Lexicon Pharmaceuticals Inc (LXRX) 2024 Q2 法說會逐字稿

Good day and welcome to the Lexicon Pharmaceuticals second-quarter 2024 financial results conference call. (Operator instructions) Please note this event is being recorded.

美好的一天，歡迎參加 Lexicon Pharmaceuticals 2024 年第二季財務業績電話會議。（操作員說明）請注意此事件正在被記錄。

I would now like to turn the conference over to Lisa de Francesco, Head Investor Relations and Corporate Strategy. Please go ahead.

我現在想將會議交給投資者關係和企業策略主管麗莎·德·弗朗西斯科 (Lisa de Francesco)。請繼續。

Thank you, Betsy. Good afternoon, and welcome to the Lexicon Pharmaceuticals second-quarter 2024 financial results conference call. Joining me today are Dr. Mike Exton, Lexicon's new Chief Executive Officer and Director; Jeff Wade, President and Chief Operating Officer; Tom Garner, Senior Vice President and Chief Commercial Officer; Dr. Craig Granowitz, Senior Vice President and Chief Medical Officer; and Dr. Alan Main, Executive Vice President, Innovation and Chemical Sciences.

謝謝你，貝特西。下午好，歡迎參加 Lexicon Pharmaceuticals 2024 年第二季財務業績電話會議。今天和我一起的還有 Lexicon 新任執行長兼董事 Mike Exton 博士；傑夫·韋德，總裁兼營運長；湯姆‧加納 (Tom Garner)，資深副總裁兼商務長； Craig Granowitz 博士，資深副總裁兼首席醫療官；以及創新和化學科學執行副總裁 Alan Main 博士。

Earlier this afternoon, Lexicon issued a press release announcing our financial results for the second quarter of 2024, 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 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，宣布我們 2024 年第二季度的財務業績，該新聞稿可在我們的網站 www.lexpharma.com 上以及透過我們向 SEC 提交的文件中獲取。我們的網站上也提供了本次電話會議的網路廣播以及幻燈片簡報。在本次電話會議期間，我們將審查新聞稿中提供的信息，提供公司最新信息，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. Relating to the safety, efficacy, clinical development, regulatory status, and therapeutic and commercial potential of INPEFA, ZYNQUISTA, LX9211, LX9851 and our other drug programs as well as our business generally. These statements may include characterizations and projections relating to our commercial launch of INPEFA in heart failure as well as the clinical development, regulatory status, and market opportunity for all of our drug programs.

在開始之前，請允許我提醒您，我們將做出前瞻性陳述。涉及 INPEFA、ZYNQUISTA、LX9211、LX9851 和我們其他藥物項目以及我們整體業務的安全性、有效性、臨床開發、監管狀況以及治療和商業潛力。這些陳述可能包括與我們在心臟衰竭方面商業推出 INPEFA 相關的特徵和預測，以及我們所有藥物項目的臨床開發、監管狀況和市場機會。

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.

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非歷史事實或資訊的其他事項有關的前瞻性陳述。

Various risks that 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.

可能導致我們的實際結果與此類前瞻性陳述中明示或暗示的結果存在重大差異的各種風險，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，以了解描述此類風險的詳細資訊。

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

我現在想把電話轉給麥克·埃克斯頓。

Thanks, Lisa, and good day, everyone. Thanks for joining us on the call. Before we begin our discussion on Lexicon's results for the second quarter of 2024, let me start by saying that even in my first few weeks here as CEO, I can already see what a tremendous opportunity we have to bring innovative new therapies to patients, transform the treatment landscape of multiple therapeutic areas and indeed transform Lexicon as a company.

謝謝麗莎，大家好。感謝您加入我們的通話。在我們開始討論Lexicon 2024 年第二季度的業績之前，我首先要說的是，即使在我擔任首席執行官的頭幾週內，我也已經看到了我們擁有多麼巨大的機會，可以為患者帶來創新的新療法、變革多個治療領域的治療景觀，確實使 Lexicon 作為一家公司發生了轉變。

Now moving on to our accomplishments for the year, which are indeed incredibly significant. First of all, our INPEFA business continued to grow modestly, and we saw progress across all areas of focus in this highly competitive market. Importantly, we also resubmitted our NDA for ZYNQUISTA and have received a PDUFA goal date of December 20, 2024, setting us up for a potential commercial launch in this untapped market in early 2025.

現在談談我們今年的成就，這些成就確實非常重要。首先，我們的 INPEFA 業務持續溫和成長，在這個競爭激烈的市場中，我們在各個重點領域都取得了進展。重要的是，我們也重新提交了 ZYNQUISTA 的 NDA，並收到了 2024 年 12 月 20 日的 PDUFA 目標日期，為我們在 2025 年初在這個尚未開發的市場進行潛在的商業發布做好了準備。

Furthermore, our Phase 3 study for sotagliflozin in hypertrophic cardiomyopathy or HCM is underway with sites already open and beginning to enroll patients. In addition, our Phase 2b study for LX9211 in diabetic peripheral neuropathic pain or DPNP is on track to meet its timelines and its objectives with top line data anticipated second quarter of 2025.

此外，我們針對 sotagliflozin 治療肥厚型心肌病變或 HCM 的 3 期研究正在進行中，研究中心已開放並開始招募患者。此外，我們針對 LX9211 治療糖尿病週邊神經病理性疼痛或 DPNP 的 2b 期研究正在按計劃實現其時間表和目標，預計將於 2025 年第二季度獲得頂線數據。

And finally, our exciting novel drug candidate, LX9851, an oral therapy for obesity and weight management, which we believe has the potential to become an innovative next gen treatment in this large market is progressing into preclinical development. These are all really solid opportunities for Lexicon, not only for next year, but well beyond.

最後，我們令人興奮的新候選藥物 LX9851 是一種用於肥胖和體重管理的口服療法，我們相信它有潛力成為這個巨大市場中的創新下一代治療方法，目前正在進入臨床前開發階段。對 Lexicon 來說，這些都是真正可靠的機會，不僅是明年的機會，也是更長遠的機會。

So let's take a look at sotagliflozin, in particular. We see a significant opportunity for value and growth with this compound across additional indications where sotagliflozin's unique mechanism of action has potential for beneficial effect. Lexicon has taken a purposeful approach in each one of the areas that we're exploring.

讓我們特別來看看 sotagliflozin。我們看到了這種化合物在其他適應症中的價值和增長的重大機會，其中 sotagliflozin 的獨特作用機制具有潛在的有益作用。Lexicon 在我們正在探索的每個領域都採取了有針對性的方法。

And as a result, we're now preparing for the next near term opportunity to commercially launch ZYNQUISTA for glycemic control in adults with type 1 diabetes and chronic kidney disease, while working towards a longer term goal of expanding sotagliflozin into HCM.

因此，我們現在正在準備下一個近期機會，將 ZYNQUISTA 商業化上市，用於 1 型糖尿病和慢性腎病成人患者的血糖控制，同時努力實現將 sotagliflozin 擴展到 HCM 的長期目標。

Now in both of these areas, there are no SGLT therapies indicated. And we believe that the dual inhibition of SGLT1 and SGLT2 offers unique advantages. These areas of unmet need are also highly concentrated in terms of treatment landscape, and they're very different from the competitive environment we're experiencing in heart failure, which currently is dominated by two larger players within a complex treatment and reimbursement environment.

目前，這兩個領域都沒有適用的 SGLT 療法。我們相信 SGLT1 和 SGLT2 的雙重抑制具有獨特的優點。這些未滿足需求的領域也高度集中在治療領域，它們與我們在心臟衰竭方面經歷的競爭環境非常不同，目前心臟衰竭由兩個較大的參與者在複雜的治療和報銷環境中主導。

These are really very exciting near and long term opportunities for Lexicon as we advance this pipeline of current and potential indications for sotagliflozin. We'll continue to weigh and consider where this unique innovation can have the most impact for patients.

隨著我們推進 sotagliflozin 的當前和潛在適應症的管道，這些對於 Lexicon 來說確實是非常令人興奮的近期和長期機會。我們將繼續權衡並考慮這種獨特的創新可以在哪些方面對患者產生最大的影響。

Now as we then go and look holistically at our pipeline, we see similar pipeline in a pill opportunities for our other candidates as well. We have the ability to potentially address unmet medical needs within large markets with development opportunities beyond their initial indications, whether pursued by Lexicon alone or with a strategic partner. And so I'm truly thrilled to have join Lexicon at this pivotal time when we can focus on unlocking the significant value that these opportunities represent.

現在，當我們全面審視我們的管道時，我們也看到其他候選人也有類似的藥物管道機會。我們有能力潛在地解決大型市場中未滿足的醫療需求，並提供超越其最初適應症的發展機會，無論是 Lexicon 單獨追求還是與戰略合作夥伴共同追求。因此，我真的很高興能在這個關鍵時刻加入 Lexicon，因為我們可以專注於釋放這些機會所代表的重大價值。

So with that overview, I'd like to now turn it over to Jeff Wade, President and COO, to discuss in detail the business and financial results. Over to you, Jeff.

因此，在概述之後，我現在想將其交給總裁兼營運長 Jeff Wade，詳細討論業務和財務表現。交給你了，傑夫。

Thank you, Mike. I'd like to begin with our INPEFA results. Net sales for the second quarter of 2024 were $1.6 million and $2.7 million for the first half of 2024. We saw improvements in filled TRx and number of new prescribers, a modest expansion in access and greater pull through. This progress is due to the strong efforts of the team assembled by and aligned under Tom Garner since he joined the company last year.

謝謝你，麥克。我想先介紹一下我們的 INPEFA 結果。2024 年第二季的淨銷售額為 160 萬美元，2024 年上半年的淨銷售額為 270 萬美元。我們看到了已完成的TRx和新處方醫生數量的改善，准入範圍的適度擴大和更大的牽引力。這項進展歸功於湯姆·加納(Tom Garner)自去年加入公司以來組建並領導的團隊的大力努力。

Achieving better market access remains the key to more significant growth for INPEFA in heart failure. Our goal has been and remains to achieve formulary access that is favorable for patients and equitable in light of INPEFA's value. And we are continuing to have discussions with payers, driven by INPEFA's value and differentiating data.

獲得更好的市場准入仍然是 INPEFA 在心臟衰竭領域中實現更顯著成長的關鍵。我們的目標一直是並且仍然是根據 INPEFA 的價值實現有利於患者且公平的處方獲取。在 INPEFA 的價值和差異化數據的推動下，我們將繼續與付款人進行討論。

Payer coverage improved slightly in the second quarter to 48%, although most of this coverage still requires step-through of competing therapies, an obstacle that we're focused on eliminating. Some payers have been taking longer to make coverage decisions due to uncertainties associated with the IRA, particularly around the prices to be announced by CMS on September 1 for the first group of products selected for negotiation, a group that includes three major heart failure medications.

第二季的付款人覆蓋率略有提高，達到 48%，儘管大部分覆蓋率仍需要逐步採用競爭療法，這是我們致力於消除的障礙。由於IRA 相關的不確定性，一些付款人需要更長的時間才能做出承保決定，特別是CMS 將於9 月1 日宣布的第一組選擇談判的產品的價格，該組產品包括三種主要的心臟衰竭藥物。

We expect improvements in coverage as these uncertainties are resolved and as we continue to demonstrate the value of INPEFA for patients, providers, and payers. It's important to note that SGLT use remains highly underpenetrated in heart failure with significant room for growth, despite strong recommendations within the ACC treatment guidelines and consensus statements for both (inaudible) recommendations that are based in substantial part on INPEFA data, especially as it relates to initiation of therapy after hospitalization.

隨著這些不確定性的解決方案以及我們繼續向患者、提供者和付款人展示 INPEFA 的價值，我們預計覆蓋範圍會有所改善。值得注意的是，儘管ACC 治療指南中提出了強有力的建議，並且這兩項建議（聽不清楚）的共識聲明大部分基於INPEFA 數據，但SGLT 在心臟衰竭中的應用仍然高度不足，具有很大大的成長空間，特別是當它涉及住院後開始治療。

I'd now like to move to ZYNQUISTA, which has the opportunity to be the first ever oral adjunct to insulin therapy indicated to improve glycemic control in adults with type 1 diabetes. Our approach with ZYNQUISTA is part of our overall strategy to expand the use of sotagliflozin beyond the competitive heart failure market into high value opportunities, where other SGLT inhibitors are not indicated and which we believe sotagliflozin's unique SGLT1 mechanism offers advantages.

我現在想轉向 ZYNQUISTA，它有機會成為第一個口服胰島素治療輔助藥物，可改善成人第 1 型糖尿病患者的血糖控制。我們與ZYNQUISTA 合作的方法是我們整體策略的一部分，旨在將sotagliflozin 的使用擴展到競爭性心臟衰竭市場之外，進入高價值機會，在這些機會中沒有其他SGLT 抑制劑，我們相信sotagliflozin 獨特的SGLT1機制具有優勢。

We've made a lot of progress this past quarter and in the time since. We resubmitted our NDA for ZYNQUISTA in June, as an adjunct to insulin in adults with type 1 diabetes and CKD. The FDA notified us in July that they considered our resubmission to be a complete response to their 2019 action letter, and they gave us a PDUFA goal date of December 20, 2024.

在上個季度以及此後的一段時間裡，我們取得了巨大進展。我們於 6 月重新提交了 ZYNQUISTA 的 NDA，作為 1 型糖尿病和 CKD 成人患者胰島素的輔助藥物。FDA 在 7 月通知我們，他們認為我們的重新提交是對其 2019 年行動函的完整回應，並給了我們 2024 年 12 月 20 日的 PDUFA 目標日期。

Based on our recent communications with FDA, it is likely we will have the opportunity for an advisory committee meeting. We look forward to the chance to present and discuss with the committee and key stakeholders, including, importantly, the patient community, the opportunity for ZYNQUISTA to address the significant unmet need for adjunctive glycemic control in this population.

根據我們最近與 FDA 的溝通，我們很可能有機會召開諮詢委員會會議。我們期待有機會向委員會和主要利益相關者（重要的是包括患者社區）展示和討論，ZYNQUISTA 有機會解決該人群輔助血糖控制方面未得到滿足的重大需求。

From our preliminary market research, we expect more than 400,000 adults in the US with type 1 diabetes and chronic kidney disease could be eligible for treatment. And we have seen strong enthusiasm for an approved adjunct to insulin among the concentrated group of endocrinologists who manage treatment decisions in type 1 diabetes.

根據我們的初步市場研究，我們預計美國有超過 40 萬名患有第 1 型糖尿病和慢性腎臟病的成年人可能有資格接受治療。我們也看到，管理第 1 型糖尿病治療決策的內分泌科醫生集中小組對經批准的胰島素輔助藥物抱有強烈的熱情。

From our payer research, we expect the market access environment to be considerably more favorable in type 1 diabetes than in heart failure. Our opportunity to be the first adjunct to insulin therapy in a market in which patients are highly engaged, and an indication that is not subject to extensive management are all important factors for achieving favorable and timely market access.

根據我們的付款人研究，我們預計第 1 型糖尿病的市場准入環境將比心臟衰竭的市場准入環境更有利。我們有機會成為患者高度參與的市場中第一個胰島素治療輔助藥物，且適應症不受廣泛管理，這些都是實現有利和及時的市場准入的重要因素。

We believe that sotagliflozin's unique dual SGLT1 and SGLT2 mechanism offers advantages in addressing the challenges in people who have type 1 diabetes and chronic kidney disease. Both are relevant to type 1 diabetes, but the inhibition of SGLT1, the primary transporter for glucose uptake from the GI tract offers particular benefits.

我們相信，sotagliflozin 獨特的雙重 SGLT1 和 SGLT2 機制在應對 1 型糖尿病和慢性腎病患者面臨的挑戰方面具有優勢。兩者都與第 1 型糖尿病相關，但抑制 SGLT1（胃腸道葡萄糖攝取的主要轉運蛋白）​​具有特殊的益處。

SGLT1 inhibition slows the uptake of glucose from meals, blunting postprandial glucose peaks and reducing glycemic variability. And unlike SGLT2 inhibition, the effects of SGLT1 inhibition do not decline with the reduced renal function that characterizes chronic kidney disease.

SGLT1 抑制可減緩飲食中葡萄糖的攝取，減弱餐後血糖高峰並減少血糖變異性。與 SGLT2 抑制不同，SGLT1 抑制的效果不會隨著慢性腎病變特徵的腎功能下降而下降。

The focus of our NDA resubmission on people with type 1 diabetes and chronic kidney disease aligns then both with a population in which a better glycemic control is more important, and also with sotagliflozin's unique mechanism of action.

我們重新提交的 NDA 的重點是 1 型糖尿病和慢性腎病患者，這既與更好的血糖控制更為重要的人群相一致，也與 sotagliflozin 獨特的作用機制相一致。

We believe that the greater benefit in this population weighs favorably against the increased risk of diabetic ketoacidosis or DKA, that has been observed in clinical studies of all SGLT inhibitors, including sotagliflozin in type 1 diabetes, and that drove the complete response letter that our resubmission addresses.

我們認為，該族群的更大益處有利於對抗糖尿病酮症酸中毒或DKA 風險的增加，這一點在所有SGLT 抑制劑（包括1 型糖尿病中的索格列淨）的臨床研究中都觀察到，這推動了我們重新提交的完整答覆信地址。

We are pleased to say that we have initiated our pivotal Phase 3 SONATA trial for HCM with the opportunity to transform the standard of care in this area of high unmet need. We are leveraging outcomes data from our score trial in heart failure, KCCQ data from soloist and other evidence, providing a strong scientific rationale for the potential of sotagliflozin in this indication.

我們很高興地說，我們已經啟動了針對 HCM 的關鍵 3 期 SONATA 試驗，並有機會改變這一需求未滿足的領域的護理標準。我們正在利用心臟衰竭評分試驗的結果數據、來自獨奏者的 KCCQ 數據和其他證據，為 sotagliflozin 在該適應症中的潛力提供強有力的科學依據。

This slide shows the design of SONATA HCM, a pivotal Phase 3 placebo controlled study with a targeted enrollment of 500 patients with obstructive or non-obstructive HCM. We have sites up and running and have commenced patient recruitment in the study.

這張投影片展示了 SONATA HCM 的設計，這是一項關鍵的 3 期安慰劑對照研究，目標招募 500 名患有阻塞性或非阻塞性 HCM 的患者。我們已建立並運行站點，並已開始在研究中招募患者。

The primary endpoint of the study is change from baseline in KCCQ score, an endpoint that has been accepted by the FDA as the primary end point in this and other label enabling HCM trials, and with which we have previously achieved success in our soloist heart failure trial.

該研究的主要終點是 KCCQ 評分相對於基線的變化，該終點已被 FDA 接受作為本試驗和其他支持 HCM 試驗的主要終點，並且我們之前已通過該終點在單獨的心臟衰竭中取得了成功審判。

Importantly, SONATA HCM is studying a broader patient population than that studied in other ongoing trials in HCM, as we are allowing patients to be on cardiac myosin inhibitors as well as allowing the use of beta blockers and calcium channel blockers.

重要的是，SONATA HCM 正在研究比其他正在進行的HCM 試驗研究的更廣泛的患者群體，因為我們允許患者服用心肌肌球蛋白抑制劑，並允許使用β 受體阻斷劑和鈣通道阻斷劑。

We are also enrolling patients with an ejection fraction down to 50%, which is lower than the studies of cardiac myosin inhibitors for which heart failure is a risk. And of course, sotagliflozin is already indicated as INPEFA to reduce heart failure, which is the major risk for these patients.

我們也招募了射血分數低至 50% 的患者，這低於有心臟衰竭風險的心肌肌球蛋白抑制劑的研究。當然，sotagliflozin 已被指定為 INPEFA 以減少心臟衰竭，這是這些患者的主要風險。

We have obtained feedback from FDA that success in this single study could support a broad label for sotagliflozin in HCM. Once again, an indication in an important area of unmet need that would be unique to sotagliflozin among SGLT inhibitors. Current estimates suggest that around 1 million patients in the United States today have HCM.

我們從 FDA 獲得回饋，這項研究的成功可以支持 sotagliflozin 在 HCM 中的廣泛標籤。這再次表明了一個未滿足需求的重要領域，這將是 SGLT 抑制劑中 sotagliflozin 所獨有的。目前估計，美國目前約有 100 萬名患者患有 HCM。

Many are not diagnosed in part because of the nonspecific nature of HCM symptoms, but diagnostic rates have been rising rapidly, a trend which is expected to continue over the next decade with an increased focus on the disease.

許多人沒有被診斷出來，部分原因是肥厚型心肌病變症狀的非特異性，但診斷率一直在迅速上升，隨著對該疾病的日益關注，這一趨勢預計將在未來十年持續下去。

Looking further into our pipeline, we have in LX9211 another opportunity to redefine the standard of care and an important area of need, in this case, in neuropathic pain. LX9211 has the potential to be the first new non-opioid treatment for neuropathic pain in over two decades.

進一步審視我們的產品線，LX9211 為我們提供了另一個重新定義護理標準和重要需求領域的機會，在本例中，是神經性疼痛。LX9211 有潛力成為二十多年來第一個治療神經性疼痛的新型非鴉片類藥物。

Our PROGRESS Phase 2b dose optimization study began enrolling towards the end of 2023, and is well on track for top line data in the first half of 2025. It is important to note that this study, like our proof of concept studies is placebo-controlled and allows patients to remain on stable dose standard of care therapy rather than removing all pain medications, consistent with how DPNP drugs are likely to be used in real world practice.

我們的 PROGRESS 2b 期劑量最佳化研究於 2023 年底開始招募，並預計在 2025 年上半年獲得頂線數據。值得注意的是，這項研究，就像我們的概念驗證研究一樣，是安慰劑對照的，允許患者保持穩定劑量標準的護理治療，而不是取消所有止痛藥物，這與DPNP 藥物在實際中的使用方式一致。

We learned a great deal in our Phase 2 relief DPN study, which we are applying to this Phase 2b progress study with a key hypothesis being that we can improve tolerability by eliminating the 10x first day loading dose in the prior study. At this point, we feel quite confident about where we are in this study and are very much looking forward to the results next year.

我們在2 期緩解DPN 研究中學到了很多東西，我們將其應用於這項2b 期進展研究，其中一個關鍵假設是，我們可以透過消除先前研究中的10 倍第一天負荷劑量來提高耐受性。至此，我們對這項研究的進展充滿信心，並且非常期待明年的結果。

Approximately 20 million patients in the United States are suffering with some type of neuropathic pain, of which about 5 million have DPNP with significant growth predicted in the future. We believe LX9211 could offer a real benefit to patients and to the clinical community who are looking for better options to improve outcomes for patients with DPNP.

美國約有 2,000 萬名患者患有某種類型的神經性疼痛，其中約 500 萬名患有 DPNP，預計未來會有顯著成長。我們相信 LX9211 可以為正在尋找更好選擇來改善 DPNP 患者預後的患者和臨床社區帶來真正的好處。

Our newest drug candidate to emerge from our Genome5000 platform is LX9851 in the exciting area of obesity and weight management. We believe that LX9851 has the potential, like our other assets, to be developed in additional indications and to be used as a combination therapy as well.

我們的 Genome5000 平台推出的最新候選藥物是 LX9851，它涉及令人興奮的肥胖和體重管理領域。我們相信 LX9851 與我們的其他資產一樣，有潛力開發更多適應症並用作聯合療法。

LX9851 is a small molecule inhibitor of the target (inaudible) synthetase 5 or ACSL5 that we believe could be given orally for chronic weight management with a target product profile that reduces body fat, spares lean body mass, and favorably affects overall metabolic profile. In preclinical studies, it has reduced cholesterol and triglycerides, improved insulin sensitivity, and demonstrated potential and additional related indications such as metabolic syndrome and MASH.

LX9851 是一種目標（聽不清楚）合成酶5 或ACSL5 的小分子抑制劑，我們認為可以口服用於長期體重管理，其目標產品特性可減少體內脂肪，保留瘦體重，並有利地影響整體代謝狀況。在臨床前研究中，它降低了膽固醇和三酸甘油酯，提高了胰島素敏感性，並證明了潛在的​​和其他相關的適應症，例如代謝症候群和 MASH。

The obesity and weight management space is an area of tremendous interest, and we're very excited about the potential for an oral once daily therapy with these mechanisms that complement and enhance current therapies. We've moved into IND enabling studies, and we are very focused on submitting data to upcoming medical meetings.

肥胖和體重管理領域是一個令人非常感興趣的領域，我們對每日一次口服療法的潛力感到非常興奮，這些療法可以補充和增強現有療法的機制。我們已經進入 IND 啟用研究，並且非常專注於向即將舉行的醫學會議提交數據。

Now we will review some of the key elements of our second quarter 2024 financial results. You can find more financial details in the press release that we issued earlier today and in our 10-Q that will be filed shortly with the SEC.

現在我們將回顧 2024 年第二季財務表現的一些關鍵要素。您可以在我們今天早些時候發布的新聞稿以及即將向 SEC 提交的 10-Q 中找到更多財務細節。

We ended the quarter with $310 million in cash and investments. As indicated in our press release this afternoon, we had $1.6 million in revenues in the second quarter of 2024, almost all from net sales of INPEFA and had minimal revenues for the same period in 2023.

本季結束時，我們擁有 3.1 億美元的現金和投資。正如我們今天下午的新聞稿所示，我們在 2024 年第二季的收入為 160 萬美元，幾乎全部來自 INPEFA 的淨銷售額，而 2023 年同期的收入很少。

R&D expenses for the second quarter of 2024 increased to $17.6 million from $14.5 million for the corresponding period in 2023, primarily due to higher external R&D expenses as our development programs progress.

2024 年第二季的研發費用從 2023 年同期的 1,450 萬美元增加到 1,760 萬美元，主要是由於隨著我們的開發項目的進展，外部研發費用增加。

SG&A expenses for the second quarter of 2024 increased to $39.2 million from $30 million for the corresponding period in 2023, reflecting the investment in the commercial launch of INPEFA. In total, net loss for the second quarter of 2024 was $53.4 million or $0.17 per share as compared to a net loss of $44.9 million or $0.22 per share in the corresponding period in 2023. For the second quarter of 2024 and 2023, net loss included noncash stock based compensation expense of $4.9 million and $3.8 million, respectively.

2024 年第二季的銷售、行政管理費用從 2023 年同期的 3,000 萬美元增加到 3,920 萬美元，反映了對 INPEFA 商業啟動的投資。整體而言，2024 年第二季的淨虧損為 5,340 萬美元，即每股 0.17 美元，而 2023 年同期的淨虧損為 4,490 萬美元，即每股 0.22 美元。2024 年和 2023 年第二季的淨虧損包括非現金股票補償費用，分別為 490 萬美元和 380 萬美元。

Now I'll turn it back over to Mike for some closing remarks.

現在我將把它轉回給麥克做一些結束語。

Yes, thanks, Jeff. Look, in summary, the next 18 months for Lexicon includes several important planned catalysts. First of all, we've got the potential to launch ZYNQUISTA in the early part of next year, which for us is an exclusive opportunity, and importantly, a much needed additional treatment option for the type 1 diabetes community.

是的，謝謝，傑夫。總而言之，Lexicon 未來 18 個月包括幾個重要的計畫催化劑。首先，我們有可能在明年初推出 ZYNQUISTA，這對我們來說是一個獨特的機會，而且重要的是，它是 1 型糖尿病社區急需的額外治療選擇。

Secondly, we've initiated our SONATA Phase 3 study of sotagliflozin in HCM, and that presents a new and promising area of focus. Thirdly, our PROGRESS Phase 2b study of LX9211 in DPNP is on track with top line data in Q2 of next year. And then finally, we've commenced IND enabling studies of LX9851 in the rapidly evolving area of obesity and weight management, where current treatments are prime for next gen and combination therapies.

其次，我們已經啟動了 sotagliflozin 在 HCM 中的 SONATA 三期研究，這提出了一個新的、有前途的重點領域。第三，我們的 DPNP 中 LX9211 的 2b 期研究進展順利，預計明年第二季將獲得頂線資料。最後，我們已經開始在快速發展的肥胖和體重管理領域對 LX9851 進行 IND 研究，目前的治療方法是下一代和聯合療法的主要治療方法。

So each of these opportunities have a lot in common. They're all in large markets. There are significant areas of unmet need where there is white space with the true need for new innovative therapies. And within each of these areas, we have the potential to be the first or only truly exclusive in our approach, unlike what we're experiencing in heart failure currently.

因此，這些機會都有很多共同點。它們都在大市場中。有一些重要的需求未被滿足的領域，其中存在對新的創新療法的真正需求的空白。在這些領域中的每一個領域，我們都有可能成為第一個或唯一真正獨特的方法，這與我們目前在心臟衰竭方面所經歷的情況不同。

And each of these opportunities are supported by thoughtful clinical development, that is informed by discussions with the FDA and designed to incorporate real world elements of how the drug would actually be used in the market.

這些機會中的每一個都得到深思熟慮的臨床開發的支持，這些臨床開發是透過與 FDA 的討論而獲得的，旨在融入藥物在市場上實際使用方式的現實世界元素。

So as we enter the back half of the year, we're currently evaluating our strategy and our resourcing in order to ensure that we are optimized for success across these programs. We believe that we'll have the opportunity over the next 18 months to significantly improve treatment paradigms, transform Lexicon as a company and create significant value for all of our stakeholders, most importantly, including the patients that we serve.

因此，當我們進入今年下半年時，我們目前正在評估我們的策略和資源，以確保我們針對這些計劃的成功進行最佳化。我們相信，在接下來的18 個月內，我們將有機會顯著改善治療模式，將Lexicon 作為一家公司進行轉型，並為所有利益相關者（最重要的是，包括我們所服務的患者）創造重大價值。

So with that, I'd like to turn it back to the operator to open up the Q&A.

因此，我想將其轉回給操作員以展開問答。

We will now begin the question and answer session. (Operator instructions)

我們現在開始問答環節。（操作員說明）

Yasmeen Rahimi, Piper Sandler.

亞斯明·拉希米，派珀·桑德勒。

Great. Thank you so much, team, for all the updates. A few questions on ZYNQUISTA. Did you mention, I think it sounded like in the prepared remarks that you guys were preparing for an (inaudible) , I guess, if you could maybe talk about whether an (inaudible) is expected, when it could occur, what could be possible topics? That's sort of like big bucket one.

偉大的。非常感謝團隊的所有更新。關於 ZYNQUISTA 的幾個問題。你有沒有提到，我認為在準備好的發言中，你們正在為（聽不清楚）做準備，我想，如果你能談談是否預期（聽不清楚），何時可能發生，可能發生什麼主題？這有點像大桶。

And then bucket two, if you could talk about commercially how you're thinking about sort of, do you need to add more salespeople? Is there any, as you will be focused on patients that are under the care of endocrinologists. What would the launch trajectory look like in a more endocrinology focused setting versus a cardiovascular focus, would appreciate any color around that as well. And I'll jump back into the queue for any other questions.

然後第二點，如果你可以談論商業方面你的想法，你是否需要增加更多的銷售人員？有沒有，因為您將重點關注內分泌科醫生護理的患者。在更注重內分泌學而不是心血管學的環境中，發射軌跡會是什麼樣子，也會欣賞周圍的任何顏色。對於任何其他問題，我將跳回隊列中。

Thanks a lot, Yasmeen. I heard two big buckets, not sure if you had a third, but let me pass the first one to Craig for the Ad Comm and what we're thinking of timing and expectations, et cetera.

非常感謝，亞斯明。我聽到了兩個大桶，不確定您是否有第三個，但讓我將第一個桶傳遞給克雷格，以供廣告委員會以及我們對時間安排和期望等的想法。

Thanks for the question, Yasmeen. At this point, we expect that we will get an Ad Comm from the FDA, and it really would focus on the risk benefit of treatment. As I think we've shared at prior calls and at other meetings and communications that we've really worked hard to find a population where the risk benefit is more favorable. But we currently are committed, and the FDA has been committed to our target action date of December 20 of this year.

謝謝你的提問，亞斯明。在這一點上，我們預計我們將從 FDA 獲得 Ad Comm，它確實會關注治療的風險效益。正如我認為我們在之前的電話會議以及其他會議和溝通中所分享的那樣，我們確實努力尋找風險收益更有利的人群。但我們目前已經承諾，FDA 也承諾我們的目標行動日期是今年 12 月 20 日。

I think I'll just take a moment on the risk benefit, in that we believe that this group of patients with chronic kidney disease are at much higher rate of disease progression to end stage disease across a range of underlying diseases such as end stage kidney disease, heart failure, stroke, myocardial infarction, severe retinopathy and other diseases.

我想我會花點時間談談風險收益，因為我們相信這群慢性腎病患者在一系列基礎疾病（例如終末期腎病）中疾病進展為終末期疾病的比率要高得多病、心臟衰竭、中風、心肌梗塞、嚴重視網膜病變等疾病。

So glycemia is actually a marker for that. And the indication we're seeking, as a reminder is a glycemia control indication with that group of patients with underlying chronic kidney disease. So we're not seeking an indication right now for preventing necessarily progression of the chronic kidney disease, but that is a marker of patients that are going to have much more rapidly progressive disease across a range of complications of type 1 diabetes.

所以血糖其實是一個標誌。提醒一下，我們正在尋找的適應症是針對患有潛在慢性腎臟疾病的患者群體的血糖控制適應症。因此，我們現在並不是在尋求一種能夠預防慢性腎病進展的跡象，而是表明患者在 1 型糖尿病的一系列併發症中疾病進展速度更快。

So I think in that regard, we've gotten great feedback from the patient and physician community on the need for this therapy, I think in prior communications from FDA, some of which publicly, that they acknowledged that insulin alone is not enough in type 1 diabetes patients.

因此，我認為在這方面，我們已經從患者和醫生群體那裡得到了關於這種療法的必要性的良好反饋，我認為在FDA 之前的溝通中，其中一些是公開的，他們承認單獨使用胰島素在類型上是不夠的1.糖尿病患者。

They've acknowledged that those that don't have tight glycemic control are at risk of progression of more rapidly progressive disease. So we look forward to the opportunity if there is an Ad Comm that we'll be able to share all of this with both the FDA and the medical community.

他們承認，那些沒有嚴格血糖控制的人面臨病情進展更快的風險。因此，如果有一個 Ad Comm，我們將能夠與 FDA 和醫學界分享所有這些訊息，我們期待這樣的機會。

Yes, Great. Thanks, Greg. We feel very confident going into that Ad Comm and look forward to presenting all of our and independent data at that time. So I'll throw it, the second question, the second big bucket to Tom, the Chief Commercial Officer, which really focusing on the commercial footprint for ZYNQUISTA and particularly around field force. Tom, if you could take that question.

是的，太棒了。謝謝，格雷格。我們對參加該廣告交流會感到非常有信心，並期待屆時將展示我們所有的獨立數據。因此，我將把第二個問題、第二個大桶拋給首席商務官 Tom，該問題真正關注的是 ZYNQUISTA 的商業足跡，特別是圍繞現場力量。湯姆，請你回答這個問題。

Absolutely. Yes, thanks, Mike, and thanks for the question, Yas. So I think as you're all aware, we've spent a significant amount of time and effort really building a highly capable commercial infrastructure and that crosses field sales, access, and going as deep as kind of patient scope programs as well.

絕對地。是的，謝謝麥克，也謝謝你的提問，亞斯。因此，我認為你們都知道，我們花了大量的時間和精力來真正建立一個強大的商業基礎設施，並且跨越現場銷售、訪問以及深入到患者範圍項目。

I've taken some time since I joined the company just to make sure that we're focusing all of our efforts in the right place with ISO and INPEFA, but kind of with knowing that ZYNQUISTA is probably going to be coming down the truck at some point in the future as well.

自從加入公司以來，我花了一些時間來確保我們將 ISO 和 INPEFA 的所有努力集中在正確的地方，但我知道 ZYNQUISTA 可能會在也包括在未來的某個時刻。

I think as you're very well aware, and Jeff mentioned this, this is going to be a somewhat more concentrated marketplace than what we see for heart failure. So we estimate that there's going to be between 3,000 to 4,000 endocrinologists who treat the (inaudible) share of these patients.

我認為您非常清楚，傑夫也提到過這一點，這將是一個比我們所看到的心臟衰竭市場更集中的市場。因此，我們估計將有 3,000 至 4,000 名內分泌科醫生治療這些患者（聽不清楚）。

So given that existing infrastructure that we have in terms of commercial, and as you know, we have around 150 representatives for INPEFA at the moment. Our plan is that we're going to try and leverage that team as far as possible to make sure that we can kind of really deliver on the value that we know we can unlock with ZYNQUISTA very quickly, just given the unmet needs that I think are very clear here, while at the same time, making sure that for INPEFA as well, we continue to support where needed as well.

因此，考慮到我們在商業方面現有的基礎設施，如您所知，我們目前有大約 150 名 INPEFA 代表。我們的計劃是，我們將嘗試盡可能地利用該團隊，以確保我們能夠真正實現我們知道可以透過 ZYNQUISTA 很快釋放的價值，只是考慮到我認為未滿足的需求在這裡非常明確，同時確保對於INPEFA來說，我們也繼續在需要的地方提供支援。

Thanks, Tom.

謝謝，湯姆。

Thank you so much.

太感謝了。

Andrew Tsai, Jefferies.

安德魯·蔡，杰弗里斯。

Hey, thanks. Appreciate you taking my question. Maybe just on the Ad Comm, actually, going back to the Ad Comm. Would it be safe to presume that you're preparing for hypothetical voting decisions or questions around the risk benefit and as well as the risk mitigation strategy of ZYNQUISTA? Or is there anything else you're specifically preparing for?

嘿，謝謝。感謝您回答我的問題。也許只是在廣告通訊上，實際上，回到廣告通訊。可以安全地假設您正在準備假設的投票決定或圍繞風險收益以及 ZYNQUISTA 的風險緩解策略的問題嗎？或是還有什麼特別準備的事情嗎？

And then secondly, do you think then based on the comments so far today that ZYNQUISTA's launch could be stronger than what you're seeing with INPEFA right now? Thanks.

其次，根據今天迄今為止的評論，您認為 ZYNQUISTA 的發布可能比您現在在 INPEFA 上看到的更強大嗎？謝謝。

Right. Same order. I'll throw it to you first, Craig, then Tom.

正確的。相同的順序。我先把它丟給你，克雷格，然後是湯姆。

Thank you, Andrew. Again, we really feel strongly that based on all of the discussions that we've had with the FDA over this past number of months that they really are going to focus on the risk benefit. I think what we've talked about is that in the subgroup, which has much higher risk of progression to the complications of diabetes, that tight glycemic control is even more important.

謝謝你，安德魯。再次，我們強烈感覺到，根據過去幾個月我們與 FDA 進行的所有討論，他們確實會關注風險收益。我認為我們討論的是，在進展為糖尿病併發症的風險更高的亞組中，嚴格的血糖控制更為重要。

And the data has shown convincingly both overall in the entire in tandem program nearly 3,000 patients, but also in that renal subgroup that you have similar and highly significant control of glycemia, whether on baseline insulin or optimized insulin therapy, and that tight glycemic control will be associated with less progressive disease.

數據令人信服地顯示，在整個串聯計劃中，近3,000 名患者，而且在腎臟亞組中，無論是使用基線胰島素還是優化胰島素治療，您都對血糖有相似且高度顯著的控制，並且嚴格的血糖控制將與進展緩慢的疾病有關。

And we've also shown and published that the risk of diabetic ketoacidosis seems to be similar in that subgroup of patients with underlying CKD than in the overall population. So we feel quite strongly that the primary questions that FDA will ask is about overall risk benefit.

我們還表明並發表了這一結論：患有潛在 CKD 的亞組患者患糖尿病酮症酸中毒的風險似乎與總體人群相似。因此，我們強烈認為 FDA 將提出的主要問題是關於整體風險效益。

Right. Thanks, Craig. And, Tom, to you.

正確的。謝謝，克雷格。湯姆，對你來說。

Absolutely. Thanks for the question, Andrew. So as we think about ZYNQUISTA for T1D versus INPEFA for heart failure, I mean, the first thing I would say is that this is going to be a very, very different space to what we encountered with heart failure.

絕對地。謝謝你的提問，安德魯。因此，當我們考慮 ZYNQUISTA 治療 T1D 與 INPEFA 治療心臟衰竭時，我想說的第一件事是，這將是一個與我們遇到的心臟衰竭非常非常不同的領域。

As Mike mentioned during his remarks, this is going to be a space that's basically untapped. We know there is some small amount of off label usage of SGLTs at the moment. But largely speaking, this is not a market that has really been brought to the [fore].

正如麥克在演講中提到的，這將是一個基本上尚未開發的空間。我們知道目前有少量 SGLT 的標籤外使用。但從很大程度上來說，這還不是一個真正被帶入市場的市場。[前]。

So we believe that given the unmet need, given the fact that we know we have a group of endocrinologists who have been kind of at the starting line of being wanting to be able to use these products for quite some time, there is clearly untapped potential there that we think we're going to be able to capture very quickly.

因此，我們認為，考慮到未滿足的需求，考慮到我們知道我們有一群內分泌學家，他們在相當長一段時間內一直希望能夠使用這些產品，因此顯然存在尚未開發的潛力我們認為我們能夠很快捕捉到。

The other thing that I would point out to you that it is going to be markedly different from heart failure. It's just payer dynamics. The challenge that we faced with INPEFA is the fact that heart failure is a tightly managed category, and we are up or against some very big competitors who have some very significant rebate dollars that they're paying.

我要向您指出的另一件事是，它與心臟衰竭有明顯不同。這只是付款人動態。我們 INPEFA 面臨的挑戰是，心臟衰竭是一個嚴格管理的類別，我們正在面對或對抗一些非常大的競爭對手，他們支付了一些非常可觀的回扣。

We're continuing to push very hard. But as we've started the same dialogue with those payers as it relates to ZYNQUISTA, I can tell you that the feedback that we're already getting on the profile, on the potential utilization management, and how they view, just the general management of this category, in particular, for T1D patients who's going to look and feel very, very different to what we face with heart failure.

我們將繼續努力推動。但是，由於我們已經開始與這些付款人進行與 ZYNQUISTA 相關的相同對話，我可以告訴您，我們已經在個人資料、潛在利用率管理以及他們如何看待總體管理方面獲得了反饋尤其是對於這一類別的T1D 患者來說，他們的外觀和感覺與我們面臨的心臟衰竭非常非常不同。

So I think, yes is the answer to your question. We do see that this will potentially be a space where we can make a very meaningful impact, pretty quickly, just given the concentrated market that we're going into.

所以我認為，是的，這就是你問題的答案。我們確實看到，考慮到我們要進入的集中市場，這可能是一個我們可以很快產生非常有意義的影響的領域。

(multiple speakers) Just if you allow me, Andrew, to just add to that is that, in fact, that's how we see the rest of the pipeline. I think as we go through this strategic review, I think we see that each of our assets offer this opportunity for a pipeline in a pill, which is multiple indications.

（多個發言者）安德魯，請允許我補充一點，事實上，這就是我們如何看待管道的其餘部分。我認為，當我們進行這次策略審查時，我認為我們看到我們的每項資產都為藥丸的管道提供了這個機會，這是多種適應症。

And those indications are in spaces where like the ZYNQUISTA, we'll be the first and only player either as an adjunct or standalone therapy. And as you're aware, that provides, as Tom explained, very different payer dynamics, very different dynamics at the provider interaction. And so we feel very, very confident that ZYNQUISTA has the opportunity to be a very significant medicine for Lexicon. So thank you.

這些適應症出現在像 ZYNQUISTA 這樣的領域，我們將成為第一個也是唯一一個作為輔助或獨立治療的參與者。正如您所知，正如湯姆所解釋的那樣，這提供了非常不同的付款人動態，以及提供者互動的非常不同的動態。因此，我們非常非常有信心 ZYNQUISTA 有機會成為 Lexicon 的一種非常重要的藥物。所以謝謝你。

Right. Congratulations on executing on that front as well as everything else.

正確的。恭喜您在這方面以及其他方面的執行。

Thanks so much.

非常感謝。

(Operator instructions) Joe Pantginis with H.C. Wainwright.

（操作員說明）Joe Pantginis 和 H.C.溫賴特。

Hey, everybody, good afternoon. Thanks for taking the question. First, I wanted to focus on the HCM program. It's good the program is up and running. And I wanted to sort of talk about your views about the evolution of the space.

嘿，大家下午好。感謝您提出問題。首先，我想專注於 HCM 專案。很高興該程式已啟動並正在運行。我想談談您對這個空間演變的看法。

So when you recently had your R&D Day, you positioned sotagliflozin sort of in between the beta blockers, et cetera, on the front end and the CMIs on the back end. In your current study, you're going to be also including for the CMIs. But I guess how do you envision sotagliflozin fitting in as of this point since you can also include the CMI population?

因此，當您最近舉行研發日時，您將 sotagliflozin 放置在前端的 β 受體阻斷劑等和後端的 CMI 之間。在您目前的研究中，您還將包括 CMI。但我想既然您也可以將 CMI 人群納入其中，那麼您認為目前對 sotagliflozin 的適應情況如何？

Yes, great question. Over to you again, Craig.

是的，很好的問題。又輪到你了，克雷格。

So again, I think they have different mechanisms of action that are complementary. And since we are enrolling patients that are symptomatic, they're symptomatic regardless of their underlying therapy. So whether they're on nothing or a beta blocker, calcium channel blocker, or a CMI or combinations thereof, the inclusion criteria is those with a KCCQ score of less than 80.

再說一次，我認為它們有不同的作用機制，是互補的。由於我們正在招募有症狀的患者，因此無論其基礎治療如何，他們都會出現症狀。因此，無論他們不服用任何藥物，或服用 β 阻斷劑、鈣通道阻斷劑、CMI 或其組合，納入標準都是 KCCQ 分數低於 80 的患者。

So we think that it provides the maximum flexibility to providers to manage the symptomatic relief in these patients, which is the key reason why patients with HCM present in general and why they require treatment and the goal of treatment and as a reminder, the other agents that are in development right now, particularly in nonobstructive disease, FDA has also allowed KCCQ as the primary endpoint, just like the primary endpoint of the SONATA HCM trial.

因此，我們認為它為提供者提供了最大的靈活性來管理這些患者的症狀緩解，這是 HCM 患者普遍出現的關鍵原因，也是他們需要治療的關鍵原因，也是治療的目標，提醒一下，其他藥物目前正在開發中，特別是在非阻塞性疾病方面，FDA 也允許KCCQ 作為主要終點，就像SONATA HCM 試驗的主要終點一樣。

That's very helpful. And then just curious about the potential timelines. I don't know if you're ready to think about that now since it's just started and disclosure. And the second question, maybe for Mike, you mentioned in the prepared comments and in the press release and in one of your answers, talking about strategy and resources and strategic review. Obviously, you're not prepared now to show your hand, but wanted to sort of get a sense of what potential outcomes or goals are you looking for as part of that?

這非常有幫助。然後只是對潛在的時間表感到好奇。我不知道你現在是否準備好考慮這個問題，因為它剛剛開始並披露。第二個問題，也許對於麥克來說，您在準備好的評論和新聞稿以及您的答案之一中提到，談論了戰略和資源以及戰略審查。顯然，您現在還不準備攤牌，但想了解您正在尋找哪些潛在結果或目標？

Fantastic. Craig, firstly, for the timeline of HCM?

極好的。克雷格，首先，HCM 的時間表？

Yes. I think we've shared in general some of the timelines previously. And again, as a reminder, we got this study up and running extraordinarily quickly. And we're really looking at having a final data towards the end of 2026, early 2027. So I think that's the timeline that we're looking at.

是的。我想我們之前已經大致分享了一些時間表。再次提醒一下，我們非常快速地啟動並執行了這項研究。我們確實希望在 2026 年底、2027 年初獲得最終數據。所以我認為這就是我們正在考慮的時間表。

As a reminder and as Jeff Wade showed in his slides, we really have a treatment duration that's quite a bit shorter because the drug has already been proven in a number of heart failure related indications. So we're looking at a 26 week treatment duration, not a 52 week treatment duration, which will accelerate timelines quite a bit.

提醒一下，正如傑夫·韋德在他的幻燈片中所展示的那樣，我們的治療持續時間確實要短得多，因為該藥物已經在許多心臟衰竭相關的適應症中得到了證明。因此，我們正在考慮 26 週的治療持續時間，而不是 52 週的治療持續時間，這將大大加快時間表。

Great. And maybe, Joe, if you allow me just to pile on a little on to the first question because, yes, while we foresee sotagliflozin potentially being adjunct to all indicated therapies for HCM, clearly, there's a huge timeline gap between initiation of basal therapies, CCBs, or beta blockers through to CMIs just because of the complexity and the logistics that the centers face in initiating those later therapies and where we have demonstrated safety profile and easy oral therapy.

偉大的。喬，也許你允許我對第一個問題多說一點，因為，是的，雖然我們預見 sotagliflozin 可能會成為 HCM 的所有指定療法的輔助藥物，但顯然，基礎療法的啟動之間存在巨大的時間差距、CCB 或β 受體阻斷劑一直到CMI，只是因為這些中心在啟動這些後續治療時面臨的複雜性和後勤工作，並且我們已經證明了安全性和簡單的口服治療。

We see that it can be form a place within that position in the treatment paradigm as the team has explained previously, but not exclusively so. And I think that gives us a unique position actually across the HCM.

我們看到，正如團隊之前所解釋的那樣，它可以在治療範式中佔據一席之地，但並非完全如此。我認為這讓我們在整個 HCM 中擁有獨特的地位。

Now I appreciate the question on the strategic review. We're well into it. I've started that with my team pretty much immediately when I started, and we're getting great insights as a part of that. What are we looking to achieve?

現在我很欣賞關於戰略審查的問題。我們對此很感興趣。我一開始就和我的團隊一起開始了這項工作，作為其中的一部分，我們得到了很好的見解。我們希望實現什麼目標？

It's overall a very simple equation and that is, we have a lot of opportunities actually, more than what a company our size probably deserves or has, and yet, we need to be very thoughtful at how we deploy our resources across those opportunities to maximize them all because they're all fantastic medicines in unique indications.

總的來說，這是一個非常簡單的等式，也就是說，我們實際上擁有很多機會，超出了我們規模的公司可能應得或擁有的機會，但是，我們需要非常仔細地考慮如何在這些機會上部署我們的資源，以最大化因為它們都是具有獨特適應症的神奇藥物。

And so that's really the answer that we're searching for is across the sort of current therapies, across our pipeline therapies, where do we place our resources and effort to maximize the return for the organization, and that's where we're at. And you're right, I'm not going to do on my hand quite yet.

因此，這確實是我們正在尋找的答案，跨越當前的療法，跨越我們的管道療法，我們將資源和努力放在哪裡，以最大限度地提高組織的回報，這就是我們所處的位置。你是對的，我還不打算親自動手。

Absolutely, no, thank you very much for all the details.

絕對不，非常感謝您提供的所有詳細資訊。

Much appreciated. Thanks.

非常感謝。謝謝。

Roanna Ruiz, Leerink Partners.

羅安娜·魯伊斯 (Roanna Ruiz)，Leerink 合夥人。

Great afternoon, everyone. So maybe continuing with questions about the Phase 3 SONATA trial in HCM. I was curious, what has the feedback been from trial sites and investigators so far as you're kicking it off? And could you remind us about what standards you plan to use to ensure tight execution of that trial as well?

大家下午好。因此，也許可以繼續回答有關 HCM 第 3 階段 SONATA 試驗的問題。我很好奇，到目前為止，試驗地點和研究人員的回饋是什麼？您能否提醒我們您計劃使用哪些標準來確保該試驗的嚴格執行？

Right. Another one for you, Craig.

正確的。另一份給你，克雷格。

Yes, Roanna, it's a great question. And the feedback I have to say has been really positive. We've identified all of the sites that we need for the trial in a number of countries around the world. I think you've seen or can see on ClinTrials.gov that the trial activated around the end of June and that we're operating in a large number of countries. But the single largest contributor of sites will be the United States. And we really have a top notch group of HCM centers around the country that are participating.

是的，羅安娜，這是一個很好的問題。我不得不說的反饋非常積極。我們已經在全球多個國家/地區確定了試驗所需的所有站點。我想您已經在 ClinTrials.gov 上看到或可以看到該試驗於 6 月底左右啟動，並且我們正在許多國家/地區開展業務。但最大的網站貢獻者將是美國。我們確實在全國範圍內擁有一批頂尖的 HCM 中心參與其中。

And I think the things I really like about the trial are many of the topics that Jeff already covered is that it's a therapy that has very little friction to get patients on, can be used either alone or on top of existing therapies. It's oral, once daily, has an ejection fraction down to 50%. You don't require all the echoes.

我認為我真正喜歡該試驗的原因是傑夫已經討論過的許多主題是，這種療法對患者來說幾乎沒有阻力，可以單獨使用，也可以在現有療法的基礎上使用。它是口服的，每天一次，射血分數低至 50%。你不需要所有的迴聲。

It has a pragmatic and straightforward and relatively easy to administer endpoint of a KCCQ. You don't have all the CPET and all the other things. So the feedback on trial execution from a study size standpoint has been very positive because it's a whole lot easier to include patients on.

它具有務實、簡單且相對容易管理的 KCCQ 端點。你沒有所有的 CPET 和所有其他東西。因此，從研究規模的角度來看，對試驗執行的回饋非常積極，因為將患者納入其中要容易得多。

I think there's also a general expectation that there's this sort of understanding that, yes, I think this drug is going to work. I mean the most common thing I hear from investigators is, yes, it makes sense, it's going to work, and, especially because many of them in obstructive disease where they said, well, (inaudible), if you remove the obstruction, is that solve the problem?

我認為人們普遍期望有這樣一種理解，是的，我認為這種藥物會起作用。我的意思是，我從研究人員那裡聽到的最常見的事情是，是的，這是有道理的，它會起作用，而且，特別是因為他們中的許多人患有阻塞性疾病，他們說，好吧，（聽不清楚）如果你消除了阻塞，那就是能解決問題嗎？

But when they think about it, many of those patients in a few years are back with symptomatic disease again. And that's why we included both obstructive and non-obstructive as the underlying genetic default and pathophysiology between the two is far more similar than dissimilar.

但當他們想到這一點時，許多患者幾年後又出現了症狀性疾病。這就是為什麼我們將阻塞性和非阻塞性都包括在內，因為兩者之間潛在的遺傳預設值和病理生理學相似性遠大於不同性。

So that's really where including both obstructive and non-obstructive on top of or instead of other therapies with an EF down to [50], KCCQ score as the primary end point, a relatively shorter duration of therapy with an agent and class that they're familiar, I think, really all stack up in a very favorable way.

因此，這實際上是在EF 降至[50] 的基礎上，包括阻塞性和非阻塞性療法或代替其他療法，以KCCQ 評分作為主要終點，使用他們認為的藥物和類別的治療持續時間相對較短。

And Roanna, you talked about what controls or mechanisms do we have to see that it gets executed appropriately. I think, in fact, Craig and his team has shown the execution excellence in clinical trials with LX9211 and have really been able to demonstrate in a study that obviously was coming from another study that had some issues.

羅安娜，您談到我們必須採取哪些控製或機制才能確保其適當執行。我認為，事實上，克雷格和他的團隊已經在 LX9211 的臨床試驗中表現出了卓越的執行力，並且確實能夠在一項研究中證明這一點顯然來自另一項存在一些問題的研究。

But he, we're on track with recruitment and that's powering along and the timeline that Craig and his team met to get SONATA up and running was incredibly tight. And so the ability to recruit the number of sites that they have ever since the protocol was finalized is pretty amazing. So we are running with this very, very fast and look forward to updating on progress in the near future.

但是他，我們的招募工作正在按部就班，而且進展順利，克雷格和他的團隊為讓索納塔啟動並運行而召開的時間表非常緊迫。因此，自從協議最終確定以來，他們招募大量網站的能力是相當驚人的。因此，我們正在非常非常快地進行這項工作，並期待在不久的將來更新進展。

And a quick follow up for me. I wanted to ask about the obesity program as well. Could you just elaborate a bit more what excites you about LX9851? And how this product profile could layer into the treatment paradigm in the future, assuming that there could be more products approved by then and more combo regimens?

並對我進行快速跟進。我也想問一下肥胖計畫。您能否詳細說明 LX9851 的哪些方面讓您感到興奮？假設屆時可能有更多產品和更多組合方案獲得批准，那麼該產品概況如何融入未來的治療範例？

Yes, absolutely. So I'll turn it over to Alan in the first instance to give a little bit of background on his baby, I mean, LX9851. And so Alan, why don't you take us through and then a couple of others may lay some other opinions on top?

是的，絕對是。因此，我將首先將其交給艾倫，以提供有關他的孩子的一些背景信息，我的意思是，LX9851。那麼艾倫，為什麼你不先帶我們去了解一下，然後其他幾個人可能會提出一些其他意見呢？

Yes. Absolutely. Obviously, the weight management field is incredibly exciting. Treatment is evolving. But despite the success of the (inaudible) agonists, I think there's still some important questions, cost and ease of use, reduction of lean body mass, and tolerability.

是的。絕對地。顯然，體重管理領域非常令人興奮。治療方法正在不斷發展。但儘管（聽不清楚）激動劑取得了成功，我認為仍然存在一些重要的問題：成本和易用性、去脂體重的減少以及耐受性。

And with LX9851, we think we're addressing all of those issues. It's a small molecule, relatively easy to manufacture. It's oral product. In our preclinical studies, in our knockout studies, we've seen a very nice reduction in fat only with no change in lean body mass.

透過 LX9851，我們認為我們正在解決所有這些問題。它是一種小分子，相對容易製造。這是口服產品。在我們的臨床前研究中，在我們的基因剔除研究中，我們發現脂肪明顯減少，而去脂體重沒有改變。

And tolerability in our preclinical studies, so far, we've never seen any evidence of diarrhea, and that includes our knockout mice. And if you think about it, the enzyme has inhibited 100% for their entire lives. And we haven't seen any diarrhea or anything like that in mice or any of the other preclinical species we've looked at.

至於耐受性，在我們的臨床前研究中，到目前為止，我們從未見過任何腹瀉的證據，這包括我們的基因敲除小鼠。如果你想一想，酵素在它們的一生中都具有 100% 的抑製作用。我們還沒有在小鼠或我們研究過的任何其他臨床前物種中發現任何腹瀉或類似情況。

So we're very excited about this agent. It's a totally new mechanism that was discovered by our gene knockout work. To our knowledge, nobody else is working on this. And we think it really addresses a lot of the current issues in terms of treatment of weight management.

所以我們對這個代理商感到非常興奮。這是我們的基因敲除工作發現的全新機制。據我們所知，沒有其他人正在從事這方面的工作。我們認為它確實解決了體重管理治療的許多當前問題。

Maybe I'll ask Craig to just throw some comments from a clinical perspective, what he views with (technical difficulty)

也許我會請克雷格從臨床角度發表一些評論，他的看法是什麼（技術難度）

I think the other important point, and Alan touched on it, but just to put a finer point on it. This enzyme is expressed really in only two tissues. It's in the apical part of the GI tract, particularly the (inaudible) and in the liver. And I think all the effects that we're seeing is really related to the weight management, and this (inaudible) brake concept, which is really driven by the gut.

我認為另一個重要的一點，艾倫也談到了，但只是為了更詳細地闡述這一點。這種酵素實際上只在兩種組織中表現。它位於胃腸道的頂端部分，特別是（聽不清楚）和肝臟。我認為我們看到的所有影響確實與體重管理有關，而這個（聽不清楚）煞車概念實際上是由腸道驅動的。

And then also some of the data that Alan has previously shared, looking at favorable effects on lipid profile and progression of plaque in the coronary arteries of susceptible animals and also in liver fat overall, I think, are indicative and reflective of the narrow distribution of the expression of this enzyme. So we're excited that it is a unique mechanism, but also one that's really tailored in the tissues, where a lot of these disease processes are taking place.

然後，艾倫之前分享的一些數據，著眼於易感動物冠狀動脈中的脂質分佈和斑塊進展以及總體肝臟脂肪的有利影響，我認為，這些數據表明並反映了該酶的表達。因此，我們很興奮，因為這是一種獨特的機制，而且是一種真正針對組織量身定制的機制，許多疾病過程都是在組織中發生的。

Roanna, you can tell that we're excited by this asset because we all want to have a say, including myself. Just commercially, of course, we don't know where the obesity weight management space will be in the years to come.

Roanna，你可以看出我們對這項資產感到興奮，因為我們都想擁有發言權，包括我自己。當然，就商業而言，我們不知道未來幾年肥胖體重管理的空間將在哪裡。

However, I think it's reasonably easy to predict that there will be combination therapies beyond the incretins. And as you know, a lot of the new medicines that are being developed are incretin based different formulations, et cetera.

然而，我認為很容易預測除了腸促胰島素之外還會有聯合療法。如您所知，許多正在開發的新藥都是基於不同配方的腸促胰島素，等等。

And other somewhat similar metabolic conditions have shown us that new mechanisms of action are always appreciated as combination therapies, diabetes being an obvious choice here. So we're pretty excited by it, and we're going to learn a lot more about the clinical development, a lot more about the biology over the coming years. And, yes, I look forward to continuing to update you all.

其他有些相似的代謝狀況向我們表明，新的作用機制總是被視為聯合療法，糖尿病是明顯的選擇。所以我們對此感到非常興奮，並且在未來幾年我們將了解更多有關臨床開發和生物學的資訊。是的，我期待繼續向大家通報最新情況。

Sounds good. Looking forward to more updates. Thanks.

聽起來不錯。期待更多更新。謝謝。

Thanks.

謝謝。

Yigal Nochomovitz, Citi.

伊格爾·諾霍莫維茨，花旗銀行。

Hey, guys. This is Ashiq Mubarack on for Yigal. Thanks for taking my question. I just wanted to ask a follow up on the last questions related to the obesity program. It sounds like on the safety front, you believe that this program might be differentiated on diarrhea. But I'm curious if you have any sense of what maybe the nausea profile might look like.

嘿，夥計們。我是阿希克·穆巴拉克 (Ashiq Mubarack)，替補伊加爾 (Yigal)。感謝您提出我的問題。我只是想跟進有關肥胖計劃的最後一個問題。聽起來在安全方面，您認為該計劃可能會在腹瀉方面有所區別。但我很好奇你是否知道噁心的情況可能會是什麼樣子。

And to the, on a similar question on safety. I think one of the things we're wondering about is that these obesity drugs seem to be, it may be necessary to dose very chronically for long periods of time. So I'm curious how long in terms of duration of therapy you've explored in these sort of preclinical models, especially on the safety side? Thanks.

關於安全方面的類似問題。我認為我們想知道的一件事是，這些肥胖藥物似乎可能需要長期長期服用。所以我很好奇您在此類臨床前模型中探索的治療持續時間有多長，特別是在安全方面？謝謝。

Right. Yes. Thanks very much. So Alan, over to you for the question on nausea and then duration of therapy, particularly from a safety perspective.

正確的。是的。非常感謝。艾倫，現在請您回答有關噁心和治療持續時間的問題，特別是從安全角度來看。

Sure, thank you. So nausea, as you probably know, that's rather difficult to look at in preclinical studies. And, but what I would say is it's important to note that the inhibition of this enzyme doesn't completely reduce the absorption of free fatty acids. What it does is it delays absorption, so that it can go further down, the fatty acids can go further down in the GI and then trigger, what Craig mentioned, the (inaudible) brake mechanism.

當然，謝謝。正如您可能知道的那樣，噁心在臨床前研究中很難觀察到。而且，但我要說的是，重要的是要注意這種酵素的抑制並不能完全減少遊離脂肪酸的吸收。它的作用是延遲吸收，這樣它就可以進一步下降，脂肪酸可以在胃腸道中進一步下降，然後觸發克雷格提到的（聽不清楚）煞車機制。

So obviously, to really look at nausea, you would have to do, we have to look to the studies in Phase 1. So far, I think most of our studies have been only about one month duration, and we'll be doing the IND enabling tox studies, which will also be one month duration in two species. But we do have plans on the preclinical side exactly as it suggested to do studies of much longer duration for three and six months.

顯然，要真正研究噁心，我們必須關注第一階段的研究。到目前為止，我認為我們的大部分研究只持續了大約一個月，我們將進行 IND 毒性研究，這對兩個物種也將持續一個月。但我們確實在臨床前方面有計劃，正如它所建議的那樣，進行持續時間更長的三到六個月的研究。

(multiple speakers) Thanks, Alan. If you allow us also, you go to elaborate a little bit more. There's also some evidence beyond our group that might suggest that nausea is not an issue, Craig, maybe you want to talk a little bit about that?

（多位發言者）謝謝，艾倫。如果您也允許，您可以再詳細說明一下。我們小組之外還有一些證據可能表明噁心不是問題，克雷格，也許你想談談這個問題？

Yes. It's a great question. And the beautiful thing is we have the knockout mouse models and the tolerability and safety of those over the life of both the mice, but also there is more recently some limited human genetics data of knockdown and knockout variance of ACSL5.

是的。這是一個很好的問題。美妙的是，我們擁有敲除小鼠模型以及小鼠一生中的耐受性和安全性，最近還有一些關於 ACSL5 敲除和敲除方差的有限人類遺傳學數據。

And those individuals seem to live a full and normal life without any issues. The only issue you see is very early in life, there is a modification of diet that is needed for the first couple of weeks. But after that, these children seem to grow on and develop normally into normal adults.

這些人似乎過著充實而正常的生活，沒有任何問題。您看到的唯一問題是在生命的早期，需要在最初幾週內調整飲食。但在那之後，這些孩子似乎會正常成長並發展成正常的成年人。

So I think we feel that both from the knockout side on with the animals and some of the human genetics that have been identified that we have something that is probably going to be able to be dosed for very, very long periods of time comfortably.

因此，我認為我們認為，從動物的淘汰方面和已確定的一些人類遺傳學來看，我們可能能夠在很長一段時間內舒適地服用藥物。

And again, as Alan said, we need to do all the long term tox in the animals and then the actual human clinical program with this particular inhibitor will need to be done. But I think we have a high degree of confidence based on what we know that they can be dosed safely for long periods of time.

正如艾倫所說，我們需要在動物身上進行所有長期毒性試驗，然後需要使用這種特定抑制劑進行實際的人體臨床計劃。但我認為，基於我們所知道的可以長期安全給藥的情況，我們有很高的信心。

Got it. That's super helpful. If I could ask one more quick one on the same topic. (inaudible) thinking about how this mechanism, if this mechanism has applicability in areas outside of diabetes, but maybe in related areas. We know that (inaudible) and diabetes as well. But, and I think more recently, some of the larger players have even talked about heart failure. I'm just wondering if this mechanism has any relevance there as well for maybe obvious reasons. Thanks.

知道了。這非常有幫助。如果我能就同一主題再問一個更快的問題。 （聽不清楚）思考這個機制如何適用，如果這個機制適用於糖尿病以外的領域，但可能適用於相關領域。我們知道這一點（聽不清楚），也知道糖尿病。但是，我認為最近一些較大的參與者甚至談到了心臟衰竭。我只是想知道這個機制是否也有任何相關性，原因可能是顯而易見的。謝謝。

Yes. The answer is yes. I could turn to Alan, where we've actually shown data in a number of metabolic conditions, as you would assume from reducing body weight and obesity. Some of it is incredibly exciting, and we're looking to present that data at medical conferences in the near future. So the short answer is yes. There's opportunity within lipidology, opportunity within other metabolic conditions as well. So looking very, very interesting mechanism here.

是的。答案是肯定的。我可以求助於艾倫，我們實際上已經展示了許多代謝條件下的數據，正如你從減輕體重和肥胖中所假設的那樣。其中一些數據非常令人興奮，我們希望在不久的將來在醫學會議上展示這些數據。所以簡短的回答是肯定的。脂質學中有機會，其他代謝條件也有機會。所以這裡看起來非常非常有趣的機制。

Got it. Thank you very much.

知道了。非常感謝。

Thanks a lot.

多謝。

This concludes our question and answer session. I would like to turn the conference back over to management for any closing remarks.

我們的問答環節到此結束。我想將會議轉交管理層發表閉幕詞。

I'd just like to thank you all for attending today's Q2 earnings call. We're incredibly pleased with the progress that has been made today. We've got a busy back half of the year and into 2025, but that provides us many, many opportunities that we're really looking forward to. So look forward to continued dialogue, and we'll speak to you all soon.

我只想感謝大家參加今天的第二季財報電話會議。我們對今天所取得的進展感到非常滿意。今年下半年到 2025 年，我們都很忙碌，但這為我們提供了許多許多我們非常期待的機會。因此，期待繼續對話，我們很快就會與大家交談。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。