Trevi Therapeutics Inc (TRVI) 2024 Q4 法說會逐字稿

Good afternoon, and welcome to the Trevi Therapeutics fourth-quarter and year-end 2024 earnings conference call. (Operator Instructions) Please note, this event is being recorded.

下午好，歡迎參加 Trevi Therapeutics 2024 年第四季和年終收益電話會議。（操作員指示）請注意，此事件正在被記錄。

Various remarks that management makes during this conference call about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995.

管理階層在本次電話會議上就公司未來預期、計畫和前景所作的各種評論均構成《1995 年私人證券訴訟改革法案》安全港條款所指的前瞻性陳述。

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent annual report on Form 10-K, which the company filed with the SEC this afternoon.

由於各種重要因素，包括公司今天下午向美國證券交易委員會提交的最新 10-K 表年度報告「風險因素」部分中討論的因素，實際結果可能與這些前瞻性陳述所示的結果存在重大差異。

In addition, any forward-looking statements represent the company's views only as of today and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so, even if its views change.

此外，任何前瞻性陳述僅代表本公司截至今日的觀點，不應被視為代表本公司在任何後續日期的觀點。儘管公司可能選擇在未來某個時間點更新這些前瞻性聲明，但公司明確表示不承擔任何此類義務，即使其觀點發生變化。

I would now like to turn the conference over to Jennifer Good, Trevi's President and CEO. Please go ahead.

現在，我想將會議交給 Trevi 總裁兼執行長 Jennifer Good。請繼續。

Good afternoon, and thank you for joining us for our fourth-quarter and year-end 2024 earnings call and business update. Joining me today on this call is my colleague, Lisa Delfini, Trevi's Chief Financial Officer. Lisa and I will make some comments on the business and financial results, then we are happy to answer any questions that you may have.

下午好，感謝您參加我們的 2024 年第四季和年終收益電話會議和業務更新。今天和我一起參加電話會議的還有我的同事、Trevi 的財務長 Lisa Delfini。Lisa 和我將對業務和財務結果發表一些評論，然後我們很樂意回答您可能提出的任何問題。

2024 was a strong year of execution by Team Trevi, which delivered three positive data readouts over the past few months: the Human Abuse Potential study, the sample size re-estimation for the CORAL study in chronic cough patients with IPF and the RIVER study in patients with refractory chronic cough, or RCC.

2024 年是 Trevi 團隊執行強勁的一年，在過去幾個月中，該團隊提供了三份積極的數據讀數：人類濫用潛力研究、針對患有 IPF 的慢性咳嗽患者的 CORAL 研究的樣本量重新估計以及針對難治性慢性咳嗽或 RCC 患者的 RIVER 研究。

These trials in total were conducted across 11 countries in approximately 75 different sites and through multiple regulatory authorities. I am proud of our team and the urgency and commitment they had to running high-quality trials. Each of these trials had data analyses that were very important to advancing the clinical development plan of Haduvio.

這些試驗總共在 11 個國家的約 75 個不同地點透過多個監管機構進行。我為我們的團隊以及他們對進行高品質試驗的緊迫感和承諾感到自豪。每項試驗的數據分析對於推進 Haduvio 的臨床開發計畫非常重要。

Let me briefly review each of these key readouts. In December, we read out positive results in our Human Abuse Potential or HAP study. We needed to bring the package on drug likability after current day standards since nalbuphine is centrally acting therapy.

讓我簡要回顧一下每個關鍵讀數。12 月，我們宣讀了人類濫用潛力或 HAP 研究的正面結果。由於納布啡是一種中樞作用療法，我們需要根據當今標準制定藥物適宜性方案。

As a reminder, injectable nalbuphine which is indicated for severe pain has been around for decades and continues to be unscheduled by the DEA. Nalbuphine belongs to a class of drugs known as mixed agonist antagonists that were designed for patients to get the efficacy of opioids, but without the abuse potential.

需要提醒的是，用於治療劇烈疼痛的注射用納布啡已經存在了幾十年，但仍未被美國緝毒局列為管制藥品。納布啡屬於混合激動劑拮抗劑類藥物，旨在讓患者取得鴉片類藥物的療效，但不會造成濫用的可能性。

There are two primary reasons for nalbuphine remaining unscheduled all these years. First, because of the new antagonism effect of the drug, which can elicit withdrawal symptoms in individuals who are using opioid class drugs. It is not preferred or sought after by these individuals.

納布啡多年來一直未被列入管制藥品目錄，主要有兩個原因。首先，由於該藥物的新的拮抗作用，可引起正在使用鴉片類藥物的個體出現戒斷症狀。它並不受這些人的青睞或追捧。

Second, in the DEA's ongoing surveillance, there are no significant issues of abuse detected. Both the 162-milligram and the 81-milligram nalbuphine doses studied show statistically significant lower relative drug liking compared to butorphanol.

其次，在美國緝毒局的持續監視中，並沒有發現重大濫用問題。所研究的 162 毫克和 81 毫克納布啡劑量均顯示出與布托啡諾相比統計學上明顯較低的相對藥物喜好。

Based on the effective doses that we are seeing in cough, it is likely that the 162-milligram dose fulfills the requirement of 3x the marketed dose to be considered super therapeutic. There's nothing else we need to do until filing our NDA, when we will submit an eight-factor plan which will include this data, and a final determination on whether there will be changes in scheduling will be made upon approval by the FDA and DEA.

根據我們在咳嗽中看到的有效劑量，162 毫克的劑量很可能滿足 3 倍市場劑量的要求，被認為是超級治療劑量。在提交 NDA 之前我們不需要做任何其他事情，屆時我們將提交包含這些數據的八因素計劃，並在獲得 FDA 和 DEA 批准後最終決定是否更改時間安排。

We do not believe we've shown anything in our program that changes the abusability risk profile of this drug and that it will remain unscheduled, but that decision will ultimately be made later.

我們認為，我們的計劃並未顯示任何可改變該藥物濫用風險狀況的內容，且該藥物仍將不受管制，但最終將在稍後做出決定。

Moving on to our clinical data. In December, we announced the results of the sample size reestimation, or SSRE, analysis in our Phase 2b study in patients with IPF chronic cough. This was a preplanned statistical look on the highest dose arm, 108-milligram BID, when 50% of the originally planned patients completed the six weeks of treatment to confirm the original powering assumptions.

繼續我們的臨床數據。12 月，我們公佈了針對 IPF 慢性咳嗽患者進行的 2b 期研究的樣本量重估（SSRE）分析結果。這是對最高劑量組（108 毫克 BID）進行的預先計劃的統計觀察，其中 50% 的原計劃患者完成了六週的治療，以證實最初的動力假設。

The analysis was done by an unblinded statistician external to the company. The only information we received back was regarding whether a change to sample size was required.

該分析是由公司外部的一位未設盲的統計學家完成的。我們收到的唯一資訊是關於是否需要改變樣本量。

We were very pleased with the result that the SSRE confirmed the original sample size of 160 patients. This positive result essentially confirms the assumptions of effect size of the study, expected variability and confirmed a conditional power at the 50% enrollment point of at least 80% or greater. This was exciting news for us and allowed us to stay on the original time line for the study and wrap up enrollment in February of this year.

我們對 SSRE 確認的原始樣本量為 160 名患者的結果感到非常滿意。這項正面結果基本上證實了研究的效果大小假設、預期變異性，並證實了 50% 入學點的條件效力至少為 80% 或更高。這對我們來說是一個令人興奮的消息，使我們能夠按照原定的研究時間表在今年二月完成招生。

Just a little color on enrollment. We had our biggest month of enrollment in December and January, which I think speaks to the excitement about a potential treatment and the significant unmet need in these IPF patients suffering from chronic cough.

入學時只需一點顏色。12 月和 1 月是我們的招生人數最多的月份，我認為這體現了人們對潛在治療方法的興奮之情，也體現了患有慢性咳嗽的特發性肺纖維化 (IPF) 患者的巨大未滿足需求。

We currently have a handful of patients completing their treatment and expect to announce data from this trial in the second quarter of this year. This is our lead indication, and we are excited to get the data from this dose-ranging study and advance the development program.

我們目前有少數患者完成治療，預計將在今年第二季公佈該試驗的數據。這是我們的主要適應症，我們很高興從這項劑量範圍研究中獲得數據並推進開發計劃。

Finally, just last week, we announced the data from our Phase 2a RIVER trial in patients with RCC, which includes those with unexplained chronic cough. RCC is a debilitating disease that affects approximately 2 million to 3 million US patients and has no approved therapies in the US.

最後，就在上週，我們公佈了針對 RCC 患者的 2a 期 RIVER 試驗數據，其中包括患有不明原因慢性咳嗽的患者。RCC 是一種使人衰弱的疾病，影響約 200 萬至 300 萬美國患者，在美國尚無核准的治療方法。

Importantly, there have been many drugs studied in this condition which have failed, all primarily peripherally acting agents, with only one drug still in late-stage development.

重要的是，針對這種疾病進行研究的許多藥物都失敗了，這些藥物主要都是外周作用藥物，只有一種藥物仍處於後期開發階段。

Our hypothesis heading into the RIVER study was that our central and peripheral mechanism could change the outcome for patients that suffer with this disease. The types of chronic cough we are studying are linked to hypersensitivity at the brain and why we believe the central aspect of our mechanism is important.

我們在 RIVER 研究中提出的假設是，我們的中樞和周邊機制可以改變患有這種疾病的患者的預後。我們正在研究的慢性咳嗽類型與大腦的超敏反應有關，這也是我們認為機制的核心面向很重要的原因。

As reported last week, Haduvio met the primary endpoint in the RIVER study with a statistically significant reduction in 24-hour objective cough frequency, achieving a p value of less than 0.0001 with a 57% placebo adjusted change from baseline and importantly showed the same strong effect across a range of cough counts, including patients with moderate or severe cough. So we are excited to progress development of Haduvio and RCC.

正如上週報導的那樣，Haduvio 達到了 RIVER 研究的主要終點，24 小時客觀咳嗽頻率顯著降低，p 值小於 0.0001，與基線相比安慰劑調整後變化率為 57%，重要的是，在包括中度或重度咳嗽患者在內的一系列咳嗽次數中均表現出同樣強大的效果。因此，我們很高興能夠推進 Haduvio 和 RCC 的開發。

As we have explained, with IPF as our lead indication and a specialty commercial sales model, we will develop Haduvio and RCC for patients which have failed prior therapy. We believe there are many patients not getting relief from the drugs currently being used off label.

正如我們所解釋的，以 IPF 作為我們的主要適應症和專業的商業銷售模式，我們將為先前治療失敗的患者開發 Haduvio 和 RCC。我們相信，許多患者並未從目前未列入藥品說明書的藥物中得到緩解。

And even if a P2X3 antagonist is approved, they have only been shown to work in the most severe coughers, which represents less than one-third of the market. So there will still remain a high unmet need for RCC patients who have exhausted available treatment options.

即使 P2X3 拮抗劑獲得批准，也僅對最嚴重的咳嗽患者有效，這佔市場份額的不到三分之一。因此，對於已經用盡可用治療方案的 RCC 患者來說，仍有大量未滿足的治療需求。

By moving to treatment failure patients in RCC, we focus on the patients with the highest unmet need, allowing us to target a subsegment of the RCC population and maintain our specialty IPF pricing.

透過轉向 RCC 治療失敗的患者，我們將重點放在未滿足需求最高的患者，這使我們能夠瞄準 RCC 人群的一個子群體並維持我們的專業 IPF 定價。

So data readouts at Trevi have been on a roll. Next up is our Phase 2b readout for the CORAL trial in IPF chronic cough patients. As I mentioned, we expect that data next quarter. The team has been busy planning for the next steps to quickly progress development of Haduvio in both IPF and RCC.

因此，特雷維的數據讀數一直很順利。接下來是我們對 IPF 慢性咳嗽患者進行 CORAL 試驗的 2b 期讀數。正如我所提到的，我們預計下個季度的數據將會公佈。該團隊一直忙於規劃下一步，以快速推進 Haduvio 在 IPF 和 RCC 方面的開發。

The next key steps in development are for the IPF cough program, we will get the data, and assuming it is positive, we'll prepare for an end of Phase 2 meeting with the FDA, which we expect will happen by the end of 2025.

開發的下一個關鍵步驟是針對 IPF 咳嗽計劃，我們將獲取數據，並假設它是積極的，我們將準備與 FDA 舉行第 2 階段會議，我們預計該會議將在 2025 年底舉行。

At the meeting, we expect to discuss our planned pivotal program, study designs and required safety database as well as any other development studies we need to do for an NDA filing.

在會議上，我們希望討論我們計劃的關鍵項目、研究設計和所需的安全資料庫以及我們為提交 NDA 申請所需做的任何其他開發研究。

For the RCC program, we are waiting on final data sets and developing a protocol for the next study. We will request a meeting with the FDA to get their input on our program and next study. We are planning on releasing more of the RIVER data at both the American Thoracic Society meeting in May in San Francisco as well as the European Respiratory Society Congress meeting in September.

對於 RCC 計劃，我們正在等待最終數據集並為下一項研究制定協議。我們將請求與 FDA 會面，以獲得他們對我們的計劃和下一步研究的意見。我們計劃在 5 月於舊金山舉行的美國胸腔科學會會議以及 9 月舉行的歐洲呼吸學會大會上發布更多 RIVER 數據。

As a side note, we are planning on being quite active at ATS in San Francisco in mid-May. So if any of you plan to attend, please let me know. We are planning on hosting a KOL panel featuring both IPF experts and an RCC doctor for investors.

順便說一句，我們計劃在五月中旬在舊金山的 ATS 上積極活動。因此，如果你們當中有人計劃參加，請告訴我。我們計劃為投資者舉辦一場由 IPF 專家和 RCC 醫生組成的 KOL 小組討論會。

As you can see, we made a lot of progress this year, and Haduvio is now the first and only therapy in clinical development to show a statistically significant reduction in chronic cough across patients with IPF and RCC. It positions Haduvio as a first-in-class therapy in IPF and potentially best-in-class across chronic cough indications.

正如您所看到的，我們今年取得了很大進展，Haduvio 現在是臨床開發中第一個也是唯一一個在 IPF 和 RCC 患者中顯示出顯著減少慢性咳嗽的療法。這使得 Haduvio 成為 IPF 領域的一流療法，並有可能成為慢性咳嗽適應症領域的最佳療法。

We have a focused plan on developing Haduvio in serious chronic cough conditions that our team can execute and we believe can generate significant value for the company and its shareholders.

我們有一個重點計劃，致力於開發用於治療嚴重慢性咳嗽疾病的 Haduvio，我們的團隊可以執行該計劃，我們相信該計劃可以為公司及其股東創造巨大的價值。

I will now turn it over to Lisa to review our financial results, then we will open it up for any questions you may have.

現在我將把它交給麗莎來審查我們的財務結果，然後我們將回答你們可能提出的任何問題。

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the 3 and 12 months ended December 31, 2024, can be found in our press release issued ahead of this call and our 10-K, which was filed with the SEC today after the market closed. For the fourth quarter of 2024, we reported a net loss of $11.4 million compared to a net loss of $7.8 million for the same quarter in 2023.

謝謝你，詹妮弗，大家下午好。截至 2024 年 12 月 31 日的 3 個月和 12 個月的完整財務業績可在我們在本次電話會議之前發布的新聞稿和今天市場收盤後向美國證券交易委員會 (SEC) 提交的 10-K 報表中找到。2024 年第四季度，我們報告淨虧損 1,140 萬美元，而 2023 年同期淨虧損為 780 萬美元。

R&D expenses were $9.3 million during the fourth quarter of 2024 compared to $6.5 million in the same quarter in 2023. The increase was primarily due to increased clinical trial costs in our Phase 2b CORAL trial, our Phase 2a RIVER trial and our HAP study, as well as an increase in personnel-related expenses.

2024 年第四季的研發費用為 930 萬美元，而 2023 年同期為 650 萬美元。增加的主要原因是我們的 2b 期 CORAL 試驗、2a 期 RIVER 試驗和 HAP 研究的臨床試驗成本增加，以及人員相關費用增加。

G&A expenses increased to $2.9 million during the fourth quarter of 2024 compared to $2.4 million in the same period of 2023, primarily due to an increase in stock-based compensation and personnel-related expenses. As of December 31, 2024, our cash, cash equivalents and marketable securities totaled $107.6 million. This included a $50 million unwritten offering we completed in December after the 2 positive data readouts that Jennifer discussed.

2024 年第四季度，一般及行政費用 (G&A) 增至 290 萬美元，而 2023 年同期為 240 萬美元，這主要是由於股票薪酬和人員相關費用增加。截至 2024 年 12 月 31 日，我們的現金、現金等價物及有價證券總額為 1.076 億美元。其中包括我們在 Jennifer 討論的 2 個積極數據讀數之後於 12 月完成的 5000 萬美元非書面報價。

This set us up nicely to not have to raise off of our positive RCC data last week. Our cash runway guidance into the second half of 2026 remains unchanged and funds completing our ongoing Phase 2b CORAL trial for chronic cough in patients with IPF, and based on our current estimates, our next RCC trial. It does not include funding for the next studies in IPF, other than some start-up costs.

這讓我們不必因為上週的積極 RCC 數據而提高利率。我們對 2026 年下半年的現金流指引保持不變，並為完成我們正在進行的針對 IPF 患者慢性咳嗽的 2b 期 CORAL 試驗提供資金，並且根據我們目前的估計，完成我們的下一項 RCC 試驗。除了一些啟動成本外，它不包括對 IPF 下一步研究的資助。

In 2025, we expect cash burn net of interest income of about $12 million to $14 million per quarter in Q1 and Q2. Over the next couple of quarters, we will be getting feedback from the FDA and planning the subsequent trial in RCC and assuming positive data trials in IPF and non-IPF ILDs. We will give additional cash burn guidance as we provide guidance on the design and start date for these trials.

到 2025 年，我們預計第一季和第二季扣除利息收入後的現金消耗將達到每季約 1,200 萬至 1,400 萬美元。在接下來的幾個季度中，我們將從 FDA 獲得反饋併計劃在 RCC 中進行後續試驗，並假設在 IPF 和非 IPF ILD 中進行積極的數據試驗。在為這些試驗的設計和開始日期提供指導時，我們將提供額外的現金消耗指導。

Our current fully diluted shares outstanding are approximately 137 million, which includes approximately 10 million stock options outstanding. This concludes our prepared remarks. I will now turn the call back over to the operator for Q&A.

我們目前已發行的完全稀釋股份約為 1.37 億股，其中包括約 1,000 萬股已發行股票選擇權。我們的準備好的演講到此結束。我現在將把電話轉回給接線員進行問答。

(Operator Instructions) Faisal Khurshid, Leerink Partners.

（操作員指示）Faisal Khurshid，Leerink Partners。

Hey. Good afternoon. Thanks for taking the question. I wanted to ask, now that you've completed enrollment in CORAL, could you speak a little bit to the patients that you enrolled? And specifically, like were there any differences in the first half of the study before the sample size your estimation in the second half of the study, like this bolus that you talked about in December and January until you completed the enrollment? And then I have a follow-up. Thank you.

嘿。午安.感謝您回答這個問題。我想問一下，現在您已經完成了 CORAL 的招募，您能否與您招募的患者聊聊？具體來說，在研究的前半部分，在您估計的樣本量與研究的後半部分相比是否存在任何差異，例如您在 12 月和 1 月談到的這種推注，直到您完成招募？然後我有一個後續問題。謝謝。

Thank you, Faisal, for the question. So you remember, we didn't get the results from this until December. And the study was almost 75%, 80% enrolled at that point. So we didn't make any changes because until we knew those results, even then, we didn't change any sites, no protocol changes. The overall study statistics look basically the same.

謝謝費薩爾提出的問題。所以你記得，我們​​直到十二月才得到結果。此時，研究的參與人數已接近 75% 至 80%。所以我們沒有做任何改變，因為直到我們知道這些結果，即使在那時，我們也沒有改變任何站點，也沒有改變協議。整體研究統計數據看起來基本上相同。

So that's an important aspect of this. We did not share these results with the sites other than to say that we did the preplanned analysis and no upsize was required because you don't want to change the script they're using at the site. So no, we've been very careful to not have any changes in the second half of this population.

這是其中一個重要的面向。我們沒有與網站分享這些結果，只是說我們做了預先規劃的分析，並且不需要擴大規模，因為您不想更改他們在網站上使用的腳本。所以，我們一直非常小心，以確保這部分人口的後半部不會有任何變化。

Got it. That's helpful. And I think before, you commented a little bit on the discontinuation rate that you were seeing earlier on in CORAL. Could you comment that -- now that you're almost done with the study dosing, how that's tracked in the back half of the study?

知道了。這很有幫助。我認為您之前曾對 CORAL 中看到的停藥率做過一些評論。您能否評論一下——現在您幾乎完成了研究劑量測定，那麼在研究的後半部分是如何追蹤的？

Jim confirmed to me about an hour ago that we're still running in single digits. So it stayed very consistent actually in the whole study. And that's total. We can only see total blinded. So I don't obviously know who's on drug and placebo, but we stayed in single digits and it stayed very consistent across the study.

大約一小時前，吉姆向我證實，我們的成績仍處於個位數。因此，在整個研究中它實際上保持了非常一致的狀態。這就是全部內容。我們只能看到完全盲目的景象。所以我顯然不知道誰服用了藥物和安慰劑，但我們保持個位數，並且在整個研究中保持非常一致。

Awesome. Thank you. Looking forward to the data.

驚人的。謝謝。期待數據。

Yeah. Thank you.

是的。謝謝。

Mayank Mamtani, B. Riley.

Mayank Mamtani，B. Riley。

Yes. Good afternoon. Thanks for taking our questions and congrats on strong execution in recent months. Could you talk a little bit about your placebo response expectation for IPF chronic cough Phase 2 study? And if you could confirm the two-week placebo run-in period that you have? And how might your -- sorry, multipart question, how might your baseline cough count differ from what you had in CANAL?

是的。午安.感謝您回答我們的問題，並祝賀您近幾個月來的出色表現。您能否談談您對 IPF 慢性咳嗽第 2 階段研究的安慰劑反應預期？您能否確認兩週的安慰劑導入期？您的—抱歉，這個問題由多個部分組成，您的基線咳嗽計數與您在 CANAL 中的計數有何不同？

Yeah. So just first of all, the two-week placebo run-in, that's not a two-week placebo run-in, that's a two-week titration period, which we will have in all of our studies. So just to be clear about that. Placebo hasn't been a big problem in IPF studies to date. It's been pretty well behaved.

是的。首先，兩週的安慰劑導入期，這不是兩週的安慰劑導入期，而是兩週的滴定期，我們在所有研究中都會有這個階段。所以只是想明確這一點。到目前為止，安慰劑在 IPF 研究中還不是什麼大問題。它表現得相當好。

So we didn't see a need to do any placebo run-in. The powering assumptions around placebo, we had assumed 66% drug effect, 30% placebo or -- so 36% placebo-adjusted change. As you know, our SSRE confirmed that we're at least at that effect size or greater. So I think we were pretty conservative on our placebo effect.

因此我們認為沒有必要進行任何安慰劑試驗。關於安慰劑的動力假設，我們假設 66% 是藥物效應，30% 是安慰劑效應，或 36% 是安慰劑調整後的變化。如您所知，我們的 SSRE 確認我們至少達到了該效果大小或更大。所以我認為我們對安慰劑效應的看法相當保守。

We've seen generally across prior IPF cough studies, of which there's not a lot but the placebo effect is ranged between about 15% and 23%. So I think we've been pretty conservative there. And then as far as baseline cough counts, we are not -- our medical monitor is looking at that, but I'm certainly not looking at that at my level, and I don't think Jim is either.

我們在先前的 IPF 咳嗽研究中普遍看到，雖然安慰劑效應不多，但其影響在 15% 到 23% 左右。所以我認為我們在這方面相當保守。就基線咳嗽計數而言，我們的醫療監測器沒有關注這一點，但我肯定不會在我的層面上關注這一點，而且我認為吉姆也沒有關注這一點。

So I don't have any commentary around what baseline cough counts look. I do know that our inclusion criteria of how you get in and there's some minimum baseline costs that are required of VAS score didn't change. So I would assume that we should be roughly in the same range.

因此，我對基線咳嗽計數的情況沒有任何評論。我確實知道，我們關於如何進入的納入標準以及 VAS 評分所需的一些最低基線成本並沒有改變。所以我認為我們應該大致處於同一範圍內。

Thank you. And if I could maybe ask about the RIVER RCC data now that it's out and being looked at by KOLs. How are you thinking of the RCC patient population being split between P2X3 and Haduvio, assuming they both are on the market in the next three- to four-year time period?

謝謝。現在 RIVER RCC 數據已經發布，並且 KOL 正在查看，我是否可以詢問一下。假設 P2X3 和 Haduvio 都在未來三到四年內上市，您認為 RCC 患者群體在 P2X3 和 Haduvio 之間的分佈如何？

Yeah. Thank you, Mayank. As we've said on commercially, we're looking at being -- treating basically patients that are treatment failure. So right now, they're all being used. They're all being tried with off-label stuff that really doesn't work that well.

是的。謝謝你，Mayank。正如我們在商業上所說的那樣，我們正在考慮治療那些治療失敗的患者。所以現在它們都正在被使用。他們嘗試了各種非說明書推薦的藥物，但效果並不好。

So all the patients ending up in these studies have already been through that layer of stuff. If a P2X3 does make it to the market, Glaxo have success -- and I hope for patients that they do -- I think we will look to -- you can try your P2X3 first. But then if you fail that, you'll get to our Haduvio therapy. So second or third-line therapy, depending on what's approved.

因此，所有參與這些​​研究的患者都已經經歷過這一層考驗。如果 P2X3 確實進入市場，葛蘭素史克就會獲得成功——我希望對於患者來說，他們會成功——我想我們會期待——您可以先嘗試 P2X3。但如果您失敗了，您可以接受我們的 Haduvio 療法。因此，二線或三線治療取決於核准的治療方法。

I think there's a lot of unmet need still. I think as you know, the P2X3s have really only had success in the severe coughers and even then haven't shown efficacy in 40% of those. So there's a lot of people who are still seeking treatment.

我認為仍有許多未滿足的需求。我認為如你所知，P2X3 實際上只對嚴重咳嗽患者有效，而且即使在這種情況下，40% 的患者也沒有顯示出療效。因此仍有許多人在尋求治療。

And this moderate and severe somewhat an arbitrary line. I think the people that are really pursuing therapy not able to get treatment that helps them. I think they'll end up in trying our Haduvio.

而這個適度和嚴重之間的界線多少有些隨意。我認為那些真正尋求治療的人無法獲得對他們有幫助的治療。我認為他們最終會嘗試我們的 Haduvio。

Thank you.

謝謝。

Annabel Samimy, Stifel.

安娜貝爾·薩米米（Annabel Samimy），Stifel。

Hi. Thanks for taking my questions. Just some more data and more questions around the data. Now that you've had about 10 days to mull it over, is there anything you can share with us regarding the efficacy that you saw max out of the 54-milligram dose?

你好。感謝您回答我的問題。只是一些更多的數據和圍繞數據的更多問題。現在您已經有大約 10 天的時間來考慮這個問題，您能和我們分享一下您在 54 毫克劑量下看到的最大療效嗎？

And if this was similar to what you saw in the initial IPF trial, did you see a maxing out of that? And if you might still be considering possibly lower dosing in the CORAL studies? I understand that you have to see it, but it seems if you had any maxing out in CANAL might indicate that you might see, potentially look at lower doses there.

如果這與您在初始 IPF 試驗中看到的情況類似，您是否看到了最大值？您是否仍在考慮在 CORAL 研究中降低劑量？我明白你必須看到它，但似乎如果你在 CANAL 中達到最大值可能表明你可能會看到，可能會在那裡看到較低的劑量。

And I say this, I guess, all with the AEs in mind and how that might be improved. Were these AEs based on initial treatment? Or do they come as they stepped up in dose? So I guess that's my first very long question.

我想，我這樣說都是考慮到 AE 以及如何改進它。這些不良事件是否基於初始治療？還是隨著劑量增加而出現這種情況？我想這是我的第一個很長的問題。

Yeah. No, I get it all, good questions. I think Annabel, we haven't seen any more data since the top line data we got, I mean, it's hard to believe it was 10 days ago. It feels like two days ago, it's been a blur. But I would say that I think the difference of CANAL, our first IPF study in here, we did not have VitaloJAK readings at each dose.

是的。不，我完全明白，這是很好的問題。我認為安娜貝爾，自從我們獲得頂線數據以來，我們還沒有看到任何其他數據，我的意思是，很難相信那是 10 天前的事了。感覺就像兩天前的事了，一切都很模糊。但我想說，我認為 CANAL 的不同之處在於，我們在這裡進行的第一個 IPF 研究，我們沒有在每次劑量時進行 VitaloJAK 讀數。

We had to rely on patient-reported outcomes, and there was a similar slope, but it did seem to show efficacy on the Pro through 108 milligrams. In this study, you're right, it clearly shows [ that peers ] the effective dose is in that 27 to 54 range. The CORAL results in IPF, the parallel arm design is going to be very informative, I think, around those.

我們必須依賴患者報告的結果，並且存在類似的斜率，但它似乎確實顯示出對 Pro 的療效，劑量為 108 毫克。在這項研究中，您是對的，它清楚地表明，有效劑量在 27 至 54 範圍內。我認為，CORAL 在 IPF 中的結果和平行臂設計將會非常有幫助。

So I definitely think -- and Jim and I have talked about this as well -- probably the 108 milligrams for RCC, we will not need. We will end up on the low end of this dose range, which is always advantageous in the direction you were heading around AEs.

因此我確實認為——吉姆和我也討論過這個問題——對於 RCC 來說，我們可能不需要 108 毫克。我們最終會處於這個劑量範圍的低端，這對於您解決 AE 問題的方向始終是有利的。

You can titrate slower, you can do one-time dosing at night for a while to get people used to the drug. It just gives you a lot more flexibility when you're not trying to move people up to effective dose early. So yes, we don't have more data.

您可以放慢劑量滴定速度，可以在晚上進行一次性給藥一段時間，以讓人們習慣這種藥物。當您不試圖讓人們提前達到有效劑量時，它只會給您更多的靈活性。是的，我們沒有更多數據。

When we do, we'll show some of that color. I probably got some of what I'm going to share at ATS, I think. But that's what we know today. Our CMC team is looking at the doses and thinking about whether we might even need one dose lower than 27. So we're doing our planning around that as well.

當我們這樣做時，我們會展示一些顏色。我想我可能已經了解了一些我將在 ATS 上分享的內容。但這就是我們今天所知道的。我們的 CMC 團隊正在研究劑量並考慮是否需要低於 27 的劑量。因此我們也在圍繞這一點進行規劃。

Got it. And then just really quickly on the RCC, the next trial. Will you be -- is it also still going to be an all-comers trial refractory population? Are you changing the inclusion criteria at all, given that you are positioning this for a third-line treatment after P2X3?

知道了。然後很快就進入 RCC，進行下一次試驗。您是否會—這是否仍將是一個全民試驗難治人群？鑑於您將其定位為 P2X3 之後的三線治療，您是否會改變納入標準？

I guess you don't really have the opportunity to position it that way in a trial. But is there anything about the inclusion criteria or the populations that you might be studying in the next trial?

我想你實際上沒有機會在試驗中以那種方式定位它。但是，關於納入標準或您在下一次試驗中可能研究的人群，有什麼資訊嗎？

No. So we'll -- in our inclusion criteria, it will be really similar to what we just did. There's got to be some minimum level of coughs. People have centered around this 8 to 10 coughs because we're not trying to go after this mild intermittent population. But other than that, we're no longer delineating between moderate and severe.

不。因此，我們的納入標準與我們剛才所做的非常相似。咳嗽必須達到最低限度。人們關注的重點是這 8 到 10 次咳嗽，因為我們不想針對這種輕微間歇性咳嗽的人。但除此之外，我們不再區分中度和重度。

The cough world doesn't do that. It's an arbitrary thing that was made up for clinical trials. And so we'll just move forward, which I think gives us a lot of advantages in recruiting and flexibility. So I think that will be quite helpful. And there was a second part of your question, I'm sorry, which I forgot?

咳嗽的世界不會這樣做。這是為了臨床試驗而任意編造出來的。因此我們將繼續前進，我認為這給我們在招募和靈活性方面帶來了很多優勢。所以我認為這會非常有幫助。您的問題還有第二部分，抱歉，我忘了？

No, it's pretty -- you pretty much covered it.

不，它很漂亮——你幾乎把它覆蓋住了。

One of the points which slip my mind. But thank you, Annabel.

這是我忘記的一點。但謝謝你，安娜貝爾。

Okay. Thanks a lot.

好的。多謝。

Leland Gershell, Oppenheimer.

利蘭·格謝爾，奧本海默。

Hey. Good afternoon, Jennifer and team. Thanks for taking the question. Wanted to just ask with respect to time lines. I know when we checked in last, which was before the RIVER readout. In addition to the efficacy data, you also need long-term exposure data to fill out the NDA package, which would impact initial approval time lines.

嘿。下午好，珍妮佛和團隊。感謝您回答這個問題。只是想問一下有關時間軸的問題。我知道我們上次登記入住的時間，那是在 RIVER 讀數之前。除了功效數據之外，您還需要長期暴露數據來填寫 NDA 包，這會影響初始批准時間表。

I'm just wondering if you are pursuing RCC in a Phase 3, and you also have, what I guess would be two Phase 3s for IPF cough, could that expedite your route to market because you may have additional safety exposure data from the patients who come from the late-stage RCC study? Thanks.

我只是想知道，如果您正在進行 RCC 的 3 期研究，並且我猜您還有兩個針對 IPF 咳嗽的 3 期研究，這是否可以加快您的上市進程，因為您可能擁有來自後期 RCC 研究的患者的額外安全暴露數據？謝謝。

Yeah. That's a good question, Leland. So to date, we haven't done any open-label extension data. We need to start doing that from here on out. As you know, our regulatory strategy is our first NDA is currently planned to be the IPF study. So will be the NDA that we negotiate with the FDA about what safety database exposures they need.

是的。這是個好問題，利蘭。所以到目前為止，我們還沒有做任何開放標籤擴展資料。我們需要從現在開始這樣做。如您所知，我們的監管策略是，我們的第一個 NDA 目前計劃進行 IPF 研究。因此，我們將與 FDA 協商有關他們需要哪些安全資料庫暴露的 NDA。

RCC will be an FNDA. So it's a follow-on. And we'll get to benefit from all the exposure data that was developed around IPF and is just one pivotal study in that strategy. So these are the kinds of things we need to really sit with the regulatory authorities and talk through. As you also know, we have a lot of safety data from our prior clinical programs, which includes 6 months and 12-month safety data.

RCC 將成為 FNDA。所以這是一個後續行動。我們將受益於圍繞 IPF 開發的所有暴露數據，這只是該策略中的一項關鍵研究。因此，我們需要與監管機構坐下來討論這些事情。如您所知，我們從先前的臨床課程中獲得了大量的安全數據，其中包括 6 個月和 12 個月的安全數據。

So how that all folds together, we'll have to sort through because I think our actual efficacy trials will not need to be very big with this effect size. So it will really probably be driven more by the safety database.

因此，我們必須對所有這些因素如何綜合起來進行分析，因為我認為，就這種效果而言，我們的實際功效試驗不需要進行非常大的規模。因此它實際上可能更多地受到安全資料庫的驅動。

All right. Thanks for the color.

好的。謝謝你的顏色。

And I'm just going to follow up, Annabel. I remembered your second question, which was around treatment failures. And just to finish that point, these people have all failed now. And I think in the next study, it will just be a matter of documenting that they've tried other things and they've failed on another antitussive therapy. And so that will start going into our protocols. And we'll satisfy that requirement from a development perspective. Next question.

我只是想跟進一下，安娜貝爾。我記得你的第二個問題，是關於治療失敗的。就這一點而言，這些人現在都失敗了。我認為在下一項研究中，只需要記錄他們嘗試過其他方法但另一種鎮咳療法失敗了的情況。這將開始納入我們的協議。我們將從發展的角度來滿足這項要求。下一個問題。

Serge Belanger, Needham & Company.

塞爾日·貝朗格（Serge Belanger），Needham & Company。

Hi. Good afternoon. I guess my first question, regarding the -- just an update on the respiratory physiology study, whether it's on track, I guess, to finish in the second half? And if you're -- it's been modified given the recent data from RCC?

你好。午安.我的第一個問題是關於呼吸生理學研究的最新進展，我猜它是否會在下半年完成？如果您——它已經根據 RCC 的最新數據進行了修改？

Yeah, it's a good question, Serge. So that study is screening, it's underway. There's been some, I would say, just operational logistics of sorting out certain things. It's a study nobody's done. So again, just typical Phase 1 stuff.

是的，這是個好問題，塞爾吉。因此該研究正在進行篩選。我想說的是，有些只是整理某些事情的營運後勤工作。這是一項尚未有人進行過的研究。所以，這只是典型的第一階段的事。

We have two good sites and have worked through that. Jim is back contemplating whether we need the 108-milligram dose in that study. So that's in the works now, I would say. We were dosing up through 108 milligram, but I think there's some thinking that maybe we won't need that study or that dose after all. So it's ongoing, still on track to be ready for our end of Phase 2 meeting when we go and discuss our data and our path forward with the agency.

我們有兩個很好的站點並且已經完成了工作。吉姆又開始考慮我們是否需要在研究中使用 108 毫克的劑量。所以我想說，現在正在進行中。我們的劑量已經增加到 108 毫克，但我認為有些人認為我們可能不再需要那項研究或那個劑量了。因此，一切仍在進行中，我們仍將為第二階段會議的結束做好準備，屆時我們將與該機構討論我們的數據和未來發展方向。

Thanks.

謝謝。

Thank you, Serge.

謝謝你，塞爾吉。

Ryan Deschner, Raymond James.

瑞安‧德施納、雷蒙‧詹姆斯。

Hi. Thanks for the question. What exploratory metrics do we expect to see at the time of the 3Q IPF cough readout, specifically thinking about exact question two or sleep cough frequency? And then I have a follow-up.

你好。謝謝你的提問。我們期望在第三季 IPF 咳嗽讀數時看到哪些探索性指標，具體考慮確切的第二個問題或睡眠咳嗽頻率？然後我有一個後續問題。

Yeah, Ryan. So that's a good question, which I don't know specifically. I know in top line, we'll obviously get the primary endpoint and some of the key secondaries, exact two will definitely be there because that's 1 of the key secondary studies in the endpoint as well as, I think, CSS. But beyond that, I don't know if we're getting any of the other secondary endpoints.

是的，瑞安。這是個好問題，具體我也不太清楚。我知道，在頂線，我們顯然會得到主要終點和一些關鍵的次要終點，確切的兩個肯定會在那裡，因為那是終點中的 1 個關鍵的次要研究，我認為，還有 CSS。但除此之外，我不知道我們是否能得到任何其他次要終點。

Okay. And then looking ahead to a late-stage RCC study, what potential stratifications like cough frequency, for example, would you consider based on what you've learned so far from RIVER?

好的。然後展望後期 RCC 研究，根據您目前從 RIVER 中了解到的情況，您會考慮哪些潛在分層，例如咳嗽頻率？

Yeah. My team here is waving at me, too. Apparently, you said Q3 for data. It's Q2, just so we're all talking the same language. Yeah, our plan going forward in RCC is no stratification.

是的。我的團隊也在向我揮手。顯然，您說的是 Q3 的數據。現在是第二季度，所以我們都說同一種語言。是的，我們在 RCC 的未來計劃是不再分層。

We saw virtually no difference in effect between moderate and severe. Obviously, we'll go through individual patient data, but it was strong. And with our mechanism, that's what we expected. It's also what we saw in IPF cough. So we're not planning to stratify at all between moderate and severe.

我們幾乎沒有發現中度和重度之間的效果差異。顯然，我們會查看個別患者的數據，但它很強大。透過我們的機制，這正是我們所期望的。這也是我們在特發性肺纖維化 (IPF) 咳嗽中看到的現象。所以我們根本不打算在中度和重度之間進行分層。

Got it. Looking forward to the 2Q readout.

知道了。期待第二季的業績。

Yeah. Thank you, Ryan.

是的。謝謝你，瑞安。

Brandon Folkes, Rodman and Renshaw.

布蘭登福克斯、羅德曼和倫肖。

Hi. Thanks for taking my questions. Maybe just from me, just following up on the placebo rate. Any scientific reason why the placebo rates in IPF would differ versus RCC? Obviously, we've seen RCC data, hearing the powering you mentioned earlier. Is that just how the studies were designed? But just any scientific rationale we should think about when we see that data when we looking at the placebo adjusted? Thank you.

你好。感謝您回答我的問題。也許只是我的想法，只是在追蹤安慰劑率。有任何科學原因可以解釋為什麼 IPF 中的安慰劑率與 RCC 中的安慰劑率不同嗎？顯然，我們已經看到了 RCC 數據，聽到了您之前提到的動力。研究是這樣設計的嗎？但是，當我們看到安慰劑調整後的數據時，我們應該思考任何科學原理嗎？謝謝。

Yeah. It's -- I've gotten this question because the CANAL IPF placebo rate was actually a little higher than RCC, which feels counterintuitive. These crossover studies are generally pretty tight, so placebo doesn't usually rear its head up until the parallel arm design. I suspect it's because the RCC studies, everybody does these in the same 10 to 15 centers, high-end cough centers, really high-end thought leaders in the space. IPF is a little more out into normal IPF centers that are doing lots of studies.

是的。我之所以會有這個問題，是因為 CANAL IPF 安慰劑率實際上比 RCC 略高，這感覺有違常理。這些交叉研究通常非常嚴格，因此安慰劑通常要到平行臂設計中才會出現。我懷疑這是因為 RCC 研究，每個人都在相同的 10 到 15 個中心進行這些研究，這些中心是高端咳嗽中心，是該領域真正的高端思想領袖。IPF 更多地進入正在進行大量研究的常規 IPF 中心。

So -- there is no -- I don't have a good scientific reason. And Jim got asked this question last week, and we didn't have a good answer. I think the good news is these are generally within what we had planned. The RCC study was very tight, but we will certainly plan for higher placebo rates in the parallel arm next study.

所以——沒有——我沒有很好的科學理由。上週吉姆被問到這個問題，但我們沒有好的答案。我認為好消息是這些基本上都在我們的計劃之內。RCC 研究非常嚴格，但我們肯定會計劃在下一次平行研究中提高安慰劑率。

Great. Thanks very much for taking my questions and congrats on all the good data of late.

偉大的。非常感謝您回答我的問題，並祝賀您最近獲得的所有好數據。

Yeah. Thank you, Brandon.

是的。謝謝你，布蘭登。

Kaveri Pohlman, Clear Street.

卡弗里‧波爾曼 (Kaveri Pohlman)，《清晰街》。

Hi. This is [Christian]. I'm on for Kaveri today. Congratulations on your recently presented RCC data. And just going forward, I guess, across indications, could you tell us what secondary endpoints do you think will matter most for driving Haduvio prescriptions and having less payer resistance?

你好。這是[基督教]。我今天代表卡弗里 (Kaveri) 出賽。恭喜您最近提交的 RCC 數據。展望未來，我想，在各種適應症中，您能否告訴我們，您認為哪些次要終點對於推動 Haduvio 處方和減少付款人阻力最重要？

Yeah. So it's a good question. I think there's some work being done around patient secondary endpoints. I think the first question is making sure the FDA is happy that your key secondary's linked to your primary endpoint of objective cough. That seems to be centering around cough severity, which isn't quite the same thing as cough frequency.

是的。所以這是一個好問題。我認為圍繞患者的次要終點正在進行一些工作。我認為第一個問題是確保 FDA 滿意您的關鍵次要終點與客觀咳嗽的主要終點之間的關聯。這似乎與咳嗽的嚴重程度有關，與咳嗽頻率不太一樣。

When you get to payers and things, things like metrics like quality of life for the patient matters. But our commercial guys involved in these next studies and which metrics will be built in the secondary endpoints. But it will be a cross between the severity scales and then some of the quality of life metrics as well.

當你涉及到付款人和其他事情時，諸如患者的生活品質等指標就很重要。但是我們的商業人員參與了接下來的研究，並將在次要終點建立哪些指標。但它將是嚴重程度量表和一些生活品質指標的交叉。

Got it. Thank you.

知道了。謝謝。

Thank you, Christian.

謝謝你，克里斯蒂安。

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

我們的問答環節到此結束。我想將會議交還給 Jennifer Good，請她做最後發言。

Thank you. We look forward to the upcoming results of our 2b CORAL trial next quarter and appreciate you joining today's call. Lisa and I are available after the call for any follow-up questions you may have.

謝謝。我們期待下個季度即將公佈的 2b CORAL 試驗結果，並感謝您參加今天的電話會議。通話結束後，Lisa 和我將回答您可能有的任何後續問題。

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

會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。