Mineralys Therapeutics Inc (MLYS) 2024 Q4 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to the Mineralys fourth quarter and fourth year 2024 earnings conference call. (operator instructions) Also note that this call is being recorded on Wednesday, February 12, 2025. And I would like to turn the conference over to Dan Ferry of Lifesci Advisors. Please go ahead, sir.

女士們、先生們，早安，歡迎參加 Mineralys 2024 年第四季和第四年收益電話會議。（操作員指示）另請注意，本次通話是在 2025 年 2 月 12 日星期三錄製的。我想將會議交給 Lifesci Advisors 的 Dan Ferry。先生，請繼續。

Thank you, operator.

謝謝您，接線生。

I would like to welcome everyone joining us today for our fourth quarter and full year 2024 conference call. Earlier this morning, we issued a press release providing our fourth quarter and full year 2024 financial results and business updates. A replay of today's call will be available on the investors section of our website approximately one hour after its completion. After our prepared remarks, we will open up the call for Q&A.

我歡迎大家今天參加我們的 2024 年第四季和全年電話會議。今天早些時候，我們發布了一份新聞稿，提供了我們 2024 年第四季和全年的財務表現和業務更新。今天的電話會議重播將在會議結束後約一小時在我們網站的投資者部分提供。在我們準備好發言之後，我們將開始問答環節。

Before we begin, I would like to remind everyone that this conference call and webcast will contain forward-looking statements about the company. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in today's press release and our SEC filings, including our annual report on Form 10K and subsequent filings.

在我們開始之前，我想提醒大家，本次電話會議和網路廣播將包含有關公司的前瞻性陳述。由於公司業務相關的風險和不確定性，實際結果可能與這些前瞻性陳述所明示或暗示的結果有重大差異。這些前瞻性陳述受到今天的新聞稿和我們向美國證券交易委員會提交的文件（包括我們的 10K 表格年度報告和後續文件）中的警示性聲明的限制。

Please note that these forward-looking statements reflect our opinions only as of today, February 12, 2025, except as required by law. We specifically disclaim any obligation to update or revise these forward-looking statements in light of new information or future events.

請注意，這些前瞻性聲明僅反映我們截至 2025 年 2 月 12 日的觀點，除非法律另有規定。我們明確表示不承擔根據新資訊或未來事件更新或修改這些前瞻性聲明的義務。

I would now like to turn the call over to John Congleton, Chief Executive Officer of Mineralys Therapeutics.

現在我想將電話轉給 Mineralys Therapeutics 執行長 John Congleton。

Thank you, Dan.

謝謝你，丹。

Good morning, everyone and welcome to our 4th quarter in full year 2024 financial results and corporate conference call. I'm joined today by Adam Levy, our Chief Financial Officer, and Dr. David Rodman, our Chief Medical Officer. I'll begin with an overview of the business. Then Dave will discuss our clinical programs and recent milestones. Then Adam will review our fourth quarter financial results before we open up the call for your questions.

大家早安，歡迎參加我們 2024 年全年第四季財務業績和公司電話會議。今天與我一起出席的還有我們的財務長亞當·利維 (Adam Levy) 和首席醫療官大衛·羅德曼 (David Rodman) 博士。我先介紹一下業務概況。然後戴夫將討論我們的臨床計劃和最近的里程碑。然後，亞當將回顧我們的第四季財務業績，之後我們再開始回答您的問題。

And looking back over the past year, it was a tremendous period for the company. I'm very proud of the work our team has done in executing and supporting our clinical strategy of targeting this regulated or elevated aldosterone in patients with uncontrolled and resistant hypertension.

回顧過去的一年，對公司來說，這是輝煌的一年。我為我們的團隊在執行和支持針對不受控制和難治性高血壓患者的這種調節或升高的醛固酮的臨床策略方面所做的工作感到非常自豪。

The data for Advance-HTN will be available this coming March and Launch-HTN will be available mid-1st half of this year. We also have our exploratory programs evaluating lore that in hypertension and chronic kidney disease, as well as hypertension and obstructive sleep apnea. Our purpose at Mineralys is to create more healthy days for people dealing with cardio renal metabolic disorders, and the trial readouts we have this year will evaluate the potential of lorundrostat to deliver on that promise.

Advance-HTN 的數據將於今年 3 月公佈，而 Launch-HTN 的數據將於今年上半年公佈。我們還有探索性項目，評估高血壓和慢性腎臟病以及高血壓和阻塞性睡眠呼吸中止症的知識。Mineralys 的目標是為患有心腎代謝紊亂的人們創造更健康的日子，我們今年的試驗結果將評估 lorundrostat 兌現這一承諾的潛力。

The first of the two ongoing pivotal trials is the Advance-HTN trial that is evaluating the efficacy and safety of lorundrostat for the treatment of uncontrolled or resistant hypertension when used as an add-on therapy to a standardized background treatment of two or three antihypertensive medications. The trial enrolled 285 subjects and the rigor of the standardized American Heart Association recommended background regimen. It was designed to ensure only subjects who were enrolled had confirmed uncontrolled or confirmed resistant hypertension.

正在進行的兩項關鍵試驗中的第一項是 Advance-HTN 試驗，該試驗正在評估當 lorundrostat 作為兩種或三種抗高血壓藥物的標準化背景治療的附加療法時，治療未控製或難治性高血壓的有效性和安全性。該試驗招募了 285 名受試者，並嚴格遵循美國心臟協會建議的標準化背景治療方案。其目的是確保只有參與研究的受試者確診患有無法控制的高血壓或難治性高血壓。

As noted, we anticipate announcing the top line data for this trial next month. The second pivotal trial is Launch-HTN with 1,083 subjects enrolled and is designed to be confirmatory to our Target-HTN proof of concept trial.

如上所述，我們預計下個月公佈此次試驗的頂線數據。第二個關鍵試驗是 Launch-HTN，共有 1,083 名受試者入組，旨在驗證我們的 Target-HTN 概念驗證試驗。

The objective is to evaluate the benefit risk of lorundrostat in a real world setting when added to a subject's previously prescribed regimen of two to five antihypertensive medications, one of which must be a diuretic. As previously guided, we anticipate top line data in the mid-1st half of this year. Upon completion of the treatment phase in the advanced HTN and launch HTN trials, participating subjects were offered the opportunity to enter the transform HTN Open label extension trial.

目的是評估在現實世界中，當將 lorundrostat 添加到受試者先前開出的兩到五種抗高血壓藥物（其中一種必須是利尿劑）的方案中時，其益處和風險。正如先前的指導，我們預計今年上半年中期將出現營收數據。在完成晚期高血壓和啟動高血壓試驗的治療階段後，參與受試者將有機會進入轉化性高血壓開放標籤擴展試驗。

As we await the announcement of these pivotal topline data, I invite everyone to revisit the KOL event we held last quarter. An archived webcast is available on the investor relations section of our website. This discussion focused on the unmet medical need and uncontrolled and resistant hypertension. The long-term impact of uncontrolled blood pressure and insights into the treatment of hypertension from these leaders in cardiovascular medicine.

在我們等待這些關鍵頂線數據公佈之際，我邀請大家重溫我們上個季度舉辦的 KOL 活動。我們的網站的投資者關係部分提供了存檔的網路廣播。這次討論的重點是未滿足的醫療需求以及未控制的難治性高血壓。這些心血管醫學領域的領導者對血壓不受控制的長期影響以及對高血壓治療的見解。

In addition, during the event, the KOLs gave their perspectives on our highly selective aldosterone synthase inhibitor, lorundrostat as a new therapy and its potential to change the current treatment paradigm.

此外，在活動期間，KOL們也就我們高選擇性醛固酮合成酶抑制劑Lorundrostat作為一種新療法以及其改變現有治療模式的潛力發表了自己的看法。

To provide more color on our clinical pipeline and recent milestones, I will now turn the call over to Dave.

為了更詳細地介紹我們的臨床流程和最近的里程碑，我現在將電話轉給戴夫。

Dave.

戴夫。

Thank you, John, and good morning, everybody. Picking up from where John just left off discussing the KOL event we just had last quarter, I agree that there were a lot of great topics discussed.

謝謝你，約翰，大家早安。從約翰剛剛討論我們上個季度剛舉辦的 KOL 活動的地方開始，我同意討論了很多精彩的話題。

The clinicians did an excellent job of highlighting the need for innovation, and there was agreement that targeting aldosterone would address an important gap in the current antihypertensive armamentarium.

臨床醫生出色地強調了創新的必要性，並且一致認為針對醛固酮將解決當前抗高血壓藥物庫中的一個重要空白。

They also agreed that a confirmation of the favorable safety and blood pressure reduction of 8 millimeters to 10 millimeters of mercury we saw in the target HTN trial would be transformative for patients. Over the next few months, we look forward to sharing the data with you for the lorundrostat from both the Advance-HTN trial and Launch-HTN trials. We're excited about the potential of lorundrostat to demonstrate a meaningful benefit in patients with uncontrolled or resistant hypertension. I would like to echo John's appreciation for the work of the Mineralys team as well as the investigators and patients in both trials to advance the hypertension development plan.

他們也一致認為，我們在目標高血壓試驗中看到的良好安全性和血壓降低 8 毫米至 10 毫米汞柱的效果的確認將對患者產生變革性的影響。在接下來的幾個月裡，我們期待與您分享 Advance-HTN 試驗和 Launch-HTN 試驗中有關 lorundrostat 的數據。我們很高興看到 lorundrostat 有可能為未控製或難治性高血壓患者帶來有意義的益處。我想同意約翰對 Mineralys 團隊以及兩項試驗中的研究人員和患者為推進高血壓發展計劃所做的工作的讚賞。

We recently had some exciting news around the rest of our clinical program, including the Explore-CKD and Explore-OSA Phase 2 proof of concept trials. Both of these trials are designed to provide data that augments the anti-hypertensive profile of the lorundrostat while also providing insight into the potential benefit in reducing overall cardiovascular risk.

我們最近發布了有關其餘臨床項目的一些令人興奮的消息，包括 Explore-CKD 和 Explore-OSA 第 2 階段概念驗證試驗。這兩項試驗旨在提供增強 Lorundrostat 抗高血壓特性的數據，同時也深入了解其在降低整體心血管風險方面的潛在益處。

Last week we announced that enrollment was completed in the Explore-CKD phase 2 trial. This trial is evaluating the efficacy and safety of lorundrostat for the treatment of hypertension in subjects with an eGFR as low as 30 and Albuminuria, despite having received stable treatment with an ACEi inhibitor or an ARB, as well as an SGLT2 inhibitor.

上週我們宣布 Explore-CKD 第二階段試驗的招募工作已經完成。該試驗正在評估 lorundrostat 在治療高血壓患者（eGFR 低至 30 且有白蛋白尿）中的有效性和安全性，儘管這些患者已經接受了 ACEi 抑制劑或 ARB 以及 SGLT2 抑制劑的穩定治療。

Hypertension and associated hypertensive nephropathy is a leading cause of kidney damage alone and in combination with other obesity associated comorbidities. This is another area with great unmet medical need where aldosterone synthase inhibition with lorundrostat has the potential for transformative benefit to patients. We look forward to announcing top line data from the trial in the 2nd quarter of 2025.

高血壓和相關的高血壓腎病變是單獨或與其他肥胖相關合併症相結合導致腎臟損傷的主要原因。這是另一個存在巨大未滿足醫療需求的領域，其中使用氯崙司他抑制醛固酮合成酶有可能為患者帶來變革性的益處。我們期待在 2025 年第二季公佈該試驗的頂線數據。

In January we announced our plans for the initiation of the Explore-OSA phase 2 trial to evaluate the effect of lorundrostat in the treatment of moderate to severe obstructive sleep apnea. During the night, blood pressure increases significantly during each hypoxic episode. This leads to resistant nocturnal hypertension that is underdiagnosed and lacks a specific therapy. We are using a novel approach in this trial to measure blood pressure continuously with each heartbeat during sleep.

今年 1 月，我們宣布了啟動 Explore-OSA 第 2 期試驗的計劃，以評估 lorundrostat 在治療中度至重度阻塞性睡眠呼吸中止症方面的效果。在夜間，每次缺氧發作時血壓都會顯著升高。這會導致頑固性夜間高血壓，並且無法充分診斷和治療。我們在這次試驗中採用了一種新方法，在睡眠期間每次心跳時都會連續測量血壓。

In addition, we anticipate that dosing or lorundrostat at bedtime will maximize aldosterone suppression during the period that it is being driven by hypoxia while still providing daytime blood pressure control and the favorable safety profile achieved with once daily dosing of lorundrostat.

此外，我們預期睡前服用洛倫司他可以最大限度地抑制因缺氧引起的醛固酮分泌，同時仍能控制白天血壓，並具有每日一次服用洛倫司他所獲得的良好安全性。

It is estimated that 60% to 85% of patients with OSA have resistant hypertension. Establishing the benefit risk of lorundrostat in treating these patients could lead to the development of lorundrostat as a unique small molecule treatment for the adverse respiratory and cardiovascular manifestations of obstructive sleep apnea.

據估計，60%至85%的OSA患者患有難治性高血壓。確定洛倫司他治療這些患者的獲益風險，可以促使洛倫司他開發成為一種獨特的小分子藥物，用於治療阻塞性睡眠呼吸中止症的不良呼吸和心血管表現。

We are very excited about our programs that are designed to evaluate the value of the scat and the associated milestones expected in the first half of this year. I will now turn the call over to Adam to review our financial results for the quarter and the full year.

我們對旨在評估 scat 的價值以及今年上半年預期的相關里程碑的計劃感到非常興奮。現在我將把電話轉給亞當來回顧我們本季和全年的財務表現。

Thank you, Dave. Good morning, everyone. Today I will discuss select portions of our fourth quarter 2024 financial results. Additional details can be found in our Form 10k, which will be filed with the SEC today, February 12th.

謝謝你，戴夫。大家早安。今天，我將討論我們 2024 年第四季財務表現的部分內容。更多詳細資訊請參閱我們的 10k 表格，該表格將於 2 月 12 日（今天）提交給美國證券交易委員會 (SEC)。

We entered the quarter with cash equivalents, and investments of $198.2 million as of December 31, 2024, compared to $239 million as of December 31, 2023. We believe that our current cash equivalents, and investments will be sufficient to fund our planned clinical studies as well as support corporate operations through the first quarter of 2026. R&D expenses for the year ended December 31, 2024, were $168.6 million compared to $70.4 million for the year end of December 31, 2023. R&D expenses for the quarter end of December 31, 2024, were $44.6 million compared to $23.7 million for the quarter end of December 31, 2023.

進入本季度，我們持有的現金等價物和投資截至 2024 年 12 月 31 日為 1.982 億美元，截至 2023 年 12 月 31 日為 2.39 億美元。我們相信，我們目前的現金等價物和投資足以資助我們計劃的臨床研究，並支持到 2026 年第一季的公司營運。截至 2024 年 12 月 31 日止年度的研發費用為 1.686 億美元，截至 2023 年 12 月 31 日止年度的研發費用為 7,040 萬美元。2024 年 12 月 31 日止季度的研發費用為 4,460 萬美元，而 2023 年 12 月 31 日止季度的研發費用為 2,370 萬美元。

The annual increase in R&D expenses was primarily due to increases of $88.7 million in pre-clinical and clinical costs driven by the initiation of the lorundrostat pivotal program in the second quarter of 2023. $10.6 million in clinical supply, manufacturing, and regulatory costs. $7 million in higher compensation expense resulting from additions to headcount, increases in salaries, and accrued bonuses, and increased stock-based compensation, and $0.9 million in other research and development expenses, partially offset by a decrease of $9 million in licensing fees associated with development milestone payments in 2023 that did not recur in 2024.

研發費用的年度成長主要是由於 2023 年第二季啟動 lorundrostat 關鍵計畫導致臨床前和臨床成本增加 8,870 萬美元，以及臨床供應、製造和監管成本增加 1,060 萬美元。由於員工人數增加、工資和應計獎金增加以及股票薪酬增加，薪酬費用增加 700 萬美元，其他研發費用 90 萬美元，但與 2023 年開發里程碑付款相關的許可費減少 900 萬美元（2024 年未再次發生）部分抵消了這一增加。

G&A expenses were $23.8 million for the year end of December 31, 2024, compared to $14.3 million for the year end of December 31, 2023. G&A expenses were $7.2 million for the quarter end of December 31, 2024, compared to $4 million for the quarter end of December 31, 2023. The annual increase in G&A expenses was primarily due to $6.6 million in higher compensation expenses resulting from additions to headcount, increases in salaries and incurred bonuses, and increased stock-based compensation. $2.6 million in higher professional fees and $0.3 million in higher other administrative expenses.

截至 2024 年 12 月 31 日止年度的一般及行政費用為 2,380 萬美元，而 2023 年 12 月 31 日止年度的一般及行政費用為 1,430 萬美元。截至 2024 年 12 月 31 日止季度的一般及行政費用為 720 萬美元，而 2023 年 12 月 31 日止季度的一般及行政費用為 400 萬美元。一般及行政費用年度增加主要是因為員工人數增加、薪資和獎金增加以及股票薪酬增加導致薪酬費用增加 660 萬美元。專業費用增加 260 萬美元，其他管理費用增加 30 萬美元。

Total other income net was $14.6 million for the year ended December 31, 2024, compared to $12.8 million for the year ended December 31, 2023. Total other income net was $2.8 million for the quarter end of December 31, 2024, compared to $3.3 million for the quarter ended December 31, 2023. The annual increase was primarily attributable to increased interest earned on the company's investments in money market funds in US treasuries.

截至 2024 年 12 月 31 日止年度的其他淨收入總額為 1,460 萬美元，而截至 2023 年 12 月 31 日止年度的其他淨收入總額為 1,280 萬美元。截至 2024 年 12 月 31 日的季度，其他淨收入總額為 280 萬美元，而截至 2023 年 12 月 31 日的季度為 330 萬美元。年度成長主要歸因於該公司對美國國債貨幣市場基金的投資所賺取的利息增加。

Net loss was $177.8 million for the year ended December 30, 2024, compared to $71.9 million for the year ended December 31, 2023. That loss was $48.9 million for the quarter end of December 31, 2024, compared to $24.4 million for the quarter end of December 31, 2023. The increase was primarily attributable to the factors I described earlier. With that, I will ask the operator to open the call for questions. Operator.

截至 2024 年 12 月 30 日止年度的淨虧損為 1.778 億美元，而截至 2023 年 12 月 31 日止年度的淨虧損為 7,190 萬美元。截至 2024 年 12 月 31 日的季度虧損為 4,890 萬美元，而 2023 年 12 月 31 日的季度虧損為 2,440 萬美元。這種增長主要歸因於我之前描述的因素。接下來，我將請接線生開始電話問答。操作員。

Thank you, sir. (Operator Instructions)

謝謝您，先生。（操作員指示）

First, we will hear from Michael DiFiore at Evercore ISI. Please go ahead, Michael.

首先，我們來聽聽 Evercore ISI 的 Michael DiFiore 的發言。請繼續，邁克爾。

Hey guys, thanks so much for taking my questions and congrats on all the products, the progress. A couple for me, I guess a hypertension question in the phase two target trial when the when the QC analysis was performed on the 50 mg QD group. You took out two additional patients that had improbable readings, leaving 12 valuable patients that were truly hypertension. This seems like a very small end to extrapolate to the larger pivotal study. So I guess my question, my first question is what gives you confidence that the SBP reduction seen in these 12 patients, and these 12 patients can be extrapolated to phase 3, and then I have two follow ups.

嘿，大家好，非常感謝你們回答我的問題，並祝賀你們的所有產品和進展。對我來說，當對 50 mg QD 組進行 QC 分析時，我猜是第二階段目標試驗中的一個高血壓問題。您剔除了另外兩名讀數不太可能的患者，剩下 12 名真正患有高血壓的有價值的患者。這似乎是一個非常小的結局，無法推論出更大的關鍵研究。所以我想我的問題，我的第一個問題是，是什麼讓您有信心在這 12 名患者身上看到的收縮壓降低，並且這 12 名患者的治療可以推斷到第 3 階段，然後我有兩個後續行動。

Yeah, Mike, thanks for the call. I appreciate it. From our standpoint is we looked at both the in-office measurement as well as the 24 hour ambulatory and as you noted. When we looked at the 24 hour ambulatory, we had some subjects that actually had baseline blood pressure below goal, and so that confounded the findings a bit, but as we looked at the totality of the evidence for the 50 QD, the 100 QD, even the 25 BID looked at the exposure response, we got very Comfortable that the 50 mg QD provided what we believe is the ideal benefit risk as far as reduction in blood pressure, as well as benefit from a safety tolerability standpoint. So obviously as we moved the 50 mg into the pivotal program, it showed our confidence in that dose to provide 24-hour blood pressure control.

是的，麥克，謝謝你的來電。我很感激。從我們的角度來看，我們既查看了辦公室內的測量數據，也查看了 24 小時的門診數據，正如您所說。當我們查看 24 小時動態血壓時，我們發現有些受試者的基線血壓實際上低於目標值，因此這稍微混淆了研究結果，但是，當我們查看 50 QD、100 QD 甚至 25 BID 的全部證據並查看暴露反應時，我們非常放心，50 mg QD 提供了我們認為在降低血壓方面理想的益處因此，當我們將 50 毫克納入關鍵計劃時，顯然表明了我們對該劑量能夠提供 24 小時血壓控制的信心。

Got it. Very helpful. And then just two files for me, one on the OSA trial, one on the CKD trial. For the OSA trial, will improvement in the apnea hypotony index after four weeks be primarily due to fluid volume reduction, or would nongenomic antifibrotic effects equally contribute over that time period? And my final question is, For the CKD trial, for the SGLT2 naive patients who start their SGLT2 for the first time in the trial, to what extent may that confound SBP and or eGFR changes.

知道了。非常有幫助。然後對我來說只有兩個文件，一個關於 OSA 試驗，一個關於 CKD 試驗。對於 OSA 試驗，四周後呼吸暫停低眼壓指數的改善是否主要歸因於液體量的減少，還是非基因組抗纖維化作用在該時間段內是否同樣有貢獻？我的最後一個問題是，對於 CKD 試驗，對於在試驗中首次開始使用 SGLT2 的 SGLT2 初治患者，這在多大程度上會混淆 SBP 和/或 eGFR 變化。

Thank you.

謝謝。

Okay, why don't I take that one. This is Dave Brodman. Thanks for the call, for the questions, and so I'm going to take the The first of those two questions, which was an OSA question.

好的，我為什麼不選擇這個呢？這是戴夫·布羅德曼。感謝您的來電和提問，所以我將回答這兩個問題中的第一個，這是 OSA 問題。

And oh wait a minute, did you want me to do, yeah, so the OSA question and your question there was about the apnea hypoxia index and what the mechanism is. So, as first of all that when you in two small trials with both spironolactone and eplerenone. The apnea hypoxia index was reduced on a pretty short-term study like two weeks to four weeks by 50%, which is pretty dramatic. We anticipate being at least as good as that with our mechanism and it may be mediated by both the decrease in MR activation and nongenomic effects. But when we look at the mechanism with MR, it's volume shifts.

哦，等一下，你想讓我做嗎，是的，所以 OSA 問題和你的問題是關於呼吸暫停缺氧指數以及其機制是什麼。因此，首先，當您對螺內酯和依普利酮進行兩次小規模試驗時。在兩週到四周的短期研究中，呼吸暫停缺氧指數降低了 50%，這是相當顯著的。我們預計我們的機制至少會達到相同的效果，並且它可能由 MR 活化的減少和非基因組效應介導。但當我們觀察 MR 的機制時，就會發現它的體積改變了。

In other words, there's something called rostrocaudal redistribution of fluid. These patients will have edema in their legs. When they lay down, that fluid will redistribute horizontally and caudally towards the head and their neck, which is already obstructed with usually with fat tissue, will then become even more obstructed. So you're right, that mechanism's volume and the combination of a diuretic plus lorundrostat should dramatically decrease that effect.

換句話說，存在著一種叫做體液沿著喙尾方向重新分佈的現象。這些患者的腿部會出現水腫。當他們躺下時，液體會水平向尾部重新分佈到頭部和頸部，而頸部已經被脂肪組織阻塞，阻塞會變得更加嚴重。所以你是對的，該機制的容量以及利尿劑和氯崙司他的組合應該會顯著降低這種影響。

Now you asked about non-genomic effects. The answer there is yes, but not fibrosis. It's inflammation most likely. So if there is a contribution, it'll be related to the genomic effects on inflammation, but also the effects on oxygen radical production in small vessels, which is non-genomic.

現在您詢問的是非基因組效應。答案是肯定的，但不是纖維化。最有可能的是發炎。因此，如果有貢獻，它將與基因組對發炎的影響有關，也與對小血管中氧自由基產生的影響有關，這是非基因組的。

Does that answer that question?

這回答了那個問題嗎？

Yes, it does.

是的。

Thank you.

謝謝。

Now SGLT2 inhibitor, we know that SGLT2 inhibitors in combination with an ASI do have some theoretical and practical advantages. I would say one of them is those are modest anti-hypertensive drugs, and it's possible that there will be some additivity between the two mechanisms. In addition, there is some loss of potassium that you have with the SGLT2 inhibitor. The three weeks as the run-in period in this trial is sufficiently long for most of those effects to already be manifest by the time that we start the drug.

現在對於 SGLT2 抑制劑，我們知道 SGLT2 抑制劑與 ASI 聯合使用確實具有一些理論和實踐優勢。我想說其中之一就是這些都是適度的抗高血壓藥物，兩種機制之間可能會有一些附加作用。此外，服用 SGLT2 抑制劑也會導致鉀的流失。本試驗的三週磨合期足夠長，以至於大多數效果在我們開始用藥時就已經顯現出來。

In addition, it's a crossover study where the in the first period, the placebo people will have that same effect. So, it's built in that we can assess exactly the effect that you are discussing, know what it is, and have a sensitivity analysis to address that possibility.

此外，這是一項交叉研究，在第一階段，服用安慰劑的人也會有同樣的效果。因此，我們可以準確評估您正在討論的影響，了解它是什麼，並進行敏感度分析來解決這種可能性。

Very helpful.

非常有幫助。

Thank you.

謝謝。

Thanks bye.

謝謝再見。

Thank you.

謝謝。

Next question will be from Rich Law at Goldman Sachs. Please go ahead, Rich.

下一個問題來自高盛的 Rich Law。請繼續，Rich。

Hey guys, good morning. Yeah, a couple of questions for me. Given your guidance for events and launch, read our timelines overlap with each other. Is there more refined guidance now, on your base case of when, each of those will be presented? First, can we assume that events will go first before launch, or is there a chance that both can go together? And then I'll follow up with that.

大家好，早安。是的，我有幾個問題。鑑於您對活動和發布的指導，請閱讀我們的時間表相互重疊。現在是否有更完善的指導，根據您的基本情況，何時會提出這些指導？首先，我們可以假設活動會在發布之前先進行，還是兩者可以同時進行？然後我會跟進此事。

Yeah, Rich, thanks for the question. As we noted in our opening remarks, we're continuing to guide Advance-HTN for March and Launch-HTN for mid first half of this year.

是的，Rich，謝謝你的提問。正如我們在開場白中提到的那樣，我們將繼續指導 3 月的 Advance-HTN 和今年上半年中期的 Launch-HTN。

Okay, got it. And then for events, I know you potentially could present that twice, one for like a top line webinar and one at ACC. Do you see something similar for Launch?

好的，明白了。至於活動，我知道您可能會展示兩次，一次是在頂級網路研討會上，一次是在 ACC。您是否發現 Launch 也存在類似的情況？

Yeah, we're certainly excited about the acceptance of the late breaking abstract for lorundrostat in the Advance-HTN trial at the upcoming ACC meeting, depending upon when we get the top line results, we'll either do a corporate announcement in conjunction with that, or if we have the results sooner than that, we would anticipate doing a corporate top line announcement, as to launch. I think it's too early to opine on what the communications would look like with that trial.

是的，我們非常高興在即將舉行的 ACC 會議上接受了 Advance-HTN 試驗中關於 lorundrostat 的最新摘要，根據我們何時獲得頂線結果，我們將同時發佈公司公告，或者如果我們在此之前獲得結果，我們預計將在發佈時發佈公司頂線公告。我認為現在就評論該試驗的溝通情況還為時過早。

Got it. And then, one final question. So the advanced trial actively tracks and enforce adherence of the treatment, but what do you expect for the compliance for patients wearing the ABPM device for that whole 24-hour period? Like, have you seen any issues of patients like taking off the device for a long period of time that could affect results? And then our patients like required not to do certain activities while wearing the device like like exercise or stuff like that.

知道了。然後，最後一個問題。因此，進階試驗會積極追蹤並強制執行治療依從性，但您對在整個 24 小時內佩戴 ABPM 設備的患者的依從性有何期望？例如，您是否看過患者出現長時間摘下設備等可能影響治療結果的問題？然後，我們的患者被要求在佩戴該設備時不要進行某些活動，例如運動或類似的活動。

Yeah, thanks.

是的，謝謝。

We, I'm glad that the team made the choice with Target-HTN to not only do the in-office measurement but the 24-hour ambulatory. It gave us as a team experience with the device, with the vendor. We're working with the same vendor and technology and Advance-HTN, so we've got that past experience as far as. How to use that device, how to teach and train sites and subjects on proper technique with that.

我們很高興團隊選擇了 Target-HTN，不僅進行辦公室內測量，還進行 24 小時門診測量。它讓我們作為一個團隊與設備和供應商有了共同的經驗。我們與 Advance-HTN 和同一家供應商合作，使用相同的技術，因此我們擁有過去的經驗。如何使用該設備，如何教授和培訓站點和主題正確的技術。

We do allow subjects when they either exercise or bathe to have breaks from that their compliance or QC requirements with the 24-hour ambulatory where we have to get a certain percentage of the, I think it's roughly 70 measurements over a 24-hour period.

我們確實允許受試者在運動或洗澡時休息一下，以遵守 24 小時動態監測的合規性或品質控制要求，我們必須獲得一定比例的測量數據，我認為在 24 小時內大約需要進行 70 次測量。

So we're very confident that we have sites and subjects well trained for that, and the experience that our team has in working with that device gives us high comfort in the data and the quality of the data that we're going to get from that. And that's why we chose 24-hour ambulatory, which, as is the gold standard, and in a trial as rigorous as Advance-HTN where we are optimizing treatment, optimizing dose, optimizing compliance, using the gold standard. Really gives us, I think, a high quality data set, particularly relative to what's been done with new innovations in this space and what's being done with other ASIs.

因此，我們非常有信心，我們擁有經過良好培訓的站點和受試者，並且我們的團隊在使用該設備方面的經驗使我們對從中獲得的數據和數據品質非常放心。這就是為什麼我們選擇 24 小時門診，它是黃金標準，並且在像 Advance-HTN 這樣嚴格的試驗中，我們使用黃金標準來優化治療、優化劑量、優化依從性。我認為，它確實為我們提供了高品質的數據集，特別是相對於該領域的新創新以及其他 ASI 所做的事情而言。

Dave had one?

戴夫有一個嗎？

Yeah, hey Rich, that's a great question. It's key to have as much good data from the primary as you can.

是的，嘿，Rich，這是一個很好的問題。關鍵是要盡可能從主資料庫中取得優質資料。

You'll never have it perfect with ABPM. But we went through the QC and the procedures as a root cause for losing data in the first trial, and we identified several ways to improve retention of informative data from those studies. We did lots of work on statistics and we're confident that we're going to have more than adequate good quality data to have the power that we imputed when we designed the size of the trial.

使用 ABPM 你永遠不可能獲得完美的結果。但是，我們認為品質控制和程序是第一次試驗中丟失資料的根本原因，我們確定了幾種方法來提高這些研究中資訊資料的保留率。我們在統計方面做了大量工作，我們相信我們將擁有足夠的高品質數據，以實現我們在設計試驗規模時所推斷的功效。

Great. And then just to follow up on that, is there any, what's the plan for like any missing data if patients take off the device and then for like say a couple of hours and then what's the plan for that?

偉大的。然後只是為了跟進這一點，如果患者摘下設備然後比如說幾個小時，那麼是否有任何丟失數據的計劃，那麼對此的計劃是什麼？

Rich, that was part of the root cause analysis. We've got that built into the algorithms. We went over it with the FDA they approve it.

里奇，這是根本原因分析的一部分。我們已經將其融入演算法中。我們與 FDA 進行了討論，他們批准了。

Okay, thank you so much.

好的，非常感謝。

Thanks, Rich.

謝謝，里奇。

Next question will be from Charlie Yang at Bank of America. Please go ahead, Charlie.

下一個問題來自美國銀行的 Charlie Yang。請繼續，查理。

Hi, this is Alice on for Charlie.

大家好，我是 Alice，為 Charlie 服務。

Thank you for taking our questions.

感謝您回答我們的問題。

So, just on the upcoming pivotal readouts, what are your latest expectations around safety and tolerability? Where do you hope to differentiate most versus typical MRAs? And even if efficacy were to be slightly less than MRAs, for example, wouldn't a cleaner drug still be a commercial winner?

那麼，就即將發布的關鍵數據而言，您對安全性和耐受性的最新期望是什麼？您希望在哪些方面將大多數 MRA 與典型的 MRA 區分開來？例如，即使療效略低於 MRA，更清潔的藥物是否仍會成為商業贏家？

Thank you.

謝謝。

Yeah, thanks for the question. I think it's important to continue to distinguish the aldosterone synthase inhibitor class from the mineralocorticoid receptor antagonist. The MRAs block the effect of aldosterone at one of the biological pathways that aldosterone affects, and that's the mineralocorticoid receptor. aldosterone synthase inhibitors, however, go to the root cause of the problem and actually reduce the amount of plasma aldosterone.

是的，謝謝你的提問。我認為繼續區分醛固酮合成酶抑制劑類和鹽皮質激素受體拮抗劑非常重要。MRA 阻斷醛固酮在醛固酮影響的生物途徑之一即鹽皮質激素受體上的作用。然而，醛固酮合成酶抑制劑找到了問題的根本原因，並真正減少了血漿醛固酮的含量。

The benefit of that is not only how aldosterone can be its effects mitigated at the mineralocorticoid receptor, but also at other pathways such as GPR30 that affects fibrosis, inflammation, and oxidative stress. So as such, the adverse events that are attributable, particularly for sperm lactone on blockade of MRAs, such as the androgenic effects such as gynecomastia and fertility issues with women. Something we don't see with this class of drugs.

這樣做的好處不僅在於可以減輕醛固酮在鹽皮質激素受體上的作用，還在於可以減輕影響纖維化、發炎和氧化壓力的其他途徑，如 GPR30。因此，可歸因於不良事件，特別是精子內酯阻斷 MRA 引起的不良事件，例如雄性激素作用，如男性女乳症和女性生育問題。我們在這類藥物中沒有看到這種情況。

I think it's also fairly well accepted that the mineralocorticoid receptor antagonists seem to have a compromised tradeoff that as you push those to get to efficacy, you invariably see a push in hyperkalemia.

我認為，人們普遍接受的觀點是，鹽皮質激素受體拮抗劑似乎存在一種折衷的權衡，即當你推動它們達到療效時，你必然會看到高血鉀的增加。

From our perspective, we think there's a more modest impact on potassium with an aldosterone and synthase inhibitor. It's something that was exhibited in Target-HTN. And so, we'll continue to evaluate that in the pivot program, but we believe that is the key distinguishing factor relative to the MRAs. I'll have Dave at a thought as well.

從我們的角度來看，我們認為醛固酮和合成酶抑制劑對鉀的影響較為溫和。這是在 Target-HTN 展出的東西。因此，我們將繼續在樞紐計劃中對此進行評估，但我們認為這是與 MRA 相關的關鍵區別因素。我也會讓戴夫考慮一下。

Yeah, so we, obviously everyone thinks about this a lot. I want to point out something about just the trial designs. When you say how are we going to compare to say MRA, as far as I know, no one's ever done a trial like our advanced trial. As rigorously to deliver the data we're going to have with advance. In other words, we're looking at confirmed you failed on two or three drugs at maximum doses. You took the drug and then we used 24-hour ambulatory to prove it.

是的，顯然我們每個人都對此考慮很多。我想指出一些關於試驗設計的事情。當您說我們如何與 MRA 進行比較時，據我所知，還沒有人做過像我們的高級試驗這樣的試驗。我們會盡可能嚴格地提前提供數據。換句話說，我們正在確認您以最大劑量服用兩種或三種藥物後仍然無效。您服用了該藥物，然後我們使用 24 小時門診來證明這一點。

So there is no benchmark. If you, the Launch trial is the closest thing to a benchmark, and so what I encourage you to do is look at these trials as they stand alone. These will be, especially the Advanced trial, but also Launch definitive establishment of the point estimate for how good these drugs are.

所以沒有基準。如果您認為啟動試驗是最接近基準的，因此我鼓勵您單獨地看待這些試驗。這些將是，特別是高級試驗，但也會啟動對這些藥物的療效的點估計的最終建立。

Thank you.

謝謝。

Thank you.

謝謝。

Next will be Annabelle Sammy at Stifel. Please go ahead.

接下來是 Stifel 的 Annabelle Sammy。請繼續。

Hi, thanks for taking my questions. Just to put things in perspective again, can you remind us what coverage payers could give you if you hit in specific ranges like, 7 to 9, 8 to10 over 10, as you did, just in the various subpopulations. So can you help us frame how payers are going to look at the different responses and where they can position you within the treatment paradigm, and then I have a follow up.

你好，謝謝你回答我的問題。為了再次說明情況，您能否提醒我們，如果您達到特定範圍，例如 7 到 9、8 到 10 以上的保險金額，那麼保險支付者可以為您提供什麼樣的保障，就像您在不同的亞群中所做的那樣。那麼，您能否幫助我們建立付款人如何看待不同的反應以及他們可以在治療範式中定位您，然後我再進行跟進。

Yeah, Annabelle, thanks for the call.

是的，安娜貝爾，謝謝你的來電。

We have to date completed four separate payer research projects in the United States and feel very bullish about our ability to get access for lorundrostat and particularly in our targeted approach. We have basically put forward a base case of an 8 millimeter to 10 millimeter mercury improvement that's well tolerated. And typically fourth line, we think that's a space we can own. So in that resistant population, particularly as Dave highlighted with the prior answer with Advance-HTN, frankly being one of the most rigorous, if not most rigorous study ever done, that kind of data set we believe based on the research gives us an opportunity to really own the resistant hypertension space. And then as we look at third line, and this is what we put in front of payers as well, when we bring forward a patient type or an endo phenotype of a responder such as those with a BMI over 30, so that more targeted approach that is viewed favorably by payers as well with that 8 millimeter to 10 millimeter mercury improvement. Now all of this obviously [Nel] is going to be based on.

到目前為止，我們已經在美國完成了四個獨立的付款人研究項目，並且對我們獲得 lorundrostat 的能力非常有信心，特別是透過我們的有針對性的方法。我們基本上提出了一個基本方案，即 8 毫米到 10 毫米汞柱的改進，這是可以接受的。通常是第四行，我們認為這是我們可以擁有的空間。因此，在難治性高血壓人群中，特別是像 Dave 在先前關於 Advance-HTN 的回答中所強調的那樣，坦率地說，這是有史以​​來最嚴格的研究之一（如果不是最嚴格的研究），我們相信基於研究的數據集讓我們有機會真正擁有難治性高血壓領域。然後，當我們看第三行時，這也是我們擺在付款人面前的，當我們提出患者類型或反應者的內鏡表型（例如 BMI 超過 30 的患者）時，因此，付款人也會對更有針對性的方法持歡迎態度，因為血壓會從 8 毫米汞柱改善到 10 毫米汞柱。現在，這一切顯然都是 [Nel] 所要依據的。

Also the pricing and the rebate strategy within that, but just that clinical profile has resonated with the payers in that resistant population and targeted third line.

其中還包括定價和回扣策略，但僅僅是臨床概況就引起了抗藥性族群和目標第三線付款人的共鳴。

Okay, and then I guess can you remind us the proportion of the population that are, truly The 3rd, 4th line population, how does each of those different, I guess, how does that position change your opportunity within the different populations that you have?

好的，然後我想您能否提醒我們真正的第三、第四線人口的人口比例，他們每個人有何不同，我想，這個位置如何改變您在不同人群中的機會？

Yeah, it's, I think the resistant populations, so those failing on 3 or more with the diuretic is a little bit more easy to Quantify it it's typically seen as about 10% to 15% of the treated population, so roughly 7.5 million to 10 million subjects are in that resistant hypertension category.

是的，我認為難治性高血壓人群，即使用 3 種或以上利尿劑仍無效的人群，更容易量化，通常佔接受治療人群的 10% 到 15%，因此大約有 750 萬到 1000 萬受試者屬於難治性高血壓類別。

Those that would be third line, so failing on two or more is a little bit difficult to triangulate to with the data, but ballpark we view that population is about 10 million as well. So collectively between those that are failing on two or those that are failing on three or more, it's roughly, 15 million to 20 million, I would say as an addressable market.

那些將是第三線，因此在兩個或兩個以上方面失敗有點難以用數據進行三角測量，但大致上我們認為人口也在 1000 萬左右。因此，我認為，在兩項或三項以上業務上失敗的企業加起來，可尋址市場規模約為 1500 萬到 2000 萬。

Okay, great. All right, thank you, that was great helpful.

好的，太好了。好的，謝謝，這很有幫助。

Thanks Annabelle.

謝謝安娜貝爾。

Next question will be from Seamus Fernandez at Guggenheim. Please go ahead.

下一個問題來自古根漢美術館的謝默斯‧費爾南德斯 (Seamus Fernandez)。請繼續。

Hi, it's Colleen on for Seamus. Thanks for taking our question. Could you just talk a little bit of where you view the threshold for hyperkalemia rates in Advance and Launch, and what needs to be shown there to be differentiated in the clinic, and then just how would you expect the addition of diuretics, required in every patient to impact the rates for what we saw on Target?

大家好，我是 Colleen，代替 Seamus 發言。感謝您回答我們的問題。您能否簡單談談您認為 Advance 和 Launch 中高血鉀發生率的閾值在哪裡，以及需要在臨床中證明什麼才能進行區分，然後您認為每個患者都需要添加利尿劑，這會對我們在 Target 上看到的高鉀血症發生率產生什麼影響？

Thanks, Colleen.

謝謝，科琳。

We've done a, as I said, a significant amount of pay research. We've also done a significant amount of physician research over the last several years.

正如我所說，我們做了大量的薪酬研究。在過去的幾年裡，我們也做了大量的醫生研究。

5% or less is what we've always tested as a rate of hyperkalemia as part of a base case, and I think that's viewed as favorable by the physicians that we've done the research with. As you may recall, we saw about a 3.6% rate in Target-HTN.

5% 或更低是我們一直以來作為基準病例測試的高鉀血症發生率，我認為與我們一起進行研究的醫生都認為這是有利的。您可能還記得，我們​​看到 Target-HTN 的利率約為 3.6%。

To your point, there is a belief that the use of a diuretic can be potassium wasting, so could offset the modest rise that we know we see with aldosterone synthase inhibitors. We saw that with lorundrostat, saw that with Baxdrostat, and on par with what you typically see with an ACE inhibitor. Or an ARB that have been used safely for decades at this point.

正如您所說，人們認為使用利尿劑會導致鉀流失，因此可以抵消我們所知的醛固酮合成酶抑制劑的適度上升。我們在 lorundrostat 和 Baxdrostat 中都看到了這種現象，並且與通常在 ACE 抑制劑中看到的情況相當。或目前已安全使用了數十年的 ARB。

So I think that'll be an interesting addition to the pivotal program where all subjects in both studies are on a diuretic and in Target-HTN where we saw that modest impact, only half of the subjects were on a diuretic because it wasn't required for protocol. Let me have Dave add a comment on top of that, Colleen.

因此，我認為這將是關鍵項目的一個有趣的補充，在這兩項研究中的所有受試者都服用利尿劑，而在 Target-HTN 中，我們看到了適度的影響，只有一半的受試者服用利尿劑，因為這不是協議所要求的。科琳，讓我讓戴夫對此添加一條評論。

Yeah, I'm going to give you a clinician perspective, and we hear this all the time.

是的，我將從臨床醫生的角度來告訴您，我們經常聽到這種說法。

This is about benefit risk. The FDA has told us that it's not p-values. It's nothing. It's really what's the benefit and what's the risk. And what that means is the bigger the blood pressure response, the more tolerance there is for changes like potassium and what that means for us is that we are looking at both.

這是關於利益風險的。FDA 告訴我們這不是 p 值。沒什麼。這實際上意味著好處和風險。這意味著血壓反應越大，對鉀等變化的耐受性就越大，對我們來說，這意味著我們要同時專注於兩者。

When you ask about the thiazides, they lower potassium, ensuring that people are taking their thiazides improves benefit risk both by increasing the response and decreasing the potassium. So think about it that way. It's benefit risk for the worst patients, the ones with CKD. The clinicians uniformly say we have great potassium binders. What we don't have are great antihypertensives, and so they're willing to tolerate almost any level of hyperkalemia and just treat it to get the maximum blood pressure response to lorundrostat is the feedback we get.

當您詢問噻嗪類藥物時，它們會降低鉀，確保人們服用噻嗪類藥物可以增加反應和降低鉀來改善效益風險。所以就這樣想吧。對於病情最嚴重的 CKD 患者來說，這是一種獲益風險。臨床醫生一致認為我們擁有優秀的鉀結合劑。我們沒有很好的抗高血壓藥物，所以他們願意容忍幾乎任何程度的高鉀血症，並對其進行治療以獲得對 lorundrostat 的最大血壓反應，這是我們得到的反饋。

Great, thank you.

太好了，謝謝。

Thank you.

謝謝。

Next question will be from Mohit Bansal at Wells Fargo. Please go ahead.

下一個問題來自富國銀行的 Mohit Bansal。請繼續。

Great, thank you very much for taking my questions. So like I have a couple of questions, so I'll start with first, do you think we'll see meaningful differences in the placebo adjusted results in terms of ABPM versus AOBP?

太好了，非常感謝您回答我的問題。所以我有幾個問題，所以我首先要問的是，您認為我們會在 ABPM 與 AOBP 的安慰劑調整結果中看到有意義的差異嗎？

And then like how do you think this, whatever, office reader, reading is for from advanced STN could read to Launch-HTN where office reading is the, is the primary endpoint, and I want to follow up.

然後就像您認為這如何，無論如何，辦公室閱讀器，閱讀是從高級 STN 可以讀取到 Launch-HTN，其中辦公室閱讀是主要終點，我想跟進。

Hey Mohit, I got your first question. Can you repeat your second one though? I'm sorry, there was a little bit of a breakup in the line.

嘿 Mohit，我收到了你的第一個問題。你能重複第二個嗎？很抱歉，通話稍微中斷了。

Sorry about that. So, what I'm saying is that, so from Advance-HTN, whatever you see in office blood pressure reduction, how much you could read that for what is the read across for Launch-HTN because Launch-HTN has AOBP as the primary endpoint.

很抱歉。所以，我的意思是，從 Advance-HTN 來看，無論您在辦公室血壓降低多少，您都可以從中讀出 Launch-HTN 的讀數，因為 Launch-HTN 以 AOBP 為主要終點。

Yeah, I, okay, thank you for clarifying that. What we saw in Target-HTN was about a four millimeter mercury change in the in-office measurement and in the 24 hour ambulatory, about a one millimeter to two millimeter mercury placebo change, so fairly tight concordance. I think it's a tribute to the team, the work they did to. Aligned to the AHA recommended best practices in measuring blood pressure, we've applied those same techniques for in-office measurement for both Advanced as well as Launch. I'd hate to opine on, are we going to see a replication of that? What's the read through from Advanced to Launch?

是的，好的，謝謝你澄清這一點。我們在 Target-HTN 中看到的是，辦公室測量值變化了大約 4 毫米汞柱，而 24 小時門診測量值變化了大約 1 毫米到 2 毫米汞柱的安慰劑變化，因此一致性相當嚴格。我認為這是對團隊及其所做工作的致敬。根據 AHA 建議的血壓測量最佳實踐，我們將相同的技術應用於 Advanced 和 Launch 的辦公室內測量。我不想發表意見，我們會看到這種事情的重演嗎？從進階到啟動的讀取過程是怎麼樣的？

There are different studies, but it's the same technology, the same technique, the training that we've done with the sites. So it's difficult to, project what it could be. I just think the team has, made the right choices as far as technology and technique that was validated and Target-HTN and that's what we're applying in Advance and Launch.

雖然有不同的研究，但採用的是相同的技術、相同的技巧以及我們在這些站點進行的培訓。因此很難預測它到底是什麼。我只是認為團隊在經過驗證的技術和技巧以及 Target-HTN 方面做出了正確的選擇，而這正是我們在 Advance 和 Launch 中應用的。

No, fair enough. That's helpful. And then the second part is that how are you thinking about the nighttime coverage with lorundrostat? The reason I'm asking is because half life is shorter here. So do you think the timing of the dose could impact the ABPM measure more than the AOBP here?

不，很公平。這很有幫助。第二部分是，您如何看待 lorundrostat 的夜間覆蓋範圍？我之所以問這個問題是因為這裡的半衰期較短。那麼，您是否認為服藥時間對 ABPM 測量的影響比對 AOBP 的影響更大？

Yeah, let me, I'll have Dave give a comment to this. I think it's important to reiterate that we think the 10 to 12 hour half-life of lorundrostat is actually ideal for, as Dave articulated earlier, the benefit risk of an ASI in the treatment of hypertension.

是的，我會讓戴夫對此發表評論。我認為有必要重申，我們認為 lorundrostat 的 10 到 12 小時半衰期實際上是理想的，正如 Dave 之前所闡述的，ASI 在治療高血壓方面的益處風險。

I'll reiterate that in Target-HTN where we saw that 8 to 10 millimeter mercury drop in in office measurement, that blood pressure measurement was in the morning at [drop] before that day's dose. So we have strong confidence in the 24 hour coverage of the lorundrostat with that 10 to 12 hour half-life. We also think it provides the ideal mix of efficacy and safety, particularly the on-target component, which is potassium and sodium.

我要重申的是，在 Target-HTN 中，我們看到辦公室測量中的血壓下降了 8 到 10 毫米汞柱，血壓測量是在當天服藥前的早晨[下降]。因此，我們對半衰期為 10 至 12 小時的 lorundrostat 的 24 小時覆蓋範圍充滿信心。我們也認為它提供了功效和安全性的理想組合，特別是目標成分，即鉀和鈉。

But Dave, do you want to add some thoughts on top of that?

但是戴夫，你想在此基礎上補充一些想法嗎？

Well, I can just add a little bit, as John said.

好吧，正如約翰所說，我只能補充一點。

We know from Novartis, and I was there that a 4 hour half-life isn't long enough. We also believe that leaving a window that recapitulates normal circadian rhythm when [aldo] does go up pre-arousal is the best way to try to treat it, restore the normal rhythm. We have 100% by our healthy volunteer study, suppression of [aldo]. With our drug we can adjust how long that 100% lasts. And so just to reiterate that last point for John, we tune that so that it's 100% for until you go to sleep essentially and that it slowly comes up to only 30% of pre-treatment baseline, which is 70% suppression and then goes back down to zero again after the morning dose. We just think that's Science based on what we know about circadian rhythm and it's the most appropriate way to treat this disorder.

我們從諾華公司了解到，而且我當時也在那裡，4 小時的半衰期是不夠長的。我們也認為，當 [aldo] 在喚醒前升高時，留下一個重現正常晝夜節律的視窗是嘗試治療、恢復正常節律的最佳方法。我們透過健康志願者研究，100% 抑制[阿爾多]。利用我們的藥物，我們可以調整 100% 的持續時間。因此，為了向約翰重申最後一點，我們對其進行了調整，使其基本上一直保持 100%，直到您入睡，然後慢慢上升到治療前基線的 30%，即 70% 的抑制，然後在早晨服藥後再次降至零。我們只是認為這是基於我們對晝夜節律的了解的科學，也是治療這種疾病最適合的方法。

Awesome.

驚人的。

Thank you very much for this. Appreciate.

非常感謝您。欣賞。

Thanks, Mohit.

謝謝，Mohit。

Next question will be from Rami Katkhuda at LifeSci Capital. Please go ahead.

下一個問題來自 LifeSci Capital 的 Rami Katkhuda。請繼續。

Good morning, guys. Thanks for taking my questions. Maybe going off a previous one, do you expect to delt in the treatment effects observed with lorundrostat in the pivotal studies, just given the slight difference between trials and the fact that patients in advance are potentially enriched with aldosterone-driven hypertension, then I have a follow up.

大家早安。感謝您回答我的問題。也許從先前的例子來看，您是否希望在關鍵研究中處理 lorundrostat 觀察到的治療效果，只是考慮到試驗之間的細微差異以及提前治療的患者可能患有醛固酮驅動的高血壓這一事實，然後我會進行跟進。

Yeah, Ray, thanks for the question. I think it's hard to predict, the response in advance, the response in launch and a differential. There are different studies as you've heard Dave articulate, I think the interesting aspect of Advance is that we have a truly confirmed uncontrolled or resistant hypertension population. On the one hand, that may be a more rigorous, challenging population to treat. On the other, it may be somewhat enriched for an aldosterone dependent form of hypertension.

是的，雷，謝謝你的提問。我認為這很難預測，提前的反應，發佈時的反應和差異。正如您所聽到的 Dave 所闡述的，有不同的研究，我認為 Advance 的有趣之處在於我們有一個真正被證實的不受控製或難治性高血壓人群。一方面，這類患者的治療可能更為嚴格，更具挑戰性。另一方面，它可能對醛固酮依賴型高血壓有一定幫助。

Launch is largely confirmatory to what we saw or what we designed and Target-HTN with the exception of all subjects and Launch, you're going to be on the diuretic, and we know there was a favorable synergy as far as more enhanced response there, so. It's difficult to predict across these two trials, we're just excited about the design of these two, I think they address key aspects of the market. Advance being as rigorous as it is really built for the specialists that are dealing with the difficult to treat patients. It's also the kind of study that gives us the opportunity to be included in the hypertension guidelines and then launches the real world setting of what the primary care physicians are going to be doing with the run that should we be able to bring it into the marketplace.

Launch 在很大程度上證實了我們所看到的或我們所設計的，並且除了所有受試者和 Launch 之外，Target-HTN 都將使用利尿劑，並且我們知道就增強的反應而言存在有利的協同作用，所以。很難預測這兩個試驗的結果，我們只是對它們的設計感到興奮，我認為它們解決了市場的關鍵方面。它的先進性和嚴謹性確實是為那些治療難治病人的專家而打造。這項研究也使我們有機會被納入高血壓指南，然後啟動現實世界的環境，看看初級保健醫生將如何進行這項工作，以便我們能夠將其推向市場。

Got it. Makes sense. And then a recent paper detailed that [BI's] aldosterone synthase inhibitor has a half life of 4 to 6 hours, which is lower than what we've seen with lorundrostat and Baxdrostat, I guess. Does this affect how you view their CKD data at all and render stats, I guess overall positioning in that population.

知道了。有道理。然後最近的一篇論文詳細說明了 [BI] 醛固酮合成酶抑制劑的半衰期為 4 到 6 小時，我猜比我們看到的 lorundrostat 和 Baxdrostat 要短。這是否會影響您如何查看他們的 CKD 數據和呈現統計數據，我猜是影響該群體的整體定位。

Well, that's a very good question, and it is reminiscent of what happened with LCI699 Osilodrostat, which is pretty much the same half-life. And if you read the papers that were written, it was recommended that a longer half-life would be required to develop a maximally efficacious dose. We agree with that. We are targeting in CKD the subset of patients who mainly have not enough control of their blood pressure, which is damaging their glomeruli, scarring them every day and driving the deterioration in eGFR. If you don't treat that adequately, get it down to gold, you will continue to have progression of the CKD.

嗯，這是一個非常好的問題，它讓人想起 LCI699 Osilodrostat 發生的情況，它們的半衰期幾乎相同。如果你讀過相關論文，你會發現其中建議需要更長的半衰期才能達到最大有效劑量。我們同意這一點。我們針對的是 CKD 患者，他們主要無法充分控制自己的血壓，這會損害他們的腎小球，使他們每天都留下疤痕，並導致 eGFR 惡化。如果您沒有充分治療，那麼 CKD 的病情將會持續惡化。

So at least with our drug, with our tunable suppression in that disease. And you'll remember we're testing 25 mg in that group, although it can be escalated in the real world. We have an optimum way to do that. I don't want to comment on somebody else's drug in their program. They probably know more than I do, but we like our approach. We also like the fact that we can add it on to an SGLT2 of choice, which we think may also be an advantage when you're mainly going after the hypertension. And not using the combination for the metabolic syndrome component mainly.

因此，至少我們的藥物可以對該疾病進行可調節的抑制。您會記得，我們​​在該組中測試了 25 毫克，儘管在現實世界中它可能會升級。我們有最佳方法來做到這一點。我不想評論別人在他們的計劃中使用的藥物。他們可能比我知道的更多，但我們喜歡我們的方法。我們也喜歡將其添加到選擇的 SGLT2 中，我們認為當您主要治療高血壓時這也可能是一個優勢。且不主要針對代謝症候群成分使用該組合。

Awesome thanks so much.

太棒了，非常感謝。

Thanks.

謝謝。

Next question will be from Matthew Caufield at H.C. Wainwright. Please go ahead.

下一個問題來自 H.C. 的 Matthew Caufield。溫賴特。請繼續。

Hi, thank you. Good morning, guys, and thanks for the updates this morning. So kind of changing gears considering obstructive sleep apnea, can you speak a bit more to the mechanism expectations for ASI benefit for those patients and then any read through from the current pivotal developments? Thanks again.

你好，謝謝。大家早安，感謝你們今天早上的更新。那麼，考慮到阻塞性睡眠呼吸中止症，您能否再多談談 ASI 對這些患者的益處的機制預期，然後從當前的關鍵發展中進行解讀？再次感謝。

So let me address that in two ways. So there are two potential benefits at this stage, near term, we're focused on the fact that these patients have 60% to 85% resistant hypertension, and on top of that, it's not being diagnosed or treated because it's at night. And so.

讓我從兩個方面來解決這個問題。因此，現階段有兩個潛在的好處，短期內，我們關注的是這些患者有 60% 到 85% 的難治性高血壓，最重要的是，由於是在夜間，所以無法進行診斷或治療。所以。

Our goal there is to look at the aldosterone dependent mechanism, which is right in the sweet spot for our hypertension program. What happens in these people, and it's often men and only postmenopausal women, is what's driving the [aldo] is the hypoxia. Remember, we say 15 apneas per hour. Think about that. Every 4 minutes. You're unable to move oxygen from your airway down into your lungs. Your body responds to that with a stress response that drives aldosterone. And so that's the mechanism for why they have such exceptionally high incidence of, dying in their sleep, arrhythmias like ventricular and atrial arrhythmias, etc. So that mechanism is directly targeted by our drug. It's part of the theory for dosing the drug for that indication at night. Even though you're trying to go after the hypertension primarily, it's a better way to do it and still get that window in our opinion. Now, the OSA, the airway obstruction itself, well, we know you can treat that with CPAP. It's not a treatment people love. And if you don't use it six hours a day, you get essentially almost no benefit on either blood pressure or survival. And so again, by adding our drug in, and we're going to study it during a two day period off the CPAP, you will get potentially additive benefits from the fact of the mechanisms I told you before occurred to you before, which is primarily fluid shift and secondarily probably some inflammation.

我們的目標是研究醛固酮依賴機制，這對我們的高血壓計畫來說正是最佳點。這些人（通常是男性，只有停經後女性）身上發生的情況是導致 [aldo] 缺氧的原因。請記住，我們說的是每小時 15 次呼吸暫停。想一想。每 4 分鐘一次。您無法將氧氣從氣道輸送到肺部。您的身體會透過壓力反應來應對這種情況，從而刺激醛固酮的分泌。這就是為什麼他們在睡眠中死亡、心室和心房性心律不整等心律不整的發生率如此之高的機制。因此，我們的藥物直接針對的是這種機制。這是針對該症狀在夜間用藥的理論的一部分。儘管您主要想治療高血壓，但我們認為這是一種更好的方法，並且仍然獲得成功。現在，對於 OSA，即氣道阻塞本身，我們知道可以使用 CPAP 進行治療。這不是人們喜歡的治療方法。如果你每天使用的時間不到六個小時，那麼對血壓或生存來說，基本上不會有任何好處。因此，再次強調，透過添加我們的藥物，我們將在兩天內停止使用 CPAP 期間對其進行研究，您將從我之前告訴您的機制中獲得潛在的附加益處，這主要是液體轉移，其次可能是一些發炎。

Very helpful. Thanks a.

非常有幫助。謝謝。

Lot guys.

很多人。

Thanks Matt.

謝謝馬特。

And at this time we have no other questions registered, so I would like to turn the call back over to John for closing remarks.

目前我們還沒有其他問題，因此我想將電話轉回給約翰，請他做最後發言。

Thank you, operator, and thank you to everyone for joining us today. We're very excited about the progress we made in 2024 and thus far in 2025 in advancing our clinical programs, and we remain enthusiastic about the upcoming data milestones planned for the first half of 2025. We look forward to keeping you updated. With that, we will close the call.

謝謝接線員，也謝謝今天加入我們的所有人。我們對 2024 年以及 2025 年迄今為止在推進臨床項目方面取得的進展感到非常興奮，並且我們對計劃於 2025 年上半年實現的即將到來的數據里程碑充滿熱情。我們期待向您提供最新資訊。至此，我們將結束通話。

Thank you, sir. Ladies and gentlemen, this does indeed conclude your conference call for today. Once again, thank you for attending and at this time, we do ask that you please disconnect your lines.

謝謝您，先生。女士們、先生們，今天的電話會議到此結束。再次感謝您的出席，此時，我們懇請您斷開線路。