Mineralys Therapeutics Inc (MLYS) 2024 Q2 法說會逐字稿

Welcome to the Mineralys Therapeutics second quarter 2024 conference call. (Operator Instructions) As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Dan Ferry of LifeSci Advisors. Please go ahead.

歡迎參加 Mineralys Therapeutics 2024 年第二季電話會議。（操作員指示）謹此提醒，本次會議正在錄製中。現在我很高興向您介紹主持人，LifeSci Advisors 的 Dan Ferry。請繼續。

Thank you, operator. Good afternoon, everyone, and welcome to our second quarter 2024 conference call. After the close of market trading today, we issued a press release providing our second quarter 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.

謝謝你，接線生。大家下午好，歡迎參加我們 2024 年的第二季電話會議。今天市場交易結束後，我們發布了一份新聞稿，提供 2024 年第二季財務業績和業務更新。今天電話會議的重播將在會議結束後大約一小時在我們網站的投資者部分提供。在我們準備好發言後，我們將開放問答環節。

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.

在開始之前，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。由於與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中明示或暗示的結果有重大差異。

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 10-K and subsequent filings. Please note that these forward-looking statements reflect our opinions only as of today, August 13. 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.

這些前瞻性陳述受到今天的新聞稿和我們向 SEC 提交的文件（包括我們的 10-K 表格年度報告和後續文件）中包含的警示性聲明的限制。請注意，這些前瞻性陳述僅反映我們截至今天（8 月 13 日）的觀點。除法律要求外，我們明確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 Mineralays therapeutics. John?

我現在想將電話轉給 Mineralays Therapy 執行長 John Congleton。約翰？

Thank you, Dan. Good afternoon, everyone. Welcome to our second quarter 2024 financial results and corporate update conference call. I'm joined today by Adam Levy, our Chief Financial Officer, and Dr. David Rodman, our Chief Medical Officer.

謝謝你，丹。大家下午好。歡迎參加我們的 2024 年第二季財務業績和公司更新電話會議。今天我們的財務長 Adam Levy 和我們的首席醫療官 David Rodman 博士也加入了我的行列。

I'll begin with an overview of the business, our clinical programs and recent milestones, followed by Adam, who will review our second quarter financial results before we open up the call for your questions. Let me start out by saying that during the first half of the year, we made tremendous progress advancing the development program for our lead asset, lorundrostat, specifically, we've been steadily moving towards several key milestones for our registration program in hypertension, which is comprised of two pivotal clinical trials, total Advance-HTN and Launch-HTN.

我將首先概述業務、我們的臨床項目和最近的里程碑，然後由 Adam 回顧我們第二季度的財務業績，然後我們開始詢問您的問題。首先我要說的是，今年上半年，我們在推進我們的主導資產氯崙司他的開發計劃方面取得了巨大進展，具體來說，我們一直在穩步邁向高血壓註冊計劃的幾個關鍵里程碑，這由兩項關鍵臨床試驗組成，即 Total Advance-HTN 和 Launch-HTN。

An open-label extension trial called Transform HTN to capture long-term safety and efficacy data and the proof of concept trial explores CKD, evaluated lorundrostat in hypertensive CKD subjects.

一項名為 Transform HTN 的開放標籤擴展試驗旨在獲取長期安全性和有效性數據，而概念驗證試驗則探索 CKD，評估了 lorundrostat 在高血壓 CKD 受試者中的作用。

Enrollment continues to progress in the Advance-HTN trial. As noted previously, this is an extremely rigorous hypertension trial designed to demonstrate the value of lorundrostat when added to standardized, optimized American Heart Association guideline treatment.

Advance-HTN 試驗的入組工作持續取得進展。如前所述，這是一項極其嚴格的高血壓試驗，旨在證明將洛崙司他添加到標準化、優化的美國心臟協會指南治療中的價值。

While we typically do not provide enrollment updates for our clinical trials, we are approximately 90% enrolled in Advance-HTN and our projections place top line data readout in the first quarter of 2025. While we're disappointed with the change in top line data timing, we remain laser focused on executing the best-in-class trial and ensuring a high quality data readout.

雖然我們通常不提供臨床試驗的註冊更新，但我們約有 90% 的患者註冊了 Advance-HTN，我們的預測將在 2025 年第一季公佈頂線數據。雖然我們對頂線數據計時的變化感到失望，但我們仍然專注於執行一流的試驗並確保高品質的數據讀出。

We continue to work with our partners at the Cleveland Clinic to ensure we deliver the most robust dataset possible. In addition, we recently met with the FDA and aligned on maintaining the original primary endpoint of the Advance-HTN trial, given that we have already accumulated or accrued substantial trial data. As such, we will maintain the original 12-week time point of change in 24 hours ambulatory systolic blood pressure from baseline for active cohorts versus placebo.

我們繼續與克利夫蘭診所的合作夥伴合作，確保我們提供盡可能強大的數據集。此外，鑑於我們已經累積或累積了大量試驗數據，我們最近與 FDA 會面，並就維持 Advance-HTN 試驗的原始主要終點達成協議。因此，我們將維持活躍組與安慰劑組的 24 小時動態收縮壓相對於基線的最初 12 週時間點變化。

We will still collect and analyze all relevant efficacy measures at the 4 week and 12 week time points. This does not impact the timing of the data readout for Advance-HTN. The planned analysis of Advance-HTN trial includes several important subset analysis. Subjects with uncontrolled hypertension, those on baseline regimen of two antihypertensives and resistant hypertension on three baseline antihypertensive treatments were separately randomized, allowing us to perform a formal test in each population. This will provide optionality and independent support for each population.

我們仍將在 4 週和 12 週時間點收集和分析所有相關療效指標。這不會影響 Advance-HTN 的資料讀出時序。Advance-HTN 試驗的計劃分析包括幾個重要的子集分析。高血壓未受控制的受試者、接受兩種抗高血壓藥物基線治療的受試者以及接受三種基線抗高血壓治療的頑固性高血壓受試者被分別隨機化，使我們能夠在每個人群中進行正式測試。這將為每個群體提供選擇性和獨立支持。

We believe that demonstrating efficacy and confirmed resistant hypertension, the area of highest unmet medical need, will be important in positioning lorundrostat for individuals with presumed aldosterone mediated hypertension, including obesity.

我們相信，證明療效和證實難治性高血壓（醫療需求未滿足的最高領域）對於將氯崙司他定位於疑似醛固酮介導的高血壓（包括肥胖症）患者非常重要。

We believe positioning lorundrostat as an important option for obese individuals with increased cardiovascular risk due to resistant hypertension will be a straightforward message to prescribers, payers, and patients.

我們相信，對於因頑固性高血壓而導致心血管風險增加的肥胖個體，將氯倫德羅他定位為一個重要選擇，這將向處方者、付款者和患者傳達一個直接的訊息。

In addition, as we accrue more experience and data with lorundrostat, we plan to continue to explore other positive and negative predictive factors, using artificial intelligence to expand the precision toolkit for targeting lorundrostat to individuals with uncontrolled and resistant hypertension, who are likely to derive long-term clinical benefit.

此外，隨著我們在lorundrostat 方面積累了更多經驗和數據，我們計劃繼續探索其他陽性和陰性預測因素，利用人工智慧擴展精準工具包，將lorundrostat 靶向治療不受控制和頑固性高血壓的個體，這些患者可能會長期臨床獲益。

Moving to Launch-HTN, which is our second pivotal trial that was initiated in the fourth quarter of 2023. We are pleased to announce that enrollment in this trial is currently ahead of schedule, and we continue to expect top line data to be available in the second half of 2025. However, the time to data may accelerate and we will keep you informed as we move forward.

接下來是 Launch-HTN，這是我們在 2023 年第四季啟動的第二個關鍵試驗。我們很高興地宣布，該試驗的入組目前已提前完成，我們仍然預計 2025 年下半年可獲得頂線數據。然而，獲取數據的時間可能會加快，我們將隨時向您通報情況。

Launch-HTN is a Phase 3 trial of lorundrostat for the treatment of subjects with uncontrolled or resistant hypertension as add-on therapy, who fail to achieve blood pressure control on their existing prescribed background treatment of two to five antihypertensive medications. Launch-HTN will enroll up to approximately 1000 adult subjects is designed with the objective of evaluating lorundrostat in a real world setting when added to a subject's previously prescribed antihypertension regimen.

Launch-HTN 是lorundrostat 的一項3 期試驗，用於治療無法控製或難治性高血壓的受試者，作為附加療法，這些受試者在現有的兩到五種抗高血壓藥物的處方背景治療中未能達到血壓控制。Launch-HTN 將招募多達約 1000 名成年受試者，其設計目的是在現實世界環境中評估將 lorundrostat 添加到受試者先前處方的抗高血壓方案中時的情況。

Subjects who fail to achieve blood pressure control on their prescribed background treatment during the run-in period will be randomized one to two to one to either placebo, once daily 50 milligrams of lorundrostat or once daily 50 milligrams of lorundrostat with the option to titrate to 100 milligrams once daily as needed at week-six. The primary endpoint for this trial will be the change in systolic blood pressure as measured by automated office blood pressure

在磨合期未能透過規定的背景治療達到血壓控制的受試者將被隨機以一比二比一的方式接受安慰劑，每日一次50 毫克洛倫德羅坦或每日一次50 毫克羅倫德羅他，並可選擇滴定至第六週時根據需要每天服用 100 毫克。該試驗的主要終點是透過自動辦公室血壓測量的收縮壓的變化

We believe this endpoint reflects real world measurements that will be relevant to the primary care provider this trial targets. Subjects from these two trials will be offered the opportunity to roll over into the ongoing open label extension trial called Transform-HTN.

我們相信該終點反映了與本試驗目標初級保健提供者相關的現實世界測量結果。這兩項試驗的受試者將有機會轉入正在進行的名為 Transform-HTN 的開放標籤擴展試驗。

In addition to our pivotal program in hypertension, we are conducting the Explore-CKD Phase 2 clinical trial for lorundrostat when added to background treatment with SGLT2 inhibitor in patients with uncontrolled or resistant hypertension, and Stage 2 to 3b chronic kidney disease. The amended protocol has been implemented and enrollment is ramping up. We anticipate announcing top line data in the first half of 2025.

除了我們在高血壓方面的關鍵項目外，我們還在對lorundrostat 進行Explore-CKD 2 期臨床試驗，將lorundrostat 添加到SGLT2 抑製劑的背景治療中，用於治療未控製或難治性高血壓以及2 至3b 期慢性腎臟病患者。修訂後的協議已經實施，入學人數正在增加。我們預計在 2025 年上半年公佈營收數據。

Explore-CKD is a within subject comparison trial designed to demonstrate the benefit of lorundrostat in reducing blood pressure and provide supportive evidence for potential benefit on chronic kidney disease on the background of stable SGLT2 inhibitor treatment. This proof of-concept trial will enroll approximately 60 subjects with hypertension in stage 2 to 3b CKD. We look forward to keeping you apprised of the status of the lorundrostat development program over the coming weeks and months.

Explore-CKD 是一項受試者內比較試驗，旨在證明 lorundrostat 在降低血壓方面的益處，並為在穩定的 SGLT2 抑制劑治療背景下對慢性腎病的潛在益處提供支持性證據。這項概念驗證試驗將招募約 60 名 2 至 3b 期 CKD 高血壓患者。我們期待在未來幾週和幾個月內隨時向您通報 lorundrostat 開發計劃的進展。

Let me now turn the call over to Adam, who will provide a financial review for the second quarter of 2024.

現在讓我將電話轉給 Adam，他將提供 2024 年第二季的財務審查。

Thank you John. Good afternoon, everyone. Today I will discuss select portions of our second quarter 2024 financial results. Additional details can be found in our Form 10-Q, which was filed with the SEC today.

謝謝約翰。大家下午好。今天，我將討論 2024 年第二季財務表現的部分內容。更多詳細資訊請參閱今天向 SEC 提交的 10-Q 表格。

We ended the quarter with cash, cash equivalents and investments of $311.1 million compared to $239 million as of December 31, 2023. We believe that our cash, cash equivalents and investments will be sufficient to allow us to fund our planned clinical trials as well as support corporate operations into 2026.

截至本季末，我們的現金、現金等價物和投資為 3.111 億美元，而截至 2023 年 12 月 31 日為 2.39 億美元。我們相信，我們的現金、現金等價物和投資將足以為我們計劃中的臨床試驗提供資金，並支持公司運作直至 2026 年。

R&D expenses for the quarter ended June 30, 2024 were $39.3 million compared to $11.9 million for the same quarter of 2023. The increase in R&D expenses was primarily due to increases of $22.8 million in preclinical and clinical costs driven by the initiation of lorundrostat pivotal program in the second quarter of 2023 and the export CKD trial in the fourth quarter of 2023.

截至 2024 年 6 月 30 日的季度研發費用為 3,930 萬美元，而 2023 年同一季度的研發費用為 1,190 萬美元。研發費用的增加主要是由於 2023 年第二季啟動 lorundrostat 關鍵項目和 2023 年第四季出口 CKD 試驗導致臨床前和臨床成本增加 2,280 萬美元。

$2.6 million in clinical supply, manufacturing and regulatory costs, $1.7 million in higher compensation expenses resulting from additions to headcount increases in salaries and accrued bonuses, and increase in stock-based compensation and $0.3 million in other research and development expenses.

臨床供應、製造和監管成本為 260 萬美元，由於員工人數增加、工資和應計獎金、股票薪酬的增加以及其他研發費用增加了 170 萬美元，薪酬費用增加了 170 萬美元。

G&A expenses were $5.9 million for the quarter ended June 30, 2024, compared to $3.9 million for the same quarter of the prior year. The increase in G&A expenses was primarily due to $1.5 million in higher compensation expenses resulting from additions to headcount increases and salaries and accrued bonuses and increased stock-based compensation and $0.5 million in higher professional fees and other administrative expenses.

截至 2024 年 6 月 30 日的季度，一般管理費用為 590 萬美元，而上年同期為 390 萬美元。G&A 費用的增加主要是由於員工人數增加、工資和應計獎金以及股票薪酬增加導致薪酬費用增加 150 萬美元，以及專業費用和其他管理費用增加 50 萬美元。

Total other income was $4.2 million for the quarter ended June 30, 2024, compared to $3.6 million for the same quarter of 2023. The increase was primarily attributable to increases in interest earned on our investments in money market funds and US Treasury.

截至 2024 年 6 月 30 日的季度其他收入總額為 420 萬美元，而 2023 年同一季度為 360 萬美元。這一增長主要歸因於我們對貨幣市場基金和美國國債的投資所賺取的利息增加。

Net loss was $41 million for the quarter ended June 30, 2024, compared to $12.1 million for the same quarter of 2023. The increase was primarily attributable to the factors I described earlier.

截至 2024 年 6 月 30 日的季度淨虧損為 4,100 萬美元，而 2023 年同一季度的淨虧損為 1,210 萬美元。這一增長主要歸因於我之前描述的因素。

With that, I will ask the operator to open the call for questions. Operator?

之後，我將要求接線員打開電話提問。操作員？

(Operator Instructions) Michael DiFiore, Evercore ISI.

（操作員說明）Michael DiFiore，Evercore ISI。

Hi, guys. Thanks so much for taking my question, two from me. Just want to get more clarity on why exactly the time lines were extended for Advance-HTN and the CKD trial.

嗨，大家好。非常感謝您提出我的問題，其中有兩個問題。只是想更清楚地了解為什麼 Advance-HTN 和 CKD 試驗的時間線被延長。

And then secondly, obviously, the Phase 2 advanced hypertension primary endpoint is now back at 12 weeks, the FDA's rationale was just because you had so much accrued data. I want to clarify that. And now that it's back at 12 weeks, are you concerned that now that the waters will be muddied at 12 weeks with the inclusion of patients on 100 milligram. Thank you.

其次，顯然，2 期晚期高血壓主要終點現在回到了 12 週，FDA 的理由只是因為你有這麼多的累積數據。我想澄清這一點。現在又回到了 12 週，您是否擔心現在 12 週時，隨著患者服用 100 毫克，水會變得渾濁。謝謝。

Yes Mike, it's Jon, good to -- glad to have the questions. The first one regarding the timing. When we originally established Q4, and I think it was late last year for guidance on Advance-HTN at that point in time, we were still earlier in the enrollment, particularly with the protocol amendment.

是的，麥克，我是喬恩，很高興能提出問題。第一個是關於時間安排的。當我們最初建立第四季度時，我認為當時 Advance-HTN 的指導是在去年年底，我們的註冊仍處於早期，特別是在方案修訂方面。

We -- as we've discussed before, the rigor and complexity of Advance-HTN and made it difficult to really tried to project when we thought we would see top line data as we've spent the last several months, six, seven, eight months since that guidance, we've obviously gotten further along in the enrollment of the study, the ability to project the time for the top line data has progressively become easier.

正如我們之前所討論的，Advance-HTN 的嚴格性和複雜性使得當我們認為我們會看到頂線數據時很難真正嘗試進行預測，因為我們在過去的幾個月、六、七個月裡，自從該指導發布以來的八個月裡，我們顯然在研究的招募方面取得了進一步的進展，預測頂線數據時間的能力也逐漸變得更加容易。

As we noted in the press release and in the on the earnings call here, we're at 90% enrolled at this point. So we have high confidence on where we're at currently with enrolled subjects where we're forecasted to continuing to enroll that will have the top line data in Q1 of 2025 kind of at a similar construct Mike, with explore CKD.

正如我們在新聞稿和財報電話會議中指出的那樣，目前我們的註冊率為 90%。因此，我們對目前註冊受試者的狀況充滿信心，預計我們將繼續註冊，這些受試者將在 2025 年第一季獲得頂線數據，類似於麥克的結構，探索 CKD。

We announced earlier this year that we were doing a protocol amendment just based on the changing dynamics within the hypertension CKD space and the utilization of SGLT2 inhibitors. We put that protocol in place, that's had the intended effect as far as improving enrollment within that study.

我們今年稍早宣布，我們正在根據高血壓 CKD 領域的動態變化和 SGLT2 抑制劑的使用進行方案修訂。我們制定了該方案，在提高研究的入學率方面達到了預期效果。

As that protocol has gone into effect and we began to enroll subjects, it's been able to give us a clearer sense of timing, and that's why we adjusted the readout for explore CKD from Q4, Q1 to Q1, Q2. And so that's really what's driven. It is just having more data, more experience with these trials. And I tried to get a really clear sense of when we anticipate that top line data.

隨著協議生效並且我們開始招募受試者，它能夠讓我們更清楚地了解時間安排，這就是為什麼我們將探索 CKD 的讀數從 Q4、Q1 調整為 Q1、Q2。這就是真正的驅動力。只是在這些試驗中擁有更多的數據和更多的經驗。我試圖真正清楚地了解我們何時預期頂線數據。

Before I turn it over to Dave to answer the Advance-HTN primary endpoint, any new follow-up on that.

在我將其交給 Dave 回答 Advance-HTN 主要終點之前，請先介紹任何新的後續行動。

Just to clarify to, you said that the protocol amendment, you may now has boosted enrollment as intended. So why wouldn't -- why were the time lines moved up if enrollment has been enhanced?

只是澄清一下，您說協議修正案現在可能已按預期增加了入學人數。那麼，如果擴大了入學人數，為什麼時間線要提前呢？

It's been enhanced relative to what it was, Mike. And we thought there was an opportunity to see that top line data in Q4 to Q1, while it's been enhanced from our perspective. It's prudent to change that guidance to Q1, Q2 at this point.

麥克，它相對於原來的情況有所增強。我們認為有機會看到第四季度到第一季的頂線數據，同時從我們的角度來看它已經得到了增強。此時，明智的做法是將該指引更改為第一季、第二季。

Got it. Okay.

知道了。好的。

Dave, do you want to address Mike's question on the primary?

戴夫，你想回答麥克關於初選的問題嗎？

Hey, Mike, it's Dave Rodman and thanks for the question. So the question just to reiterate, let me know if I got it right, is are we going to encounter less more confusion, or less clarity, let's say, at 12 weeks because we have a some people on 50 milligrams straight through and others who could have their that dose increased to 100. Is that your question?

嘿，麥克，我是戴夫·羅德曼，謝謝你的提問。因此，我想重申一下，如果我說得對的話，請告訴我，我們是否會遇到更多的混亂或不那麼清晰，比方說，在12 週時，因為我們有一些人直接服用50 毫克，而有些人則服用50 毫克。這是你的問題嗎？

That's correct. And also want to clarify, if the FDA's rationale for keeping it at 12 weeks was just purely because you had so much data already accumulated?

這是正確的。我還想澄清一下，FDA 將其保留在 12 週的理由是否純粹是因為您已經累積瞭如此多的數據？

Got it. I'll answer the second first. The answer to that is yes, it was just simply that we're past halfway enrollment. They just thought, stayed the course at that point.

知道了。我先回答第二個。答案是肯定的，只是我們的入學已經過了一半。他們只是想，當時就堅持到底。

So in terms of your other question, it's a good question, we're going to kind of have our cake and eat it too in a sense because we are going to do the full analysis at 4 weeks that we proposed and we're going to do the 12-week analysis.

所以就你的另一個問題而言，這是一個很好的問題，從某種意義上說，我們將魚與熊掌兼得，因為我們將在我們提議的4 週內進行全面分析，並且我們將進行 12 週分析。

So we'll have the clarity of should be analysis when everybody is on 50 milligrams at four weeks, but then the primary it's going to be done at 12 weeks. So the only difference is really what -- when is that primary going to be done. That's kind of just a key value question, if you will. We'll have the clarity at four weeks that will allow us to have lots of power for subset analyses like obesity, et cetera.

因此，當每個人在 4 週內服用 50 毫克時，我們將進行清晰的分析，但隨後將在 12 週時進行初步分析。所以唯一的區別實際上是什麼——什麼時候完成主要工作。如果你願意的話，這只是一個關鍵價值問題。我們將在四個星期內獲得清晰的結果，這將使我們能夠擁有強大的能力進行子集分析，例如肥胖等。

So we don't really lose anything there. And we'll still have apples to apples between the two trials because of that as well. Did I answer your question?

所以我們並沒有真正失去任何東西。正因為如此，在兩次試驗之間我們仍然會有同類的結果。我回答你的問題了嗎？

Yeah, very much. Thanks so much.

是的，非常喜歡。非常感謝。

Thanks, Mike.

謝謝，麥克。

Richard Law, Goldman Sachs.

理查德·勞，高盛。

Hey, guys, thanks for taking my question. Just following up on that, what patients will be included in the 12 week endpoint analysis for Advance-HTN. So what are the patients in that 50 mg to 100 mg cohort, would those be included in the 12-week primary analysis? And also what is the powering on just a pure 50 mg group alone? And I have a couple more questions.

嘿，夥計們，謝謝你提出我的問題。接下來，哪些患者將被納入 Advance-HTN 的 12 週終點分析中。那麼 50 毫克至 100 毫克隊列的患者有哪些，這些患者是否會被納入 12 週的初步分析中？純 50 毫克組的功率是多少？我還有幾個問題。

Good question. So the primary analysis at 12 weeks is a comparison between placebo and each of the active arms there. They're not co-primaries where you have to hit those. They're just dual primaries. And so the way that works is we'll take everybody who started on 50 and ended on 50 in well, and they started on 50 in that second arm. They'll all be essentially treated with 50 milligrams compared to placebo.

好問題。因此，第 12 週時的主要分析是安慰劑組與每個活性組之間的比較。它們不是你必須參加的聯合初選。他們只是雙重初選。因此，有效的方法是，我們將把所有以 50 開始並以 50 結束的人納入其中，他們在第二組中以 50 開始。與安慰劑相比，他們基本上都接受 50 毫克的治療。

And then the other arm, if they went up to 100, they're still included in the analysis. So it doesn't matter if they end on 50 or 100, there's a second. So and that's again versus placebo. So that's for the p-values, you'll see two, one for the arm two one for arm three.

然後另一組，如果達到 100，它們仍然包含在分析中。所以無論最後是 50 還是 100，都沒關係，還有第二個。這又是與安慰劑的對比。這就是 p 值，您會看到兩個，一個用於第二組，一個用於第三組。

There's also a key thing here, which is what we want to know is in arm three, the reason we're doing it is if you're a clinician and somebody doesn't respond to 50 milligrams, you think they belong on the drug and everything else looks good, potassium, everything else, what you want to know is can I just double the drug safely and rescue that guy and get him the benefit. I think he should accrue.

這裡還有一個關鍵的事情，我們想知道的是第三組，我們這樣做的原因是如果你是臨床醫生並且有人對 50 毫克沒有反應，你認為他們屬於該藥物其他一切看起來都很好，鉀，其他一切，你想知道的是我可以安全地加倍藥物並拯救那個人並讓他受益。我認為他應該累積。

That's best within subject question, right. Check a person who hasn't responded given the drug and now you say did it get better from that point. So that's what's going to happen at 12 weeks. Let me stop there and see if that was responsive to your question.

這最好在主題問題內，對吧。檢查一個對藥物沒有反應的人，現在你說從那時起情況是否有所改善。這就是第 12 週時會發生的情況。讓我停在這裡，看看這是否能回答你的問題。

Yeah. So the patients who are on the 50 to 150 mg arm, so just that titration cohort. Can you pull those 50 mg patients who did not get the titrate 100 mg? Can you put them into the other like the pure 50 mg cohort? Or are these patients completely separate -- like separately analyzed by self?

是的。接受 50 至 150 毫克治療的患者，就是滴定組。你能把那些沒有滴定到100毫克的50毫克患者拉出來嗎？你能把它們像純 50 毫克組一樣放入另一個組嗎？或者這些患者是完全獨立的──就像自我單獨分析一樣？

Yeah, it's a good question. So in terms of 12 weeks, no, you can't pool them. But in terms of the four week analysis, absolutely. And so and we know from the Target-HTN n trial that we saw the full benefit by four weeks. So we'll also be looking at 4 weeks and 12 weeks in the same people and asked the question, did they maintain the benefit within subjects?

是的，這是一個好問題。所以就 12 週而言，不，你不能將它們合併起來。但就四周的分析而言，絕對是如此。因此，我們從 Target-HTN n 試驗中得知，我們在四週後就看到了全部好處。因此，我們也將對同一個人進行 4 週和 12 週觀察，並提出這樣的問題：他們是否在受試者中保持了益處？

And so that will also be answered. Now I forgot to answer your powering question and let me just repeat that. You said what's our power going to be for just the 50 milligram arm at 12 weeks. Is that what you're asking?

這也將得到答案。現在我忘了回答你的供電問題，讓我重複一次。你說過 12 週時我們的 50 毫克手臂的力量是多少。這就是你問的嗎？

Yeah.

是的。

Yeah. So our initial power calculations were designed to have 90% power for to do that, and we were looking at I think something like maybe a 6 or 7 was a 7 millimeter mercury difference. So that's where our pairing estimates were. Obviously at the end, we'll redo that based on a bunch of other things. And it's, -- the statistics are obviously complicated, but that's the bottom line. 90% power differences, 7 in any drugs.

是的。因此，我們最初的功率計算被設計為具有 90% 的功率來做到這一點，我們正在研究我認為 6 或 7 之類的東西可能是 7 毫米汞柱的差異。這就是我們的配對估計值。顯然，最後，我們將根據許多其他事情重做。統計數據顯然很複雜，但這是底線。 90% 的功效差異，任何藥物均為 7。

I see. So is the data for that 50 mg to 100 mg cohort for the patient who did not get titrated to 100 mg, is there any use for that 12 week data point for those patients?

我懂了。那麼，對於未滴定至 100 mg 的患者，50 mg 至 100 mg 隊列的數據是這樣的嗎？

Yes, absolutely. So we can do a sensitivity analysis on that and we will. We can do a pooling analysis as you suggested. All of those are essentially sort of sensitivity analysis kind of questions. And so there probably won't be enough power. We could ask do the people who finish on 50 mg different from the people who increased to 100 mg. But there's just so much you can do. But to answer your question, yes, there's going to be use to them. Those things will be deep in the data, but they'll be available.

是的，絕對是。所以我們可以對此進行敏感度分析，我們會的。我們可以按照您的建議進行總結分析。所有這些本質上都是敏感度分析類型的問題。因此可能沒有足夠的電力。我們可以問一下，最終攝取 50 毫克的人與增加到 100 毫克的人有什麼不同。但您能做的事情實在太多了。但要回答你的問題，是的，它們會有用。這些東西將深藏在數據中，但它們將是可用的。

Got it. And then the last question from me is that do you control or cap the number of patients coming into the study who've previously been exposed to MRA or spironolactone? And if not, what proportion of these patients do expect to be enrolled in the Advance-HTN study?

知道了。我的最後一個問題是，你們是否控製或限制參與研究且之前接觸過 MRA 或螺內酯的患者數量？如果沒有，這些患者中有多少比例希望參加 Advance-HTN 研究？

So they all have to wash out of any MRA or an ENaC blocker. On the other hand, they will have a medical history. So if we choose to do so, we could do a look back, but we're not going to -- they can't come in and just switch into the new regimen right off of the MRI that has to be washed out.

因此，它們都必須清除任何 MRA 或 ENaC 阻斷劑。另一方面，他們會有病史。因此，如果我們選擇這樣做，我們可以回顧一下，但我們不會——他們不能進來並在必須清除的 MRI 後立即切換到新的治療方案。

Okay. Got it. Great. Thank you.

好的。知道了。偉大的。謝謝。

Thanks, Rich.

謝謝，里奇。

Annabel Samimy, Stifel.

安娜貝爾·薩米米，斯蒂菲爾。

Hi. Thanks for taking my question. Just on the four week measurement. Can you remind us the rationale for wanting to look at the four week time point in the first place? I just want to make sure I understand what importance that four week time point is for you and I have some follow-ups from that.

你好。感謝您提出我的問題。就在四個星期的測量上。您能否提醒我們先考慮四周時間點的理由？我只是想確保我了解這四個星期的時間點對您來說有多重要，並且我對此有一些後續行動。

Hi Annabelle, it's Dave. So to your question, just to repeat, if I got it right is what was the rationale for wanting to make the change or why are we looking at it just on basic principles?

嗨，安娜貝爾，我是戴夫。因此，對於你的問題，重複一遍，如果我說得對，那麼想要做出改變的理由是什麼，或者為什麼我們只根據基本原則來看待它？

Well, why are we looking at it and base for basic principles. Just, you had a 4 week endpoint and 12 week endpoint. I'm just curious what the 4 week endpoint measurement was going to give you. Just (inaudible) just the importance of that endpoint.

好吧，我們為什麼要研究它以及基本原則的基礎。只是，您有 4 週終點和 12 週終點。我只是好奇 4 週終點測量會為你帶來什麼。只是（聽不清楚）只是該端點的重要性。

So it's a good question. By 4 weeks you've achieved the maximum benefit and by having two data points, so baseline, but then 4 weeks and 12 weeks, you manage a lot of issues. To answer the question, we think 4 weeks will be the maximum. Is it predictive of 12 weeks? In other words, is there any loss of activity over at least the 12 week time period? Because we only went out to 8 weeks before and didn't see any loss.

所以這是一個好問題。到 4 週時，您已經獲得了最大收益，並且有了兩個數據點（因此是基線），但在 4 週和 12 週後，您就解決了很多問題。為了回答這個問題，我們認為最多 4 週。是預測12週嗎？換句話說，至少在 12 週的時間內是否有活動損失？因為我們只出去到8週前，並沒有看到任何損失。

From a statistical standpoint, it allows you to, let's just say somebody later in the trial has a problem or whatever and you stop their drug, as long as we have the 4 week, we do have mechanisms for imputation that can be used.

從統計的角度來看，它允許你，假設有人在試驗後期出現問題或其他什麼，你停止他們的藥物，只要我們有 4 週的時間，我們就有可以使用的估算機制。

Now, that's a complicated thing, but as long as they stay in the study, that four4 week data point is informative for the modeling. So there are a couple reasons to do it. The third one is the ability to pool the two groups that are replicates up to 4 weeks. And so you do have at four weeks superpower in terms of getting a point estimate.

現在，這是一件複雜的事情，但只要他們繼續研究，那 44 週的數據點就可以為建模提供資訊。所以有幾個理由這樣做。第三個是能夠將兩組重複長達 4 週的組合併。所以你在四個星期內確實擁有獲得分數估計的超能力。

Okay, that's helpful. Thank you. And then just a question that we grappling with some investors. Just can you remind us again, what the difference was in the patients who saw 24 hour blood pressure monitoring benefits and target versus those who did not. And I guess how it could have been the AOBP measurements overall, such a strong response at 24 hour could not. So I just want to try to reconcile those two figures.

好的，這很有幫助。謝謝。這就是我們與一些投資者爭論的一個問題。您能否再次提醒我們，看到 24 小時血壓監測益處和目標的患者與沒有看到的患者有什麼區別？我想這怎麼可能是 AOBP 測量結果，24 小時內不可能有如此強烈的反應。所以我只是想嘗試協調這兩個數字。

If I understand your question, I'm not sure. Let me just say what we saw. So, first of all, ABPM, because of the replicate measures every 20 to 30 minutes over the course of the day, you get lots of measurements. So the precision is better when you average it, so the standard deviation is smaller.

如果我理解你的問題，我不確定。我就簡單說一下我們看到的情況吧。首先，ABPM，由於一天中每 20 到 30 分鐘重複測量一次，因此您會獲得大量測量值。所以平均的時候精確度會更好，所以標準差會更小。

But remember, a normal person's blood pressure goes down significantly overnight, and so the average blood pressure over the course of 24 hours will be lower with ABPM than the automated office done just in the morning.

但請記住，正常人的血壓在一夜之間會顯著下降，因此 ABPM 24 小時內的平均血壓將低於自動化辦公室在早上測得的血壓。

The same is true of changes then, because you're changing from a lower baseline. So typically what you'll see is a lower baseline pressure with ABPM and a smaller treatment effect, but a smaller standard deviation. So we saw extremely good concordance between AOBP and ABPM, but there is this systematic difference of smaller numbers.

那麼改變也是如此，因為你是從較低的基線開始改變的。因此，通常您會看到 ABPM 的基線壓力較低，治療效果較小，但標準差較小。因此，我們看到 AOBP 和 ABPM 之間具有極好的一致性，但存在較小數字的系統差異。

Now, the other thing that happened, however, is there is this phenomenon of white coat hypertension. In other words, when you get an AOBP, when you come into the clinic at 10:00 AM in the morning, you've got a lot of adrenergic tone because you had to find a parking space, you had to walk up two flights of stairs, you had to wait in the waiting room, et cetera and so that all goes away with a 24 hours.

然而，現在發生的另一件事是出現了白大衣高血壓的現象。換句話說，當您得到 AOBP 時，當您早上 10:00 進入診所時，您會感到腎上腺素緊張，因為您必須找到停車位，必須走兩層樓樓梯，您必須在候診室等，等等，這樣一切都會在24 小時內消失。

And so we have this thing where people have hypertension with AOBP, but not with ABPM. And we tend to assume they don't have true hypertension that leads to adverse outcomes, but rather they just have apparent hypertension. Was that the question kind of you were thinking of asking?

因此，我們發現人們患有 AOBP 高血壓，但 ABPM 則不然。我們傾向於假設他們沒有真正的高血壓會導致不良後果，而只是有明顯的高血壓。這是你想問的問題嗎？

A little bit. I'm just curious. So the ABPM, where you reach statistical significance, when you reach statistical significance, after you move some outliers of the study. So I'm just trying to understand what those outliers were. They made you comfortable that it was a fair assessment. And how do you control for those outliers in this next coming trial, so that you don't have some of those divergences?

一點點。我只是好奇。因此，ABPM，當您達到統計顯著性時，在移動研究的一些異常值之後。所以我只是想了解那些異常值是什麼。他們讓你感到放心，這是一個公平的評估。在下一次試驗中，您如何控制這些異常值，以免出現一些分歧？

Yeah, good question. So first of all, those were small trials ends of 30 with ABPM and all the technical issues with it are extremely challenging to get to statistics. And for instance, it was a few patients. There was one patient in particular who on the office blood pressures had a 60 millimeter mercury, I think increase in blood pressure recorded, in other words, an implausible value. It just can't be accurate.

是的，好問題。首先，這些都是為期 30 次的小規模試驗，涉及 ABPM，其中的所有技術問題對於統計數據來說都極具挑戰性。例如，有幾個病人。特別是有一位患者在診室血壓為 60 毫米汞柱，我認為記錄的血壓升高，換句話說，這是一個令人難以置信的值。它只是不準確。

And that's what kind of thing we censored we just numbers that were just not plausible and not reproduce. So there was only a few. It was really the white coat hypertension where most of the loss of information from ABPM was the issue.

這就是我們審查的內容，我們只是提供了不合理且無法複製的數字。所以只有幾個。這實際上是白大衣高血壓，其中大部分 ABPM 資訊遺失都是問題所在。

And Annabel, just to add to Dave's point, the distinction between target and advance in target AOBP, was part of the randomization rule, not ABPM and AOBP was the primary endpoint. In this case of Advance-HT, they have to be hypertensive on the 24 hour, ABPM to be randomized. And so that rule a randomization rule itself should eliminate that phenomenon that we saw in Target-HTN.

Annabel，只是為了補充 Dave 的觀點，目標 AOBP 中的目標和提前之間的區別是隨機化規則的一部分，而不是 ABPM，而 AOBP 是主要終點。在 Advance-HT 的情況下，他們必須在 24 小時 ABPM 上患有高血壓才能進行隨機分組。因此，隨機化規則本身應該會消除我們在 Target-HTN 中看到的這種現象。

Okay, great. Thank you. That's helpful.

好的，太好了。謝謝。這很有幫助。

Yeah. Thanks, Annabel.

是的。謝謝，安娜貝爾。

Mohit Bansal, Wells Fargo.

莫希特·班薩爾，富國銀行。

Great. Thank you very much for taking my questions. I have two, but I'll ask one by one. So, first question, I'm a little bit confused by all the talk about Advance-HTN and then 12-week thing. If I go back to the Launch trial, can you just help us understand what was the confounding issue that probably made FDA to ask you to move to 6 weeks versus 12 weeks? Because the way I see the trial, there are three different arms.

偉大的。非常感謝您回答我的問題。我有兩個，不過我會一一問。所以，第一個問題，我對所有有關 Advance-HTN 和 12 週的討論感到有點困惑。如果我回到啟動試驗，您能否幫助我們了解可能導致 FDA 要求您從 12 週改為 6 週的混淆問題是什麼？因為在我看來，審判分為三個不同的部分。

There is 150 milligram, there is under 50 milligram moving to 100 milligram. So you can still compare the 50 milligram arm to the placebo arm. So I'm a little bit confused by the change here. Thank you.

有150毫克，有50毫克以下，到100毫克。因此，您仍然可以將 50 毫克組與安慰劑組進行比較。所以我對這裡的變化有點困惑。謝謝。

So it wasn't them telling us what to do, it was us suggesting that it would be better to do it that way. It doesn't have to do with the primary. It didn't matter in that trial, as big as it was, if you did the primary at 4 weeks or 12 weeks, it has to do with power for the subset analysis. In other words, because you have two replicate arms, both at 50 milligram, we can do the independent tests for the primary, each arm versus placebo.

因此，不是他們告訴我們要做什麼，而是我們建議這樣做會更好。和初級沒有關係。在那次試驗中，儘管試驗規模很大，但如果您在 4 週或 12 週時進行初步試驗，這並不重要，這與子集分析的功效有關。換句話說，因為您有兩個重複組，劑量均為 50 毫克，所以我們可以對主要組（每個組與安慰劑）進行獨立測試。

But let's say we want to ask a question. Does it matter whether you're African-American? Well, we expect maybe 40% of the subjects will be African-American, so now you're down to half the sample size. But by pooling the two, now you get back up to the number, and so you get much more precision to get accurate answers to the subsets.

但假設我們想問一個問題。你是不是非裔美國人重要嗎？好吧，我們預計 40% 的受試者可能是非裔美國人，所以現在樣本量減少到了一半。但透過將兩者合併，現在您可以恢復到數字，因此您可以獲得更高的精度來獲得子集的準確答案。

So that's what we went back to the Agency with and said, in this big data set, we want to make sure that we can fully realize the power of the study, and we think for the subsets we'd be better at six weeks. And basically the decision was, okay, if you're going to do that, let's just do the primary at six weeks too.

這就是我們回到 FDA 並說的，在這個大數據集中，我們希望確保我們能夠充分認識到這項研究的力量，我們認為對於子集，我們在六週時會更好。基本上，我們的決定是，好吧，如果你要這樣做，那麼我們也可以在六週後進行初選。

Got it. So that is basically to make sure that you can do the subgroup analysis properly because it's a bigger data set here.

知道了。這基本上是為了確保您可以正確進行子組分析，因為這裡的資料集更大。

It just makes it much more simple and higher productivity. It's just a good, good idea.

它只是讓它變得更加簡單和更高的生產力。這只是一個好主意。

Got it. And then I have one more question. So we have seen a couple of readouts from MRAs, so obviously, no had some data which was not that successful. But then Bayer had some data in Type 2 diabetes related CKD, and that was quite successful. So how do you see, like, obviously different classes, but related, how do you see these two data sets and what do you learn from them? Those data sets to inform your own CKD studies?

知道了。然後我還有一個問題。我們已經看到了 MRA 的一些讀數，很明顯，沒有一些數據不那麼成功。但後來拜耳獲得了一些第 2 型糖尿病相關 CKD 的數據，而且非常成功。那麼，您如何看待明顯不同但相關的類，您如何看待這兩個資料集以及您從中學到了什麼？這些數據集可以為您自己的 CKD 研究提供資訊嗎？

Well, first of all, MRAs generally are pretty similar. It doesn't matter if it's spironolactone from 1959 or a very new one. The only difference are the steroidal side effects, things like breast development in men and impotence and vaginal bleeding and that kind of stuff. As far as everything else, mechanistically, they're the same.

嗯，首先，MRA 通常非常相似。無論是 1959 年的螺內酯還是全新的螺內酯，都沒關係。唯一的區別是類固醇的副作用，例如男性乳房發育、陽痿和陰道出血之類的東西。就其他一切而言，從機制上講，它們是相同的。

What we observe with the MRAs is almost always you are unable to achieve the maximum therapeutic benefit on something like blood pressure because you're limited by the on target increases in potassium and also sodium going down, those kinds of things.

我們透過 MRA 觀察到的情況是，您幾乎總是無法在血壓等方面獲得最大的治療效果，因為您受到鉀的目標增加和鈉的下降等因素的限制。

For instance, with spironolactone, the maximum efficacious dose is probably 200 milligrams. The conventional dose that's used is 25 milligram, 50 milligram by nephrology specialists sometimes. That's different. So we found in our drug, we can go above the maximum efficacious dose. 100 milligram is the same as 50 milligram. So we can safely give 50 milligram, which is the maximum efficacious dose.

例如，螺內酯的最大有效劑量可能是 200 毫克。腎臟科醫師有時使用的常規劑量是25毫克、50毫克。那是不同的。所以我們發現在我們的藥物中，我們可以超過最大有效劑量。 100毫克和50毫克是一樣的。所以我們可以安全地給予50毫克，這是最大有效劑量。

So, overall, what I would say is the biggest difference that's apparent in the trials we're running is that the benefit risk, the ability to dose people all the way up to their applications, dose from getting rid of aldo is probably more achievable with an ASI like ours than an MRA.

所以，總的來說，我想說的是，我們正在進行的試驗中明顯的最大區別是，受益風險、為人們一直劑量到應用劑量的能力、擺脫阿爾多的劑量可能更容易實現與我們這樣的ASI 相比，MRA 更有效。

Now, long term, there are a lot of aldo effects that aren't blood pressure and kidney, their effects on adipocytes, on insulin sensitivity, on inflammation, on heart and blood vessel fibrosis. And not all of them are mediated through the MR that's blocked by those MRAs.

現在，從長遠來看，除了血壓和腎臟之外，還有很多奧爾多效應，它們對脂肪細胞、胰島素敏感性、發炎、心臟和血管纖維化的影響。並非所有這些都是透過被這些 MRA 阻止的 MR 來調節的。

And, in fact, if you give an MRA, you increase aldosterone by 200% or 300%, and you drive it into these other pathways. So, if you did a longer trial and looked at things like vascular stiffness, maybe even have that. I think eventually they would differentiate, but that's for us, something to define, once we're in the market for hypertension, we will certainly be looking at that. Those are really the two aspects we would say, that look pretty likely to differentiate and show the advantage of ASI over MRA.

事實上，如果進行 MRA，醛固酮就會增加 200% 或 300%，並將其驅動到其他途徑。因此，如果您進行了更長時間的試驗並觀察了血管僵硬等情況，甚至可能會發生這種情況。我認為最終他們會有所不同，但這對我們來說是需要定義的，一旦我們進入高血壓市場，我們肯定會注意這一點。這確實是我們要說的兩個方面，看起來很可能區分並顯示 ASI 相對於 MRA 的優勢。

Okay. Thank you very much, Make sense.

好的。非常感謝，有道理。

Thanks, Mohit.

謝謝，莫希特。

(Operator Instructions) Rami Katkhuda, LifeSci Capital.

（操作員說明）Rami Katkhuda，LifeSci Capital。

Hey, guys. Thanks for taking my questions as well. First, I just wanted to make sure that I heard you correctly in that you'll be able to do a subset analysis of lorundrostat efficacy in uncontrolled and resistant hypertensive patients in advance, I guess. Do you expect a difference in efficacy between these populations?

嘿，夥計們。也感謝您回答我的問題。首先，我只是想確保我沒有聽錯，因為我想，您將能夠提前對不受控制和頑固性高血壓患者進行洛崙司他療效的子集分析。您預期這些族群之間的療效是否有差異？

Well, I can answer the first question. So we separately block randomized, uncontrolled, and resistant. In other words, if we have 150 people who are resistant and we have 200 people who are uncontrolled, we'll have 200 uncontrolled placebo and 150 resistant placebo.

嗯，我可以回答第一個問題。所以我們分別封鎖隨機的、不受控制的和抗藥性的。換句話說，如果我們有 150 人有抗藥性，而有 200 人不受控制，那麼我們將有 200 名不受控制的安慰劑和 150 名有抗藥性的安慰劑。

They're matched in terms of the randomization and so that means we have full statistical power to do those comparisons, and they're informative. Now, your question of can I be prophetic and tell you whether it's going to work better in one or the other? I can't answer that. In the Target-HTN trial, when we asked that question, we didn't see a difference. But let's wait and see on this trial. I don't want to predict.

它們在隨機化方面是匹配的，因此這意味著我們擁有完整的統計能力來進行這些比較，並且它們提供了豐富的資訊。現在，你的問題是我是否可以預言並告訴你它是否會在其中一種或另一種中效果更好？我無法回答這個問題。在 Target-HTN 試驗中，當我們提出這個問題時，我們沒有看到差異。但讓我們拭目以待這次審判。我不想預測。

Fair enough. And then maybe switching to CKD, I guess, given the previous results we saw with Beringer's ASI, the recent failure with the MRA, is there a threshold of systolic blood pressure reductions that you're looking for in explorer to advance lorundrostat into a larger trial?

很公平。然後也許會轉向CKD，我想，考慮到我們之前在Beringer 的ASI 上看到的結果，最近MRA 的失敗，是否存在您在探索者中尋找的收縮壓降低閾值，以將lorundrostat 推進到更大的範圍審判？

For CKD? -- So where we think our drug is going to differentiate is we made the primary hypertension and the secondary is going to be albuminuria. And the reason for that is we're going to be dosing at antihypertensive doses in people who have both a hypertensive component to their CKD and probably also a metabolic syndrome component.

對於慢性腎臟病？ ——因此，我們認為我們的藥物將區分原發性高血壓和繼發性蛋白尿。原因是我們將為既患有 CKD 高血壓成分又可能患有代謝症候群成分的患者服用抗高血壓劑量。

And so we believe that by targeting that subpopulation, we will define a niche where our drug can differentiate from other approaches which are much more a general CKD population. That's the possible -- that's why, even though it's a crowded field with multiple players, we still think we've probably got the best-in-class ASI, and it has potential in that way.

因此，我們相信，透過針對該亞人群，我們將定義一個利基市場，使我們的藥物可以與其他更針對一般 CKD 人群的方法區分開來。這就是可能的——這就是為什麼，儘管這是一個有多個參與者的擁擠領域，我們仍然認為我們可能擁有一流的 ASI，並且它在這方面具有潛力。

Got it. And I guess one more, if you don't mind, can you just remind us of the rationale for using the 25 mg dose instead of 50 mg in the Explore-CKD study? Is it just hyperkalemia and lower eGFR patients, or is there more to it?

知道了。我想還有一點，如果您不介意的話，您能否提醒我們在 Explore-CKD 研究中使用 25 毫克劑量而不是 50 毫克劑量的基本原理？只是高血鉀和 eGFR 較低的患者，還是有其他原因？

Right, so it's an abundance of caution at this exploratory stage. We didn't want to take on the hyperkalemia risk. Now, I'll tell you, our nephrology advisors say they're perfectly comfortable using potassium binders if needed to get the blood pressure down in these patients. So this is just the first step on the journey, but that's the main reason.

是的，所以在這個探索階段需要非常謹慎。我們不想承擔高血鉀的風險。現在，我告訴你，我們的腎臟科顧問說，如果需要降低這些病人的血壓，他們非常願意使用鉀結合劑。所以這只是旅程的第一步，但卻是主要原因。

Makes sense. Thanks so much.

有道理。非常感謝。

Thanks, Rami.

謝謝，拉米。

Thank you. There are no further questions at this time. I would like to turn the floor back over to Jon Congleton for closing comments.

謝謝。目前沒有其他問題。我想請喬恩·康格爾頓 (Jon Congleton) 發表結束評論。

Thank you, operator, and thank you to everyone for joining us today. We're very excited about the programs, some progress to date that we've made in the first half of 2024 and advancing our clinical programs. And we remain very enthusiastic about the upcoming milestones for the rest of the year and into 2025. We look forward to updating you as our pivotal program for runners that continues to advance. With that, we will close the call.

謝謝運營商，也謝謝大家今天加入我們。我們對這些計畫感到非常興奮，我們在 2024 年上半年取得了一些進展，並推進了我們的臨床計畫。我們仍然對今年剩餘時間和 2025 年即將到來的里程碑充滿熱情。我們期待為您提供最新信息，作為我們持續進步的跑步者的關鍵計劃。這樣，我們就結束通話了。

Thank you, and that concludes today's conference. All parties may disconnect.

謝謝大家，今天的會議到此結束。所有各方都可以斷開連接。