動圖檢查。坦白說，我認為 HCM 中的許多問題都與迴聲有關，因為 CMI 會降低射血分數。所以我認為我們沒有這個問題，對嗎？我們是一種治療心臟衰竭的藥物，無論您是患有低射血分數心臟衰竭還是正常射血分數心臟衰竭。我認為 HCM 領域正在發生的部分事情已經因藥物水平而發生了改變，事實上，目前已獲批准或正在研究的藥物實際上在設計上對心臟有負離子作用。

And because of that, getting an echo and following ejection fraction closely is a very important safety signal, which is the basis of the REMS that exist. So I think FDA will probably label our drug the way that we studied it, that there'll be an echo, but I think that the requirement or the necessity of the echo from a patient suitability standpoint might be less with sota, even though following the echo and following ejection fraction in patients with symptomatic heart failure is sort of standard of care today anyways, at least in the United States.

正因為如此，獲取迴聲並密切追蹤射血分數是一個非常重要的安全訊號，這是現有 REMS 的基礎。因此，我認為 FDA 可能會按照我們研究的方式對我們的藥物進行標記，即會有迴聲，但我認為從患者適用性的角度來看，對於 SOTA 來說，迴聲的要求或必要性可能會較低，儘管對於有症狀的心臟衰竭患者來說，跟踪迴聲和跟踪射血分數無論如何都是當今的護理標準，至少在美國是這樣。

Great thank you guys.

非常感謝你們。

I would now like to turn the call back over to Mike Exton for any 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。

Yeah, Well, thanks very much for joining, everyone, and thanks for the questions, folks. I really appreciate those.

是的，非常感謝大家的加入，也感謝大家的提問。我真的很感激這些。

So I've done a number of these quarterly earnings calls since I've been here. And the last couple, we've had some major announcements with data readouts with a refocus on strategy and all of those have been very important announcements. But I think so far in my short tenure here, this is probably the quarter that I'm most proud of, mostly because of two things. One, that the team has really driven all programs in parallel to the point of their next stage of catalyst, to their next sort of inflection point, to their next natural development.

自從我來到這裡以來，我已經召開過多次季度收益電話會議。最近幾天，我們發布了一些重要公告，包括數據解讀和重新關注策略，所有這些都是非常重要的公告。但我認為，在我短暫的任期內，這可能是我最自豪的一個季度，主要因為兩件事。第一，團隊確實推動了所有專案的平行發展，達到了下一階段的催化劑、下一個轉折點和下一個自然發展階段。

And importantly, we've done so in a way where we have really focused our resources and are allocating capital in a way that's really focused on adding value for us and all stakeholders. So both of those things have resulted in a quarter where the pipeline has advanced dramatically, and we've done so revising the outlook for expenses for the year, mostly because of 9851, but some of it due just to looking at all of our expenses and making sure we're spending wisely. So I couldn't be prouder of the team. Looking forward to Q3 as we go through a number of important developments over the next three months and updating you all then.

重要的是，我們這樣做的目的是真正集中我們的資源，並以真正注重為我們和所有利害關係人增加價值的方式分配資本。因此，這兩件事都導致本季管道取得了顯著進展，我們也因此修改了今年的支出前景，主要是因為 9851，但部分原因是因為我們審查了所有支出，並確保我們明智地支出。所以我為這個團隊感到無比驕傲。我們期待第三季的到來，因為在接下來的三個月裡，我們將經歷許多重要的發展，然後向大家更新最新情況。

So thanks very much.

非常感謝。

Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.

謝謝。會議到此結束。感謝您的參與。您現在可以斷開連線。