Crinetics Pharmaceuticals Inc (CRNX) 2020 Q4 法說會逐字稿

Greetings. Welcome to the Crinetics Pharmaceuticals, Inc. 2021 Clinical Strategy and 2020 Financial Results Conference Call. (Operator Instructions) Please note, this conference is being recorded.

問候。歡迎來到 Crinetics 製藥公司。2021 年臨床戰略和 2020 年財務業績電話會議。（操作員說明）請注意，本次會議正在錄製中。

I will now turn the conference over to your host, Corey Davis. You may begin.

現在我將會議交給主持人科里·戴維斯。你可以開始了。

Thanks, Alex, and thank you all for participating in today's conference call.

謝謝亞歷克斯，也感謝大家參加今天的電話會議。

Before we start, I'd like to point out there is a slide deck that is going to accompany today's presentation. The deck can be viewed using the webcast link provided on the Investor page of the Crinetics website. Also posted on this web page is a news release issued earlier today, announcing Crinetics' 2021 clinical plans and fourth quarter and full year 2020 financial results.

在開始之前，我想指出今天的演示將附帶一個幻燈片。可以使用 Crinetics 網站投資者頁面上提供的網絡廣播鏈接觀看該套牌。該網頁上還發布了今天早些時候發布的新聞稿，宣布了 Crinetics 的 2021 年臨床計劃以及 2020 年第四季度和全年財務業績。

I'd like to remind everyone listening that some of the information contained in the news release and on this call is covered under the safe harbor provisions of the Private Securities Litigation Reform Act and contains forward-looking statements based on current expectations, including statements about the initiation of planned clinical trials. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to the risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Crinetics' SEC filings including on its annual report Form 10-K.

我想提醒各位聽眾，新聞稿和本次電話會議中包含的一些信息受到《私人證券訴訟改革法案》安全港條款的保護，並包含基於當前預期的前瞻性陳述，包括有關以下內容的陳述：啟動計劃的臨床試驗。此類前瞻性陳述並非業績保證，由於與公司業務相關的風險和不確定性，公司的實際結果可能與此類陳述中明示或暗示的結果存在重大差異。這些前瞻性陳述完全符合今天的新聞稿、公司其他新聞稿以及 Crinetics 向 SEC 提交的文件（包括其年度報告 10-K 表格）中包含的警示性陳述。

I'd also like to point out that the content of this call contains time-sensitive information that is accurate only as of the date of broadcast, March 30, 2021. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this call.

我還想指出的是，本次電話會議的內容包含時效性信息，僅截至發布之日（2021 年 3 月 30 日）準確。Crinetics 沒有義務修改或更新任何前瞻性陳述以反映本次電話會議之後發生的事件或情況。

With that, I'd like to turn it over to Dr. Scott Struthers, Founder and CEO of Crinetics. Scott, go ahead.

接下來，我想將其交給 Crinetics 創始人兼首席執行官 Scott Struthers 博士。斯科特，繼續吧。

Thanks, Corey, and thanks to all of you listening this afternoon. I'm joined today by Dr. Alan Krasner, our Chief Medical Officer; and Marc Wilson, our Chief Financial Officer. Although we're reporting our 2020 fourth quarter and year-end financial results, the primary purpose of hosting today's call is to provide some additional color on our development strategy and our clinical programs for what we believe will continue to be an exciting year for Crinetics.

謝謝科里，也謝謝大家今天下午的聆聽。今天我們的首席醫療官 Alan Krasner 博士也加入了我的行列。和我們的首席財務官馬克·威爾遜。儘管我們正在報告 2020 年第四季度和年底的財務業績，但舉辦今天電話會議的主要目的是為我們的發展戰略和臨床項目提供一些額外的信息，我們相信這對 Crinetics 來說將繼續是令人興奮的一年。

Now before we get into what we have in store for the balance of the year, I'd like to first touch on some of the recent accomplishments that have set us up for success. Last October, we reported positive Phase II data in acromegaly patients demonstrating that once-daily oral paltusotine allowed patients to maintain their IGF-1 levels when switching from the current standard of care, which are injected octreotide and lanreotide depot therapies. This represented a significant accomplishment as IGF-1 is the biomarker used by physicians to manage acromegaly patients around the world. Once we became comfortable that patients could effectively and seamlessly switch from injectable to our once-a-day oral pill, we approached the FDA and other regulators in order to design a robust Phase III program to support our goal to obtain a broad label and position paltusotine as a differentiated product with a competitive advantage. Following these data and a recent productive meeting with the FDA, we are now advancing paltusotine into a Phase III program. Alan will walk you through that design in a moment.

現在，在我們討論今年剩餘時間的計劃之前，我想首先談談最近取得的一些成就，這些成就為我們的成功奠定了基礎。去年 10 月，我們報告了肢端肥大症患者的 II 期積極數據，表明每天一次口服帕妥索汀可以使患者在從目前註射奧曲肽和蘭瑞肽長效治療的標準治療轉變時維持 IGF-1 水平。這是一項重大成就，因為 IGF-1 是世界各地醫生用來管理肢端肥大症患者的生物標誌物。一旦我們確信患者可以有效、無縫地從注射劑切換到每天一次的口服藥，我們就與 FDA 和其他監管機構接洽，以設計一個強大的 III 期計劃，以支持我們獲得廣泛標籤和地位的目標帕妥索汀作為具有競爭優勢的差異化產品。根據這些數據以及最近與 FDA 舉行的富有成效的會議，我們現在正在將帕圖索汀推進到 III 期項目。艾倫稍後將引導您完成該設計。

We also recently expanded our clinical stage pipeline advancing CRN04894 and CRN04777 in the Phase I clinical trial. As a reminder, 4894 is an investigational oral ACTH antagonist being developed for Cushing's disease and congenital adrenal hyperplasia, while 4777 is an investigational oral SST5 agonist being developed for congenital hyperinsulinism. It's worth noting that just as was the case for paltusotine, many products in endocrinology can be derisked early in clinical development if the use of biomarkers can be predictive of clinical success in later trials. Many of these key biomarkers have also been accepted as primary end points in registrational trials. Therefore, these 2 Phase I endocrine programs have the potential to provide more meaningful outcomes than traditionally found in other therapeutic areas of drug development.

我們最近還擴大了我們的臨床階段管道，在 I 期臨床試驗中推進 CRN04894 和 CRN04777。提醒一下，4894是一種在研口服ACTH拮抗劑，正在開髮用於治療庫欣病和先天性腎上腺增生症，而4777是一種在研口服SST5激動劑，正在開髮用於治療先天性高胰島素血症。值得注意的是，就像帕妥索汀的情況一樣，如果生物標誌物的使用可以預測後期試驗中的臨床成功，許多內分泌學產品可以在臨床開發早期避免風險。其中許多關鍵生物標誌物也已被接受為註冊試驗的主要終點。因此，這兩個 I 期內分泌項目有可能提供比傳統藥物開發的其他治療領域更有意義的結果。

These clinical accomplishments were also complemented by the achievement of key regulatory milestones as the U.S. FDA granted paltusotine an Orphan Drug Designation for the treatment of acromegaly. And CRN04777 received a rare pediatric disease designation for the treatment of congenital hyperinsulinism.

這些臨床成就還得到了關鍵監管里程碑的補充，美國 FDA 授予帕妥索汀用於治療肢端肥大症的孤兒藥資格。CRN04777 還獲得了用於治療先天性高胰島素血症的罕見兒科疾病資格。

Collectively, the advancements of our clinical pipeline have left us poised to solidify our position as a leader in the de novo design and development of novel small molecule drugs for endocrine diseases. We're also well positioned financially as we ended 2020 with over $170 million in cash and investments. Based on our current expectations and in line with previous guidance, this will provide us funding into 2023.

總的來說，我們臨床管線的進步使我們準備鞏固我們作為內分泌疾病新型小分子藥物從頭設計和開發的領導者的地位。我們的財務狀況也十分良好，截至 2020 年底，我們擁有超過 1.7 億美元的現金和投資。根據我們目前的預期並符合之前的指導，這將為我們提供到 2023 年的資金。

Now I'd like to preview Alan's section of the call by giving a high-level overview of our Phase III acromegaly program for paltusotine, which we have now named PATHFNDR. PATHFNDR program, which was developed on -- based on feedback from a recently completed meeting with the FDA as well as interactions with other regulators, consists of 2 well-controlled Phase III trials that we believe could support paltusotine's approval in the U.S. and European Union. These 2 independent placebo-controlled pivotal trials are intended to support a broad label for paltusotine that we believe would allow for its use as both a first-line medical therapy and support seamless switching for patients currently on injectables and looking for a more convenient, less painful alternative.

現在，我想預覽艾倫在電話會議中的部分，對我們的帕妥索汀第三期肢端肥大症計劃（我們現在將其命名為 PATHFNDR）進行高度概述。PATHFNDR 計劃是根據最近完成的與 FDA 會議的反饋以及與其他監管機構的互動而製定的，由 2 項控制良好的 III 期試驗組成，我們相信這些試驗可以支持帕圖索汀在美國和歐盟的批准。這兩項獨立的安慰劑對照關鍵試驗旨在支持帕妥索汀的廣泛標籤，我們相信這將允許其用作一線藥物治療，並支持目前使用注射劑並尋找更方便、更少藥物的患者的無縫切換。痛苦的替代方案。

In support of this goal, our Phase III trials will enroll a broad cross-section of acromegaly patients. Both studies will be placebo-controlled, and the primary end point for both studies is the proportion of patients who are responders achieving biochemical control. Regulators define a responder as a patient whose IGF levels are at or below 1x the upper limit of normal.

為了支持這一目標，我們的 III 期試驗將招募廣泛的肢端肥大症患者。這兩項研究都將採用安慰劑對照，這兩項研究的主要終點是達到生化控制的緩解患者的比例。監管機構將應答者定義為 IGF 水平等於或低於正常上限 1 倍的患者。

The first of these trials, PATHFNDR-1, focuses on patients switching from the current standard of care and will enroll patients who are already biochemically controlled on injectable octreotide or lanreotide . Our second Phase III trial, PATHFNDR-2, focuses on untreated patients who are biochemically uncontrolled, meaning their IGF levels are above 1x the upper limit of normal. Together, if successful, we believe these trials could support registration of paltusotine in the U.S. and EU for all acromegaly patients who require pharmacotherapy, including both untreated patients and those switching from standard of care, regardless of whether they have been biochemically controlled on these prior therapies. This would best position paltusotine to take advantage of the acromegaly market opportunity and most importantly, increase the number of acromegaly patients who would stand to benefit from the advantages of paltusotine's once-daily oral dosing.

這些試驗中的第一個 PATHFNDR-1 重點關注從當前護理標準轉變的患者，並將招募已經通過注射奧曲肽或蘭瑞肽進行生化控制的患者。我們的第二項 III 期試驗 PATHFNDR-2，重點關註生化失控的未經治療的患者，這意味著他們的 IGF 水平高於正常上限的 1 倍。總之，如果成功，我們相信這些試驗可以支持在美國和歐盟為所有需要藥物治療的肢端肥大症患者註冊帕妥索汀，包括未經治療的患者和那些從標準護理轉換的患者，無論他們之前是否已在這些治療中得到生化控制。療法。這將使帕圖索汀能夠最好地利用肢端肥大症市場機會，最重要的是，增加肢端肥大症患者的數量，他們將受益於帕圖索汀每日一次口服給藥的優勢。

With that, I'll now hand the call over to our Chief Medical Officer, Dr. Alan Krasner, who will dive into the details of the PATHFNDR-1 and 2 study design. Alan?

現在，我將把電話轉交給我們的首席醫療官 Alan Krasner 博士，他將深入探討 PATHFNDR-1 和 2 研究設計的細節。艾倫？

Thank you, Scott, and good afternoon, everyone. I'd like to start by describing the design of the PATHFNDR-1 study on Slide 5. It was designed based on feedback from the FDA and other regulators and mirrors the design of other recently approved products for acromegaly in the U.S. As Scott mentioned, PATHFNDR-1 will enroll patients who are biochemically controlled on octreotide or lanreotide depot monotherapy. Target enrollment for this study is 52 patients.

謝謝斯科特，大家下午好。我想首先在幻燈片 5 上描述 PATHFNDR-1 研究的設計。它是根據 FDA 和其他監管機構的反饋而設計的，並反映了美國最近批准的其他肢端肥大症產品的設計，正如 Scott 提到的， PATHFNDR-1將招募接受奧曲肽或蘭瑞肽長效單一療法生化控制的患者。本研究的目標入組人數為 52 名患者。

These patients will remain on their injected depot monotherapy through a 1- to 3-month screening period, during which time we will establish baseline values for parameters such as IGF-1 growth hormone and total acromegaly symptoms diary score. After completing the screening period, patients will be randomized to receive once-daily oral doses of paltusotine or placebo. IGF-1 assessments will be conducted each month throughout the study's 9-month treatment period. Patients randomized to paltusotine will start at a 40-milligram per day dose.

這些患者將在 1 至 3 個月的篩選期內繼續接受注射儲庫單一療法，在此期間我們將建立 IGF-1 生長激素和肢端肥大症症狀總日記評分等參數的基線值。篩選期結束後，患者將被隨機分配接受每日一次口服帕圖索汀或安慰劑。在該研究的 9 個月治療期間，每個月都會進行 IGF-1 評估。隨機接受帕妥索汀治療的患者將從每天 40 毫克的劑量開始。

If during months 2 to 6, a patient's IGF-1 level rises above 0.9x the upper limit of normal, that patient's dose will be increased to 60 milligrams as some patients may need a higher dose. Alternatively, the dose can be decreased in 20-milligram decrements if necessary for tolerability reasons. Patients will then be maintained on the dose that was established during the first 6 months of the treatment period. An average of the 3 IGF-1 assessments measured at weeks 32, 34 and 36 will serve to determine IGF-1 responder status.

如果在第 2 至 6 個月期間，患者的 IGF-1 水平升至正常上限的 0.9 倍以上，則該患者的劑量將增加至 60 毫克，因為某些患者可能需要更高的劑量。或者，出於耐受性原因，如有必要，可以將劑量減少 20 毫克。然後患者將維持治療期前 6 個月期間確定的劑量。第 32、34 和 36 週測量的 3 次 IGF-1 評估的平均值將用於確定 IGF-1 應答者狀態。

The primary end point of PATHFNDR-1 is a responder analysis comparing the percentage of control patients in the active arm to those in the placebo arm. For statistical success, paltusotine needs to demonstrate superiority to placebo in this responder analysis in order to meet the primary objective. This study is over 90% powered to do this.

PATHFNDR-1 的主要終點是一項反應者分析，比較活性組中對照患者的百分比與安慰劑組中的對照患者的百分比。為了在統計上取得成功，帕圖索汀需要在應答者分析中證明其優於安慰劑，以實現主要目標。這項研究的功效超過 90%。

Because this is a placebo-controlled trial, procedures are in place to rescue patients with standard injection therapy, if necessary. Patients who have 2 consecutive IGF-1 measurements above 1.3x the upper limit of normal, plus an exacerbation of acromegaly clinical symptoms while on the maximal dose, will receive rescue therapy. Patients require rescue therapy are counted as nonresponders.

由於這是一項安慰劑對照試驗，因此如有必要，已製定程序以標準注射療法搶救患者。如果患者連續 2 次 IGF-1 測量值高於正常上限的 1.3 倍，並且在最大劑量下肢端肥大症臨床症狀惡化，則將接受挽救治療。需要搶救治療的患者被視為無反應者。

Looking ahead, we expect to initiate PATHFNDR-1 in the second quarter of the year, in line with previous guidance for our Phase III program. Top line data from this study is expected in 2023, and the study will be followed by an open-label extension for eligible patients.

展望未來，我們預計將在今年第二季度啟動 PATHFNDR-1，這與我們之前對第三階段計劃的指導一致。這項研究的主要數據預計將於 2023 年獲得，隨後該研究將對符合條件的患者進行開放標籤擴展。

I'll now shift gears a bit to Slide 6 and speak about our PATHFNDR-2 study, which has been designed to enable paltusotine use in untreated biochemically uncontrolled patients. This study will enroll medication-naive patients or patients who have not received medication in the previous 4 months as well as patients receiving octreotide who agreed to washout under supervision to demonstrate a rise in IGF-1 above the upper limit of normal. Target enrollment for the study is 74 patients.

現在我將轉向幻燈片 6，談談我們的 PATHFNDR-2 研究，該研究旨在使帕圖索汀能夠用於未經治療的生化失控患者。這項研究將招募未曾接受藥物治療的患者或在過去 4 個月內未接受過藥物治療的患者，以及接受奧曲肽治療並同意在監督下進行沖洗以證明 IGF-1 升高至正常上限以上的患者。該研究的目標入組人數為 74 名患者。

As in PATHFNDR-1, baseline values of IGF-1 will be established during the screening period. However, the PATHFNDR-2 population will consist of patients with elevated IGF-1 levels initiating treatment, whereas PATHFNDR-1 will consist of those with normal IGF levels on treatment who switched their treatment to paltusotine. The combination of these 2 studies will capture the spectrum of acromegaly patients who require medical therapy.

與 PATHFNDR-1 一樣，IGF-1 的基線值將在篩選期間建立。然而，PATHFNDR-2 人群將由開始治療的 IGF-1 水平升高的患者組成，而 PATHFNDR-1 將由接受治療時 IGF 水平正常但轉用帕妥索汀治療的患者組成。這兩項研究的結合將捕獲需要藥物治療的肢端肥大症患者的範圍。

After completing the screening period, PATHFNDR-2 patients will be randomized to receive once-daily oral doses of paltusotine or placebo. IGF-1 assessments will be scheduled periodically throughout the study's planned 12-week treatment period. The study's primary end point is a responder analysis based on the mean IGF-1 measurements at weeks 10 and 12 comparing paltusotine to placebo. As in PATHFNDR-1, the target dose range for patients in this study will be 40 to 60 milligrams per day. Rescue criteria will also be in place for this study. While we are still finalizing the rescue criteria for PATHFNDR-2, we can say that they will be also based on IGF-1 levels and clinical acromegaly symptoms.

篩選期結束後，PATHFNDR-2 患者將被隨機分配接受每日一次口服帕妥索汀或安慰劑。IGF-1 評估將在研究計劃的 12 周治療期間定期安排。該研究的主要終點是基於第 10 周和第 12 週的平均 IGF-1 測量值對帕圖索汀與安慰劑進行比較的反應者分析。與 PATHFNDR-1 一樣，本研究中患者的目標劑量範圍為每天 40 至 60 毫克。這項研究還將製定救援標準。雖然我們仍在最終確定 PATHFNDR-2 的救援標準，但我們可以說它們也將基於 IGF-1 水平和臨床肢端肥大症症狀。

Looking ahead, we expect to initiate PATHFNDR-2 in the second half of the year, with top line data also expected in 2023. As in the case with PATHFNDR-1, we expect the trial to have statistical power greater than 90%, and eligible patients will have the option to participate in an open-label extension study.

展望未來，我們預計將在今年下半年啟動 PATHFNDR-2，預計頂線數據也將在 2023 年發布。與 PATHFNDR-1 的情況一樣，我們預計該試驗的統計功效大於 90%，符合條件的患者將可以選擇參加開放標籤擴展研究。

Now that we have walked through the design of our Phase III program in detail, I'd like to take a step back and give a high-level summary on Slide 7 of what's next for paltusotine. As I mentioned, we expect to initiate both of the PATHFNDR studies this year, with PATHFNDR-1 to begin in the second quarter and PATHFNDR-2 expected to begin in the second half of 2021. We also plan to initiate a Phase II trial evaluating paltusotine as a treatment for patients with neuroendocrine tumors or NETs complicated by carcinoid syndrome in 2021. The positive data we've generated to date in our acromegaly trials gives us confidence in this program, because the same octreotide and lanreotide depots currently used to treat acromegaly are also used to treat NETs.

現在我們已經詳細介紹了 III 期項目的設計，我想退後一步，在幻燈片 7 上對 paltusotine 的下一步進行高度總結。正如我提到的，我們預計今年啟動兩項 PATHFNDR 研究，其中 PATHFNDR-1 將於第二季度開始，PATHFNDR-2 預計將於 2021 年下半年開始。我們還計劃於 2021 年啟動一項 II 期試驗，評估帕妥索汀治療神經內分泌腫瘤或併發類癌綜合徵的 NET 患者。迄今為止，我們在肢端肥大症試驗中獲得的積極數據讓我們對該計劃充滿信心，因為目前用於治療肢端肥大症的奧曲肽和蘭瑞肽長效製劑也可用於治療 NET。

Looking a bit further down the road, we expect to report top line data from our PATHFNDR-1 and -2 studies in 2023. I'd like now to review our fundamental goals in both Phase III studies.

展望未來，我們預計將在 2023 年報告 PATHFNDR-1 和 -2 研究的主要數據。我現在想回顧一下我們在兩項 III 期研究中的基本目標。

Our PATHFNDR trials will be deemed a success if they demonstrate paltusotine's ability to outperform placebo in a responder analysis. Given the pharmacologic activity demonstrated by paltusotine in our Phase I and II studies, we are confident we can meet this goal, which we believe will support approval in the U.S. and European Union. I'd also like to remind you that we are targeting a broad label with these studies as we hope paltusotine will be accessible both as a first-line pharmacotherapy and as an alternative to burdensome octreotide or lanreotide injections.

如果我們的 PATHFNDR 試驗在應答者分析中證明帕妥索汀優於安慰劑的能力，則將被視為成功。鑑於帕妥索汀在我們的 I 期和 II 期研究中所證明的藥理活性，我們有信心能夠實現這一目標，我們相信這將支持美國和歐盟的批准。我還想提醒您，我們的這些研究目標是廣泛的標籤，因為我們希望帕圖索汀既可以作為一線藥物療法，也可以作為繁重的奧曲肽或蘭瑞肽注射劑的替代品。

Now before I hand it off to Marc to summarize our recent financial results, I'd like to talk briefly about our plans for 4894 and 4777 programs. Let me first start on Slide 8 by saying that our approach to endocrinology provides the opportunity to explore the safety and efficacy of drug candidates early in the development process. The beauty of drug development in endocrinology is its ability to translate from preclinical to patient studies. Endocrine systems are similar between mammals, and we can study the pharmacology of drug candidates on hormone levels in animal models and in healthy volunteers in a way that provides meaningful proof of concept and dose selection guidance for later clinical studies in patients.

現在，在我交給 Marc 總結我們最近的財務業績之前，我想簡要談談我們的 4894 和 4777 計劃計劃。首先讓我從幻燈片 8 開始說，我們的內分泌學方法提供了在開發過程早期探索候選藥物安全性和有效性的機會。內分泌學藥物開發的美妙之處在於其能夠從臨床前研究轉化為患者研究。哺乳動物之間的內分泌系統是相似的，我們可以在動物模型和健康志願者的激素水平上研究候選藥物的藥理學，為以後的患者臨床研究提供有意義的概念證明和劑量選擇指導。

Our plan for the Phase I studies with 4894 and 4777 is analogous to what we did in our initial Phase I healthy volunteer study of paltusotine, which provided important early information for that program. In these Phase I studies, we will of course evaluate safety, tolerability and pharmacokinetics. But in addition to this, we aim to understand the pharmacodynamic effects on relevant hormone levels to give us a strong sense of the molecule's pharmacology and potency to produce the desired therapeutic effects in patients.

我們對 4894 和 4777 進行 I 期研究的計劃與我們在帕妥索汀的初始 I 期健康志願者研究中所做的類似，該研究為該計劃提供了重要的早期信息。在這些 I 期研究中，我們當然會評估安全性、耐受性和藥代動力學。但除此之外，我們的目標是了解藥效學對相關激素水平的影響，以使我們對該分子的藥理學和效力有強烈的認識，從而在患者中產生所需的治療效果。

As some of you may know, CRN04894 is an investigational oral nonpeptide ACTH antagonist that we are developing for Cushing's disease and congenital adrenal hyperplasia or CAH. It entered a Phase I trial pictured on Slide 9 in healthy volunteers earlier this year, and we expect to report preliminary data from the single ascending dose portion of the study by the end of June, with data from the multiple ascending dose portion coming in the second half of the year.

你們中有些人可能知道，CRN04894 是一種在研口服非肽 ACTH 拮抗劑，我們正在開髮用於治療庫欣病和先天性腎上腺增生或 CAH。今年早些時候，它在健康志願者中進入了 I 期試驗（如幻燈片 9 所示），我們預計在 6 月底之前報告該研究的單劑量遞增部分的初步數據，多劑量遞增部分的數據將在下半年。

While it is typical for Phase 1 trials to assess safety, tolerability and pharmacokinetics, we expect this study to provide added value by establishing clinical proof of concept for 4894 in CAH and Cushing's disease. We are able to do this by measuring hormonal biomarkers used in our animal model studies, which are the same hormones that endocrinologists measure every day in practice. These hormones are also key end points that regulators use to evaluate new drugs for approval in these conditions.

雖然 1 期試驗通常評估安全性、耐受性和藥代動力學，但我們預計這項研究將通過建立 4894 在 CAH 和庫欣病中的臨床概念驗證來提供附加值。我們可以通過測量動物模型研究中使用的激素生物標誌物來做到這一點，這些生物標誌物與內分泌學家每天在實踐中測量的激素相同。這些激素也是監管機構用來評估新藥在這些情況下獲得批准的關鍵終點。

Both CAH and Cushing's disease are characterized by excess ACTH secretion, which results in adrenal gland oversecretion of adrenal androgens in the case of CAH or cortisol in the case of Cushing's disease. Both adrenal androgens and cortisol can be readily measured in healthy volunteers and in patients.

CAH和庫欣病的特徵都是ACTH分泌過多，導致腎上腺過度分泌腎上腺雄激素（對於CAH）或皮質醇（對於庫欣病）。健康志願者和患者的腎上腺雄激素和皮質醇都可以輕鬆測量。

In our ongoing Phase I study, we are evaluating the ability of 4894 to block the action of ACTH on the adrenal glands, which should be predictive of the molecule's efficacy. To make this assessment, we are administering ACTH to healthy volunteers and measuring levels of cortisol in the blood. This is a well-established technique to assess adrenal function that has been used by endocrinologists for many years.

在我們正在進行的一期研究中，我們正在評估 4894 阻斷 ACTH 對腎上腺作用的能力，這應該可以預測該分子的功效。為了進行這項評估，我們給健康志願者註射促腎上腺皮質激素（ACTH）並測量血液中皮質醇的水平。這是一種成熟的評估腎上腺功能的技術，已被內分泌學家使用多年。

Now if I can turn your attention to the diagram on the right side of the slide, I'll briefly explain how we are adapting this technique to explore the pharmacology of 4894. On day minus 1, a healthy volunteer receives an injection of ACTH. We then take blood draws 30, 60 and 120 minutes later to see how cortisol output from the adrenals respond to the ACTH injection. The next day, we treat study participants with oral 4894, repeat the ACTH stimulation, and again measure blood cortisol levels to determine how 4894 affects the adrenal response.

現在，如果我可以將您的注意力轉向幻燈片右側的圖表，我將簡要解釋我們如何採用該技術來探索 4894 的藥理學。在負 1 天，一名健康志願者接受 ACTH 注射。然後，我們在 30 分鐘、60 分鐘和 120 分鐘後抽血，觀察腎上腺分泌的皮質醇對 ACTH 注射的反應。第二天，我們給研究參與者口服 4894，重複 ACTH 刺激，並再次測量血液皮質醇水平，以確定 4894 如何影響腎上腺反應。

Upon the completion of this study, what we are hoping to see is dose-dependent suppression of ACTH-stimulated peak cortisol with 4894. This would provide clinical proof of concept in both Cushing's disease and CAH, which in turn derisks the clinical program. Such data will also provide insights into therapeutically relevant doses of 4894, which will be useful when designing subsequent studies in patients.

這項研究完成後，我們希望看到 4894 對 ACTH 刺激的皮質醇峰值產生劑量依賴性抑制。這將為庫欣病和 CAH 提供臨床概念證明，從而降低臨床計劃的風險。這些數據還將提供對 4894 治療相關劑量的深入了解，這在設計患者的後續研究時將非常有用。

I'll now shift gears again to Slide 10 and talk about CRN04777, our investigational oral nonpeptide SST5 agonist being developed as a treatment for congenital hyperinsulinism or congenital HI. Like the 4894 Phase I trial I just described, the 4777 Phase I study is designed to assess safety, tolerability and pharmacokinetics as well as to provide early clinical proof of concept in relevant indication. Once again, we are able to do this in Phase I because we are developing a drug for an indication with well-established biology and blood-based biomarkers.

現在我將再次切換到幻燈片 10，談論 CRN04777，我們正在開發的研究性口服非肽 SST5 激動劑，用於治療先天性高胰島素血症或先天性 HI。與剛剛描述的 4894 I 期試驗一樣，4777 I 期研究旨在評估安全性、耐受性和藥代動力學，並提供相關適應症的早期臨床概念證明。我們能夠在第一階段再次做到這一點，因為我們正在開發一種藥物，用於具有完善的生物學和血液生物標誌物的適應症。

As the name implies, congenital hyperinsulinism is caused by excess insulin secretion even in the face of low blood glucose levels, which can lead to dangerous hypoglycemic episodes. In our ongoing Phase I study, we are evaluating the ability of 4777 to reduce insulin secretion, which should be predictive of efficacy in congenital HI. I should emphasize here that 4777 is designed to act at the SST5 receptor, which is independent of many of the mutations that cause congenital HI. This is significant as it should allow 4777 to be broadly applicable to congenital HI patients with various underlying mutations.

顧名思義，先天性高胰島素血症是即使在低血糖水平下胰島素分泌過多也會引起的，這可能導致危險的低血糖發作。在我們正在進行的 I 期研究中，我們正在評估 4777 減少胰島素分泌的能力，這應該可以預測先天性 HI 的療效。我應該在這裡強調，4777 被設計為作用於 SST5 受體，該受體獨立於許多導致先天性 HI 的突變。這很重要，因為它應該允許 4777 廣泛適用於具有各種潛在突變的先天性 HI 患者。

Turning our attention now to the right side of this slide. You can see that we are utilizing 2 separate techniques to explore the pharmacology of 4777. The first technique is an intravenous glucose tolerance test. The premise for this test is relatively simple: administration of exogenous glucose stimulates the secretion of endogenous insulin. So to evaluate the ability of 4777 to suppress insulin secretion, we take healthy volunteers and infuse them intravenously with a bolus of glucose on day minus 1, and then measure insulin and blood glucose changes that result from the glucose injection. The next day, we treat study participants with oral 4777, repeat the intravenous glucose administration, and again measure insulin and glucose responses to determine if 4777 is able to reduce insulin secretion.

現在將我們的注意力轉向這張幻燈片的右側。您可以看到，我們正在利用 2 種獨立的技術來探索 4777 的藥理學。第一種技術是靜脈內葡萄糖耐量測試。該測試的前提相對簡單：施用外源性葡萄糖刺激內源性胰島素的分泌。因此，為了評估4777抑制胰島素分泌的能力，我們選取健康志願者，在負1天給他們靜脈注射葡萄糖，然後測量葡萄糖注射引起的胰島素和血糖變化。第二天，我們對研究參與者口服 4777，重複靜脈注射葡萄糖，並再次測量胰島素和葡萄糖反應，以確定 4777 是否能夠減少胰島素分泌。

The second technique being employed in this Phase I trial is a sulfonylurea challenge test. Sulfonylureas are a well-known class of diabetes drug that stimulate insulin secretion. The use of sulfonylureas can pharmacologically mimic the most common mutations that are found in about half of congenital HI patients. Thus, sulfonylureas are a useful tool to evaluate 4777's pharmacologic activity.

第一階段試驗中採用的第二種技術是磺酰脲挑戰試驗。磺酰脲類藥物是一類眾所周知的刺激胰島素分泌的糖尿病藥物。磺酰脲類藥物的使用可以在藥理學上模擬約一半先天性 HI 患者中發現的最常見突變。因此，磺酰脲類藥物是評估 4777 藥理活性的有用工具。

As you can see in the diagram on the bottom right of the slide, we plan to first administer a sulfonylurea to healthy volunteers, and then measure their levels of insulin and glucose for a period of 9 hours. During this time, participants will receive intravenous glucose as needed, in order to prevent the sulfonylurea from causing low blood glucose levels or hypoglycemia. This precise infusion of glucose is referred to as a glucose clamp technique, because the subject's glucose level is being clamped in the normal range. The amount of IV glucose required to keep the subject's glucose level normal is a quantitative measure of the sulfonylurea effect.

正如您在幻燈片右下角的圖表中所看到的，我們計劃首先給健康志願者服用磺酰脲類藥物，然後在 9 小時內測量他們的胰島素和葡萄糖水平。在此期間，參與者將根據需要接受靜脈注射葡萄糖，以防止磺酰脲類藥物引起低血糖或低血糖。這種精確的葡萄糖輸注被稱為葡萄糖鉗夾技術，因為受試者的葡萄糖水平被箝制在正常範圍內。保持受試者的葡萄糖水平正常所需的IV葡萄糖的量是磺酰脲效應的定量測量。

1 or 2 days later, participants will again receive a sulfonylurea while on a glucose clamp. An hour after receiving the sulfonylurea, participants will then be given oral 4777. Insulin and other blood-based biomarkers will again be assessed for a 9-hour period. 4777 is expected to reduce insulin secretion in response to IV glucose or a sulfonylurea challenge, which for the patient could mean fewer episodes of debilitating hypoglycemia. Demonstrating this would significantly derisk this clinical program, while also providing valuable dosing information to aid in the design of subsequent studies in patients.

1 或 2 天后，參與者將在進行葡萄糖鉗夾時再次接受磺酰脲類藥物。接受磺酰脲類藥物一小時後，參與者將口服 4777。將再次評估 9 小時內的胰島素和其他血液生物標誌物。4777 預計會減少靜脈注射葡萄糖或磺酰脲類藥物激發後的胰島素分泌，這對患者來說可能意味著更少的衰弱性低血糖發作。證明這一點將極大地降低該臨床計劃的風險，同時也提供有價值的劑量信息以幫助設計後續的患者研究。

With that, I'll turn the call over to Marc Wilson, our Chief Financial Officer, to discuss our financial results for the fourth quarter and full year 2020. Marc?

接下來，我將把電話轉給我們的首席財務官 Marc Wilson，討論我們 2020 年第四季度和全年的財務業績。馬克？

Thanks, Alan, and good afternoon, everyone. I'm pleased to report that in 2020, Crinetics was able to maintain a strong financial position, while making significant advancements in its clinical and drug discovery programs. Our unrestricted cash, cash equivalents and investments improved to $170.9 million at the end of 2020 compared to $118.4 million at the end of 2019. Based on our current expectations, our financial runway extends into 2023, through the anticipated top line data readouts from the paltusotine PATHFNDR studies.

謝謝艾倫，大家下午好。我很高興地向大家報告，2020 年，Crinetics 能夠保持強勁的財務狀況，同時在臨床和藥物發現項目方面取得重大進展。2020 年底，我們的無限制現金、現金等價物和投資增至 1.709 億美元，而 2019 年底為 1.184 億美元。根據我們目前的預期，通過帕圖索汀 PATHFNDR 研究的預期頂線數據讀數，我們的財務跑道延伸至 2023 年。

As of February 28, 2021, the company had roughly 33 million common shares outstanding. Total operating expenses for the fourth quarter and full year 2020 were approximately $21.8 million and $75 million, respectively. This represented an increase over total operating expenses for the same periods in 2019, which were $15.5 million and $55 million, respectively.

截至 2021 年 2 月 28 日，該公司已發行普通股約 3300 萬股。2020 年第四季度和全年的總運營費用分別約為 2180 萬美元和 7500 萬美元。這比 2019 年同期的總運營支出有所增加，2019 年同期的總運營支出分別為 1,550 萬美元和 5,500 萬美元。

Research and development expenses for the fourth quarter and full year 2020 were $16.8 million and $57 million, respectively, compared to $12.1 million and $41.5 million for the same periods in 2019. Increases in R&D spend were primarily attributable to clinical development and manufacturing activities for paltusotine as well as progress in the company's preclinical programs.

2020年第四季度和全年的研發費用分別為1680萬美元和5700萬美元，而2019年同期為1210萬美元和4150萬美元。研發支出的增加主要歸因於帕妥索汀的臨床開發和生產活動以及公司臨床前項目的進展。

General and administrative expenses also increased for the fourth quarter and full year 2020, growing from $3.4 million and $13.5 million in 2019 to $5 million and $18 million for the same periods in 2020. These increases were primarily due to personnel costs to support the company's growth.

2020 年第四季度和全年的一般和管理費用也有所增加，從 2019 年的 340 萬美元和 1,350 萬美元增至 2020 年同期的 500 萬美元和 1,800 萬美元。這些增長主要是由於支持公司增長的人員成本。

Finally, net loss for the fourth quarter of 2020 was $21.6 million compared to a net loss of $14.5 million for the same period in 2019. For the full year 2020, the company's net loss was $73.8 million compared to a net loss of $50.4 million for the full year 2019.

最後，2020 年第四季度的淨虧損為 2160 萬美元，而 2019 年同期的淨虧損為 1450 萬美元。2020年全年，該公司的淨虧損為7380萬美元，而2019年全年的淨虧損為5040萬美元。

And with that, I'll hand it back to Scott.

有了這個，我會把它交還給斯科特。

Thanks, Marc.

謝謝，馬克。

Before we open the line for questions, I'd like to take a moment to recognize all our employees, investigators, site staff and patients around the world. Thanks to their talent and dedication amid the pandemic, we have gone from a company that had a single clinical-stage asset to one with an active pipeline of 3 clinical programs, with more on the way from discovery.

在我們開始提問之前，我想花點時間向我們在世界各地的所有員工、調查人員、現場工作人員和患者致以謝意。得益於他們在疫情期間的才華和奉獻精神，我們已經從一家擁有單一臨床階段資產的公司發展成為擁有 3 個臨床項目的活躍管道的公司，並且還有更多的項目正在進行中。

As you can see on the table on this slide, this progress has left us poised to achieve a steady cadence of milestones over the coming months. By the end of the year, we expect to have initiated both Phase III PATHFNDR studies as well as the Phase II trial evaluating paltusotine in patients with NETs complicated by carcinoid syndrome. We also expect to have established proof of concept for our 4894 and 4777 programs, as our Phase I trials will assess the ability of these candidates to modulate the relative peptide hormone receptors in healthy volunteers. This should be highly predictive of efficacy in patients.

正如您在這張幻燈片的表格中看到的那樣，這一進展使我們做好了在未來幾個月內實現穩定里程碑的準備。到今年年底，我們預計將啟動 III 期 PATHFNDR 研究以及評估帕圖索汀治療患有類癌綜合徵的 NET 患者的 II 期試驗。我們還希望為我們的 4894 和 4777 項目建立概念驗證，因為我們的 I 期試驗將評估這些候選藥物調節健康志願者中相關肽激素受體的能力。這應該可以高度預測患者的療效。

This early stage derisking strategy has been validated by our paltusotine program, which was the driving force behind our IPO a few years ago and was executed at the time when paltusotine has completed its first Phase I healthy volunteer study. Collectively, we expect the execution of our clinical milestones to solidify our position as a leader in the field of endocrinology. We look forward to the year ahead and remain committed to working to improve the lives of our patients.

這一早期階段的去風險策略已得到我們的帕圖索汀計劃的驗證，該計劃是我們幾年前首次公開募股的推動力，並在帕圖索汀完成其第一個一期健康志願者研究時執行。總的來說，我們期望臨床里程碑的執行能夠鞏固我們作為內分泌領域領導者的地位。我們展望未來的一年，並繼續致力於改善患者的生活。

With that, I'd like to thank everyone for joining our call today. We'll now open the call to questions, and I'll ask the operator to moderate them.

在此，我要感謝大家今天加入我們的電話會議。我們現在將開始提問，我將請接線員主持這些問題。

(Operator Instructions) Our first question is from Charles Duncan with Cantor Fitzgerald.

（操作員說明）我們的第一個問題來自查爾斯·鄧肯（Charles Duncan）和坎托·菲茨杰拉德（Cantor Fitzgerald）。

Congrats, Scott and team, to a good year of progress. Really like the slides, they're very well organized, so definitely appreciate all the detail.

祝賀斯科特和他的團隊，今年取得了良好的進展。真的很喜歡這些幻燈片，它們組織得很好，所以一定要欣賞所有的細節。

First question, though, is timelines to data, data in '23. I mean, very well-organized program for PATHFNDR in Phase III. And I guess I'm wondering what do you anticipate to be the biggest rate-limiting step? Will it be enrollment or identification of the best patients for this trial, appropriate patients for the trial? What is really governing that '23 timeline?

不過，第一個問題是數據的時間表，23 年的數據。我的意思是，第三階段的 PATHFNDR 計劃組織得非常好。我想我想知道您預計最大的速率限制步驟是什麼？是否會招募或確定本次試驗的最佳患者、適合試驗的患者？真正控制 '23 時間表的是什麼？

Thanks, Chaz. I appreciate the question. Maybe I'll take that one. And Alan, jump in if you think I'm missing anything.

謝謝，查茲。我很欣賞這個問題。也許我會選擇那個。艾倫，如果你認為我遺漏了什麼，請加入。

But patient enrollment is always a challenge in rare disease studies, but we've learned a lot from our Phase II program. And we've implemented a range of things to enhance enrollment, not the least of which is letting patients and their investigators know that this drug can switch patients who are on standard of care to paltusotine without loss of IGF-1 control. So that's huge.

但患者入組始終是罕見病研究中的一個挑戰，但我們從二期項目中學到了很多東西。我們已經實施了一系列措施來提高入組率，其中最重要的是讓患者及其研究人員知道這種藥物可以將接受標準護理的患者轉為帕圖索汀，而不會失去 IGF-1 的控制。所以這是巨大的。

The other thing is that we'll be using centers all around the world to conduct this study. Probably with these studies, approximately 100 different centers in multiple different countries.

另一件事是我們將利用世界各地的中心來進行這項研究。這些研究可能涉及多個不同國家的大約 100 個不同的中心。

So it's always a challenge. We're going to be working hard on site activations and patient recruitment through multiple mechanisms, but we're pretty confident in that forecast for 2023.

所以這始終是一個挑戰。我們將通過多種機制努力激活站點並招募患者，但我們對 2023 年的預測非常有信心。

Alan, did you want to add anything?

艾倫，你想補充什麼嗎？

No, I agree with that very much, Scott. I also want to remind everyone that these studies have open-label extension periods, both of them. And that is always -- that always helps with recruitment, particularly in the rare disease state, particularly in studies which are placebo-controlled. All patients who are eligible and complete the trials would have an opportunity to potentially enroll in the OLE.

不，我非常同意這一點，斯科特。我還想提醒大家，這些研究都有開放標籤的延長期，兩者都是。這總是有助於招募，特別是在罕見疾病狀態下，特別是在安慰劑對照的研究中。所有符合資格並完成試驗的患者都有機會參加 OLE。

Okay, and then if I may, a follow-up. It seems like stat sig relative to placebo, certainly in PATHFNDR-1, is relatively low bar. But I guess I'm wondering beyond statistical significance, what kind of response rate would you like to see in terms of clinically significant results out of that PATHFNDR study?

好的，如果可以的話，我會進行後續跟進。看起來 stat sig 相對於安慰劑（當然在 PATHFNDR-1 中）相對較低。但我想我除了統計顯著性之外還想知道，就 PATHFNDR 研究的臨床顯著結果而言，您希望看到什麼樣的緩解率？

Alan, do you want to take that?

艾倫，你想接受這個嗎？

Sure. Well, so the end point is designed to be inherently clinically significant. And this is the preferred end point from the FDA and regulatory community, that is percentage of patients with normal IGF-1. So showing as a increased responder rate that is significant in patients who normalize their IGF-1 is inherently clinically significant, and we know that is the preferred approach from the regulators.

當然。嗯，所以終點的設計具有內在的臨床意義。這是 FDA 和監管機構的首選終點，即 IGF-1 正常的患者百分比。因此，對於 IGF-1 正常化的患者來說，反應率的增加具有內在的臨床意義，我們知道這是監管機構的首選方法。

Okay. Maybe I'll just add to that, that we've shown in Phase II that paltusotine can achieve levels of IGF-1 that are equivalent or on par with those obtained with current standard of care. So in PATHFNDR-1 where we're starting with patients already on injectable that are controlled, we would expect very high levels of responses -- responders, so 70%-plus.

好的。也許我要補充一點，我們在第二階段已經證明，paltusotine 可以達到與當前護理標準所獲得的 IGF-1 水平相當或相當的水平。因此，在 PATHFNDR-1 中，我們從已經註射受控注射的患者開始，我們預計反應水平非常高——反應者，因此 70% 以上。

If -- in naive patients or patients not on therapy, that might be substantially lower as it's been shown for the peptides. So we'd expect those to be down around 1/3, as we previously discussed for patients who are new to somatostatin analog therapy.

如果——在未接受治療的患者或未接受治療的患者中，該值可能會大大降低，正如肽所顯示的那樣。因此，我們預計這些數字會下降 1/3 左右，正如我們之前針對剛開始接受生長抑素類似物治療的患者所討論的那樣。

That's helpful, Scott. Last question, moving on to the earlier pipeline, 4894 and 4777. Using the stim test in human volunteers, I get that endocrinology or endocrine systems are fairly well, I guess, conserved. I'm wondering could you anticipate using a stimulation test when you move into patients to identify patients who may be responders and perhaps use that as an enrichment marker?

這很有幫助，斯科特。最後一個問題，繼續討論之前的管道 4894 和 4777。通過對人類誌願者進行刺激測試，我發現內分泌學或內分泌系統相當保守，我猜。我想知道當您進入患者體內時，您是否可以預期使用刺激測試來識別可能有反應的患者，並可能將其用作富集標記？

Alan, do you want to...

艾倫，你想...

I think that's possible, Chaz. I mean that's something that we would evaluate after having seen Phase I healthy volunteer data. It certainly is intriguing to think of it as a companion sort of diagnostic.

我認為這是可能的，查茲。我的意思是，這是我們在看到第一階段健康志願者數據後將進行評估的事情。將其視為一種伴隨診斷確實很有趣。

The only thing I would say, though, is sort of we know that the -- we know sort of the ultimate markers that need to be controlled in these disease states. And in addition to showing the kinds of stimulation results where we hope to show in Phase I, we'll need to show, for example in Cushing's disease, that the overall cortisol output is reduced. Usually, this is measured using urine free cortisol collections. So we'll be looking at a large host of markers, including cortisol output and stimulation type results.

不過，我唯一想說的是，我們知道在這些疾病狀態下需要控制的最終標誌物。除了顯示我們希望在第一階段顯示的刺激結果之外，我們還需要顯示，例如在庫欣病中，總體皮質醇輸出減少。通常，這是使用不含尿液的皮質醇集合來測量的。因此，我們將關注大量標記，包括皮質醇輸出和刺激類型結果。

Okay.

好的。

But maybe if I can take -- thanks, Chaz, but maybe if I can just add a little bit to Alan's comment. I don't actually think it's going to be necessary to enrich patients in either congenital adrenal hyperplasia or in Cushing's disease. We know in both cases that the patients are all responsive at the level of the adrenal to ACTH. And therefore, blocking ACTH should lower adrenal steroid levels for any patient with that disease.

但也許我可以接受——謝謝查茲，但也許我可以在艾倫的評論中添加一點內容。我實際上並不認為有必要豐富先天性腎上腺增生症或庫欣病患者的營養。我們知道，在這兩種情況下，患者的腎上腺水平都對促腎上腺皮質激素有反應。因此，阻斷 ACTH 應該可以降低任何患有該疾病的患者的腎上腺類固醇水平。

So I don't think we need to worry much about enrichment. We just need to get this drug into patients at the doses that we figure out here in this Phase I study.

所以我認為我們不需要太擔心豐富性。我們只需要將這種藥物按照我們在第一階段研究中確定的劑量注射到患者體內即可。

Our next question is from Tyler Van Buren with Piper Sandler.

我們的下一個問題來自泰勒·範布倫和派珀·桑德勒。

Thanks for all the updates. I have questions on a couple of topics. I guess PATHFNDR-1 is kind of as expected, maybe some pushes and pulls relative to some other trials. The dose titration up to 60 mg should ensure that you have a lot of patients controlled.

感謝您的所有更新。我對幾個主題有疑問。我想 PATHFNDR-1 有點像預期的那樣，可能相對於其他一些試驗有一些推動和拉動。劑量滴定至 60 毫克應確保控制大量患者。

But I guess I wanted to ask about PATHFNDR-2. I guess why haven't -- why didn't your closest competitor do a similar trial for approval or for the label? Is that because maybe you think that they were unsure if they were going to be able to get the same level of control of standard of care, or maybe that it would be more difficult to enroll these patients? And is there anything about the study that would make it easier to enroll maybe the shorter 12-week time period?

但我想我想問一下 PATHFNDR-2。我想為什麼沒有 - 為什麼你最接近的競爭對手沒有進行類似的試驗以獲得批准或標籤？這是因為您可能認為他們不確定是否能夠獲得相同水平的護理標準控制，或者可能會更難以招募這些患者？這項研究是否有什麼東西可以讓註冊變得更容易（也許是更短的 12 週時間段）？

And then the second is why didn't you do a PATHFNDR-3 looking at uncontrolled treatment-experienced patients like ACROBAT, as if I'm not mistaken, if I'm not mixing those 2 up.

第二個是為什麼你不做 PATHFNDR-3 來觀察像 ACROBAT 這樣不受控制的有治療經驗的患者，就好像我沒有弄錯一樣，如果我沒有把這兩者混淆的話。

Let me -- thanks, Tyler. Let me take a shot at that.

讓我——謝謝，泰勒。讓我試一下。

So PATHFNDR-2, the whole point about that is to make sure that we don't have a requirement in the label that says patients need to have tried or responded to the injectable therapies before they could use paltusotine. So that's why we study the treatment-naive or untreated patients. I mean why put some poor patient through an unnecessary round of injectable therapy, instead of just putting them immediately on paltusotine once they're first diagnosed and ready for medical therapy. So that was the motivation behind PATHFNDR-2.

因此 PATHFNDR-2 的重點是確保我們在標籤中沒有要求患者需要先嘗試注射療法或對注射療法有反應才能使用帕圖索汀。這就是我們研究未接受治療或未經治療的患者的原因。我的意思是，為什麼要讓一些可憐的患者接受一輪不必要的注射治療，而不是在他們首次診斷並準備好接受藥物治療後立即使用帕圖索汀。這就是 PATHFNDR-2 背後的動機。

Now PATHFNDR-3, -4, -5, I think -2 is enough for now. In particular, we've already shown in Phase II that in those patients on medical therapy that had not achieved normal, that we could keep their IGF levels the same as the standard of care. So I consider that box already checked.

現在 PATHFNDR-3, -4, -5，我認為 -2 現在就足夠了。特別是，我們已經在第二階段證明，對於那些接受藥物治療但未達到正常水平的患者，我們可以將其 IGF 水平保持與護理標準相同。所以我認為該框已經選中。

But I do think as part of our commercial effort in a couple of years, we may do additional Phase IV-type studies to help flesh out the label, provide guidance on usage in combination with other therapies, for example. And excited for the long time we have to spend with this molecule. Because remember, we've still got patent coverage out to the 2040s. So we're going to invest in getting the best possible label, best possible guidance to physicians and patients in this molecule.

但我確實認為，作為我們幾年內商業努力的一部分，我們可能會進行額外的 IV 期研究，以幫助充實標籤，例如提供與其他療法結合使用的指導。我們很高興能與這個分子一起度過很長一段時間。因為請記住，我們的專利覆蓋範圍仍然持續到 2040 年代。因此，我們將投資獲得盡可能最好的標籤，為醫生和患者提供該分子的最佳指導。

Our next question is from Joseph Schwartz with SVB Leerink.

我們的下一個問題來自 SVB Leerink 的 Joseph Schwartz。

I'm Joori dialing in for Joe. I was just wondering if you could just dig a little bit deeper on your PATHFNDR-2 trial duration. I was just wondering where the 2 weeks -- where that came from. And also, do you think that's enough to capture the efficacy of paltusotine in treatment-naive patients?

我是 Joori，正在為 Joe 撥通電話。我只是想知道您是否可以更深入地了解 PATHFNDR-2 試用期限。我只是想知道這兩周是從哪裡來的。另外，您認為這足以說明帕圖索汀對初治患者的療效嗎？

Joori, thank you. Alan, why don't you answer that question?

喬裡，謝謝你。艾倫，你為什麼不回答這個問題呢？

Yes. I just want to clarify the trial duration for PATHFNDR-2, the treatment duration is 3 months. And yes, it's adequate time for paltusotine to reach a steady state and for the IGF-1 response to paltusotine to reach a steady state. This is evidenced from both our Phase I and Phase II data to date. These are patients who are untreated and start out with high IGF-1 levels. It's a placebo-controlled trial. So it's appropriate to limit the duration to that, which is necessary to show the treatment effect. 3 months is very reasonable for that purpose.

是的。我只是想澄清一下PATHFNDR-2的試驗期限，治療期限是3個月。是的，對於帕圖索汀達到穩定狀態以及 IGF-1 對帕圖索汀的反應達到穩定狀態來說，這是足夠的時間。迄今為止，我們第一階段和第二階段的數據都證明了這一點。這些患者未經治療，開始時 IGF-1 水平較高。這是一項安慰劑對照試驗。因此，將持續時間限制在這個範圍內是適當的，這對於顯示治療效果是必要的。3個月對於這個目的來說是非常合理的。

Okay. Great. Thanks for clarifying that.

好的。偉大的。感謝您澄清這一點。

Yes. And as a reminder, they will all also be eligible -- they should be eligible for an open-label extension to provide additional data on long-term durability of response and safety. And that's true for all our both Phase II and Phase III studies.

是的。提醒一下，他們也都有資格——他們應該有資格獲得開放標籤延期，以提供有關長期反應持久性和安全性的額外數據。我們所有的 II 期和 III 期研究都是如此。

Okay. And then I was just wondering if you could just help set expectations with your new formulation that can be dosed twice as high. How are you thinking about this translating to efficacy in your Phase III? Are you expecting it could be higher? Or like what percentage of your patients do you think you're going to have to get to the higher dose to get meaningful efficacy?

好的。然後我只是想知道您是否可以幫助設定劑量為兩倍高的新配方的期望。您如何看待將其轉化為 III 期療效？你預計它會更高嗎？或者，您認為您必須服用更高劑量才能獲得有意義的療效，您認為您的患者中有多少比例？

Yes, so in our Phase II program, we showed that 40 milligrams should be adequate for the majority of patients. But we added 60 milligrams just for those patients, which we expect to be a smaller proportion, that may need a little higher exposure levels or weren't getting the full exposure they needed out of 40 for one reason or another. So again, the goal is to provide adequate coverage for all the patients in the study.

是的，所以在我們的 II 期計劃中，我們表明 40 毫克對於大多數患者來說應該足夠了。但我們只為那些患者添加了 60 毫克，我們預計這一比例較小，他們可能需要稍高的暴露水平，或者由於某種原因未能在 40 名患者中獲得所需的全部暴露。同樣，我們的目標是為研究中的所有患者提供足夠的覆蓋範圍。

Our next question is from Douglas Tsao with H.C. Wainwright.

我們的下一個問題來自 Douglas Tsao 和 H.C.溫賴特。

Just I know after the Phase II data, there was some discussion about potentially using, I think, going up to an 80-milligram dose. I'm just curious why ultimately you sort of settled on 60.

據我所知，在 II 期數據之後，有一些關於可能使用劑量高達 80 毫克的討論。我只是好奇為什麼你最終選擇了60。

And also, I think with PATHFNDR-1, I think I saw that you're going to measure the primary end point on -- at 3 time points. But in PATHFNDR-2, it looked like there's only maybe 2 end points. So I'm just curious why you're sort of using those 2 different sort of benchmarks, if you will.

而且，我認為通過 PATHFNDR-1，我想我看到您將在 3 個時間點測量主要終點。但在 PATHFNDR-2 中，看起來可能只有 2 個端點。所以我只是好奇為什麼你要使用這兩種不同類型的基準（如果你願意的話）。

Thanks, Doug. Alan, do you want to answer that?

謝謝，道格。艾倫，你想回答這個問題嗎？

Sure. On the latter question, so the PATHFNDR-2 study is a shorter treatment period, shorter periods of the final dose stabilization period. So we're sort of more limited in terms of our time frame there. And generally, 2 or 3 to constitute an average IGF-1 is adequate in this kind of setting. And I'm sorry, what was your first question, Doug?

當然。關於後一個問題，所以PATHFNDR-2研究是一個較短的治療期，較短的最終劑量穩定期。因此，我們在那裡的時間框架更加有限。一般來說，在這種情況下，2 或 3 個 IGF-1 就足夠了。抱歉，你的第一個問題是什麼，道格？

Just in terms of the dosing that you did, I think there was some conversation about testing higher doses after the first studies. And it doesn't sound like you've -- and I think sort of maybe the 80 was even -- even potentially going to an 80 milligram. And obviously, it doesn't seem like you're going there. So just curious about what was sort of the decision for you in terms of coming to that decision, in reaching that.

就您所做的劑量而言，我認為在第一次研究後有一些關於測試更高劑量的討論。聽起來你並沒有——我認為 80 可能是均勻的——甚至可能達到 80 毫克。顯然，你似乎不會去那裡。所以只是好奇你在做出這個決定時做出了什麼樣的決定。

Yes, so this is all based on dose response and exposure response modeling work that's been done and shared with the FDA. And we really believe that as Scott mentioned, 40 milligrams should cover the vast majority of patients and only a small number of outlier patients with the increased exposure. And 60 milligrams should cover that degree of exposure needed in that setting according to the modeling.

是的，所以這一切都是基於已完成並與 FDA 共享的劑量反應和暴露反應建模工作。我們確實相信，正如 Scott 提到的，40 毫克應該覆蓋絕大多數患者，僅覆蓋少數暴露量增加的異常患者。根據模型，60 毫克應該可以滿足該環境下所需的暴露程度。

Okay. And then just one final question, just typically when you have an untreated patient going on to an injectable therapy, typically how long does it take for them to reach biochemical control?

好的。然後還有最後一個問題，通常當未經治療的患者接受注射治療時，通常需要多長時間才能達到生化控制？

Well, so typically, you would give -- typically, the long-acting injections are given once per month. And so typically, to reach steady state, you would wait to assess the full effect after 3 injections or about 3 months in clinical practice.

嗯，通常情況下，你會給予——通常情況下，長效注射劑每月注射一次。因此，通常情況下，要達到穩定狀態，您需要等待 3 次注射或臨床實踐中大約 3 個月後才能評估全部效果。

In the case of paltusotine, which is a much more rapidly absorbed agent and taken on a daily basis, the time to steady-state effect and PK would be much shorter than that.

對於帕妥索汀來說，它是一種吸收更快的藥物，每天服用，達到穩態作用的時間和 PK 會比這短得多。

And presumably, along those lines, just given your ability to dose titrate much quicker should give you a much longer window than what you typically see with an injectable?

據推測，沿著這些思路，只要您能夠更快地滴定劑量，就應該給您一個比通常使用注射劑看到的更長的窗口？

A much longer window to assess...

一個更長的評估窗口......

Or not -- or you have more -- relative to that 3-month period end point, to reach sort of your optimal steady state, if you will. Does that make sense?

如果你願意的話，或者不——或者你有更多——相對於三個月的結束點，以達到你的最佳穩定狀態。那有意義嗎？

Yes.

是的。

Although I would say, almost -- this is not exactly what one would traditionally mean by dose titration. Because we're starting at a dose that we expect to be efficacious for the vast majority of the patients, and then we just offer a higher dose just in case for those patients who might need a little bit more. So it's not really dose titration. We're just trying to hit it with the right dose the first time, and then we have a backup plan in case it's not quite enough.

儘管我想說，幾乎——這並不完全是劑量滴定的傳統含義。因為我們從預期對絕大多數患者有效的劑量開始，然後我們只是提供更高的劑量，以防那些可能需要更多劑量的患者。所以這並不是真正的劑量滴定。我們只是想在第一次就以正確的劑量達到目標，然後我們有一個備用計劃，以防萬一還不夠。

And Scott, why was the decision to start with 40 and not potentially, sort of, just given how quickly you can pivot, start with 20 and then move to 40?

斯科特，為什麼決定從 40 開始，而不是潛在地，只是考慮到你可以多快地轉變，從 20 開始，然後轉向 40？

Well, there's just no reason to -- I'm thinking ahead to when this is on the market. And there's really no reason for patients to risk a period of lack of control. So we start directly with 40.

好吧，沒有理由——我正在考慮這款產品何時上市。患者確實沒有理由冒一段時期失控的風險。所以我們直接從40開始。

Now there is a nuance in PATHFNDR-2, where we have a brief period where they have a starting dose of 20 milligrams and then they go to 40. And that's simply because in patients who are new to somatostatin analogs, they tend to have some GI side effects the first week or 2 of therapy. And so we just wanted to give them a little more gentle introduction to the drug.

現在 PATHFNDR-2 有一個細微差別，我們有一個短暫的時期，他們的起始劑量為 20 毫克，然後增加到 40 毫克。這僅僅是因為對於剛開始使用生長抑素類似物的患者來說，他們在治療的第一周或第二週往往會出現一些胃腸道副作用。所以我們只是想讓他們更溫和地介紹一下這種藥物。

Our final question is from Daniel Wolle with JPMorgan.

我們的最後一個問題來自摩根大通的 Daniel Wolle。

This is Daniel for Jessica Fye. First, starting maybe with PATHFNDR-1. Is there a washout period after the screening period right before the 9-month treatment period is initiated?

我是傑西卡·菲伊的丹尼爾。首先，可能從 PATHFNDR-1 開始。篩選期後、9 個月治療期開始前是否有清洗期？

Hi, Daniel. You want to answer that, Alan?

嗨，丹尼爾。你想回答這個問題嗎，艾倫？

No, no, these are patients in PATHFNDR-1 who are on octreotide or lanreotide. And we screen them, and we find that they have a normal IGF-1. And then they randomize to paltusotine versus placebo at the time they're due for their next injection.

不，不，這些是 PATHFNDR-1 中正在服用奧曲肽或蘭瑞肽的患者。我們對它們進行篩查，發現它們的 IGF-1 正常。然後，他們在下次注射時隨機選擇帕妥索汀與安慰劑。

So no, there's no washout involved in PATHFNDR-1 initially. But this is a 9-month study. And during that period, their preexisting injections will washout as the paltusotine is taking over control of IGF-1.

所以不，PATHFNDR-1 最初不涉及沖洗。但這是一項為期9個月的研究。在此期間，隨著帕圖索汀接管 IGF-1 的控制，他們先前註射的藥物將會被淘汰。

Got it. Okay. And then regarding the rescue criteria definition, is it dependent on the 2 consecutive IGF-1 greater than equal to 1.3x upper limit of normal and exasperation of symptoms? Or is it just failure on the 2 consecutive IGF-1 scores?

知道了。好的。那麼關於拯救標準的定義，是否取決於連續2次IGF-1大於等於1.3倍正常上限和症狀加劇？或者只是連續 2 次 IGF-1 分數不及格？

It's based on both IGF-1 and symptoms. And this is a precedented criterion used previously for the most recent acromegaly drug approval. So we do know this is a successful way to manage patients safely through these kinds of placebo-controlled trials.

它基於 IGF-1 和症狀。這是最近批准肢端肥大症藥物之前使用的先例標準。因此，我們確實知道這是通過此類安慰劑對照試驗安全管理患者的成功方法。

Okay. And then for PATHFNDR-2, given that these patients are not well controlled, does it make sense to go against placebo? Why not an active agent in the control arm to create a stronger efficacy profile for paltusotine?

好的。那麼對於 PATHFNDR-2，考慮到這些患者沒有得到很好的控制，反對安慰劑有意義嗎？為什麼不在對照組中使用活性藥物來為帕圖索汀創造更強的功效？

Well, we do expect them -- you see, these are untreated patients. So once they're treated with paltusotine, we do expect them to achieve control.

嗯，我們確實期待他們——你看，這些都是未經治療的病人。因此，一旦他們接受帕妥索汀治療，我們確實希望他們能夠控制病情。

I would say that in terms of why is it a placebo controlled, well, it's clear that placebo-controlled studies give -- are simpler designs that help the regulators assess safety more accurately related to drug. We do know that the regulators, particularly the FDA, are more comfortable with placebo-controlled design trials.

我想說的是，就為什麼它是安慰劑對照而言，很明顯，安慰劑對照研究給出了更簡單的設計，可以幫助監管機構更準確地評估與藥物相關的安全性。我們確實知道監管機構，尤其是 FDA，更願意接受安慰劑對照設計試驗。

This kind of trial in this kind of patient population is also a precedented Phase III trial for another approved acromegaly product. So we think scientifically, it's the most rigorous. It will give us the clear answers we need in a reasonable period of time, and we know it is most acceptable to the regulators.

這種針對此類患者人群的試驗也是另一種已獲批准的肢端肥大症產品的先例 III 期試驗。所以我們從科學的角度來說，這是最嚴謹的。它將在合理的時間內給我們所需的明確答案，我們知道這是監管機構最能接受的。

But I'd also add, Daniel, that we've got a great deal of baseline control data already with the ACROBAT EDGE study. And we'll be having in PATHFNDR-1 baseline control data to compare with paltusotine as well. So there'll be plenty of active control comparison, just not a head to head in these current studies.

但我還要補充一點，丹尼爾，我們已經通過 ACROBAT EDGE 研究獲得了大量基線控制數據。我們還將獲得 PATHFNDR-1 基線對照數據來與帕圖索汀進行比較。因此，在當前的研究中，將會有大量的主動控制比較，但不是面對面的比較。

Got it. Okay. And the last one, what's the rationale for PATHFNDR's -- sorry, that has been answered.

知道了。好的。最後一個問題是 PATHFNDR 的基本原理是什麼——抱歉，已經得到解答。

But the other question is given the shorter duration of treatment period for PATHFNDR-2, how come data is still reading out in 2023 along with PATHFNDR-1, which has a longer treatment period?

但另一個問題是，考慮到 PATHFNDR-2 的治療週期較短，為什麼到 2023 年仍然會與治療週期較長的 PATHFNDR-1 一起讀出數據？

Well, studies are always controlled by a mix of recruitment rates and treatment periods. We did pretty extensive feasibility on both studies at sites around the world.

嗯，研究總是受到招募率和治療週期的綜合控制。我們在世界各地的地點對這兩項研究進行了相當廣泛的可行性研究。

So that's why we started PATHFNDR-1 first. The treatment period is a little bit longer. And in PATHFNDR-2, it's a little shorter. So that's why we expect them to finish at about the same time.

這就是我們首先啟動 PATHFNDR-1 的原因。治療時間稍微長一些。而在 PATHFNDR-2 中，它要短一些。這就是為什麼我們期望他們大約在同一時間完成。

Thank you. We have reached the end of the question-and-answer session, and I will now turn the call over to Dr. Scott Struthers for closing comments.

謝謝。我們的問答環節已經結束，我現在將把電話轉給斯科特·斯特拉瑟斯 (Scott Struthers) 博士進行總結評論。

Thank you, everyone. I just want to thank you one more time for joining us on the call. And we look forward to continuing the advancement of our clinical and discovery programs. We'll keep everyone updated along the way as best as we can. And have a safe spring. Thank you.

謝謝大家。我只想再次感謝您加入我們的電話會議。我們期待繼續推進我們的臨床和發現項目。我們將盡最大努力向大家通報最新情況。並度過一個安全的春天。謝謝。

This concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation, and have a great day.

今天的會議到此結束，此時您可以掛斷電話了。感謝您的參與，祝您有美好的一天。