Trevi Therapeutics Inc (TRVI) 2022 Q4 法說會逐字稿

Good afternoon, and welcome to the Trevi Therapeutics Q4 and Year-End 2022 Earnings Conference Call. (Operator Instructions) Please note this event is being recorded.

下午好，歡迎來到 Trevi Therapeutics 第 4 季度和 2022 年年終收益電話會議。 （操作員說明）請注意正在記錄此事件。

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. 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.

管理層在本次電話會議上就公司未來預期、計劃和前景發表的各種評論構成了根據 1995 年《私人證券訴訟改革法》規定的安全港條款的前瞻性陳述。實際結果可能與這些陳述的結果存在重大差異由於各種重要因素而做出的前瞻性陳述，包括公司今天下午向美國證券交易委員會提交的 10-K 表格的最新年度報告的風險因素部分中討論的那些因素。

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公司截至今天的觀點，不應被視為代表公司在任何後續日期的觀點。雖然公司可能會選擇在未來某個時候更新這些前瞻性陳述，但公司特別聲明不承擔任何義務，即使其觀點發生變化也是如此。

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

我現在想將電話會議轉交給 Trevi 的總裁兼首席執行官 Jennifer Good。請繼續。

Good afternoon, and thank you for joining our fourth quarter and year-end earnings call and business update. Joining me today on this call are Lisa Delfini, Trevi's Chief Financial Officer; and Dr. David Clark, Trevi's Chief Medical Officer. Lisa and I have some prepared remarks, then the 3 of us will be available for questions.

下午好，感謝您加入我們的第四季度和年終財報電話會議和業務更新。今天和我一起參加這次電話會議的有 Trevi 的首席財務官 Lisa Delfini；以及 Trevi 的首席醫療官 David Clark 博士。麗莎和我準備了一些評論，然後我們 3 個人可以回答問題。

2022 was a transformational year for Trevi with regard to validating the broad utility of the mechanism of our drug, Haduvio. With our trials in IPF cough and prurigo nodularis both reading out positive, it left us in a strong position to decide how best to grow the company for our stakeholders. Based on the strength of the cough data and IPF as well as the lack of competition in that space, we feel we can carve out a strong and unique position in therapy for IPF. We also believe that because of the differentiated central and peripheral mechanism of our drug, we have the potential to provide therapy across a range of chronic cough indications regardless of what the underlying disease is.

2022 年是 Trevi 轉型的一年，它驗證了我們的藥物 Haduvio 機制的廣泛用途。由於我們在 IPF 咳嗽和結節性癢疹方面的試驗均呈陽性，這使我們處於有利地位，可以決定如何最好地為我們的利益相關者發展公司。基於咳嗽數據和 IPF 的實力以及該領域缺乏競爭，我們認為我們可以在 IPF 治療中開拓出強大而獨特的地位。我們還相信，由於我們藥物的中樞和外周機制不同，我們有潛力提供針對一系列慢性咳嗽適應症的治療，無論潛在疾病是什麼。

So with those decisions made and strong capital raising in 2022, we are now buckled in and focused on executing against our plans for the next stage of development. Let me now provide an update on each of our programs, starting with our lead program in chronic cough and IPF. IPF is a serious end-of-life disease and chronic cough is a major cause of morbidity, significantly impacting the patient's quality of life. It is estimated that up to 85% of IPF patients are suffering from chronic coughing.

因此，在做出這些決定並在 2022 年進行大量融資後，我們現在全力以赴並專注於執行我們下一階段發展的計劃。現在讓我介紹一下我們每個項目的最新情況，首先是我們在慢性咳嗽和 IPF 方面的主要項目。 IPF 是一種嚴重的臨終疾病，慢性咳嗽是發病的主要原因，嚴重影響患者的生活質量。據估計，高達 85% 的 IPF 患者患有慢性咳嗽。

As we prepare for our next trials in this indication, there are many learnings we can take from the development work occurring in refractory chronic cough. However, there are also unique aspects of the IPF patient population related not only to a potential effect on the underlying disease, but safety in this frail patient population that we also need to keep in mind.

在我們準備針對該適應症的下一次試驗時，我們可以從難治性慢性咳嗽的開發工作中學到很多東西。然而，IPF 患者群體也有一些獨特的方面，不僅與對潛在疾病的潛在影響有關，而且我們也需要牢記這一虛弱患者群體的安全性。

We are planning to conduct 2 studies in parallel during this next phase of development in our IPF chronic cough program. The first is a Phase IIb dose-ranging trial that will study 3 doses. The doses we are planning to study are 27, 54 and 108 milligrams BID. Based on the data from the Phase II CANAL study, we have dropped the highest dose as it appears the efficacy occurred very early in that trial and at the lower doses. Because of the severity of illness in these patients, it will be important to understand the minimally effective dose.

我們計劃在我們的 IPF 慢性咳嗽計劃的下一階段開發中同時進行 2 項研究。第一個是 IIb 期劑量範圍試驗，將研究 3 個劑量。我們計劃研究的劑量是 27、54 和 108 毫克 BID。根據 II 期 CANAL 研究的數據，我們已經降低了最高劑量，因為它似乎在該試驗的早期和較低劑量下出現了療效。由於這些患者病情嚴重，了解最低有效劑量很重要。

We are planning for approximately 50 subjects per arm for a total end in the study of 200 and dosing for approximately 6 weeks. We are planning on conducting this study in multiple countries to be able to complete enrollment in a timely manner. We will give better guidance on enrollment time lines once we initiate the study.

我們計劃每組約 50 名受試者，總計 200 名受試者並給藥約 6 週。我們計劃在多個國家開展這項研究，以便能夠及時完成招募。一旦我們啟動研究，我們將在註冊時間表上提供更好的指導。

In parallel, we are planning for a Phase Ib respiratory physiology study. As you may know, all opioids have a class label black box warning regarding respiratory depression. This is not something we have seen in our safety data across our various studies to date. But because of the lung impairment in IPF patients, we feel this is an important question to study early. We plan to run an inpatient study in IPF patients with levels of varying disease severity and increasing doses of Haduvio to determine if we see a clinically significant impact on respiratory depression. These 2 studies will help define the optimal dose or doses and the patient population in our pivotal program.

與此同時，我們正計劃進行 Ib 期呼吸生理學研究。您可能知道，所有阿片類藥物都有關於呼吸抑制的類別標籤黑框警告。這不是我們迄今為止在各種研究中的安全數據中看到的。但由於 IPF 患者的肺功能受損，我們認為這是一個需要及早研究的重要問題。我們計劃在患有不同疾病嚴重程度和增加 Haduvio 劑量的 IPF 患者中進行一項住院研究，以確定我們是否看到對呼吸抑制的臨床顯著影響。這 2 項研究將有助於確定我們關鍵計劃中的最佳劑量和患者群體。

We have submitted the respiratory physiology protocol to the FDA and are awaiting their feedback. We are also preparing for submissions in the U.K. and Europe to support these trials. There is a new regulatory process in the EU called CTIS, which became mandatory as of January 31, 2023. Under the new process, the health authority and the ethics committees perform their reviews in parallel. As a result, there's more information required upfront to make the submission. In theory, this new process will streamline the review process, although there is little data to show how the implementation is going and companies expect there will be growing pains. So we will keep you informed of our expected time lines, but I wanted to make you aware there is a new process in play, which makes time lines difficult to estimate.

我們已將呼吸生理學方案提交給 FDA，正在等待他們的反饋。我們還準備在英國和歐洲提交支持這些試驗的材料。歐盟有一個名為 CTIS 的新監管程序，自 2023 年 1 月 31 日起強制執行。在新程序下，衛生當局和倫理委員會並行進行審查。因此，提交之前需要更多信息。從理論上講，這一新流程將簡化審查流程，儘管幾乎沒有數據表明實施情況如何，而且公司預計會有成長的煩惱。因此，我們會隨時通知您我們的預期時間表，但我想讓您知道，有一個新的流程正在進行中，這使得時間表難以估計。

In parallel, our clinical operations team is preparing for these studies so that we can initiate once we have regulatory agreement on the protocol and an open IND. We expect to initiate both of these IPF studies in the second half of 2023, and we will provide guidance on the overall final design as well as the estimated timing for the trial once we begin the studies.

與此同時，我們的臨床運營團隊正在為這些研究做準備，一旦我們就協議和開放的 IND 達成監管協議，我們就可以啟動。我們預計將在 2023 年下半年啟動這兩項 IPF 研究，一旦我們開始研究，我們將提供有關總體最終設計的指導以及試驗的預計時間。

In addition to the preparations in IPF cough, we are also developing a protocol for a Phase II refractory chronic cough study. That study will look a lot like the CANAL trial and will seek to establish proof-of-concept in refractory chronic cough. There have been a lot of trials in this condition, with only one mechanism which has been successful, the P2X3s. P2X3s work peripherally in the lung. However, we believe there is still a significant opportunity for a mechanism that works both centrally in the brain and peripherally in the lungs and has the potential to provide strong and consistent efficacy in a broader set of RCC patients.

除了 IPF 咳嗽的準備工作，我們還在製定 II 期難治性慢性咳嗽研究的方案。該研究看起來很像 CANAL 試驗，並將尋求在難治性慢性咳嗽中建立概念驗證。在這種情況下已經進行了很多試驗，只有一種機制是成功的，即 P2X3s。 P2X3s 在肺外周工作。然而，我們認為仍有很大機會開發一種既在大腦中樞又在肺部外周起作用的機制，並有可能在更廣泛的 RCC 患者中提供強大而一致的療效。

Our cough data generated to date has continued to garner a lot of attention globally and has been presented at various respiratory meetings by KOLs in pulmonology. During the fourth quarter, Dr. Philip Molyneaux presented data at the British Thoracic Society meeting. We have also finalized a manuscript on the trial results and we'll be submitting it for publication shortly. On March 29, there will be another presentation at the Annual German Pulmonology meeting. On Monday, May 22 in Washington, D.C., additional results from CANAL will be presented at the American Thoracic Society meeting. And on June 9 through 10 in Reston, Virginia at the American Cough Conference, there will be a presentation on our central and peripheral mechanism of action and why it is unique and could be important broadly in cough.

迄今為止，我們生成的咳嗽數據繼續在全球範圍內引起廣泛關注，並已在肺病學 KOL 的各種呼吸會議上進行了展示。在第四季度，Philip Molyneaux 博士在英國胸科學會會議上展示了數據。我們還完成了關於試驗結果的手稿，我們將很快將其提交出版。 3 月 29 日，德國肺病學年會上將有另一場演講。 5 月 22 日星期一在華盛頓特區，CANAL 的更多結果將在美國胸科學會會議上公佈。 6 月 9 日至 10 日在弗吉尼亞州雷斯頓舉行的美國咳嗽會議上，將介紹我們的中樞和外周作用機制，以及為什麼它是獨一無二的，並且在咳嗽中可能具有廣泛的重要性。

I think it is important to note that almost all of our conference submissions have been chosen for oral presentations. I think this speaks to the medical community's interest in our program and the importance of the unmet medical need we are trying to address.

我認為值得注意的是，我們幾乎所有的會議提交都被選為口頭報告。我認為這說明了醫學界對我們計劃的興趣以及我們正在努力解決的未滿足醫療需求的重要性。

The other program where we have ongoing work is for the treatment of prurigo nodularis, or PN, which is a serious and debilitating disease characterized by papules and nodules on the skin as well as incessant and severe itching. In June of last year, we also reported positive data in the Phase IIb/III PRISM trial in PN. The trial achieved statistical significance on the primary and all key secondary endpoints. During the first quarter of 2023, we completed the 1-year open-label extension study that was associated with PRISM. We should receive the data from that study in the second quarter and we'll prepare for an end of Phase II meeting with the FDA, which we expect to have this year.

我們正在進行的另一個項目是治療結節性癢疹 (PN)，這是一種嚴重且使人衰弱的疾病，其特徵是皮膚上出現丘疹和結節以及持續且劇烈的瘙癢。去年6月，我們在PN的IIb/III期PRISM試驗中也報告了陽性數據。該試驗在主要終點和所有關鍵次要終點上取得了統計學意義。在 2023 年第一季度，我們完成了與 PRISM 相關的為期 1 年的開放標籤擴展研究。我們應該在第二季度收到該研究的數據，我們將為結束與 FDA 的第二階段會議做準備，我們預計今年會舉行。

Finally, we also commenced a human abuse liability study in the fourth quarter of last year. The objective of this study is to compare the abuse potential of oral nalbuphine to butorphanol. The injectable version of nalbuphine is currently unscheduled in the U.S. by the Drug Enforcement Agency, or DEA. Butorphanol is a Schedule IV drug. This study is a randomized, double-blind, active and placebo-controlled 5-way crossover design. The study is conducted in 2 parts, with the first part characterizing various butorphanol doses. One butorphanol dose will be selected to be studied in the second part of the protocol to determine the abuse potential of oral nalbuphine relative to the selected dose of butorphanol. The company is currently completing Part 1 of the study and expects top line data from the complete trial by the end of 2023.

最後，我們還在去年第四季度開始了一項人類虐待傾向研究。本研究的目的是比較口服納布啡與布托啡諾的濫用可能性。納布啡的注射劑目前在美國未被美國緝毒局 (DEA) 列入管制範圍。布托啡諾是一種附表 IV 藥物。本研究是一項隨機、雙盲、主動和安慰劑對照的 5 路交叉設計。該研究分兩部分進行，第一部分描述了各種布托啡諾劑量的特徵。將選擇一種布托啡諾劑量在方案的第二部分進行研究，以確定口服納布啡相對於選定劑量的布托啡諾的濫用可能性。該公司目前正在完成研究的第 1 部分，預計到 2023 年底將獲得完整試驗的頂級數據。

It is a busy time at Trevi working to initiate or conduct 4 separate studies and completing the open-label extension in PN. This is a critical part of the process to get right, and David and his team are making good progress against each of these. We will announce the start of each study with more details as we initiate each one.

Trevi 忙於發起或進行 4 項獨立研究並完成 PN 的開放標籤擴展。這是實現正確過程的關鍵部分，David 和他的團隊在解決每一個問題上都取得了很好的進展。我們將在啟動每項研究時宣布每項研究的開始，並提供更多詳細信息。

As I look back on 2022, I am extremely proud of the execution by our team and the positive trial results in both of our lead indications. The trial data and subsequent financings have positioned us well to continue the development of Haduvio in not only IPF chronic cough, but also other serious chronic cough conditions such as RCC and cough in interstitial lung diseases. For PN, we are in discussions with potential partners to advance that program into the next stage of clinical development. The end of Phase II meeting with the FDA will help determine next steps for this program.

當我回顧 2022 年時，我為我們團隊的執行力和我們兩個先導適應症的積極試驗結果感到非常自豪。試驗數據和隨後的融資使我們能夠很好地繼續開發 Haduvio，不僅用於 IPF 慢性咳嗽，還用於其他嚴重的慢性咳嗽疾病，如 RCC 和間質性肺病咳嗽。對於 PN，我們正在與潛在合作夥伴討論將該項目推進到臨床開發的下一階段。與 FDA 的第二階段會議結束將有助於確定該計劃的後續步驟。

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

我現在將其轉交給麗莎審查我們的財務結果，然後我們將公開提問。

Thank you, Jennifer, and good afternoon, everyone. The full financial results for the 3- and 12-months ended December 31, 2022 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.

謝謝你，詹妮弗，大家下午好。截至 2022 年 12 月 31 日的 3 個月和 12 個月的完整財務業績可以在我們在本次電話會議之前發布的新聞稿和今天收市後向美國證券交易委員會提交的 10-K 中找到。

I'll start with fourth quarter 2022 results. For the fourth quarter of 2022, we reported a net loss of $5.5 million compared to a net loss of $8.5 million for the same quarter in 2021. This is a net loss per share for the quarter of $0.06 as compared to a net loss per share of $0.28 for the same quarter of 2021. R&D expenses were $4.3 million during the fourth quarter of 2022 compared to $6.2 million in the same quarter of 2021. The decrease was primarily due to decreased clinical trial costs, reflecting the completion of both the blinded portion of the PRISM and CANAL trials prior to the fourth quarter of 2022, partially offset by an increase in costs related to the human abuse liability study, which we initiated in the fourth quarter of 2022.

我將從 2022 年第四季度的結果開始。 2022 年第四季度，我們報告淨虧損 550 萬美元，而 2021 年同期為 850 萬美元。與每股淨虧損相比，本季度每股淨虧損 0.06 美元2021 年同期為 0.28 美元。研發費用在 2022 年第四季度為 430 萬美元，而 2021 年同期為 620 萬美元。減少的主要原因是臨床試驗成本下降，反映了盲法部分的完成2022 年第四季度之前的 PRISM 和 CANAL 試驗，部分被與我們在 2022 年第四季度啟動的人類虐待責任研究相關的成本增加所抵消。

G&A expenses were $2.3 million during the fourth quarter of 2022 compared to $2.1 million in the same period of 2021. The increase was primarily due to higher legal fees associated with intellectual property filings and other professional fees. Other income net was $1.1 million in the fourth quarter of 2022 compared to other expense net of $300,000 in the same period of 2021. The change was primarily due to an increase in interest income in 2022 as a result of investing the funds from our capital raises completed during 2022, coupled with higher interest rates than were available in the fourth quarter of 2021.

G&A 費用在 2022 年第四季度為 230 萬美元，而 2021 年同期為 210 萬美元。增加的主要原因是與知識產權申請相關的法律費用和其他專業費用增加。 2022 年第四季度的其他收入淨額為 110 萬美元，而 2021 年同期的其他費用淨額為 300,000 美元。這一變化主要是由於 2022 年的利息收入增加，這是因為我們將籌資所得的資金用於投資2022 年完成，利率高於 2021 年第四季度。

Now turning to the full year results. For the year ended December 31, 2022, we reported a net loss of $29.2 million compared to a net loss of $33.9 million for 2021. Our net loss was lower in 2022 as a result of decreased R&D expenses, which were $19.8 million during the full year 2022 compared to $23 million in 2021. This was offset by increased G&A expenses, which were $10.1 million for the full year 2022 compared to $9.5 million in 2021. Other income net was $0.7 million in 2022 compared to other expense net of $1.5 million in the same period of 2021. The drivers of these changes were largely the same as the drivers I just discussed related to the fourth quarter changes.

現在轉向全年業績。截至 2022 年 12 月 31 日止年度，我們報告的淨虧損為 2920 萬美元，而 2021 年的淨虧損為 3390 萬美元。由於研發費用減少，我們在 2022 年的淨虧損較低，全年為 1980 萬美元與 2021 年的 2300 萬美元相比，2022 年的增長被增加的 G&A 費用所抵消，2022 年全年為 1010 萬美元，而 2021 年為 950 萬美元。2022 年的其他收入淨額為 70 萬美元，而 2022 年的其他費用淨額為 150 萬美元2021 年同期。這些變化的驅動因素與我剛才討論的與第四季度變化相關的驅動因素在很大程度上是相同的。

A few comments on cash and cash runway. During the fourth quarter of 2022, we received $3.1 million in gross proceeds from the underwriters' option for the greenshoe related to our September offering. These funds, together with the funds we raised earlier in the year, enabled us to end the year with cash, cash equivalents and marketable securities of $120.5 million. This gives us cash runway into 2026, which includes completing the trials that Jennifer laid out today and paying off our term loan in accordance with its terms.

關於現金和現金跑道的一些評論。在 2022 年第四季度，我們從與我們 9 月發行相關的綠鞋承銷商選擇權中獲得了 310 萬美元的總收益。這些資金，連同我們今年早些時候籌集的資金，使我們能夠在年底以現金、現金等價物和有價證券 1.205 億美元。這為我們提供了進入 2026 年的現金跑道，其中包括完成 Jennifer 今天提出的試驗並根據其條款還清我們的定期貸款。

Finally, I want to take a moment to address recent events related to SVB. As many of you know, last Friday, the FDIC closed SVB and appointed the FDIC as receiver. We bank with SVB. However, the substantial majority of our cash, cash equivalents and investments were held in custody accounts in our name at another large financial institution, so we had very limited exposure. On Monday, the FDIC announced that all SVB deposits are protected. So this has now become largely an operational matter, which we are managing through.

最後，我想花點時間談談最近與 SVB 相關的事件。眾所周知，上週五，FDIC 關閉了 SVB，並指定 FDIC 為接管人。我們與 SVB 銀行合作。然而，我們的絕大部分現金、現金等價物和投資都以我們的名義在另一家大型金融機構的託管賬戶中持有，因此我們的風險敞口非常有限。週一，FDIC 宣布所有 SVB 存款都受到保護。因此，這在很大程度上已成為我們正在管理的運營問題。

This concludes our prepared remarks. I will now turn the call back over to the operator for Q&A.

我們準備好的發言到此結束。我現在將把電話轉回接線員進行問答。

(Operator Instructions) Our first question comes from Leland Gershell with Oppenheimer.

（操作員說明）我們的第一個問題來自 Leland Gershell 和 Oppenheimer。

I want to ask, Jennifer -- both my questions are really dosing-related questions. As you approach the abuse liability study, will you be looking to harmonize the doses of nalbuphine that you can test with the dose-ranging study that you're starting up as well? Or will you look at maybe higher doses to see if there is any untoward activity that occurs?

我想問，詹妮弗——我的兩個問題都是與劑量相關的問題。當您進行濫用傾向性研究時，您是否希望協調您可以測試的納布啡劑量與您也正在啟動的劑量範圍研究？或者您是否會考慮更高的劑量以查看是否發生任何不良活動？

And similarly for the trial in RCC, if you're able to share at this point, how might the doses in the RCC study look versus the doses you've looked at so far and the doses that are being tested in the IPF IIb?

同樣對於 RCC 試驗，如果您此時能夠分享，RCC 研究中的劑量與您目前觀察的劑量以及 IPF IIb 中正在測試的劑量相比如何？

Thank you, Leland, for the question. David, I'll take the first one on the house since I lived through that. And then why don't you take the RCC dose since you're working on that protocol, as we speak.

謝謝你，利蘭，提出這個問題。戴維，自從我經歷了那件事以來，我會拿房子裡的第一個。然後你為什麼不服用 RCC 劑量，因為你正在製定該協議，正如我們所說的那樣。

So Leland, the process and the how, we actually already ran through that to identify the dose for nalbuphine. We did that a year or 2 ago, where you essentially try to find a maximum tolerated dose. And so we sort of pushed up and really, there's a limit in the guidance that says once you get to 3x your effective dose in the market, you can stop, which is what we were able to get to. We have not found an MTD on nalbuphine.

所以利蘭，這個過程以及如何，我們實際上已經通過它來確定納布啡的劑量。我們在一兩年前就這樣做了，您基本上是在嘗試找到最大耐受劑量。所以我們有點推高了，實際上，指導中有一個限制，說一旦你達到市場有效劑量的 3 倍，你就可以停止，這就是我們能夠達到的。我們尚未發現納布啡的 MTD。

So the exact dose is, I think, 480. David might correct me a little bit. But that dose will be compared to the work being done on butorphanol, which is also basically 3x what's in the marketplace. So the doses will get nailed down, and it will be sort of 3x what you see in our clinical trials. Okay? And then, David, do you want to talk about RCC and how you're thinking about dosing?

所以我認為確切的劑量是 480。大衛可能會糾正我一點。但該劑量將與布托啡諾所做的工作進行比較，布托啡諾基本上也是市場上的 3 倍。所以劑量會被確定下來，它會是你在我們的臨床試驗中看到的劑量的 3 倍。好的？然後，大衛，你想談談 RCC 以及你是如何考慮劑量的嗎？

Yes, yes. And by the way, you're quite right that the top dose in -- used in the HAL study is 486, as you say, Jennifer. So yes, we will be bringing the doses together. For the RCC study, which as Jennifer explained, the design will be very similar to the CANAL, this 2-way crossover design in approximately 60 subjects.

是的是的。順便說一下，正如你所說，HAL 研究中使用的最高劑量是 486，你說得很對，Jennifer。所以是的，我們將把劑量放在一起。正如 Jennifer 所解釋的，對於 RCC 研究，其設計將與 CANAL 非常相似，這種 2 向交叉設計涉及大約 60 個受試者。

The top dose we would plan to study there would be 108 milligrams due to the good signal that was seen at the lower and the intermediate doses in the CANAL study in the IPF chronic cough population. So -- and in the Phase IIb chronic cough IPF study also, that's a dose-ranging study, as you know. 27, 54 and 108 would be the 3 selected doses versus placebos for that. So yes, we are planning to run these doses together in the 2 programs.

我們計劃研究的最高劑量為 108 毫克，因為在 IPF 慢性咳嗽人群的 CANAL 研究中，在較低和中間劑量下看到了良好的信號。所以——正如你所知，在 IIb 期慢性咳嗽 IPF 研究中，這是一項劑量範圍研究。 27、54 和 108 將是與安慰劑相比的 3 個選定劑量。所以是的，我們計劃在 2 個程序中同時運行這些劑量。

Our next question comes from Thomas Smith with SVB Securities.

我們的下一個問題來自 SVB 證券公司的 Thomas Smith。

This is Nat Charoensook on for Thomas Smith. First question is like what are the gating factors to initiate a Phase IIb dose-ranging study in chronic cough with IPF, which is now expected in the second half of '23? And I have a follow-up.

這是 Thomas Smith 的 Nat Charoensook。第一個問題是啟動 IPF 慢性咳嗽 IIb 期劑量範圍研究的門控因素是什麼，現在預計在 23 年下半年進行？我有一個後續行動。

I didn't catch the first part of that, like what are the gating factors to getting the Phase IIb going? Is that what you asked?

我沒聽懂第一部分，比如讓 IIb 階段進行的門控因素是什麼？那是你問的嗎？

Yes.

是的。

Okay. I mean, basically -- David, why don't you talk about the Phase IIb and sort of how we get from here to starting up since you're sort of managing that daily?

好的。我的意思是，基本上 - 大衛，你為什麼不談談 IIb 階段以及我們如何從這裡開始，因為你每天都在管理它？

Yes. Yes, I mean as Jennifer said in the introduction, the -- we'll give precise guidance on the conduct phase for that study once we've finalized our planning. But studies of this sort of size that we're talking about, 200 subjects, you would usually aim for about a 12-month recruitment phase. We can give that as general guidance.

是的。是的，我的意思是正如 Jennifer 在介紹中所說的那樣——一旦我們完成了我們的計劃，我們將對該研究的實施階段提供精確的指導。但是我們正在談論的這種規模的研究，200 個受試者，你通常會瞄準大約 12 個月的招募階段。我們可以將其作為一般指導。

The real gating factor has been a slight delay in the study start for that study, primarily driven by global supply chain issues with packaging materials, as it would happen. So we have packaging materials that were substantially coming in later than we would have planned. And that's probably the largest driver of the study start to change.

真正的限制因素是該研究的研究開始略有延遲，這主要是由於包裝材料的全球供應鏈問題，因為它會發生。因此，我們的包裝材料比我們計劃的要晚得多。這可能是研究開始發生變化的最大驅動力。

And then the other piece that Jennifer alluded to in terms of study trial conduct, the precision on what our estimate would be for how long the study will conduct, the other major factor there is this new EU CTIS process that you will have heard of.

然後是 Jennifer 在研究試驗行為方面提到的另一篇文章，我們對研究將進行多長時間的估計的精確度，另一個主要因素是你會聽說的這個新的 EU CTIS 流程。

So there's a new global EU clinical trial submission process. It's no longer optional, it's mandatory this year. And the expectation is that will slow down a lot of the EU's -- that process will be anything up to 3-plus months slower for starting EU countries because of this new process. So those are the 2 biggest factors.

因此，有一個新的全球歐盟臨床試驗提交流程。它不再是可選的，今年是強制性的。預計這將放慢很多歐盟的進程——由於這個新進程，啟動歐盟國家的進程最多會慢 3 個多月。所以這些是兩個最大的因素。

Got it, that's very helpful. And maybe another one, like so you guide the full data from the open-label extension operation in second quarter '23. So what do you plan to report? And what are your expectations on the data?

明白了，這很有幫助。也許還有另一個，就像你在 23 年第二季度指導開放標籤擴展操作的完整數據一樣。那麼你打算報告什麼？您對數據有何期望？

Yes, we get this question a lot. And we haven't sorted that out yet. I think we want to see the data, sort of what does it show, what's there. We will definitely report it at a medical meeting. It's got a lot of interest by the dermatology community, for sure.

是的，我們經常收到這個問題。我們還沒有解決這個問題。我想我們想看看數據，看看它顯示了什麼，那裡有什麼。我們一定會在醫學會議上報告。當然，皮膚病學界對它很感興趣。

How we handle it sort of from an IR perspective, if you will, we still need to sort out the best way to do that. So I'm going to defer that once we see the data and sort out the messaging from it. We'll figure out the best way to do that.

我們如何從 IR 的角度處理它，如果你願意，我們仍然需要找出最好的方法來做到這一點。因此，一旦我們看到數據並從中整理出消息，我就會推遲。我們會想出最好的方法來做到這一點。

Got it. And last one, if I may. So what is your expectation on the R&D and SG&A expenses in '23 compared to 2022?

知道了。最後一個，如果可以的話。那麼與 2022 年相比，您對 23 年的研發和 SG&A 支出有何期望？

I think R&D expenses will increase in 2023 as we conduct all of these studies that were -- that Jennifer referred to, as opposed to 2022.

我認為研發費用將在 2023 年增加，因為我們進行了詹妮弗提到的所有這些研究，而不是 2022 年。

And G&A, please, might as well.

還有 G&A，拜託，也可以。

I think G&A will also increase slightly.

我認為 G&A 也會略有增加。

(Operator Instructions) Our next question comes from Sean Kim with Jones Trading.

（操作員說明）我們的下一個問題來自 Jones Trading 的 Sean Kim。

So I guess one question on the Phase Ib respiratory physiology study. Can you give a little more color on what dosing levels you're intending to try out for the trial? And also, how that might inform the potential Phase III programs and other trials in the pipeline?

所以我猜一個關於 Ib 期呼吸生理學研究的問題。您能否詳細說明您打算在試驗中嘗試的劑量水平？而且，這可能如何為潛在的 III 期項目和其他正在進行的試驗提供信息？

Yes, David, go ahead.

是的，大衛，繼續。

Yes. So most likely, we will go to the 162 dose that was included at the highest dose that was titrated to in the CANAL study. So that is likely to be -- will titrate in a similar manner to the CANAL study. And sorry, what was the other component of your question?

是的。所以最有可能的是，我們將使用 162 劑量，該劑量包含在 CANAL 研究中滴定到的最高劑量中。所以這很可能 - 將以與 CANAL 研究類似的方式進行滴定。抱歉，您問題的另一個組成部分是什麼？

And how to inform, David, that Phase III program, and what doses we use.

大衛，如何告知 III 期計劃，以及我們使用的劑量。

So these 2 studies really are critical coming together. So for Phase III, what we need to know is how broad a population of the IPF patients and their comorbidities. Co-morbidities including comorbidities such as disordered sleep breathing, such as sleep apnea. And we include -- so the respiratory physiology study will really answer that question for us because, as we have explained in the introductory comments, that study will include subjects with increased severity and with these comorbidities that were not included in Phase II to allow us to make that call for Phase III.

所以這兩項研究真的很關鍵。因此，對於 III 期，我們需要知道的是 IPF 患者及其合併症的人群範圍。合併症包括合併症，例如睡眠呼吸障礙，例如睡眠呼吸暫停。我們包括 - 所以呼吸生理學研究將真正為我們回答這個問題，因為正如我們在介紹性評論中所解釋的那樣，該研究將包括嚴重程度增加的受試者以及 II 期未包括的這些合併症，以便我們呼籲第三階段。

Okay. And just one quick follow-up question on the Phase IIb dose ranging study. So now that the trial is set to initiate in second half '23, what would be the expectations for the top line readout in terms of timing?

好的。還有一個關於 IIb 期劑量範圍研究的快速跟進問題。因此，既然試驗定於 23 年下半年開始，那麼在時間上對頂線讀數的期望是什麼？

Yes, Sean, I'm going to defer sort of giving hard guidance on that until we actually initiate it. I mean, David told you in sort of his last answer that we're planning for roughly a 12-month recruiting process. It's going to be a 6-month dosing -- or 6-week dosing, I'm sorry.

是的，肖恩，在我們真正啟動它之前，我將推遲對此提供硬性指導。我的意思是，大衛在他的最後一個回答中告訴你，我們計劃進行大約 12 個月的招聘流程。這將是 6 個月的劑量——或 6 週的劑量，對不起。

So it's not a long trial. But I thought I want to wait until we actually get it initiated and then we'll give some better time line guidance. But that allows you to kind of do the math in your head and think about where you think it could come in. Thank you for your report this week. I appreciate it.

所以這不是一個漫長的審判。但我想我想等到我們真正啟動它，然後我們會提供一些更好的時間線指導。但這可以讓你在腦海中做一些數學運算，並思考你認為它可以發揮作用的地方。感謝你本週的報告。我很感激。

Our next question comes from Sir Mamtani with B. Riley Securities.

我們的下一個問題來自 B. Riley Securities 的 Mamtani 爵士。

I appreciate the level of detail. So about the CANAL abstract being accepted at PDS, if you could comment on that. But also -- my understanding is that there's the PAciFy trials as well as expected from Dr. Molyneaux both for morphine, post the [test] in IPF. Do you have any thoughts on your expectation for that on any relevant safety efficacy data points that could be relevant to Haduvio? And then I have a follow-up.

我很欣賞細節水平。那麼關於 CANAL 摘要在 PDS 上被接受，如果你能對此發表評論的話。而且——我的理解是，有 PAciFy 試驗以及 Molyneaux 博士對嗎啡的預期，在 IPF 中發布[測試]。您對可能與 Haduvio 相關的任何相關安全有效性數據點的期望有何想法？然後我有一個後續行動。

Yes, sounds good, Mayank. So our poster, I know exactly what it's about. I know they've been tugging and pulling on all different looks at the data. So David, I don't know. Do you know exactly what's being covered there? Might be the anti-fibrotic data, but I'm not sure. Go ahead.

是的，聽起來不錯，Mayank。所以我們的海報，我很清楚它是關於什麼的。我知道他們一直在拖拉和拉動對數據的所有不同看法。所以大衛，我不知道。你知道那裡到底涵蓋了什麼嗎？可能是抗纖維化數據，但我不確定。前進。

Yes. There will be additional analyses, including some additional end points that haven't been disclosed before. That's right presented there.

是的。將進行額外的分析，包括一些之前未披露的額外終點。那是正確的。

Yes. And I think, Mayank, you were asking about the Philip Molyneaux trial in the U.K. around morphine. Is that what you were asking me about and how I think that's relevant to our program?

是的。我想，Mayank，你問的是英國關於嗎啡的 Philip Molyneaux 試驗。這是你問我的問題嗎？我認為這與我們的計劃有什麼關係？

That's correct. And I think there will be some data at APS around that also.

這是正確的。而且我認為 APS 上也會有一些數據。

Yes. No, that's great. I think from our perspective, we're excited about that study because I think it just builds more critical evidence around the mechanism here in this whole opioid pathway.

是的。不，那太好了。我認為從我們的角度來看，我們對這項研究感到興奮，因為我認為它只是圍繞整個阿片類藥物途徑中的機制建立了更多關鍵證據。

Morphine has its own set of issues, certainly around respiratory depression and also just the whole scheduling, Schedule II. But from our perspective, we think it just continues to build critical scientific evidence around the pathway.

嗎啡有其自身的一系列問題，當然是圍繞呼吸抑制以及整個時間表，附表 II。但從我們的角度來看，我們認為它只是繼續圍繞該途徑建立關鍵的科學證據。

So I think it should work. They use low doses of morphine now. And as I've heard from several KOLs, it's really the only thing that works in cough. It's part of what drew us to the space. But we felt that, first of all, we work on 2 receptors, and we felt that because of more of the safety profile and abuse addiction profile around our drug, that we could be a much better chronic option.

所以我認為它應該有效。他們現在使用低劑量的嗎啡。正如我從幾個 KOL 那裡聽說的那樣，它真的是唯一對咳嗽有效的東西。這是吸引我們進入太空的部分原因。但我們覺得，首先，我們在 2 個受體上工作，我們覺得由於我們藥物的安全性和濫用成癮性更強，我們可能是一個更好的慢性選擇。

So I'm excited to see it. I would expect that it should work. And I don't feel threatened by it because of all the things I just mentioned to you. And they're going to have a hard time patenting that. So likely people may use it off label, but there's other challenges with prescribing morphine in today's environment.

所以我很高興看到它。我希望它能工作。我並沒有因為我剛才跟你提到的所有事情而感到受到威脅。他們將很難申請專利。人們很可能會在標籤外使用它，但在當今環境下開嗎啡處方還存在其他挑戰。

Got it. And then about the 2 studies, Phase IIb IPF and RCC, could you just comment on the different placebo responses you're factoring in? And obviously, based on your learning from CANAL, but also some of the dry run going on P2X3 development programs?

知道了。然後關於 2 項研究，IIb 期 IPF 和 RCC，您能否評論一下您考慮的不同安慰劑反應？很明顯，基於你從 CANAL 中學到的知識，還有一些 P2X3 開發計劃的試運行？

Yes. And again, when we lay these studies out, we can get into that a little better. I would say in the IPF, which is probably a little more advanced here, we -- there's a sort of accepted rate around 25%. We saw slightly lower, roughly 23% in our study.

是的。再一次，當我們展開這些研究時，我們可以更好地了解它。我想說的是，在 IPF 中，這裡可能更先進一些，我們 — 有一種大約 25% 的接受率。在我們的研究中，我們看到略低，大約 23%。

But when you look across the trials that have been done, that's a pretty good estimate. I think in RCC, we're working with sort of the experts here in the space who have all the data. David, I don't know if you know the powering assumptions we're using on placebo. You've been working on that protocol.

但是當你查看已經完成的試驗時，這是一個非常好的估計。我認為在 RCC 中，我們正在與該領域的專家合作，他們擁有所有數據。大衛，我不知道你是否知道我們在安慰劑上使用的有力假設。你一直在研究那個協議。

Absolutely. And I just agree totally with what you said on the IPF. For the IPF, including recent studies, they've been below 30% for placebo response consistently. The RCC, the key there is that it's a 2-way crossover design like CANAL.

絕對地。我完全同意你在 IPF 上所說的話。對於 IPF，包括最近的研究，他們對安慰劑的反應一直低於 30%。 RCC，關鍵在於它是像 CANAL 一樣的 2 路交叉設計。

Now in RCC studies like that, including recent RCC studies, the placebo response has been around about 20%. So it's not -- it's quite a different placebo response than has been seen in the longer-duration parallel group studies in RCC.

現在，在像這樣的 RCC 研究中，包括最近的 RCC 研究，安慰劑反應大約在 20% 左右。所以它不是 - 它與 RCC 的持續時間更長的平行組研究中看到的安慰劑反應完全不同。

I'm not showing any further questions. This concludes our question-and-answer session. I would like to turn the call back over to Jennifer Good for closing remarks.

我不會再提出任何問題。我們的問答環節到此結束。我想將電話轉回給 Jennifer Good 作結束語。

We would like to thank everybody for participating in today's call and hope to talk with some of you at the Needham Investor Conference being held April 17 through the 20th virtually. Thank you.

我們要感謝大家參加今天的電話會議，並希望在 4 月 17 日至 20 日以虛擬方式舉行的 Needham 投資者會議上與你們中的一些人交談。謝謝。

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。您現在可以斷開連接。