Rigel Pharmaceuticals Inc (RIGL) 2024 Q3 法說會逐字稿

Greetings and welcome to Rigel Pharmaceuticals' financial conference call for the third quarter 2024.(Operator Instructions) As a reminder, this conference is being recorded.

問候並歡迎參加 Rigel Pharmaceuticals 2024 年第三季財務電話會議。提醒一下，本次會議正在錄音。

It is now my pleasure to introduce our first speaker, Ray Furey, Rigel's Executive Vice President, General Counsel, and Corporate Secretary. Thank you. Mr. Furey, you may begin.

現在我很高興介紹我們的第一位發言者，Rigel 的執行副總裁、總法律顧問兼公司秘書 Ray Furey。謝謝。弗瑞先生，您可以開始啦。

Hello, welcome to our third-quarter 2024 financial results and business update conference call. The financial press release for the third quarter 2024 was issued a short while ago and can be viewed along with the slides for this presentation in the News and Events section of our Investor Relations site on rigel.com.

您好，歡迎參加我們 2024 年第三季財務業績和業務更新電話會議。2024 年第三季的財務新聞稿剛剛發布，您可以在 rigel.com 上的投資者關係網站「新聞和活動」部分中與本簡報的幻燈片一起查看。

As a reminder during today's call, we may make forward-looking statements regarding our financial outlook and our plans and timing for regulatory product development. These statements are subject to risks and uncertainties that may cause actual results to differ in those forecast.

在今天的電話會議上提醒大家，我們可能會就我們的財務前景以及監管產品開發計劃和時間做出前瞻性陳述。這些聲明受風險和不確定性的影響，可能導致實際結果與預測不同。

A description of these risks can be found in our most recent annual report on Form 10-K for the year ended December 31, 2023, and subsequent filings with the SEC including our Q3 quarterly report on Form 10-Q on file with the SEC. Any forward-looking statements are made only as of today's date, and we undertake no obligation to update these forward-looking statements to reflect subsequent events or circumstances.

這些風險的描述可在我們最新的截至 2023 年 12 月 31 日的 10-K 表年度報告以及隨後向美國證券交易委員會提交的文件（包括我們向美國證券交易委員會提交的第三季度 10-Q 表季度報告）中找到。任何前瞻性陳述均僅截至今日為止，我們不承擔更新這些前瞻性陳述以反映後續事件或情況的義務。

At this time, I'd like to turn the call over to our President and Chief Executive Officer, Raul Rodriguez. Raul?

現在，我想將電話轉給我們的總裁兼執行長 Raul Rodriguez。勞爾？

Thank you, Ray, and thank you, everyone, for joining today. Also with me today are Dave Santos, our Chief Commercial Officer; Lisa Rojkjaer, our Chief Medical Officer; and Dean Schorno, our Chief Financial Officer. I will begin on slide 4 with an overview of Rigel's business and our third-quarter results.

謝謝 Ray，也謝謝大家今天的參與。今天與我一起的還有我們的首席商務官戴夫桑托斯 (Dave Santos)；我們的首席醫療官 Lisa Rojkjaer；以及我們的財務長 Dean Schorno。我將從第 4 張投影片開始概述 Rigel 的業務和我們的第三季業績。

In the first three quarters of the year, we made significant progress in our strategy to grow our hematology and oncology business. Our corporate strategy is focused on three main objectives: one, expanding our commercial portfolio and increasing product sales; two, advancing and growing our pipeline through strategic collaborations and importantly, internal pipeline development; and three, maintaining financial discipline. I will now summarize each of these.

今年前三個季度，我們的血液學和腫瘤學業務成長策略取得了重大進展。我們的企業策略集中在三個主要目標：一、擴大我們的商業組合併增加產品銷售；二、透過策略合作以及重要的內部產品線開發來推動和擴大我們的產品線；三是保持財務紀律。我現在將對上述內容進行總結。

Firstly, in the third quarter, we generated strong growth across our commercial portfolio with a total net sales of $38.9 million. This was up 44% compared to the third quarter of 2023. This robust revenue growth was driven by the addition of GAVRETO, which generated $7.1 million in net product sales for its first full quarter with Rigel as we transitioned the majority of patients and prescribers into our network. In addition, we saw continued year-over-year growth for TAVALISSE and REZLIDHIA with both achieving another record quarter for bottles shipped to patients and clinics.

首先，第三季度，我們的商業投資組合實現了強勁成長，總淨銷售額達到 3,890 萬美元。與 2023 年第三季相比，成長了 44%。這一強勁的收入成長得益於 GAVRETO 的加入，隨著我們將大多數患者和處方者轉移到我們的網絡，GAVRETO 在與 Rigel 合作的第一個完整季度創造了 710 萬美元的淨產品銷售額。此外，我們看到 TAVALISSE 和 REZLIDHIA 繼續實現同比增長，兩個季度運送給患者和診所的藥瓶數量均創下新高。

We continue to expand our product presence outside the US as well this quarter with a new Kissei agreement to develop and commercialize REZLIDHIA in Japan, the Republic of Korea, and Taiwan. This agreement included a $10 million upfront payment that we received in Q3 and the potential for up to $152 million in future development, regulatory, and commercial milestone payments.

本季度，我們繼續擴大美國以外地區的產品影響力，與 Kissei 簽訂了一項新的協議，以在日本、韓國和台灣開發和商業化 REZLIDHIA。該協議包括我們在第三季收到的 1,000 萬美元預付款，以及未來可能高達 1.52 億美元的開發、監管和商業里程碑付款。

Secondly, regarding our objective to grow our pipeline, we continue to advance the development of R289, our dual IRAK 1 and 4 inhibitor in a Phase 1b study in lower risk MDS. Initial safety and efficacy data from that trial was published in an ASH abstract earlier this week and we look forward to sharing additional data from a more recent data cut at the ASH meeting in December. Also, at ASH, we will have additional data for [olutasidenib].

其次，關於我們擴大產品線的目標，我們繼續推進 R289（我們的雙重 IRAK 1 和 4 抑制劑）在低風險 MDS 的 1b 期研究中的開發。該試驗的初步安全性和有效性數據已於本週稍早在 ASH 摘要中發表，我們期待在 12 月的 ASH 會議上分享最新數據。此外，在 ASH 上，我們將獲得以下方面的額外數據[奧魯地尼]。

Our strategic collaborations with MD Anderson and CONNECT are progressing well. These trials provide us with the opportunity to explore REZLIDHIA in a broad range of IDH1 mutant cancers in a cost- and time-efficient manner. Our first trial with MD Anderson evaluating REZLIDHIA in a combination with two other agents in patients with mutant IDH1 AML enrolled its first patient in September.

我們與MD Anderson和CONNECT的策略合作進展順利。這些試驗為我們提供了以經濟且時間高效的方式探索 REZLIDHIA 在廣泛 IDH1 突變癌症中的作用的機會。我們與 MD Anderson 合作進行的首次試驗評估了 REZLIDHIA 與其他兩種藥物聯合治療突變型 IDH1 AML 患者的效果，並在 9 月招募了第一位患者。

And as we did with the REZLIDHIA and GAVRETO earlier this year, we continue to evaluate opportunities to in-license or acquire late-stage hematology and/or oncology assets to further expand our portfolio. In 2025 we will discuss our development plans for both R289 in lower risk MDS and olutasidenib.

正如我們今年稍早對 REZLIDHIA 和 GAVRETO 所做的那樣，我們將繼續評估許可或收購後期血液學和/或腫瘤學資產的機會，以進一步擴大我們的產品組合。2025 年，我們將討論針對低風險 MDS 的 R289 和奧魯他尼的開發計畫。

Lastly, as we execute on our strategy to grow our business, we are doing so in a financially disciplined manner. Our strong commercial execution and cost-effective approach to clinical development has enabled us, for the first time, to generate positive third-quarter and year-to-date net income.

最後，當我們執行業務成長策略時，我們會以財務紀律嚴明的方式進行。我們強大的商業執行力和具有成本效益的臨床開發方法使我們首次在第三季和年初至今實現了正的淨收入。

In summary, in the third quarter, we made significant progress in growing our business while achieving net income breakeven. We are well positioned to continue to drive value as we head into 2025.

總結一下，第三季我們在業務成長方面取得了重大進展，同時實現了淨收入盈虧平衡。隨著我們邁向 2025 年，我們已準備好繼續創造價值。

And with that, I'll turn the call over to Dave to provide a commercial update. Dave?

說完這些，我會把電話轉給戴夫，讓他提供商業更新。戴夫？

Thank you, Raul. We are very pleased with the strong growth in revenues in Q3. Moving to slide 6, you see how our quarterly and annual sales have evolved since 2021.

謝謝你，勞爾。我們對第三季營收的強勁成長感到非常高興。前往投影片 6，您可以看到自 2021 年以來我們的季度和年度銷售額的變化。

We have grown each quarter's sales over the previous year, and that growth continues particularly from last year to this year. We started the first quarter of 2023 with $23.8 million and are now reporting $38.9 million in the third quarter of 2024. That's an incremental $15.1 million, representing 63% growth in quarterly revenue over seven quarters.

我們每季的銷售額都比前一年有所成長，而且這種成長勢頭從去年一直延續到今年。2023 年第一季我們的營收為 2,380 萬美元，目前報告指出 2024 年第三季我們的營收為 3,890 萬美元。這意味著增加了 1,510 萬美元，代表七個季度內季度營收成長了 63%。

Net growth has been driven by our strong commercial execution in consistently building quarterly demand for TAVALISSE and driving broader awareness of REZLIDHIA through the first two years of its launch. The addition of GAVRETO and our ability to successfully transition it to our portfolio has also significantly expanded our top line. Compared to the third quarter of 2023, we generated 44% growth in the third quarter of 2024.

淨成長得益於我們強大的商業執行力，在 TAVALISSE 推出後的頭兩年內持續提升季度需求，並提高 REZLIDHIA 的知名度。GAVRETO 的加入以及我們成功將其轉變為產品組合的能力也顯著擴大了我們的營收。與 2023 年第三季相比，我們在 2024 年第三季實現了 44% 的成長。

As you can see, we're well on our way to delivering a record year of net product sales. Our commercial team is focused on execution, driving continued momentum for TAVALISSE, improving both institutional and community demand for REZLIDHIA and successfully transitioning all GAVRETO patients and accounts to Rigel-label product. My sincere thanks to the entire team for all their hard work to grow our business in 2024.

如您所見，我們正穩步邁向創紀錄的年度淨產品銷售額。我們的商業團隊專注於執行，推動 TAVALISSE 的持續發展，改善機構和社區對 REZLIDHIA 的需求，並成功地將所有 GAVRETO 患者和帳戶過渡到 Rigel 標籤產品。我衷心感謝整個團隊為 2024 年業務成長所做的一切努力。

Moving to slide 7, I'll first discuss our performance with TAVALISSE in the third quarter. On slide 8, you'll see our FDA-approved indication, which is for adult patients with chronic immune thrombocytopenia or CITP, who've had an insufficient response to a previous treatment.

轉到第 7 張投影片，我會先討論我們與 TAVALISSE 在第三季的表現。在第 8 張幻燈片上，您會看到我們獲得 FDA 批准的適應症，該藥物適用於對先前的治療反應不足的慢性免疫性血小板減少症或 CITP 的成年患者。

Moving to slide 9. I'm pleased to report another strong quarter for TAVALISSE with 2,797 bottles shipped to patients and clinics in the third quarter, a 16% increase versus the third quarter of 2023, and our eighth consecutive quarterly record high. We sold 2,793 bottles to our distribution network, resulting in $26.3 million in net product sales during the third quarter, an 8% increase from the same period last year. We continue to grow TAVALISSE demand both through refills for patients who stay on the product and new prescriptions for patients who are trying TAVALISSE for the very first time.

移至幻燈片 9。我很高興地報告 TAVALISSE 又一個強勁的季度，第三季度向患者和診所運送了 2,797 瓶，比 2023 年第三季度增長了 16%，這是我們連續第八個季度創下歷史新高。我們向分銷網絡銷售了 2,793 瓶，第三季淨產品銷售額達 2,630 萬美元，比去年同期成長 8%。我們持續增加對 TAVALISSE 的需求，不僅為繼續使用該產品的患者提供續藥，也為首次嘗試 TAVALISSE 的患者提供新處方。

Moving to slide 10, now, I'd like to take a few minutes to discuss our growing REZLIDHIA sales. On slide 11, you'll see our FDA-approved indication for REZLIDHIA which is for adult patients with relapsed or refractory acute myeloid leukemia with the susceptible IDH1 mutation as detected by an FDA-approved test.

現在轉到第 10 張投影片，我想花幾分鐘討論我們不斷成長的 REZLIDHIA 銷售額。在第 11 張幻燈片上，您會看到 FDA 批准的 REZLIDHIA 適應症，該藥物適用於經 FDA 批准的檢測檢測出易感 IDH1 突變的複發或難治性急性髓細胞白血病成年患者。

Moving to slide 12, we shipped 444 bottles of REZLIDHIA to patients and clinics in Q3, more than doubling the demand generated in the same period a year ago. We sold 429 bottles of REZLIDHIA as our distribution channel reduced inventory by 15 bottles. This resulted in $5.5 million in third quarter net product sales, again, more than doubling compared to the prior year. We continue to stay focused on improving REZLIDHIA adoption both in institutions and the community by raising awareness of REZLIDHIA's efficacy particularly in patients who have failed upfront therapy with venetoclax.

轉到第 12 張投影片，我們在第三季度向患者和診所運送了 444 瓶 REZLIDHIA，是去年同期需求的兩倍多。由於我們的分銷通路庫存減少了 15 瓶，我們銷售了 429 瓶 REZLIDHIA。這使得第三季的淨產品銷售額達到 550 萬美元，與前一年相比再次成長了一倍多。我們將繼續致力於提高機構和社區對 REZLIDHIA 療效的認識，特別是對前期使用維奈克拉治療失敗的患者。

Moving to slide 13, we are incredibly excited about our work to expand access to olutasidenib in markets outside the US. We're expanding our partnership with Kissei, who currently markets and distributes TAVALISSE in Japan to include a license agreement to develop and commercialize REZLIDHIA in Japan, Korea, and Taiwan.

轉到第 13 張投影片，我們對擴大奧魯他尼在美國以外市場的應用工作感到非常興奮。我們正在擴大與 Kissei 的合作夥伴關係，Kissei 目前在日本行銷和分銷 TAVALISSE，並簽署一項授權協議，在日本、韓國和台灣開發和商業化 REZLIDHIA。

We believe Kissei is the right partner in these markets as we further our goal to make REZLIDHIA accessible globally. And we're continuing to explore other opportunities for partnerships outside the US to bring this beneficial product to AML patients in need in other markets around the globe.

我們相信，Kissei 是這些市場中合適的合作夥伴，因為我們進一步實現了讓 REZLIDHIA 在全球普及的目標。我們將繼續探索在美國以外建立合作的機會，以便將這種有益的產品帶給全球其他市場有需要的 AML 患者。

Moving to slide 14, I'll now discuss our third-quarter performance for GAVRETO, the first full quarter in which GAVRETO was available through Rigel. On slide 15, I'll begin by reviewing the FDA-approved indications for GAVRETO, which include the treatment of adult patients with metastatic RET fusion, positive non-small cell lung cancer, as well as adult and pediatric patients 12 years of age and older with advanced RET-fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory.

轉到投影片 14，我現在將討論 GAVRETO 第三季的表現，這是 GAVRETO 透過 Rigel 推出的第一個完整季度。在第 15 張幻燈片上，我將首先回顧 FDA 批准的 GAVRETO 適應症，包括治療轉移性 RET 融合陽性非小細胞肺癌的成年患者，以及需要全身治療且對放射性碘有抵抗力的 RET 融合陽性晚期甲狀腺癌的成年和 12 歲及以上的兒童患者。

For the first full quarter with GAVRETO in our portfolio, we shipped 717 bottles to patients and clinics and sold 752 bottles of GAVRETO. Please note that GAVRETOis available in bottles of either 60- or 90-count capsules, and for reporting purposes, we report the total number of 60-count equivalent bottles.

在包含 GAVRETO 的第一個完整季度，我們向患者和診所運送了 717 瓶 GAVRETO，並銷售了 752 瓶 GAVRETO。請注意，GAVRETO 有 60 粒或 90 粒膠囊的瓶裝，出於報告目的，我們報告的是 60 粒當量瓶裝的總數。

This resulted in $7.1 million in GAVRETO third-quarter net product sales. We have now sold a total of $9 million of GAVRETO since transitioning it in late two. We are very happy that both the first full quarter of demand and net sales indicate that we are successfully transitioning over GAVRETO of patients, prescribers, and accounts to Rigel's distribution network.

這使得 GAVRETO 第三季淨產品銷售額達到 710 萬美元。自 2010 年底轉型以來，我們已累計售出價值 900 萬美元的 GAVRETO。我們非常高興，第一季的需求和淨銷售額都表明我們正在成功地將患者、處方者和帳戶從 GAVRETO 轉移到 Rigel 的分銷網絡。

Moving to slide 17, I'd like to wrap up my comments with some early insights on what we saw during our first full quarter with GAVRETO. We are incredibly pleased with the progress we've made to ensure both current patients taking GAVRETOas well as those newly prescribed continue to have access without interruption and that prescribers can feel confident knowing that their patients can continue getting the therapy they need.

轉到第 17 張投影片，我想用一些關於我們在 GAVRETO 第一個完整季度看到的早期見解來總結我的評論。我們對所取得的進展感到非常高興，我們確保目前服用 GAVRETO 的患者以及新開處方的患者都能繼續不間斷地獲得藥物，並且開處方的醫生可以放心，他們的患者可以繼續得到他們需要的治療。

Based on the first full-quarter shipping GAVRETO to patients and clinics, we have seen an exceptionally smooth transition of patients through our hub, RIGEL ONECARE, and the specialty pharmacies in our network. And we have also seen solid ordering by many of the direct accounts we had expected to order through our specialty distributors.

根據第一個完整季度向患者和診所運送 GAVRETO 的情況，我們看到患者通過我們的樞紐 RIGEL ONECARE 和我們網絡中的專業藥房的過渡異常順利。我們也看到許多直接客戶的訂單量穩定，而我們原本預計這些客戶會透過專業經銷商進行訂購。

Our distributors have shipped 320 bottles to accounts, representing about 45% of our business. Specialty pharmacies ship 397 bottles to patients making up most of our business. We did expect that there would be more of our business coming through direct accounts and have noticed that a handful of expected top direct accounts still have not yet placed an order. In addition, in the specialty pharmacy data, we are seeing that the majority of patients are prescribed GAVRETO below the standard dose of 400 mg once a day, indicating we may have an opportunity to reinforce dosing and administration and particularly the starting dose of GAVRETO.

我們的經銷商已向客戶運送了 320 瓶，約占我們業務的 45%。專業藥房向患者運送了 397 瓶藥物，這佔了我們業務的大部分。我們確實預計會有更多業務來自直接帳戶，並且注意到少數預期的頂級直接帳戶仍未下訂單。此外，在專科藥房數據中，我們發現大多數患者服用的 GAVRETO 劑量低於每天一次 400 毫克的標準劑量，這表明我們可能有機會加強劑量和給藥，特別是 GAVRETO 的起始劑量。

Overall, GAVRETO, REZLIDHIA, and TAVALISSE have all contributed to our strong year-over-year revenue growth. And we look forward to further expanding our impact on patients with our growing portfolio as we move forward to 2025.

總體而言，GAVRETO、REZLIDHIA 和 TAVALISSE 都為我們強勁的年收入成長做出了貢獻。隨著我們邁向 2025 年，我們期待透過不斷增長的產品組合進一步擴大對患者的影響。

Thanks for your attention, and I will now turn the call over to Lisa to discuss our development progress. Lisa?

感謝您的關注，現在我將把電話轉給麗莎，討論我們的開發進度。麗莎？

Thanks, Dave. Moving to slide 19, I'd like to begin by highlighting a series of abstracts that will be presented at posters at the upcoming ASH Annual Meeting in December.

謝謝，戴夫。現在轉到第 19 張投影片，我首先想重點介紹一下將於 12 月舉行的 ASH 年會上以海報形式展示的一系列摘要。

As Raul mentioned, initial data from the dose escalation part of our Phase 1b study of R289 and patients with relapsed or refractory lower risk MDS will be presented during the poster session on Monday, December 9. Updated results using a data cut-off date of October 25 will be shared at the meeting. Additionally, a number of presentations related to olutasidenib abuse in patients with IDH1 mutated AML and MDS are planned.

正如 Raul 所提到的，我們將於 12 月 9 日星期一的海報展示會上展示 R289 1b 期研究劑量遞增部分的初步數據以及復發或難治性低風險 MDS 患者治療的初步數據。使用 10 月 25 日資料截止日期更新的結果將在會議上分享。此外，我們還計劃進行多場與 IDH1 突變 AML 和 MDS 患者濫用奧魯他尼相關的演講。

Moving to slide 20, we continue to execute on our strategy to expand our hematology and oncology pipeline. First, we're making meaningful progress advancing olutasidenib into new clinical indications alongside our partners, MD Anderson, and the CONNECT cancer consortium.

轉到第 20 張投影片，我們繼續執行擴大血液學和腫瘤學產品線的策略。首先，我們與合作夥伴 MD Anderson 和 CONNECT 癌症聯盟一起，在奧魯他尼用於新的臨床適應症方面取得了有意義的進展。

We believe olutasidenib has potential in several cancers, where mutated IDH1 plays a role such as additional AML segments, myelodysplastic syndrome or MDS, and glioma, either as monotherapy or in combination. One clinical trial is now active under MD Anderson collaboration, and we're continuing to advance olutasidenib and glioma with CONNECT.

我們相信奧魯他尼在多種癌症中具有潛力，其中突變的IDH1在額外的AML片段、骨髓增生異常綜合徵或MDS和神經膠質瘤中發揮作用，無論是單一療法還是聯合療法。目前，一項臨床試驗正在與 MD Anderson 合作開展，我們正在繼續利用 CONNECT 推進奧魯他尼和膠質瘤的治療。

R289 is our novel dual IRAK 1/4 inhibitor that is currently being evaluated in a Phase 1b study in patients with relapse refractory lower-risk MDS. Enrollment in the fifth dose level is ongoing, and we expect that the DLT observation period will be completed within December.

R289 是我們新型的雙重 IRAK 1/4 抑制劑，目前正在針對復發難治性低風險 MDS 患者進行 1b 期研究。第五劑量水準的招募正在進行中，我們預計 DLT 觀察期將在 12 月內完成。

We also remain focused on evaluating potential opportunities to in-license or acquire products that would be a strategic fit for our portfolio. We're looking for differentiated products in the hematology, oncology, or related areas, products that are late stage, possibly with registrational data, soon to have registrational data or more advanced, and products that can leverage our hematology and oncology infrastructure. As demonstrated with our acquisitions of olutasidenib and pralsetinib, our goal is to continue to find assets that align with our organization pipeline and ability to execute.

我們也將繼續專注於評估獲得許可或購買符合我們產品組合策略的產品的潛在機會。我們正在尋找血液學、腫瘤學或相關領域的差異化產品，這些產品處於後期階段，可能具有註冊數據，即將擁有註冊數據或更先進的產品，以及可以利用我們的血液學和腫瘤學基礎設施的產品。正如我們對 olutasidenib 和 pralsetinib 的收購所表明的那樣，我們的目標是繼續尋找與我們的組織管道和執行能力相符的資產。

Slide 21 provides an overview of our strategic alliance with the MD Anderson Cancer Center to advance olutasidenib more broadly into AML, MDS and beyond. We're very proud of this collaboration and have previously shared that in September, the first patient was dosed -- or was enrolled in a Phase 1b/2 triplet therapy trial in IDH1-mutated AML, evaluating olutasidenib, decitabine and venetoclax.

幻燈片 21 概述了我們與 MD 安德森癌症中心的戰略聯盟，旨在將奧魯他尼更廣泛地推進到 AML、MDS 及其他領域。我們對此次合作感到非常自豪，並曾在 9 月分享過這一消息，第一位患者接受了治療——或者說參加了 IDH1 突變 AML 的 1b/2 期三聯療法試驗，該試驗評估了奧魯他尼、地西他濱和維奈克拉的療效。

It is also planned to evaluate olutasidenib as a monotherapy in patients with IDH-mutated CCUS and lower risk MDS, in combination with an HMA in high-risk MDS, and as monotherapy as a post-transplant maintenance therapy for patients with IDH1-mutated hemologic malignancies. We expect these trials to position us to conduct a subsequent registrational trial or trials.

此外，還計劃評估奧魯他尼作為單一療法治療 IDH 突變 CCUS 和低風險 MDS 患者、與 HMA 聯合治療高風險 MDS 患者以及作為單一療法治療 IDH1 突變血液系統惡性腫瘤患者的移植後維持療法。我們希望這些試驗能讓我們有能力進行後續的註冊試驗。

Moving to slide 22, another important development collaboration we have is with the CONNECT Global Neuro-oncology Consortium to conduct a Phase 2 trial in patients with IDH1 mutated high-grade glioma. Gliomas account for around 30% of CMS tumors in children, adolescents, and young adults. Approximately a third of these are high-grade gliomas, translating to approximately 800 to 1,000 new cases each year in the US.

轉到第 22 張投影片，我們另一個重要的開發合作是與 CONNECT 全球神經腫瘤學聯盟合作，對 IDH1 突變高級別膠質瘤患者進行 2 期試驗。神經膠質瘤佔兒童、青少年和年輕人中 CMS 腫瘤的 30% 左右。其中約三分之一是高惡性度膠質瘤，相當於美國每年約有 800 至 1,000 例新病例。

High-grade gliomas are a leading cause of cancer-related death in adolescents and young adults. Despite available therapies, the five-year survival of this population is less than 10%. Based on preliminary safety and efficacy results from a Phase 1b/2 clinical trial, evaluating olutasidenib in heavily pre-treated patients with relapsed or refractory IDH1-mutated glioma, we believe that olutasidenib has potential in glioma treatment.

高惡性度膠質瘤是青少年和年輕人癌症死亡的主要原因。儘管有治療方法，但該族群的五年存活率仍不到 10%。根據 1b/2 期臨床試驗的初步安全性和有效性結果，該試驗評估了奧魯他尼對復發或難治性 IDH1 突變型膠質瘤中接受過大量治療的患者的效果，我們認為奧魯他尼在膠質瘤治療方面具有潛力。

A Phase 2 study of olutasidenib in combination with temozolomide called TarGet-D will be included as a treatment arm in CONNECT's target study, a molecularly guided Phase 2 umbrella clinical trial for high-grade glioma. The goal of this study is to determine whether the combination of olutasidenib and temozolomide, followed by olutasidenib monotherapy can prolong the progression-free survival of patients with IDH1-mutated high-grade glioma when given following radiotherapy.

奧魯他地尼與替莫唑胺聯合治療的 2 期臨床試驗（名為 TarGet-D）將作為 CONNECT 目標研究的一個治療組，該研究是一項針對高級別膠質瘤的分子引導 2 期傘狀臨床試驗。本研究的目的是確定奧魯他地尼和替莫唑胺聯合治療，隨後進行奧魯他地尼單藥治療是否可以延長放射治療後 IDH1 突變高級別膠質瘤患者的無進展生存期。

We, along with CONNECT, are excited about olutasidenib's potential to provide a much-needed new treatment option to this underserved patient population. We anticipate this trial will be activated by the end of this year.

我們和 CONNECT 一樣對奧魯他尼為這個醫療資源不足的患者群體提供急需的新治療選擇的潛力感到興奮。我們預計該試驗將於今年底啟動。

Next, I'd like to provide some background information on our clinical development program in lower risk MDS with our novel dual IRAK 1 and 4 inhibitor, R289, which you will see on slide 23. Lower risk MDS is an area of high unmet need in a primarily elderly patient population, facing progressive cytopenias, particularly anemia, resulting in transfusion dependency and increased risk of infections and a risk of progression to acute leukemia.

接下來，我想提供一些有關我們的低風險 MDS 臨床開發計劃的背景信息，該計劃採用了我們的新型雙重 IRAK 1 和 4 抑製劑 R289，您可以在幻燈片 23 上看到它。低風險 MDS 是主要針對老年患者群體的一個未滿足需求的領域，面臨進行性血球減少症，特別是貧血，導致輸血依賴和感染風險增加以及進展為急性白血病的風險。

Transfusion burden is high with more than 80% of patients requiring red cell transfusions as supportive therapy. Long-term survival rates are poor due to transfusion burden and its associated morbidities as well as a lack of curative therapies, other than allogeneic stem cell transplantation, which a minority of patients are eligible for due to their advanced age and underlying health conditions.

輸血負擔很高，超過80％的患者需要輸紅血球作為支持性治療。由於輸血負擔及其相關疾病，以及缺乏除異基因幹細胞移植以外的治癒療法，長期生存率較低，而只有少數患者由於年齡較大及存在潛在健康狀況而適合進行異基因幹細胞移植。

The primary goal of therapy is to reduce transfusion burden. Initial treatment options include ESAs if eligible and lenalidomide for del(5q) patients. For transfusion-dependent patients, luspatercept and imetelstat have recently been approved post ESAs or for ESA in eligible patients. In later lines of therapy, durable responses are difficult to attain and toxicity becomes more of an issue.

治療的主要目標是減輕輸血負擔。初始治療方案包括（如果符合條件）ESA和（對於del(5q) 患者）來那度胺。對於輸血依賴患者，luspatercept 和 imetelstat 最近已獲批准用於符合條件的患者進行 ESA 後治療或用於 ESA 治療。在後續的治療中，很難獲得持久的反應，而且毒性變得更為嚴重。

There are no standard therapies for lower risk MDS patients with recurrent or refractory disease. In fact, hypo-methylating agents were approved about 20 years ago, underscoring the need for new, safe, effective therapies for these patients. We believe that R289 has the potential to address the unmet needs in this patient population by targeting inflammatory signaling.

對於患有復發性或難治性疾病的低風險 MDS 患者，尚無標準療法。事實上，低甲基化藥物大約 20 年前就已獲批准，這凸顯了對這些患者進行新的、安全、有效的治療方法的必要性。我們相信，R289 有可能透過靶向發炎訊號來滿足該患者群體尚未滿足的需求。

Moving to slide 24, I'd like to highlight why we're excited about R289. Dysregulation of the immune and inflammatory signaling pathways is associated with MDS with chronic stimulation of both the toll-like and IL-1 receptor pathways involving IRAK 1 and IRAK 4, leading to a pro-inflammatory marrow environment and cytopenia. IRAK 1 and 4 activation independent of this pathway may also lead to persistent inhibition of hematopoietic cell differentiation.

轉到第 24 張投影片，我想強調我們為何對 R289 感到興奮。免疫和發炎訊號通路失調與 MDS 有關，伴隨涉及 IRAK 1 和 IRAK 4 的 toll 樣和 IL-1 受體通路的慢性刺激，導致促發炎骨髓環境和血球減少。獨立於該路徑的 IRAK 1 和 4 活化也可能導致造血細胞分化的持續抑制。

Co-targeting both IRAK 1 and 4 may fully suppress inflammation and restore hematopoesis and MDS. Clinically, IRAK 4 inhibitors in MDS and AML have thus far shown only modest activity supporting this concept.

同時靶向 IRAK 1 和 4 可能完全抑制發炎並恢復造血和 MDS。臨床上，IRAK 4 抑制劑在 MDS 和 AML 中迄今僅表現出適度的活性，支持這一概念。

In preclinical and healthy volunteer studies, R835, a dual IRAK 1/4 inhibitor was previously shown to suppress pro-inflammatory cytokine production. R289 is an oral pro-drug that is rapidly converted to R835 in the gut that is currently being evaluated in lower risk MDS.

在臨床前和健康志願者研究中，雙重 IRAK 1/4 抑制劑 R835 已被證明可以抑制促炎細胞因子的產生。R289 是一種口服前藥，可在腸道中快速轉化為 R835，目前正在對 R835 在低風險 MDS 中的應用進行評估。

Slide 25 shows the design of our ongoing open-label Phase 1b study of R289 in patients with relapsed refractory lower risk MDS, which has a dose escalation phase with a standard 3+3 design and a dose expansion cohort for confirmatory safety. The primary endpoints for this trial are safety and selection of the recommended dose for expansion, and secondary endpoints include hemologic improvement, response rates, and PK.

投影片 25 展示了我們正在進行的 R289 針對復發難治性低風險 MDS 患者的開放標籤 1b 期研究的設計，該研究採用標準 3+3 設計的劑量遞增階段和用於確認安全性的劑量擴展隊列。該試驗的主要終點是安全性和選擇建議的擴展劑量，次要終點包括血液學改善、反應率和 PK。

Based on emerging data from the study, we've recently included two additional cohorts with twice-daily dosing regimens for a total of five dose levels. The study continues to progress well and enrollment in the fifth dose level, a split dose of 500 milligrams and 250 milligrams daily is nearing completion.

根據研究中出現的數據，我們最近又增加了兩個群組，採用每日兩次的給藥方案，總共五種劑量水平。研究繼續進展順利，第五個劑量水平（每日 500 毫克和 250 毫克的分劑量）的招募即將完成。

We expect the DLT evaluation period of this dose level will be completed in December. We're encouraged by the preliminary safety and efficacy data from the study thus far in this elderly patient population with a high transfusion burden as summarized in the recently published ASH abstract.

我們預計該劑量水準的 DLT 評估期將於 12 月完成。正如最近發表的 ASH 摘要中所總結的，迄今為止針對這一輸血負擔較高的老年患者群體的研究的初步安全性和有效性數據令我們感到鼓舞。

Lastly on slide 26, our RIPK1 inhibitor programs are progressing well with our partner, Lilly. RIPK1 is implicated in a broad range of inflammatory cellular processes and plays a key role in tumor necrosis factor signaling. Ocadusertib, our non-CNS-penetrant RIPK1 inhibitor, previously referred to as R552, is currently being studied in an adapted Phase 2a/2b clinical trial in up to 380 patients with active moderate to severe rheumatoid arthritis. Phase 2a enrollment of approximately 100 patients is advancing well with preliminary analysis of the Phase 2a results anticipated within the first half of 2025.

最後在幻燈片 26 上，我們的 RIPK1 抑制劑專案與我們的合作夥伴禮來公司合作進展順利。RIPK1 與多種發炎細胞過程有關，並在腫瘤壞死因子訊號傳導中發揮關鍵作用。Ocadusertib 是我們的非中樞神經系統滲透性 RIPK1 抑制劑，之前稱為 R552，目前正在對多達 380 名活動性中度至重度類風濕性關節炎患者進行適應性 2a/2b 期臨床試驗。階段 2a 約 100 名患者的招募進展順利，預計第 2a 階段結果的初步分析將在 2025 年上半年完成。

Our pre-clinical CNS-penetrant RIPK1 inhibitor program is also progressing for a lead candidate nomination. We're excited about the progress of our programs and their broad potential in rheumatoid arthritis and other immune and CNS diseases.

我們的臨床前中樞神經系統滲透性 RIPK1 抑制劑計畫也正在進行主要候選藥物提名。我們對我們的計畫的進展及其在類風濕性關節炎和其他免疫和中樞神經系統疾病方面的廣泛潛力感到非常興奮。

Now, I'll pass the call to Dean to discuss our financial results for the quarter.

現在，我將電話轉給迪恩，討論本季的財務表現。

Thank you, Lisa. I'm on slide number 28. During the third quarter, we shipped 2,793 bottles of TAVALISSE to our specialty distributors. 2,797 bottles of TAVALISSE were shipped to patients and clinics while four bottles decrease the levels remaining in the distribution channels at the end of the quarter.

謝謝你，麗莎。我在第 28 號投影片。第三季度，我們向專業經銷商運送了 2,793 瓶 TAVALISSE。 2,797 瓶 TAVALISSE 被運送給患者和診所，而截至本季末，分銷管道中剩餘的庫存減少了 4 瓶。

We shipped 429 bottles of REZLIDHIA to our specialty distributors. 444 bottles of REZLIDHIA were shipped to patients and clinics, while 15 bottles decreased the levels remaining in our distribution channels at the end of the quarter.

我們向我們的專業經銷商運送了 429 瓶 REZLIDHIA。 444 瓶 REZLIDHIA 被運送給患者和診所，而 15 瓶減少了本季末我們分銷管道中的剩餘庫存。

We shipped 752 bottles of GAVRETO to our specialty distributors. 717 bottles of GAVRETO were shipped to patients and clinics, while 35 bottles increased the levels remaining in the distribution channels at the end of the quarter.

我們向我們的專業經銷商運送了 752 瓶 GAVRETO。 717 瓶 GAVRETO 被運送給患者和診所，而截至本季末，分銷管道中的剩餘庫存增加了 35 瓶。

We reported net product sales of TAVALISSE at $26.3 million in the third quarter, a growth of 8% compared to $24.5 million in the same period in 2023. We reported net product sales from REZLIDHIA of $5.5 million in the third quarter, a growth of 107% compared to $2.7 million in the same period in 2023. And finally, we reported net product sales from GAVRETO of $7.1 million in the third quarter, the first full quarter of GAVRETO sales.

我們報告稱，第三季 TAVALISSE 的淨產品銷售額為 2,630 萬美元，較 2023 年同期的 2,450 萬美元成長 8%。我們報告稱，REZLIDHIA 第三季的淨產品銷售額為 550 萬美元，較 2023 年同期的 270 萬美元成長了 107%。最後，我們報告稱，第三季（GAVRETO 銷售的第一個完整季度）GAVRETO 的淨產品銷售額為 710 萬美元。

Our net product sales from TAVALISSE, REZLIDHIA, and GAVRETO were recorded net of estimated discounts, chargebacks, rebates returns, co-pay assistance and other allowances of $17.4 million. For the third quarter of 2024, our gross-to-net adjustment for TAVALISSE, REZLIDHIA, and GAVRETO was approximately 36%, 22%, and 15% of gross product sales respectively.

我們從 TAVALISSE、REZLIDHIA 和 GAVRETO 獲得的淨產品銷售額扣除預計折扣、退款、回扣、共同支付援助和其他津貼後為 1,740 萬美元。2024 年第三季度，我們對 TAVALISSE、REZLIDHIA 和 GAVRETO 的毛利與淨利調整分別約為總產品銷售額的 36%、22% 和 15%。

We'd like to highlight that during the fourth quarter, we made certain changes to our distribution channel arrangements for TAVALISSE that will result in continued high-quality access or reducing our distribution costs and favorably impacted our gross-to-net adjustment into the future. While this change is not expected to impact our bottle shipped to patients at clinics during the quarter, we may see a reduction in bottles remaining in our distribution channels at the end of the quarter as inventories normalize. Finally, for the fourth quarter, we expect our gross-to-net adjustment for TAVALISSE, REZLIDHIA, and GAVRETO to be approximately 35%, 21%, and 22% of gross product sales respectively.

我們想強調的是，在第四季度，我們對 TAVALISSE 的分銷管道安排做出了某些更改，這將使我們繼續獲得高品質的訪問或降低分銷成本，並對我們未來的毛利對淨利調整產生有利影響。雖然這項變更預計不會影響我們在本季度運送給診所患者的瓶子，但隨著庫存恢復正常，我們可能會在本季度末看到剩餘在分銷管道中的瓶子數量減少。最後，對於第四季度，我們預期 TAVALISSE、REZLIDHIA 和 GAVRETO 的毛利與淨利調整分別約為總產品銷售額的 35%、21% 和 22%。

Onto the next slide, in addition to the net product sales, our contract revenues from collaborations were $16.4 million in the third quarter. Contract revenues from collaborations consisted of $13 million from Kissei, $3.3 million from Grifols, and $100,000 from Medison. The $13 million in revenues from our Kissei collaboration includes $10 million related to an upfront fee from sub-licensing REZLIDHIA and $3 million for the delivery of drug supplies.

下一張投影片中，除了淨產品銷售額外，我們第三季的合作合約收入為 1,640 萬美元。合作合約收入包括來自 Kissei 的 1300 萬美元、來自 Grifols 的 330 萬美元以及來自 Medison 的 10 萬美元。我們與 Kissei 合作產生的 1,300 萬美元收入包括 REZLIDHIA 再授權的前期費用 1,000 萬美元以及藥品供應運送費用 300 萬美元。

Moving on to costs and expenses, our cost of product sales was approximately $8 million for the third quarter of 2024. Total cost and expenses were $41.3 million compared to $32.6 million in the same period for 2023. The increase in cost and expenses was primarily due to higher cost of product sales driven primarily by increased product sales, a $2.3 million sub-licensing revenue fee paid to Forma, increased royalties, and amortization of intangible assets. In addition, there was an increase in personnel-related costs and commercial-related expenses.

談到成本和費用，我們 2024 年第三季的產品銷售成本約為 800 萬美元。總成本和費用為 4,130 萬美元，而 2023 年同期為 3,260 萬美元。成本和費用的增加主要是由於產品銷售成本增加，主要由於產品銷售額增加、向 Forma 支付的 230 萬美元分許可收入費、特許權使用費增加以及無形資產攤銷。此外，人員相關成本和商業相關費用也有所增加。

This quarter, we reported net income of $12.4 million compared to a net loss of $5.7 million in the same period in 2023. We ended the quarter with cash, cash equivalents, and short-term investments of $61.1 million, up from $49.1 million as of the end of the second quarter. We look to maintain our focused and disciplined financial approach into the future.

本季度，我們報告淨收入為 1,240 萬美元，而 2023 年同期淨虧損為 570 萬美元。本季末，我們的現金、現金等價物和短期投資為 6,110 萬美元，高於第二季末的 4,910 萬美元。我們希望在未來繼續保持專注且嚴謹的財務方針。

With that, I'd like to turn the call back over to Raul. Raul?

說到這裡，我想把電話轉回給勞爾。勞爾？

Thank you, Dean. And moving on to slide 30 please, this is really an exciting time for Rigel. During the first three quarters of '24, we delivered on our goals that we set earlier in the year. First, we generated strong growth in our commercial business. We've achieved another record demand quarter for TAVALISSE and REZLIDHIA and grew our net product sales year over year.

謝謝你，迪恩。請轉到第 30 張幻燈片，這對 Rigel 來說確實是一個激動人心的時刻。在2024年的前三個季度，我們實現了年初設定的目標。首先，我們的商業業務實現了強勁成長。我們 TAVALISSE 和 REZLIDHIA 的需求又創下了一個新紀錄，而我們的淨產品銷售額則是年增。

We expanded our portfolio with the addition of GAVRETO, our third commercial product, which generated $7.1 million in net product sales in its first full quarter with us. We leveraged our commercial capabilities to transition the product to us and are now focused on maximizing its potential. And we're well on our way to deliver another record quarter of revenues for calendar year 2024.

我們擴大了產品組合，增加了第三款商業產品 GAVRETO，該產品在我們這裡上市的第一個完整季度實現了 710 萬美元的淨產品銷售。我們利用我們的商業能力將產品轉移給我們，現在專注於最大限度地發揮其潛力。我們正朝著在 2024 年曆年再創一個創紀錄季度營收的目標邁進。

Second, we made significant advancements in our development pipeline. We continue to progress R289, and we are incredibly excited to present additional safety and efficacy data from our Phase 1b study in lower risk MDS at the ASH meeting next month. Our strategic collaborations with MD Anderson and CONNECT continue to advance, and we now have the first trial with MD Anderson underway.

第二，我們的開發流程取得了重大進展。我們繼續推進 R289，並且我們非常高興能夠在下個月的 ASH 會議上展示我們在低風險 MDS 中的 1b 期研究的更多安全性和有效性數據。我們與MD Anderson和CONNECT的策略合作不斷推進，目前我們正在與MD Anderson進行首次試驗。

And lastly, as we made great strides in these areas, we continue to focus on maintaining financial discipline. All of these efforts have enabled us to generate positive net income for the three quarters and year-to-date.

最後，隨著我們在這些領域取得巨大進步，我們將繼續致力於維護財務紀律。所有這些努力使得我們在前三個季度和今年迄今實現了正的淨收入。

Now on slide 31. As we think about the future for Rigel and our progress in '24 and how it positions us to deliver continued growth in '25 and beyond, our corporate strategy remains focused on our major objectives, executing and expanding our commercial portfolio to generate top-line growth, advancing and growing our development pipeline, and operating in a financially disciplined manner. Becoming a profitable company will allow us to be self-sustaining and importantly to reinvest in our own development pipeline. And we will outline our internal development plans for R289 and olutasidenib in 2025.

現在轉到第 31 張投影片。當我們思考 Rigel 的未來和我們在 24 年的進展，以及我們如何在 25 年及以後實現持續成長時，我們的企業策略仍然專注於我們的主要目標，執行和擴大我們的商業組合以實現營收成長，推進和發展我們的開發管道，並以財務紀律嚴明的方式運營。成為一家盈利的公司將使我們能夠自給自足，更重要的是，我們可以重新投資於我們自己的開發管道。我們將概述 2025 年 R289 和 olutasidenib 的內部開發計劃。

We've made significant progress in '24 and remain focused on continuing in this momentum as we close out the year and head into 2025. Again, I'd like to thank you for your interest in Rigel.

我們在 2024 年取得了重大進展，在結束這一年並邁向 2025 年之際，我們仍將繼續致力於保持這一勢頭。再次感謝您對 Rigel 的關注。

And with that, we will now open the call to your questions. Operator?

現在，我們將開始回答大家的提問。操作員？

Thank you. (Operator Instructions)

謝謝。（操作員指令）

Joe Pantginis, H.C. Wainright.

喬潘特吉尼斯，H.C.溫賴特。

Hey, everybody. Good afternoon. Thanks for taking the questions. Nice to see the approved products progress. So two questions if you don't mind. So first, was hoping to see if you can provide any more color with regard to TAVALISSE and the balance or mix between refills and new prescriptions.

嘿，大家好。午安.感謝您回答這些問題。很高興看到批准產品取得進展。如果您不介意的話，我有兩個問題。因此首先，希望看看您是否可以提供有關 TAVALISSE 以及補充藥物和新處方之間的平衡或混合的更多詳細資訊。

Dave, would you provide some commentary on that?

戴夫，你能對此發表一些評論嗎？

Sure. Thanks for the question, Joe. As you know, TAVALISSE is a product that patients take and will continue taking as long as their platelets are controlled -- are elevated, and sometimes that takes a while. So I will say that the majority of our business is carry over.

當然。謝謝你的提問，喬。如您所知，TAVALISSE 是一種患者需要服用的產品，只要他們的血小板得到控制（升高），他們就會繼續服用，有時這需要一段時間。所以我想說的是，我們大部分的業務都是結轉的。

Once we have patients on board, they will tend to stay on therapy, and that is the majority of our business. And because we've grown new patient starts over the last couple of years, I think we're seeing that growth and carryover go along with that. So that's what I meant to say -- or that's what I was referring to when I said our growth is both from new patients starting as well as carryover, but the majority is carryover.

一旦我們有了病人，他們就會繼續接受治療，這就是我們的業務的主要內容。而且由於過去幾年我們的新患者數量不斷增長，我認為我們看到了隨之而來的增長和延續。這就是我要說的 - 或者當我說我們的增長既來自新患者也來自結轉患者時，我指的是這個，但大多數是結轉患者。

Got it. Appreciate that clarification and color. And then the second question that I have, I want to make sure if I heard correctly. So nice to see the early traction with GAVRETO. And if I heard you correctly, it said that several top centers have not -- have still not placed orders. I was just curious, is this really just based on logistics or how would you characterize it?

知道了。欣賞你的澄清和色彩。然後我的第二個問題是，我想確認我是否聽得正確。很高興看到 GAVRETO 早期的進展。如果我沒聽錯的話，據說幾個頂級中心還沒下訂單。我只是好奇，這真的只是基於物流嗎或你如何描述它？

First of all, what I said in my prepared comments just to be clear is I said, there's a handful of top centers that we haven't seen direct orders from. And so we had expected to see that, and we haven't. So we're trying to understand that a little bit. But the good thing about our data is we have a significant portion through the specialty pharmacy network.

首先，為了明確起見，我在準備好的評論中已經說過，有少數頂級中心我們還沒有看到直接訂單。所以我們原本期望看到這一點，但並沒有。因此我們正嘗試稍微理解一下這一點。但我們數據的優點是，我們透過專業藥局網路獲得了很大一部分數據。

So what we could be seeing is patients are in the specialty pharmacy network when they transition to the Rigel network versus the institution buying the drug and then filling it there. But overall, actually, what I said in my prepared marks was that 45% of our business was through the distribution channel to direct accounts in Q3. When we just looked at this for October, it's up to 50-50. So I think this is improving, and it is more like what we expected, more of our business coming through the direct channel. Hope that helps, Joe.

因此，我們可以看到，當患者轉到 Rigel 網路時，他們處於專業藥房網路中，而不是由機構購買藥品然後在那裡配藥。但總體而言，實際上，我在準備好的分數中說過，我們第三季 45% 的業務是透過分銷管道直接向帳戶進行的。當我們查看十月份的情況時，發現這一比例已達到 50-50。所以我認為這種情況正在改善，而且更像我們預期的那樣，我們的更多業務來自直接管道。希望這對你有幫助，喬。

Yigal Nochomovitz, Citi.

花旗的 Yigal Nochomovitz。

Hi, team. This is [Ashiq] on for Yigal. Thanks for taking my questions and appreciate all the updates here. I just had a follow-up on the last question on the GAVRETO relaunch. How much of a stocking benefit was there -- the sort of initial phase of the launch, at least with you guys.

大家好。這是 Yigal 的 [Ashiq]。感謝您回答我的問題並感謝這裡的所有更新。我剛剛對 GAVRETO 重新啟動的最後一個問題進行了跟進。在發布的初始階段，有多少庫存福利呢？

And on the reported sales, $7 million looks like it's at least on a similar run rate for the quarter compared to what the prior entity did with it last year. So how should we think about the growth trajectory from here? If we should be thinking about it in a more aggressive way or maybe more modestly from here given the sort of restart. Thanks.

從報告的銷售額來看，700 萬美元的銷售額看起來至少與去年同期的銷售額持平。那我們該如何看待未來的成長軌跡呢？考慮到重新開始的方式，我們應該以更積極的方式，或從更謹慎的方式來考慮這個問題。謝謝。

Dave, you want to take that?

戴夫，你想拿走那個嗎？

Sure. Thanks for the question. First of all, remember that at the end of Q2, right at the very end, we filled some orders to our distributors, and that was what I would refer to as stocking. It was about $1.9 million in sales. This quarter, we sold 717 bottles -- or we shipped 717 bottles, and we had just a slight more -- 750-odd bottles sold. So there were another maybe 30 some bottles built up in the channel.

當然。謝謝你的提問。首先，請記住，在第二季末，就在最後，我們向經銷商下了一些訂單，這就是我所說的備貨。銷售額約190萬美元。本季度，我們銷售了 717 瓶（或者說，我們運送了 717 瓶），並且銷售量略多一些（750 多瓶）。因此，大概還有 30 多個瓶子堆積在水渠中。

So I would just say that the majority is demand that we saw in -- the overwhelming majority of what we saw in Q3 is true demand, patient demand, account demand. And what I will say is that, obviously, we started the quarter with some level of shipments going out to patients and clinics. We ended the quarter with a much higher level of shipments going out to patients and clinics as more people transitioned over.

所以我只想說，我們看到的大部分需求——我們在第三季度看到的絕大多數需求是真實需求、患者需求和帳戶需求。我要說的是，顯然，我們在本季開始時就向患者和診所發送了一定數量的貨物。隨著越來越多的人轉為結核病患者，我們在本季末向患者和診所發出的藥品發貨量大幅增加。

So I can't really comment any more than that. But we would expect to see some continued demand growth as we move forward.

因此我實在無法再發表更多評論。但我們預計，隨著時間的推移，需求將持續成長。

And translated specifically into bottle counts, we had 228 bottles of increase in our distribution channel or our inventory that Dave described in Q2, and that was essentially the full amount of revenue. And then we had an incremental build of that inventory of 35 bottles. The remainder of the bottles in Q3 were from shipments to patients and clinics. Right?

具體來說，換算成瓶數，正如戴夫在第二季度所描述的，我們的分銷管道或庫存增加了 228 瓶，這基本上就是全部收入。然後我們逐漸將庫存增加到 35 瓶。第三季剩餘的瓶子是運送給病人和診所的。正確的？

(Operator Instructions)

（操作員指令）

Kalpit Patel, B. Riley Securities.

Kalpit Patel，B. Riley 證券。

Yeah. Hey, good afternoon. Thanks for taking the questions. For the proof of concept data in in lower risk MDS, first, to the extent that you can share here, the Grade 3, 4 adverse events that are listed in the abstract, was there any indication that these were dose-dependent or generally occurring in doses of 500 milligrams or higher?

是的。嘿，下午好。感謝您回答這些問題。對於低風險 MDS 的概念驗證數據，首先，就您可以在這裡分享的程度而言，摘要中列出的 3 級、4 級不良事件，是否有跡象表明這些事件是劑量依賴性的或通常發生在 500 毫克或更高的劑量下？

Yeah, thanks for the question. I think that we that will be shared in more detail in December.

是的，謝謝你的提問。我認為我們將在 12 月分享更多詳細資訊。

At the ASH meeting in the poster presentation.

在 ASH 會議上的海報展示中。

Okay. Got it. And how much more data should we expect then at ASH in terms of maybe the number of patients and the number of cohorts and things like that?

好的。知道了。那麼，就患者數量、隊列數量等而言，我們應該預期 ASH 會有多少數據呢？

Right. So for the abstract, we use the data cut-off date of July 15, and we're updating that to October 25. So it's going to be about another three months or so of data. So you'll see data on the patients from the fourth dose level and a little bit beyond that.

正確的。因此對於摘要，我們使用的數據截止日期為 7 月 15 日，並且我們將其更新為 10 月 25 日。因此這將會是另外三個月左右的數據。因此，您將看到第四劑量水平及稍高於該劑量水平的患者的數據。

Farzin Haque, Jeffries.

法爾津·哈克，杰弗里斯。

Hi, good afternoon. Thank you for taking my question. To start off with the four -- with R289 in the lower risk MDS patients, how should we think about the bar for success? And what would you need to see in Phase 1b to advance the program forward?

嗨，下午好。感謝您回答我的問題。首先從這四個面向開始－對於低風險 MDS 患者使用 R289，我們應該如何考慮成功的標準？您需要在第 1b 階段看到什麼來推動該計劃向前發展？

I'll let Lisa comment. Let me just preface this by saying that we're really excited about this data. This data -- this molecule was a molecule discovered here at Rigel. We own full rights to it. We think definitely the most advanced IRAK 1 and 4 inhibitor that there is available.

我會讓麗莎發表評論。首先我要說的是，我們對這些數據感到非常興奮。此數據－該分子是在 Rigel 發現的分子。我們擁有它的全部權利。我們認為這絕對是目前最先進的 IRAK 1 和 4 抑制劑。

We are excited to study it here in low-risk MDS, where we see a very good mechanism to indication. And we're really interested to try it here, and we're delighted to present the data that you saw in the abstract and substantially much more detail in the poster to come.

我們很高興在低風險 MDS 中對其進行研究，我們看到了非常好的指示機制。我們真的很感興趣在這裡嘗試一下，我們很高興能夠展示您在摘要中看到的數據，並在即將發布的海報中提供更詳細的資訊。

In terms of the bar, Lisa, maybe do you want to comment on that?

關於酒吧，麗莎，也許你想對此發表評論？

Yeah. I think that if we look at the treatment landscape and lower risk MDS, obviously, we've got the first-line agents -- patients if they're eligible for having ESAs. They will have ESAs followed by luspatercept -- these are transfusion-dependent patients I'm talking about now -- and imetelstat, and there's really nothing afterwards until HMA. So that's kind of quite a gap.

是的。我認為，如果我們看一下治療前景和降低風險的 MDS，顯然，我們已經獲得了第一線藥物 — — 如果患者有資格獲得 ESA。他們將先接受 ESA 治療，然後接受 luspatercept 治療（我現在談論的就是輸血依賴型患者）和 imetelstat 治療，之後直到接受 HMA 治療實際上沒有任何治療。所以這是一個相當大的差距。

And in terms of efficacy, HMAs, in terms of improving transfusion or reducing transfusion requirements, they have about a 20% transfusion independence associated with them. So that's pretty low on one end. And then, our study is unique in that it's enrolling patients that have previously received HMAs, as well as luspatercept, imetelstat, et cetera.

就功效而言，HMA 在改善輸血或減少輸血需求方面具有約 20% 的輸血獨立性。因此，從一端來看，這是相當低的。而且，我們的研究是獨一無二的，因為它招募了以前接受過 HMA 以及 luspatercept、imetelstat 等治療的患者。

So I would say that the response rates for first line, it's around 40%. But like I said, our study is unique in that we are including relapsed/refractory patients that weren't included in those first-line settings. So I don't know that I would put a number on it right now. I think we're very encouraged by what we're seeing based on the preliminary safety and efficacy data thus far.

所以我想說第一行的回應率大約是 40%。但就像我說的，我們的研究是獨一無二的，因為我們納入了那些第一線治療中未包括的復發/難治性患者。所以我現在不知道是否應該給它一個數字。我認為，根據迄今為止的初步安全性和有效性數據，我們看到的結果讓我們感到非常鼓舞。

That's helpful. And then for GAVRETO, I was just curious for the new safety signal related to the risk of severe and fatal infection, how rate limiting do you expect it to be for uptake? Does Retevmo, the competitive program, have the same issue?

這很有幫助。然後對於 GAVRETO，我只是好奇與嚴重和致命感染風險相關的新安全訊號，您預計它對吸收的限制速率有多大？競爭性計劃 Retevmo 是否存在同樣的問題？

Lisa, do you want to comment on that?

麗莎，你想對此發表評論嗎？

I would say that from -- yeah, and then maybe Dave can comment. So from the clinical perspective, this really isn't something new. Looking at the ARROW study, we were aware that infections were reported. This is in the label already in the safety section.

我想說的是——是的，然後也許戴夫可以評論一下。因此從臨床角度來看，這並不是什麼新鮮事。透過 ARROW 研究，我們了解到有感染報告。這已經在安全部分的標籤中了。

We know that mechanistically, there's a rationale for why this is happening. We know that in addition to RET inhibition that these increased risk of infections may stem from the off-target, inhibition of JAK1 and JAK2, which are not the primary targets, but nonetheless, there is some off-target activity there.

我們知道，從機制上來說，發生這種情況是有原因的。我們知道，除了 RET 抑制之外，這些感染風險的增加可能源於脫靶、JAK1 和 JAK2 的抑制，這些都不是主要靶點，但儘管如此，那裡仍存在一些脫靶活動。

And we know also in terms, most of the infections were pneumonias, which are very common in this patient population, about 80% of patients get pneumonia with lung cancer and receiving treatment for lung cancer. So this is a situation that oncologists are very familiar with managing.

我們也知道，大多數感染都是肺炎，這在這群患者中非常常見，大約 80% 的患者患有肺癌並接受肺癌治療。這是腫瘤學家非常熟悉的處理的情況。

If you want to comment on what you've heard from [sets in]?

如果你想評論你所聽到的[開始]？

Sure. Patient safety is paramount, and I'm very proud to say that we sent the DHCP to more than 10,000 health care providers. That said, we haven't received any calls to our medical information line regarding that update.

當然。病人安全至關重要，我很自豪地說我們已經將 DHCP 發送給了 10,000 多家醫療保健提供者。儘管如此，我們還沒有接到任何關於該更新的醫療資訊熱線。

And as Lisa said, this is non-small cell lung cancer. These are oncologists who treat very sick patients all the time. You have two RET inhibitors on the market with the significant warnings and precautions on both and different sets of warnings and precautions. So we don't see any -- at this point, we don't see any changes in how we look at the opportunity for GAVRETO moving forward in the RET fusion-positive non-small cell cancer space.

正如麗莎所說，這是非小細胞肺癌。這些腫瘤科醫師一直在治療病情十分嚴重的患者。市面上有兩種 RET 抑制劑，兩者都有重要的警告和注意事項，並且警告和注意事項有不同的集合。因此，我們目前沒有看到任何變化——我們沒有看到我們對 GAVRETO 在 RET 融合陽性非小細胞癌領域前進的機會的看法有任何變化。

Kalpit Patel, B. Riley Securities.

Kalpit Patel，B. Riley 證券。

Yeah. Thanks for taking the follow-up. I just had one more on the lower risk MDS program. There was another agent, Curis's IRAK inhibitor that was started in an investigator-sponsored study but then later withdrawn for the same indication. So I guess if you had to highlight a few differentiated factors with R289 versus the others, what would they be?

是的。感謝您的跟進。我剛剛又參加了一次低風險 MDS 計劃。還有另一種藥物，即 Curis 公司的 IRAK 抑制劑，該藥物在一項研究者贊助的研究中啟動，但後來因同一適應症而被撤回。所以我想，如果您必須強調 R289 與其他產品的幾個不同因素，它們會是什麼？

It's hard to comment on other people's. I would say ours is an IRAK 1 and 4 inhibitor. I believe theirs was an IRAK 4 inhibitor. That is a significant difference. I think Lisa highlighted in one of the slides where we showed that inhibiting both 1 and 4 provides a more profound inhibition of inflammatory cytokines, presumably in the bone marrow in this case. So that is that important difference between those two.

很難評論其他人的事情。我想說我們的是 IRAK 1 和 4 抑制劑。我相信他們有 IRAK 4 抑制劑。這是一個顯著的差異。我認為 Lisa 在其中一張投影片中強調了這一點，我們展示了同時抑制 1 和 4 可以更深層次地抑制發炎細胞因子，在本例中大概是在骨髓中。這就是兩者之間的重要差異。

And as I said earlier, I don't believe there's another IRAK 1 and 4 inhibitor in development and certainly not in more advanced development available. So we -- this is the first to work on a 1/4. And that rationale, the more profound cytokine inhibition was one of the reasons we liked 1 and 4 over 4. And Lisa, any other comments?

正如我之前所說，我不相信有另一種 IRAK 1 和 4 抑制劑正在開發中，當然也沒有更先進的開發成果。因此我們 — — 這是第一次研究 1/4。基於此，更深層的細胞激素抑制是我們喜歡 1 和 4 而不是 4 的原因之一。還有麗莎，還有其他評論嗎？

No, I think that pretty well summarizes it.

不，我認為這已經很好地概括了這一點。

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

謝謝。目前沒有其他問題。我想把發言權交還給勞爾·羅德里格斯先生，請他作最後評論。

Thank you, and thank you everyone for joining on the call today and your continued interest in Rigel. I can say it's a very exciting time for the company, having data to share an exciting product and more coming. I think it is really a great place to be.

謝謝大家，也謝謝大家今天的電話會議以及對 Rigel 的持續關注。我可以說，對於公司來說這是一個非常令人興奮的時刻，我們擁有數據來分享令人興奮的產品，並且即將推出更多產品。我認為這真是一個很棒的地方。

The year has gone very well for us in terms of commercial growth in addition to the portfolio and advancements in our development. And we look forward to telling you more about that in the 2025. So with that, I'd like to also just always thank our employees for their continued commitment to our cause and improving the lives of patients and look forward to updating you further in other calls. Take care.

這一年，我們在商業成長、產品組合和發展方面都取得了巨大的成績。我們期待在 2025 年向您介紹更多相關資訊。因此，我還要感謝我們的員工對我們的事業和改善患者生活的持續承諾，並期待在其他電話中向您進一步通報最新情況。小心。

And this concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation.

今天的電話會議到此結束。現在您可以斷開您的線路。感謝您的參與。