Kymera Therapeutics Inc (KYMR) 2024 Q1 法說會逐字稿

Good day and welcome to the Kymera Therapeutics first-quarter 2024 results conference call. (Operator Instructions)

美好的一天，歡迎參加 Kymera Therapeutics 2024 年第一季業績電話會議。 （操作員說明）

Please note that this event is being recorded. I would now like to turn the conference over to Justine Koenigsberg. Please go ahead.

請注意，該事件正在被記錄。我現在想把會議交給賈斯汀·科尼斯堡。請繼續。

Thank you. Good morning and welcome to Kymera's quarterly update call. Joining me this morning are Nello Mainolfi, President and CEO; Jared Gollob, our Chief Medical Officer; and Bruce Jacobs, our Chief Financial Officer.

謝謝。早安，歡迎參加 Kymera 的季度更新電話會議。今天早上和我一起來的還有總裁兼執行長 Nello Mainolfi； Jared Gollob，我們的首席醫療官；和我們的財務長布魯斯·雅各布斯。

Following our prepared remarks, we will open the call to questions. To have enough time to address everyone's questions, we ask that you please limit your questions to one and a relevant follow-up.

在我們準備好的發言之後，我們將開始提問。為了有足夠的時間來解決每個人的問題，我們要求您將問題限制為一個和相關的後續問題。

Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, I'll now turn the call over to Nello.

在我們開始之前，我想提醒您，今天的討論將包括有關我們未來的期望、計劃和前景的前瞻性陳述。這些陳述存在風險和不確定性，可能導致實際結果與預測有重大差異。這些風險的描述可以在我們最近向 SEC 提交的 10-Q 中找到。任何前瞻性陳述僅代表今天的情況，我們不承擔更新今天電話會議上所做的任何前瞻性陳述的義務。這樣，我現在會把電話轉給 Nello。

Thank you, Justine. Good morning, everybody. It's been a very productive beginning of 2024 starting in January with an extensive update at our immunology R&D Day and a subsequent financing to provide capital that we will invest in our expanding clinical development efforts and growing pipeline. First quarter has been focused on execution on both our preclinical and clinical pipeline as well as external engagement across a variety of business and medical conferences.

謝謝你，賈斯汀。大家早安。從1 月開始，2024 年是一個非常富有成效的開端，我們在免疫學研發日進行了廣泛的更新，並隨後進行了融資，以提供資金，我們將投資於不斷擴大的臨床開發工作和不斷增長的產品線。第一季的重點是我們的臨床前和臨床管道的執行以及各種商業和醫學會議的外部參與。

Today, our plan is to share a brief update on our programs as well as timelines for news and coverage we're expecting through the rest of this year and early '25. As we shared earlier this year, we believe we have a significant opportunity to address and expand the existing treatment paradigms within immunology by developing compelling oral small molecule degrader medicines with biologics-like activity.

今天，我們的計劃是分享我們計劃的簡要更新，以及我們預計今年剩餘時間和 25 年初的新聞和報道時間表。正如我們今年早些時候分享的那樣，我們相信，透過開發具有類似生物製劑活性的引人注目的口服小分子降解藥物，我們有一個重要的機會來解決和擴展免疫學領域的現有治療範例。

As had been the case all the way back to the financing of the company, we have taken a differentiated approach to target selection and focused on critical molecular pathways that are well validated through human genetics, clinical evidence and/or the success of approved drugs.

正如公司融資以來的情況一樣，我們採取了差異化的目標選擇方法，並專注於透過人類遺傳學、臨床證據和/或已批准藥物的成功得到充分驗證的關鍵分子途徑。

Many of these pathways play a key role in immune-mediated disease pathology. And while injectable biologics dominate these markets often due to their strong clinical activity, they're not without limitations, which in many instances, can limit penetration.

其中許多途徑在免疫介導的疾病病理學中發揮關鍵作用。儘管注射生物製劑通常因其強大的臨床活性而在這些市場佔據主導地位，但它們並非沒有局限性，在許多情況下，這可能會限制滲透。

As a result, we believe developing convenient oral options with biologics-like activity and a good safety profile represents an enormous opportunity to expand patient access in many of these markets and are currently dominated by injectable agents. IRAK-4 program, which was our first program to enter clinical development, exemplifies a target in a pathway that has the potential for a broad patient impact.

因此，我們相信，開發具有類似生物製劑活性和良好安全性的便捷口服選擇，為擴大許多此類市場的患者獲取機會提供了巨大的機會，而目前這些市場主要由注射劑主導。 IRAK-4 項目是我們第一個進入臨床開發的項目，它體現了一個可能對患者產生廣泛影響的途徑中的目標。

We have talked in the past about our reasons for enthusiasm around IRAK-4 as a target and our rationale for pursuing it. IRAK-4 is an obligate node in the L-1/TLR signaling, and we believe its degradation is the only approach to fully block the pathway, creating multiple development opportunities in large, high unmet need indications.

我們過去曾討論過我們熱衷於以IRAK-4為目標的原因以及我們追求這一目標的理由。 IRAK-4 是 L-1/TLR 訊號傳導中的一個專性節點，我們相信其降解是完全阻斷該路徑的唯一方法，從而在大量未滿足的需求適應症中創造多種開發機會。

In KT-474 IRAK-4 Phase 1 trial, we observed deep and well-tolerated degradation, early signs of clinical efficacy, and high fidelity of translation from preclinical models to patients, which provide key insights for our growing immunology pipeline and physician infusion programs, such as our STAT6 and TYK2 degraded programs for success.

在KT-474 IRAK-4 1 期試驗中，我們觀察到深度且耐受性良好的降解、臨床療效的早期跡像以及從臨床前模型到患者的高保真度翻譯，這為我們不斷增長的免疫學管道和醫生輸液計劃提供了關鍵見解，例如我們的 STAT6 和 TYK2 降級程序取得成功。

In March, we had the opportunity to showcase our proprietary immunology blockbuster program, KT-621, our STAT6 degrader; and KT-294, our TYK2 degrader at the American Academy of Dermatology Annual Meeting. The posted presentations, which marked the first data from a STAT56 targeted agent and a TYK2 degrader to be shared at a major medical meeting, highlighted our robust preclinical packages and support the significant potential of our oral degraders in this pathway.

3 月份，我們有機會展示我們專有的免疫學重磅計畫 KT-621，我們的 STAT6 降解劑；以及我們在美國皮膚病學會年會上展示的 TYK2 降解劑 KT-294。發布的簡報標誌著STAT56 標靶藥物和TYK2 降解劑的首個數據將在一次重要的醫學會議上分享，強調了我們強大的臨床前包裝，並支持我們的口服降解劑在這一途徑中的巨大潛力。

In our KT-621 AAD poster, we highlight the preclinical efficacy studies comparing to KT-621 to [dupilumab] in a preclinical atopic dermatitis model. Importantly, KT-621 showed robust activity in vivo in this model equal or superior to the dupilumab. KT-621 degradation of STAT6 was well tolerated in multiple preclinical safety studies at doses at concentration up to 44-fold above the projected human efficacious concentration. If we can indeed deliver biologics-like activity, a good safety profile, and oral once-daily dosing, we believe KT-621 could change the treatment paradigm for millions of patients suffering from Th2-driven inflammation.

在我們的 KT-621 AAD 海報中，我們重點介紹了在臨床前異位性皮膚炎模型中將 KT-621 與 [dupilumab] 進行比較的臨床前療效研究。重要的是，KT-621 在該模型中顯示出與 dupilumab 相同或優於 dupilumab 的強大體內活性。在多項臨床前安全性研究中，KT-621 對 STAT6 的降解具有良好的耐受性，其劑量濃度比預期的人類有效濃度高出 44 倍。如果我們確實能夠提供類似生物製劑的活性、良好的安全性和每日一次口服劑量，我們相信 KT-621 可以改變數百萬患有 Th2 驅動發炎的患者的治療模式。

In terms of timing, KT-621 is currently an IND-enabling study and is on track to enter Phase 1 testing in the second half of 2024. It's our intent to conduct the Phase 1 healthy volunteer study to assess single and multiple ascending doses of KT-621 and move quickly from there into patients. We have finalized our clinical development plans and strategy, and we look forward to sharing more details as we move closer into clinical development.

就時間安排而言，KT-621目前是一項支持IND 的研究，預計在2024 年下半年進入1 期測試。劑量的KT-621 並從那裡迅速轉移到患者體內。我們已經敲定了臨床開發計劃和策略，我們期待在接近臨床開發時分享更多細節。

More into TYK2, we shared a poster at AAD that demonstrated picomolar degradation, potency, and low nanomolar inhibition of the IL-23, IL-12, and type 1 interferon pathways, showing KT-294's potential to recapitulate the biology of human TYK2 loss of function mutation.

關於TYK2，我們在AAD 分享了一張海報，展示了IL-23、IL-12 和1 型乾擾素途徑的皮摩爾降解、效力和低納摩爾抑制，顯示KT-294 具有重現人類TYK2 損失生物學的潛力的功能突變。

The biological differentiation of KT-294 from allosteric to small molecule inhibitors was demonstrating through IL-10 sparing compared to supra, which is important in inflammatory bowel syndrome as well as was shown through superior inhibition of type 1 interferon pathway compared to TAK-279, which is relevant for the treatment of several diseases, including interferon-driven diseases.

KT-294 從變構抑制劑到小分子抑制劑的生物學差異已透過與上文相比的IL-10 保留得到證明，這在發炎性腸道症候群中很重要，並且與TAK-279 相比透過對1 型乾擾素途徑的卓越抑制已被證明，這與多種疾病的治療有關，包括幹擾素引起的疾病。

Additionally, KT-294 demonstrated deep and sustained TYK2 knockdown in vivo with low daily doses. We believe that these data demonstrate that a TYK2 degrader has the potential to deliver best-in-class TYK2 pathway blockade with productivity across multiple IL-12, 23, and type 1 interferon-driven immune inflammatory diseases.

此外，KT-294 在體內以較低的每日劑量表現出深度且持續的 TYK2 敲低。我們相信這些數據表明 TYK2 降解劑有潛力提供同類最佳的 TYK2 通路阻斷，並且能夠有效治療多種 IL-12、23 和 1 型乾擾素驅動的免疫發炎性疾病。

We intend to continue to share updates across our pipeline and medical meetings in 2024. In fact, later this month, we presented poster highlighting KT-621 and its potential to treat Th2 allergic diseases at both the American Thoracic Society International Conference in San Diego as well as at the Digestive Disease Week in DC.

我們打算在2024 年繼續分享我們的產品線和醫療會議的最新資訊。 Th2 過敏性疾病的潛力。

These presentations, which build on what was previously shared at R&D Day, will include new, exciting additional preclinical data. To sum up my intro here, since our founding 8 years ago, a milestone which we will commemorate just in a few days, we have demonstrated consistent scalable innovation, including strong preclinical to clinical translation of degradation, safety, and activity across the whole pipeline. We have also achieved early proof of concept in both immunology and oncology, which we believe is a significant accomplishment for the new modality.

這些演示以先前在研發日分享的內容為基礎，將包括新的、令人興奮的額外臨床前數據。總結我的介紹，自我們8 年前成立以來，我們將在幾天內紀念這一里程碑，我們展示了一致的可擴展創新，包括整個管道中降解、安全性和活性的強大臨床前到臨床轉化。我們也在免疫學和腫瘤學方面取得了早期概念驗證，我們認為這是新模式的重大成就。

As we are transitioning from early to mid-late development across our pipeline, we remain committed to building on early success in expanding our team and capabilities to deliver on the substantial clinical and commercial opportunities that our programs offer to ultimately become a global commercial-stage medicine company. In the meantime, we look forward to important near-term data readouts in this year in oncology and multiple readouts from our immunology pipeline in '25.

隨著我們的管道從早期開發過渡到中後期開發，我們仍然致力於在擴大我們的團隊和能力方面取得早期成功，以提供我們的專案提供的大量臨床和商業機會，最終成為全球商業階段醫藥公司。同時，我們期待今年腫瘤學領域重要的近期數據讀數，以及 25 年免疫學管道的多個讀數。

I'll pass you and ask Jared to provide an update on our clinical program. Jared?

我會經過您並請賈里德提供我們臨床計劃的最新資訊。賈里德？

Thanks, Nello. I'll round out the immunology discussion this morning of IRAK-4 and then give an update on our two clinical oncology programs.

謝謝，尼洛。我將完成今天早上 IRAK-4 的免疫學討論，然後介紹我們兩個臨床腫瘤學課程的最新情況。

Our first-in-class oral IRAK- degrader, KT-474, is progressing into Phase 2 trials in hidradenitis suppurativa and atopic dermatitis. These trials are being conducted by Sanofi under our collaboration, and we expect to be in a position to share top line data in the first half of 2025. Recall that Sanofi moved this program into Phase 2 studies based on the early clinical data we generated in HS and AD patients in Phase 1 trial.

我們一流的口服 IRAK 降解劑 KT-474 正在進入化膿性汗腺炎和異位性皮膚炎的 2 期試驗。這些試驗是由賽諾菲在我們的合作下進行的，我們預計能夠在2025 年上半年分享頂線數據。期研究。

In that study, not only did we achieve our study objectives in terms of PK/PD and safety, but we also delivered encouraging signs of clinical activity that we will also evaluate over a longer dosing period in the Phase 2 trials. These randomized, placebo-controlled trials represent an opportunity to demonstrate the potential for IRAK4 degradation generally and KT-474 specifically to transform the treatment of complex inflammatory diseases and to offer HS and AD patients a well-tolerated, effective, and convenient oral medicine.

在這項研究中，我們不僅實現了PK/PD 和安全性方面的研究目標，而且還提供了令人鼓舞的臨床活性跡象，我們還將在2 期試驗中對更長的給藥期進行評估。這些隨

So switching gears now to oncology, I'll start by noting that we recently presented scientific data on our oncology pipeline in both the late-breaking poster session and during the major symposium at the AACR Annual Meeting.

因此，現在轉向腫瘤學，我首先要指出的是，我們最近在最新的海報會議和 AACR 年會的主要研討會上展示了有關我們腫瘤學管道的科學數據。

As we shared in the past, our preclinical and early clinical findings, highlighted last month at the meeting, support the advantages of degraders over other existing technologies and agents and further validate our differentiated molecular design, target selection, and translational strategy to advance the new generation of medicines for patients. KT-253, our highly potent degrader of MDM2, E3 ligase, that modulates most common tumor suppressor, p53, is currently in development for the treatment of liquid and solid tumors.

正如我們過去分享的那樣，我們上個月在會議上強調的臨床前和早期臨床發現支持了降解劑相對於其他現有技術和製劑的優勢，並進一步驗證了我們的差異化分子設計、標靶選擇和轉化策略，以推進新的為患者生產藥物。 KT-253 是我們的 MDM2、E3 連接酶的高效降解劑，可調節最常見的腫瘤抑制因子 p53，目前正在開發用於治療液體和實體腫瘤。

Preliminary data from the Phase 1 clinical trial showed evidence of target engagement and p53 pathway activation, along with initial signs of antitumor activity without dose-limiting toxicities, including typical hematological toxicities. These findings support our therapeutic hypothesis for MDM2 degraders and the potential to improve the therapeutic index compared to MDM2 small molecule inhibitors.

1 期臨床試驗的初步數據顯示了標靶參與和 p53 通路活化的證據，以及抗腫瘤活性的初步跡象，沒有劑量限制性毒性，包括典型的血液學毒性。這些發現支持了我們對 MDM2 降解劑的治療假設，以及與 MDM2 小分子抑制劑相比改善治療指數的潛力。

As we finish dose escalation and the Phase 1 trial this year, we hope to see antitumor activity in a variety of tumor types. And coupled with our biomarker selection strategy, we plan to assess these data collectively to inform next steps.

當我們今年完成劑量遞增和一期試驗時，我們希望看到多種腫瘤類型的抗腫瘤活性。結合我們的生物標記選擇策略，我們計劃集體評估這些數據，以便為下一步行動提供資訊。

Finally, on MDM2, we are announcing today that we've had an abstract accepted for a poster presentation at ASCO in June, where we will provide a clinical data update. Once the trial is completed, we expect to present the full data set at a medical meeting later in the year.

最後，關於 MDM2，我們今天宣布，我們已接受 6 月在 ASCO 上進行海報展示的摘要，屆時我們將提供臨床數據更新。一旦試驗完成，我們預計將在今年稍後的醫學會議上展示完整的數據集。

KT-333, our highly selective degrader, STAT3, traditionally undrugged transcription factor recognized as a key component of the JAK STAT3 signaling pathway with both tumor cell intrinsic and tumor cell extrinsic effects on the tumor microenvironment. It's currently in development for the treatment of multiple STAT3-dependent pathologies, including hematological malignancies and solid tumors.

KT-333 是我們的高度選擇性降解劑，STAT3 是傳統上未加藥的轉錄因子，被認為是 JAK STAT3 訊號通路的關鍵組成部分，對腫瘤微環境具有腫瘤細胞內在和外在影響。目前正在開發用於治療多種 STAT3 依賴性病變的藥物，包括血液惡性腫瘤和實體腫瘤。

Preliminary data from the Phase 1 trial demonstrated early signs of anti-tumor activity at doses that were generally well tolerated and associated with substantial STAT3 knockdown in blood and tumor. Our preclinical to clinical translation showed some early but encouraging responses in both CTCL and Hodgkin's lymphoma.

1 期試驗的初步數據表明，在通常耐受性良好的劑量下，抗腫瘤活性的早期跡象與血液和腫瘤中 STAT3 的大量敲低有關。我們的臨床前到臨床轉化顯示了 CTCL 和霍奇金淋巴瘤的一些早期但令人鼓舞的反應。

We also demonstrated simulation of an interferon gamma response in tumor and blood, which is encouraging given the correlation between interferon gamma and how tumors respond to anti-PD-1 drugs. Since escalation, the KT-333 Phase 1 study is ongoing with the goal to further assess safety and anti-tumor activity in both liquid and solid tumors. We expect to complete the study this year and deliver additional proof-of-concept data to define KT-333's path to late-stage development.

我們也模擬了腫瘤和血液中的干擾素 γ 反應，鑑於幹擾素 γ 與腫瘤對抗 PD-1 藥物的反應之間的相關性，這是令人鼓舞的。自升級以來，KT-333 1 期研究正在進行中，目的是進一步評估液體和實體腫瘤的安全性和抗腫瘤活性。我們預計今年將完成這項研究，並提供額外的概念驗證數據，以確定 KT-333 的後期開發之路。

We are also announcing that we've had an abstract accepted for presentation at the European Hematology Association or EHA meeting in June, where we will present a clinical update. We plan to present the full data set at a medical meeting later in the year.

我們還宣布，我們已接受一份摘要，以便在 6 月的歐洲血液學協會或 EHA 會議上進行演示，我們將在會議上介紹臨床更新。我們計劃在今年稍後的醫學會議上展示完整的數據集。

Now I will hand the call over to Bruce to share financials for the quarter. Bruce?

現在我將把電話轉交給布魯斯，讓他分享本季的財務狀況。布魯斯？

Thanks, Jared. I'll quickly review our first quarter 2024 financial highlights and you can certainly reference tables found in today's press release. Revenue for the first quarter of 2024 is $10.3 million. All of that was attributable to our Sanofi collaboration. And just as a quick reminder, we had received or have received $55 million in total milestones as a result of the start into two Phase 2 studies in the fourth quarter of last year.

謝謝，賈里德。我將快速回顧我們 2024 年第一季的財務亮點，您當然可以參考今天新聞稿中的表格。 2024 年第一季的營收為 1,030 萬美元。這一切都歸功於我們與賽諾菲的合作。順便提醒一下，由於去年第四季啟動了兩項 2 期研究，我們已經收到或已經收到了 5500 萬美元的里程碑資金。

With respect to operating expenses, R&D for the quarter was $48.8 million. About $6.1 million of that represented non-cash stock based comp, resulting in an adjusted cash R&D spend of $42.7 million, a 10% decrease from the comparable amount in the fourth quarter of 2023.

就營運費用而言，本季的研發費用為 4,880 萬美元。其中約 610 萬美元為非現金股票補償，調整後的現金研發支出為 4,270 萬美元，比 2023 年第四季的可比金額減少 10%。

On the G&A side, our spending for the quarter was $14.4 million, of which $5.9 million was stock non-cash stock-based comp. The adjusted cash G&A spend of $8.5 million, again, excluding the stock-based comp, reflects a 1% decrease from the comparable quarter -- sequential quarter.

在 G&A 方面，我們本季的支出為 1,440 萬美元，其中 590 萬美元是股票非現金補償。調整後的現金 G&A 支出為 850 萬美元，不包括股票比較，較上一季下降 1%。

Our cash balance at the end of the first quarter was $745 million. In January, as we mentioned, we realized approximately $300 million in net proceeds from our equity offering, and our cash balance is expected to provide a runway into the first half of '27. That will enable us to execute on multiple data readouts, including oncology proof-of-concept results in 2024, KT-474 Phase 2 data expected in the first half of 2025, and several clinical inflection points for our STAT6 and TYK2 programs also in 2025.

第一季末我們的現金餘額為 7.45 億美元。一月份，正如我們所提到的，我們透過股票發行實現了約 3 億美元的淨收益，我們的現金餘額預計將為 27 年上半年提供一條通道。這將使我們能夠執行多個數據讀數，包括 2024 年的腫瘤學概念驗證結果、預計 2025 年上半年的 KT-474 2 期數據，以及 2025 年我們的 STAT6 和 TYK2 計畫的幾個臨床轉折點。

So this concludes our prepared remarks. We'd be happy to take your questions. Operator, if you can open the line for questions. Thank you.

我們準備好的演講到此結束。我們很樂意回答您的問題。接線員，您是否可以打開提問線路。謝謝。

(Operator Instructions) Brad Canino, Stifel.

（操作員說明）Brad Canino，Stifel。

Great. Thanks so much for the question. It looks like we're going to get two bites of the apple for MDM2 this year. And generally, I would assume that the completed 1A and the biomarker data later this year would be most material. So just to not overlook what's coming at ASCO, can I have you talk about the decision to present here? What should be the focus and how should investors view within the broader trial and strategy for the asset? Thank you.

偉大的。非常感謝您的提問。看來今年我們將在 MDM2 中獲得兩口蘋果。一般來說，我認為今年稍後完成的 1A 和生物標記數據將是最重要的。因此，為了不要忽視 ASCO 即將發生的事情，我可以請您談談在這裡演講的決定嗎？在更廣泛的資產試驗和策略中，重點應該是什麼？謝謝。

So thanks, Brad. So just taking a step back, this is a program that we started clinical development in the second half, roughly the middle of last year. And our first update would have been our quarterly call in November, if you recall, of last year. And we presented really limited data. As we since then recruited many more patients in the solid tumor and lymphoma arm as well as open the AML arm, we thought it would be important to connect with the medical community and obviously the investor community to give an update on the progress we've made in both arms of the trial that I believe will shine more light on the potential though MDM2 across the subset of patients and also create more enthusiasm, hope if we can, to continue to recruit the right type of patients to our study.

所以謝謝，布拉德。退一步來說，這是我們在下半年（大約去年年中）開始臨床開發的計畫。如果你還記得的話，我們的第一次更新是去年 11 月的季度電話會議。我們提供的數據非常有限。從那時起，我們在實體瘤和淋巴瘤部門招募了更多患者，並開放了 AML 部門，我們認為與醫學界以及投資者界建立聯繫以提供我們的最新進展非常重要我相信，這項試驗的兩個方面都取得了進展，這將更多地揭示MDM2 在患者亞組中的潛力，並創造更多的熱情，希望如果可以的話，繼續招募合適類型的患者參加我們的研究。

So obviously, when we share data, there are multiple audiences and the investor community being one of them. The goal is to complete, as we said in the press release, is this Phase 1 dose escalation study by the end of the year and then, yes, provide a full update as well as plans for further development later in the year. But given the substantial data of patients recruited between November and now, we thought this would be a good update to showcase the progress of the program.

顯然，當我們共享數據時，有多個受眾，投資者社群就是其中之一。正如我們在新聞稿中所說，我們的目標是在今年年底前完成第一階段劑量遞增研究，然後提供完整的更新以及今年稍後進一步開發的計劃。但考慮到 11 月至今招募的患者的大量數據，我們認為這將是展示該計劃進展的一個很好的更新。

Okay, thanks for that. And then Nello, I know you took part in Targeted Protein Degradation symposium at AACR. I'd just love to hear what your general insights were, thoughts were exiting that about the evolution of this therapeutic area. Thank you.

好的，謝謝。然後 Nello，我知道你參加了 AACR 的靶向蛋白質降解研討會。我很想聽聽您對這一治療領域的發展的整體見解和想法。謝謝。

Yeah, that's a great question, Brad. So firstly, it was a great meeting, I believe I told you that. It was very well attended, let's call it, symposium with many companies presenting. I actually hadn't been in the CPC focused symposium in probably too long. And so it was great to see a huge amount of interest from many stakeholders in this phase. I saw many physicians. I saw small and large companies. So I think the level of interest it is increasing with the data, especially clinical data that different companies are sharing.

是的，這是一個很好的問題，布拉德。首先，這是一次很棒的會議，我相信我已經告訴你了。參加人數非常多，我們可以稱之為研討會，許多公司都出席了會議。事實上，我可能已經太久沒有參加以中國共產黨為中心的研討會了。因此，很高興看到許多利害關係人在此階段表現出巨大的興趣。我看過很多醫生。我看到了大大小小的公司。因此，我認為人們對數據的興趣程度隨著數據的增加而增加，尤其是不同公司共享的臨床數據。

I also came home with the great feeling that companies like Kymera are really leading the field here in terms of capability, target selection, sophistication of approach. And so I think generally there is still a lot of work to do for the field, but I'm glad that we and others are leading and providing hopefully good examples for others to follow.

回到家時，我也有一種強烈的感覺，像 Kymera 這樣的公司在能力、目標選擇和方法的複雜性方面確實處於領先地位。因此，我認為總體上該領域還有很多工作要做，但我很高興我們和其他人正在發揮領導作用，並有望為其他人提供良好的榜樣。

Ellie Merle, UBS.

艾莉·梅爾，瑞銀。

Hey, it's Sam on for Ellie. I guess just in line with the previous question, from the MDM2 update at ASCO, can you provide any color on, I guess, like the extent of data that we could be expecting from this study? And I guess what kind of efficacy measures we should anticipate to look for? And what are you guys looking for from the data as you think about the development hence forward?

嘿，艾莉是山姆。我想與上一個問題一致，來自 ASCO 的 MDM2 更新，您能否提供任何顏色，我想，就像我們可以從這項研究中期待的數據範圍一樣？我想我們應該尋找什麼樣的功效衡量標準？當你們思考未來的發展時，你們想從數據中尋找什麼？

Hey, thanks for the question. I mean, this is really planned to be a clinical update for the Phase 1a dose escalation, so really to show the progress that we've made since last November. So the goal here is to share additional information on the types of patients who enrolled, both solid tumor patients as well as patients with hematologic malignancies to share the safety that we've been seeing as we've been dose escalating to share more data on the pharmacodynamic effect of the drug.

嘿，謝謝你的提問。我的意思是，這確實計劃成為 1a 期劑量遞增的臨床更新，因此實際上是為了展示我們自去年 11 月以來的進展。因此，這裡的目標是分享有關入組患者類型的更多信息，包括實體瘤患者和血液惡性腫瘤患者，以分享我們在劑量逐步增加時所看到的安全性，以分享更多的數據藥物的藥效學作用。

Recall that back in November, we did show an impact on GDF-15, which is this key biomarker just downstream of MDM2, so our aim is to show more data and that provides that sort of information on pharmacologic engagement, and of course, to provide whatever response data we have -- clinical response data we have for patients with solid tumors and patients with hematologic malignancies.

回想一下，早在11 月份，我們確實顯示了對GDF-15 的影響，GDF-15 是MDM2 下游的關鍵生物標誌物，因此我們的目標是顯示更多數據，並提供有關藥物參與的此類信息，當然，提供我們擁有的任何反應數據——實體瘤患者和血液惡性腫瘤患者的臨床反應數據。

Okay, great. Thank you so much. And I guess just a quick follow-up. Just any color on the updates for the biomarker patient selection strategy you guys are pursuing and how is the progress kind of going there?

好的，太好了。太感謝了。我想這只是一個快速的跟進。你們正在追求的生物標記患者選擇策略的更新有什麼顏色嗎？

Yeah, I think that's an important question. I think Nello mentioned that earlier, which has been an important part of the program for MDM2, in addition to being able to demonstrate that the therapeutic index with our degrader is superior to that seen with MDM2 inhibitors to be -- eventually to be able to evolve a patient selection strategy or biomarker strategy for selecting patients who we think would be most sensitive to this treatment.

是的，我認為這是一個重要的問題。我認為 Nello 早些時候提到過，這是 MDM2 計劃的重要組成部分，此外還能夠證明我們的降解劑的治療指數優於 MDM2 抑製劑的治療指數，最終能夠制定患者選擇策略或生物標誌物策略，以選擇我們認為對該治療最敏感的患者。

We don't plan on providing that particular update at ASCO. But our anticipation is that later in the year, preferably at a medical meeting, we'll provide more of those data showing our progress preclinically and even perhaps some of our clinical data that have been forming our ability to develop a patient selection biomarker strategy, focusing on those patients who we think and we'll be able to predict would be most sensitive to MDM2 degradation.

我們不打算在 ASCO 上提供該特定更新。但我們的預期是，在今年晚些時候，最好是在一次醫學會議上，我們將提供更多的數據來顯示我們的臨床前進展，甚至可能提供一些臨床數據，這些數據已經形成了我們開發患者選擇生物標記策略的能力，重點關注那些我們認為並且能夠預測對 MDM2 降解最敏感的患者。

Michael Schmidt, Guggenheim Securities.

邁克爾·施密特，古根漢證券公司。

Hey, good morning. This is [Gayle] for Michael. We want to get your thoughts on the recent Rinvoq data that showed superiority over Dupixent as you think about the opportunity for your IRAK4 and STAT degraders. Do the level of results shift the bar for an oral agent in AD and potential other indications? And as a related question, what's your strategy on future head-to-head studies against biologics for your overall portfolio? Thank you.

嗨，早安。這是麥可的[蓋爾]。當您考慮 IRAK4 和 STAT 降解劑的機會時，我們希望了解您對 Rinvoq 數據最近的看法，該數據顯示出優於 Dupixent 的優勢。結果等級是否會改變口服藥物治療 AD 和潛在其他適應症的標準？作為一個相關的問題，您未來針對整個投資組合的生物製劑進行頭對頭研究的策略是什麼？謝謝。

Yeah, it's a great question. So I don't think we've learning today that inhibiting JAK kinase is extremely powerful anti-inflammatory mechanism. In fact, I think if you look across several indications, not only in AD, you see JAK inhibitors being extremely, extremely active. So I don't believe we learn anything new. I think what we are proposing here at Kymera is to use protein degradation to go after targets that provide the best efficacy to safety profile.

是的，這是一個很好的問題。所以我認為我們今天還沒有了解到抑制 JAK 激酶是極其強大的抗發炎機制。事實上，我認為如果你看一下幾種適應症，不僅是在 AD 中，你會發現 JAK 抑制劑非常非常活躍。所以我不相信我們學到任何新東西。我認為我們在 Kymera 提出的建議是利用蛋白質降解來追求能夠提供最佳安全效果的目標。

So the opportunity here is to have an oral drug that is well-tolerated that does not require blood or monitor -- blood testing or monitoring of patients for severe cardiovascular events. So I don't think the bar has moved at all. I think we -- the field is still looking for oral agents that are active and have a very well-tolerated profile. And that's really what we're trying to do for both IRAK4 and STAT6 and TYK2 in different way. Obviously, we have discussed each program individually.

因此，這裡的機會是擁有一種耐受性良好的口服藥物，不需要血液或監測——血液檢測或監測患者的嚴重心血管事件。所以我認為酒吧根本沒有移動。我認為我們—該領域仍在尋找活性且具有良好耐受性的口服藥物。這正是我們正在嘗試以不同方式為 IRAK4、STAT6 和 TYK2 所做的事情。顯然，我們已經單獨討論了每個程序。

Eric Joseph, JPMorgan.

艾瑞克‧約瑟夫，摩根大通。

Hi, good morning. Just wanted to get a little bit of a better sense of what your internal bar is for moving 253 and forecast later-stage development? I wonder whether opportunities in heme malignancies will be strategically attractive enough or do you want to think broader and encompasses solid tumors as well? And additionally, is the focus more on moving forward with a monotherapy strategy or would you be amenable to combination approaches? Thanks.

早安.只是想更了解行動 253 的內部標準並預測後期開發？我想知道血紅素惡性腫瘤的機會在策略上是否具有足夠的吸引力，或者您是否想考慮更廣泛的領域並涵蓋實體腫瘤？此外，重點是更注重推進單一療法策略還是您願意採用組合療法？謝謝。

Yeah, thanks, Eirc. Maybe I'll start and then pass it to Jared. So first, I would say the reason why we got involved with MDM2, which, as we all know, is a target that is being pursued by the whole industry in the past 15 years or so. So the reason for us to do so is really [marquee]. It was their idea of tumor types that we have seen are extremely sensitive to removal of MDM2, which is quite different in our view, from inhibition of MDM2, [PT/CT] interaction that small molecule inhibitors so. So as Jared was saying, we have developed a same steep demand, let's say, across tumor types that point to the subset of tumors in which we've seen preclinically -- and we'll start sharing some clinical data, but we've seen preclinically second stage so far to be extremely sensitive to these mechanisms when those go across protein as well as solid tumors.

是的，謝謝，Eirc。也許我會開始然後將其傳遞給賈里德。首先，我想說我們為什麼要參與MDM2，眾所周知，這是過去15年左右整個產業都在追求的目標。所以我們這樣做的原因確實是[選框]。我們看到的是他們對腫瘤類型的想法對MDM2的去除極為敏感，這與我們認為小分子抑制劑對MDM2、[PT/CT]相互作用的抑制有很大不同。因此，正如賈里德所說，我們已經對各種腫瘤類型產生了同樣強烈的需求，這些需求指向我們在臨床前看到的腫瘤子集——我們將開始分享一些臨床數據，但我們已經迄今為止，在臨床前第二階段，當這些機制跨越蛋白質和實體腫瘤時，它們對這些機制極為敏感。

I think we've shown already preclinically that AML, especially both the single agent as well as combo, and we've seen some really, really, almost best-in-class activity. And this is an area that we would pursue independently of the opportunity in solid tumors, given the high unmet need still be relevant commercial opportunity for both first line but also for refractory AML. So I think I would say that the AML opportunity is in a way independent from solid tumor. But I also would want to say that the impetus to work on MDM2 was to go also beyond heme oncology. So we have, hopefully, exciting plan that we can share with you based on a biomarker strategy this year expanding in solid as well.

我認為我們已經在臨床前展示了 AML，尤其是單藥和組合藥物，並且我們已經看到了一些非常非常幾乎一流的活性。鑑於未滿足的高度需求仍然是一線藥物和難治性 AML 的相關商業機會，因此我們將獨立於實體瘤領域尋求這一領域。所以我想我會說 AML 機會在某種程度上獨立於實體腫瘤。但我還想說，MDM2 工作的動力不僅限於血紅素腫瘤學。因此，我們希望有一個令人興奮的計劃，我們可以根據今年的生物標記策略與您分享，該策略也將得到紮實擴展。

Kalpit Patel, B. Riley.

卡爾皮特·帕特爾，B.萊利。

Hi, this is Jeff for Kalpit. Thanks for taking my question. Just one on the STAT6 program. The question is if you have the opportunity to discuss a divestment on your STAT6 with Sanofi? If so, could you share any insights into why perhaps Sanofi opted to collaborate with another STAT6 degrader company instead? Thank you.

大家好，我是卡爾皮特的傑夫。感謝您提出我的問題。 STAT6 程式中只有一個。問題是您是否有機會與賽諾菲討論 STAT6 的撤資？如果是這樣，您能否分享一下賽諾菲為何選擇與另一家 STAT6 降解劑公司合作的見解？謝謝。

Yeah. So as we've said repeatedly in the past, I say it again today, we started this program a few years ago. We have built a conviction around our ability to use oral degraders in immunology, starting from the early days in IRAK4. And we have decided that we have no interest in partnering our immunology pipeline in order to think -- at least in the foreseeable future in order to fulfill our vision to building a global integrated company.

是的。正如我們過去反​​覆說過的那樣，我今天再說一遍，我們幾年前就開始了這個計劃。從 IRAK4 的早期開始，我們就堅信我們有能力在免疫學中使用口服降解劑。我們已經決定，我們沒有興趣透過合作我們的免疫學管道來思考——至少在可預見的未來，以實現我們建立全球綜合公司的願景。

I'm not going to publish the share discussions that we've had with Sanofi. But I would say generally, this is a program that has been pursued from other parties quite heavily in terms of potential partnership. But our communication has been very clear that we believe this is a program that we want to develop as a stand-alone independent company for the foreseeable future.

我不會公佈我們與賽諾菲的股票討論。但我想說的是，總的來說，這是一個其他各方在潛在合作夥伴關係方面大力推行的計劃。但我們的溝通非常明確，我們相信這是一個我們希望在可預見的未來作為獨立公司開發的專案。

I will also remind everybody that we are the first company to take a STAT6 degrader. Actually, I would say STAT6 agent overall in the clinic, we're the first company to demonstrate the preclinical activity of such an agent. And you know, everybody else is obviously years behind us.

我還要提醒大家，我們是第一家採用 STAT6 降解劑的公司。實際上，我想說的是臨床上的 STAT6 藥物，我們是第一家展示此類藥物臨床前活性的公司。你知道，其他人顯然都落後我們很多年。

Andy Chen, Wolfe Research.

安迪陳，沃爾夫研究中心。

Hi, good morning. Thank you for taking our question. Two related questions also on STAT6. Just curious if you can talk about tissue distribution. And so I see deep degradation in the skin in non-human primates. I'm just curious how well this tissue distribution translates to humans.

早安.感謝您提出我們的問題。 STAT6 上還有兩個相關問題。只是好奇你是否可以談論組織分佈。所以我看到非人靈長類動物的皮膚深度退化。我只是好奇這種組織分佈在人類身上的表現如何。

I'm curious if you can cite several precedents where this nonhuman primary distribution is highly correlated to humans. And also in the first half of '25, are we going to gain any insight on this exact topic? What kind of metrics will we have when determining whether STAT6 is indeed acting on the skin in humans? Thank you.

我很好奇您是否可以引用幾個先例，其中這種非人類主要分佈與人類高度相關。同樣在 25 年上半年，我們是否會對這個確切的主題有任何見解？當確定 STAT6 是否確實作用於人類皮膚時，我們會有什麼樣的指標？謝謝。

No, it's a great question. So first, for people that have followed us over the past few years know that we don't discuss preclinical data of PK and distribution besides the degradation that we show in our presentations. And that's only because we believe those are highly confidential and important data that we want to keep for ourselves at this point. But I will say that if you look at the data we presented, we've shown that KT-621 degrade STAT6 equally effectively in several tissues in skin, in lung, in blood, and I believe in spleen too. I'm not sure we've shown that or not.

不，這是一個很好的問題。首先，過去幾年關注我們的人都知道，除了我們在演示中展示的降解之外，我們不會討論 PK 和分佈的臨床前數據。這只是因為我們相信這些是高度機密且重要的數據，我們目前希望為自己保留。但我要說的是，如果你看一下我們提供的數據，我們發現 KT-621 在皮膚、肺、血液中的多個組織中同樣有效地降解 STAT6，我相信在脾臟中也是如此。我不確定我們是否已經證明了這一點。

But we've shown that our distribution of the drug allows for, I would say, generally equivalent degradation across all Th2 relevant tissues. And so we -- our expectation is to see in the clinic the same level of response. And we've seen good translation of preclinical into clinical in terms of distribution across different species. I would say that, yes, in the first half of '25, our goal is to share a Phase 1 data as it's been publicly disclosed, and the Phase 1 data will involve both blood and skin biomarkers.

但我想說，我們已經證明，我們的藥物分佈可以在所有 Th2 相關組織中實現大致相同的降解。因此，我們的期望是在診所中看到相同程度的反應。我們已經看到從不同物種的分佈來看，臨床前到臨床的良好轉化。我想說的是，是的，在 25 年上半年，我們的目標是共享已公開披露的第一階段數據，第一階段數據將涉及血液和皮膚生物標記。

Derek Archila, Wells Fargo.

德里克·阿奇拉，富國銀行。

Hey, guys, good morning. This is Eva on for Derek. Thanks for taking our question. So quick one from us kind of like following up on the last question. On the STAT6 Phase 1 study, will you be including a cohort of patients to achieve this proof-of-concept kind of like you did with like 474? Or will this only be including like healthy volunteers? Thanks.

嘿，夥計們，早安。這是伊娃為德里克代言。感謝您提出我們的問題。我們很快就回答了最後一個問題。在 STAT6 1 期研究中，您是否會納入一組患者來實現這種概念驗證，就像您對 474 所做的那樣？或者這只會包括健康的志工？謝謝。

Well, at this point, I think all we said today was that the initial evaluation been healthy volunteers. We'll share more at a later date.

好吧，在這一點上，我想我們今天所說的只是最初的評估是健康的志工。我們稍後會分享更多內容。

Divya Rao, TD Cowen & Company.

Divya Rao，TD Cowen & Company。

Hi, guys. This is Divya on for Marc. Thanks for taking our question. Can I go to earlier question? What is the scope of kind of the disclosure that we should get from KT-333 at EHA? And then as a follow-up, I guess, what do you need to see in this Phase 1 trial, which I guess you're planning on completing at the end of the year and liquid tumors to continuing development in both liquid and solid tumors?

嗨，大家好。這是 Divya 替 Marc 發言。感謝您提出我們的問題。我可以轉到之前的問題嗎？我們應該從 EHA 的 KT-333 獲得的揭露類型範圍是什麼？然後，作為後續行動，我想，在這個一期試驗中您需要看到什麼，我想您計劃在今年年底完成該試驗，液體腫瘤將繼續在液體和實體瘤中發展？

I'll take the second. I'll let Jared answer the first part of your question. So the second part was around what so we need to see. As I said in the past also, our power for continuing investment is having meaningful opportunity with a clear path to a sizable patient population with big clinical and commercial impact. And so obviously, the more obvious answer to your question is solid tumor opportunities would be able to make a much easier case for further investment.

我就拿第二個。我會讓賈里德回答你問題的第一部分。所以第二部分是圍繞著我們需要看到的內容。正如我過去所說，我們持續投資的力量是擁有有意義的機會，為大量患者群體提供明確的途徑，並產生巨大的臨床和商業影響。顯然，你的問題更明顯的答案是實體瘤機會將能夠為進一步投資提供更容易的理由。

As I have said in the past, we don't expect to see single agent activity in solid tumor as we haven't seen pre-clinically, but we're evaluating the biomarker, the tumor biomarker effect to then tie with preclinical data that we've already demonstrated in this potential solid tumor combo opportunities. So that is one.

正如我過去所說，我們預計不會在實體瘤中看到單一藥物的活性，因為我們在臨床前沒有看到過，但我們正在評估生物標記、腫瘤生物標記的效果，然後與臨床前數據聯繫起來我們已經展示了這種潛在的實體瘤組合機會。這就是其中之一。

And then obviously having strong antitumor activity as a single agent in liquid tumor is important for two reasons. One, because there are potential liquid tumor opportunities that are sizable enough to be interesting, but also to confirm that the drug is active and it's worthwhile further investment in expanding the opportunity.

顯然，作為單一藥物在液體腫瘤中具有強大的抗腫瘤活性很重要，原因有二。第一，因為存在潛在的液體腫瘤機會，其規模足夠大，足以引起人們的興趣，而且還可以確認該藥物是活躍的，並且值得進一步投資來擴大機會。

Jared, you want to comment a bit on the expectations for EHA.

Jared，您想談談對 EHA 的期望。

Sure. Recall that at ASH this past December, we presented data on 29 patients that we had enrolled so far and we show very encouraging safety data, which was allowing us to continue to dose escalate. We showed very strong pharmacodynamic data, including strong statutory knockdown in blood and tumor as well as strong immunomodulatory effects in blood and tumor, such as that interferon gamma response that was predictive of potential combination with anti-PD-1.

當然。回想一下，去年 12 月的 ASH 上，我們展示了迄今為止已入組的 29 名患者的數據，我們展示了非常令人鼓舞的安全數據，這使我們能夠繼續增加劑量。我們展示了非常強大的藥效學數據，包括血液和腫瘤中強大的法定敲除作用以及血液和腫瘤中強大的免疫調節作用，例如乾擾素γ反應可預測與抗PD-1的潛在組合。

And we also showed these promising clinical responses in CTCL as well as in Hodgkin's lymphoma. So the aim for the EHA presentation is really to build on that as we continue to dose escalate to provide further data around safety, as we've been dose escalating, to provide additional pharmacologic data on target knockdown and immunomodulation in blood and whatever we may have in tumor and to provide additional clinical response data.

我們也在 CTCL 以及霍奇金淋巴瘤中展示了這些有希望的臨床反應。因此，EHA 演示的目的實際上是在此基礎上，隨著我們繼續劑量遞增，以提供有關安全性的進一步數據，因為我們一直在劑量遞增，以提供有關血液中目標敲低和免疫調節以及我們可能提供的任何資訊的額外藥理學數據並提供額外的臨床反應數據。

Again, as you said that this is meant to be a clinical update. And then the plan will be then later in the year of what we anticipate completing dose escalation to provide final data set at a medical meeting later in 2024.

再次，正如您所說，這意味著臨床更新。然後該計劃將在我們預計完成劑量升級的那年晚些時候進行，以便在 2024 年稍後的醫學會議上提供最終數據集。

Thomas Smith, Leerink Partners.

托馬斯史密斯，Leerink 合夥人。

Good morning, this is Natin line for Thomas Smith. Thanks for taking the question. We have two, both in I&I. The first one is like what's the gating factor to initiate a Phase 1 trial for KT-621? And what data can we expect from the readout you spent first half '25? So we have hard time indications for the subsequent development in I&I indication.

早安，這是托馬斯史密斯的 Natin 線路。感謝您提出問題。我們有兩個，都在 I&I 中。第一個問題是啟動 KT-621 第一階段試驗的限制因素是什麼？從 25 年上半年的讀數中我們可以期待什麼數據？因此，對於I&I指示的後續發展，我們有困難的指示。

Okay, great. So as we said on the call today and in the press release, so we're in IND-enabling studies and we're going to leave it at that. We don't usually provide a specific update on where exactly we are on the process. So obviously, completed that phase, filing an IND, and initiating Phase 1 is what's between us and that.

好的，太好了。正如我們在今天的電話會議和新聞稿中所說，我們正在進行 IND 支持的研究，我們將就此結束。我們通常不會提供有關流程具體進展的具體更新資訊。顯然，完成該階段、提交 IND 並啟動第一階段是我們之間的任務。

In terms of indication prioritization for STAT6, I think the only thing I would say is, as we've said in the past, also, we are focused on getting this drug to as many patients as possible, starting with, large indications where we've seen injectables can really, really have low penetration for many, many reasons. So I would say we're prioritizing the larger indications. But that doesn't mean we will not pursue others. I think that will happen. But just in a probably different stage, phase, and manner.

就 STAT6 的適應症優先順序而言，我認為我唯一要說的是，正如我們過去所說，我們也致力於將這種藥物提供給盡可能多的患者，從我們的大適應症開始我們已經看到注射劑的滲透率確實非常低，原因有很多很多。所以我想說我們會優先考慮更大的適應症。但這並不代表我們不會追求別人。我認為這將會發生。但可能只是在不同的階段、階段和方式。

Got it. And for the IRAK4 program with data expected in first half as well of next year, Sanofi will make the decision of going forward or not. But you also have an opt-in decision. Like how are you approaching the opt-in? And what do you need to see to make a decision?

知道了。對於IRAK4項目，預計上半年和明年都會有數據，賽諾菲將做出是否繼續的決定。但您也有選擇加入的決定。例如您如何選擇加入？您需要看到什麼才能做出決定？

Yeah, so after Phase 2, before Phase 3. So Phase 3 needs to be in the planning stage when we will have the opportunity to decide to opt-in or not. And the decision will be based on obvious reasons, the excitement we have around the opportunity with the drug, the investment that we have across the pipeline, the cash needs that will be needed across the investments across our pipeline.

是的，所以在第二階段之後，第三階段之前。該決定將基於顯而易見的原因，我們對藥物機會的興奮，我們在整個管道上的投資，以及我們整個管道上的投資所需的現金需求。

I would say, maybe bit naively, the base case is if the drug is active as we expected it will be, it will be value accretive for us to obtain. And so it would be probably an easy decision to make. But as you know, it's hard to make decisions in a vacuum. So one word there. We will make the decisions based on all the other parameters I mentioned.

我想說，也許有點天真，基本情況是，如果該藥物如我們預期的那樣具有活性，那麼我們獲得的價值將會增加。因此，這可能是個很容易做出的決定。但如您所知，很難在真空中做出決定。所以有一句話。我們將根據我提到的所有其他參數做出決定。

Vikram Purohit, Morgan Stanley.

維克拉姆‧普羅希特，摩根士丹利。

Hi, good morning. Thanks for taking our questions. So we also had a couple of questions on 474. Apologies if you mentioned this in your prior Q&A; we missed it. But we were just curious on how you and Sanofi are currently thinking about indication expansion 474 beyond HS and AD and when some of those decisions could be made and how you're thinking about them for the time being ahead of you just in 80 datasets coming in the first half of next year?

早安.感謝您回答我們的問題。所以我們也有幾個關於 474 的問題。我們錯過了。但我們只是好奇您和賽諾菲目前如何考慮 HS 和 AD 之外的適應症擴展 474 以及何時可以做出其中一些決定，以及您目前在 80 個即將到來的數據集中如何考慮它們明年上半年？

And then secondly, on a more logistical point, should we hold the expectation that the HS and AD data sets would come together? Or is that not necessarily the case? And if you have any visibility at this point, which venues or which forms might be appropriate to showcase those data sets? That would be helpful color to get from your perspective. Thanks.

其次，從更邏輯的角度來看，我們是否應該期望 HS 和 AD 資料集會合併在一起？或者說情況不一定如此？如果您現在有任何了解，哪些場所或哪些形式可能適合展示這些資料集？從你的角度來看，這將是有幫助的顏色。謝謝。

Hi, Vikram. You got three questions in. Well done. So I start with the last one. It's hard for us to know, actually both the timing and where. As the program timelines have been presented in clinicaltrials.gov or disclosures from both Sanofi and us, we're seeing that both studies should be able to read out in the first half of '25. I still feel we're too early to know whether they'll be disclosed together or separately until -- give us more time. I think when we're closer, we might be able to answer that question.

嗨，維克拉姆。你提出了三個問題。所以我從最後一個開始。我們很難知道具體時間和地點。由於該計劃時間表已在 ClinicalTrials.gov 中公佈或賽諾菲和我們雙方均已披露，因此我們看到這兩項研究應該能夠在 25 年上半年公佈。我仍然覺得我們還為時過早，無法確定它們是否會一起披露或單獨披露，直到給我們更多時間。我想當我們更接近時，我們也許能夠回答這個問題。

In terms of the indication expansion, as I said, in the past, we've -- Sanofi and Kymera have worked diligently on evaluating many other opportunities. Many of these are obvious other indications that these biology has been validated or known to be relevant. I think there is sensitivity about disclosing what they are just because I think the team right now is focused on executing on these studies. I believe Sanofi will be the one maybe disclosing other indications first, and then we'll be happy to provide more color.

在適應症擴展方面，正如我所說，過去，我們——賽諾菲和 Kymera 一直在努力評估許多其他機會。其中許多是明顯的其他跡象，表明這些生物學已被驗證或已知是相關的。我認為披露它們是什麼是很敏感的，因為我認為團隊現在專注於執行這些研究。我相信賽諾菲可能會首先披露其他適應症，然後我們將很樂意提供更多顏色。

In terms of timing, again, I can't speak for them. But let's say for now, we're focused on executing on these studies. And I believe this is a personal opinion as we get through some of these inflection points, we'll be able to share more.

再說一遍，就時間安排而言，我無法代表他們說話。但目前來說，我們的重點是執行這些研究。我相信這是個人觀點，當我們度過其中一些轉折點時，我們將能夠分享更多。

Geoff Meacham, Bank of America.

傑夫‧米查姆，美國銀行。

Hey, thank you. So I guess I have a quick question on given capital constraints, do you think that there's a scenario where you guys might partner out some of your oncology assets? Like what factors would you take into consideration when evaluating the potential for a partnership?

嘿，謝謝你。因此，我想我對給定的資本限制有一個簡單的問題，您認為您是否可能會合作出售一些腫瘤學資產？例如在評估合作潛力時您會考慮哪些因素？

Yeah. So thanks for the question. So generally, as we've said, we believe partnering is an option to continue to grow the company and needs to serve the purpose. Rarely, not always, but rarely I would say that financial drives partnerships, but it has to be really -- financials only raises. There will have to be a win-win opportunity. I think partnering in oncology is something that we know we've discussed in the past. It might be something that we'd be open to do for some of our oncology programs.

是的。謝謝你的提問。因此，總的來說，正如我們所說，我們相信合作是公司持續發展的一種選擇，並且需要服務於這一目標。很少，並非總是，但我很少會說財務推動了合作夥伴關係，但它必須是真的——財務只會籌集資金。一定會有雙贏的機會。我認為我們過去已經討論過在腫瘤學方面的合作。我們可能願意為我們的一些腫瘤學專案做一些事情。

I just can't speak to specifics, given that we're still in the midst of generating important data that will, first of all, tell us the level of commitment that Kymera on its own wants to invest in the program. I think after that, we'll be able to have a clear view of what's the best path for value creation for our oncology pipeline.

我只是無法透露具體細節，因為我們仍在產生重要數據，這些數據首先會告訴我們 Kymera 本身希望投資該專案的承諾程度。我認為在那之後，我們將能夠清楚地了解腫瘤學管道創造價值的最佳途徑是什麼。

As always, partnership is a tool that any company should use to think about long-term value creation as we can't reinvent wheel in every single program.

一如既往，合作關係是任何公司都應該用來思考長期價值創造的工具，因為我們無法在每個專案中重新發明輪子。

Okay. Great. And then what are your key priorities for this year?

好的。偉大的。那麼今年您的主要優先事項是什麼？

Say that again.

再說一次。

Yeah, business development.

是的，業務發展。

Yeah. I mean, I have I think I've answered the question already.

是的。我的意思是，我想我已經回答了這個問題。

Kelly Shi, Jefferies.

施凱莉，傑弗里斯。

Thank you for taking my questions. I also have a question IRAK4 (inaudible) we see the clinical development is expanding in this space and the oral agents like JAK inhibitor and BTK inhibitor, [especially interesting efficacy signal curious], how should I look for degrader repositioned to other oral therapeutic candidates? What would be the differentiated clinical features to be anticipated based on targeting strategy and also the anomaly of degrader design?

感謝您回答我的問題。我還有一個問題IRAK4（聽不清楚），我們看到這個領域的臨床開發正在擴大，JAK 抑制劑和BTK 抑制劑等口服藥物，[特別有趣的功效訊號好奇]，我應該如何尋找重新定位到其他口服治療候選藥物的降解劑？根據標靶策略以及降解劑設計的異常情況，預計會有哪些差異化的臨床特徵？

So it was a bit -- the sound was not great, but maybe if I understood correctly, you were talking about how the IRAK4 compare to like other small molecule at JAK or BTK inhibitors in immunology. Jared, you want to take some of that?

所以這有點——聲音不太好，但也許如果我理解正確的話，你正在談論 IRAK4 與免疫學中 JAK 或 BTK 抑製劑的其他小分子的比較。賈里德，你想拿一些嗎？

Yeah, I mean, I think certainly the differentiation is there potentially both for efficacy based on the mechanism as well as on safety. We know that 474, IRAK4 degrader because it's impacting and the IL-1 receptor pathway as well as the toll-like receptor pathway, has the ability to impact multiple different pro-inflammatory cytokine essentially with a single compound, whereas many other agents in the I&I space, targeted agents in particular, have a more restricted effect on all of these pro-inflammatory cytokine.

是的，我的意思是，我認為基於機制和安全性的功效肯定存在潛在的差異。我們知道 474，IRAK4 降解劑，因為它影響 IL-1 受體途徑以及 Toll 樣受體途徑，具有基本上用單一化合物影響多種不同促炎細胞因子的能力，而許多其他藥物在I&I 空間，特別是標靶藥物，對所有這些促發炎細胞因子的影響更為有限。

And so to have a broader effect, multiple different cytokine, we think, can give us broader development opportunities within autoimmune and other inflammatory diseases. I think that is one important differentiating factor. I think safety factors, I think, which also know can't be overlooked, we presented before or summarized before the fact that there are adult human IRAK4 genetic knockouts who in adults, we do not have any phenotype or any susceptibility to infections.

因此，我們認為，為了產生更廣泛的作用，多種不同的細胞激素可以為我們在自體免疫和其他發炎性疾病領域提供更廣泛的發展機會。我認為這是一個重要的差異化因素。我認為安全因素，我認為，這也知道不能被忽視，我們之前提出或總結過這樣一個事實，即有成年人人類IRAK4基因敲除，在成年人中，我們沒有任何表型或對感染的任何易感性。

And so I think being able to potentially maximize knock down the IRAK4 chronically and to essentially optimize efficacy without compromising safety, I think, is a real essential game changer in differentiating factor from other drugs like JAK inhibitors, for example. The JAK inhibitors do have broad anti-inflammatory effect but they have significant safety liability in terms of risk of infection, risk of cytopenias, risk of malignancies. That is not something that has been seen in either human IRAK4 knockout individuals are even in preclinical studies.

因此，我認為能夠最大限度地長期抑制 IRAK4 並在不影響安全性的情況下從本質上優化療效，是區分與其他藥物（例如 JAK 抑製劑）的真正重要的遊戲規則改變者。 JAK抑制劑確實具有廣泛的抗發炎作用，但它們在感染風險、血球減少風險、惡性腫瘤風險方面具有顯著的安全責任。即使在臨床前研究中，這在任何人類 IRAK4 敲除個體中都沒有見過。

And so I think this ability to potentially really strongly degrade and knockdown IRAK4 chronically to maximize efficacy while not having any safety issues could really allow this drug to be broadly developed across multiple different indications, also not just in moderate to severe patients but also in milder patients.

因此，我認為這種長期潛在地強烈降解和敲低IRAK4 以最大限度地提高療效而不存在任何安全問題的能力確實可以讓該藥物在多種不同的適應症中廣泛開發，不僅適用於中度至重度患者，也適用於輕度患者患者。

I mean, I think this really provides an optionality that really can't be seen or challenged by other modalities. And so we think that this is what are the real value propositions of 474, both the differentiation on potentially efficacy standpoint as well as on the safety standpoint.

我的意思是，我認為這確實提供了一種其他方式無法看到或挑戰的選擇性。因此，我們認為這就是 474 的真正價值主張，無論是在潛在功效角度還是在安全角度上的差異化。

Jeff Jones, Oppenheimer.

傑夫瓊斯，奧本海默。

Good morning, guys. And thanks for taking the question. Just two quick ones from us.

早上好傢伙。感謝您提出問題。我們只有兩個快的。

There's some evidence of improved efficacy and targeting IL-7A and F versus just IL-17A [albini] versus secukinumab, and could you comment on whether targeting IRAK4 would be expected to impact the pathway for both forms? Just a technical question. And then on the financial side, how should we be thinking about the Sanofi collaboration revenues going forward versus milestone payments? Thanks.

有一些證據表明，與僅使用IL-17A [albini] 和蘇金單抗相比，靶向IL-7A 和F 的療效有所改善，您能否評論一下靶向IRAK4 是否會影響這兩種形式的途徑？只是一個技術問題。然後在財務方面，我們應該如何考慮賽諾菲未來的合作收入與里程碑付款？謝謝。

Jared will take the first and then --

賈里德會拿下第一，然後——

Yeah, the question around the activity of IL-17A/F targeting versus A especially in diseases like HS where there may be an advantage. I think more broadly speaking, further, I think, speaks to the advantage of having a broader anti-inflammatory effect versus a more restricted one. I mean, here it's still restricted to IL-17, but being able to hit the AF isoform rather than just A is already showing you that as you broaden out the impact, you potentially can increase efficacy.

是的，關於 IL-17A/F 靶向活性與 A 相比的問題，尤其是在 HS 等疾病中可能具有優勢。我認為更廣泛地說，我認為這進一步說明了具有更廣泛的抗發炎作用相對於更有限的抗發炎作用的優勢。我的意思是，這裡它仍然僅限於 IL-17，但能夠攻擊 AF 同工型而不僅僅是 A 已經向您表明，當您擴大影響範圍時，您可能會提高功效。

Now even though IRAK4 does specifically target the IL-17 pathway. We know that by impacting the IL-1 family cytokine and pathways as well as the toll-like receptor pathway, we do impact IL-17 production. And while we haven't looked specifically at A versus F isoform, we would assume that in fact, it's probably broad across multiple different IL-17 isoforms.

現在，儘管 IRAK4 確實專門針對 IL-17 途徑。我們知道，透過影響 IL-1 家族細胞激素和路徑以及 Toll 樣受體通路，我們確實會影響 IL-17 的產生。雖然我們沒有具體研究 A 與 F 同工型，但我們假設事實上，它可能廣泛存在於多種不同的 IL-17 同工型中。

So I think, coming back to the point I was making earlier, which is that having a drug that have a broader anti-inflammatory effect within these autoimmune diseases that have very clear trophic inflammation that includes both HS and AD and many others is an advantage. And since the 17A/F versus A is just another way to sort of highlight the advantage of going broader and having more efficacy versus being more restricted and narrow.

所以我認為，回到我之前提出的觀點，即擁有一種在這些自體免疫疾病中具有更廣泛抗炎作用的藥物是一個優勢，這些自體免疫疾病具有非常明顯的營養性炎症，包括HS和AD 等許多其他疾病。因為 17A/F 與 A 只是強調更廣泛和更有效相對於更受限制和更狹窄的優勢的另一種方式。

And Jeff, just to answer your question on revenues, while we don't obviously guide to collaboration revenues, you can see in our balance sheet, the deferred revenue number. It's just over $46 million. That's that amount of revenue we expect to recognize over the near term as we fulfill our performance obligation. The inclusion, though, of additional milestones, there's no additional milestones are included in that number. So anything that is achieved with respect to future milestones, those would be largely recognized at that point in time. So that's what I can tell you on that.

傑夫，只是為了回答你關於收入的問題，雖然我們沒有明顯指導合作收入，但你可以在我們的資產負債表中看到遞延收入數字。剛剛超過 4600 萬美元。這是我們在履行履約義務時預計在短期內確認的收入金額。儘管包含了其他里程碑，但該數字中並未包含其他里程碑。因此，任何與未來里程碑相關的成就，都會在那時得到很大程度上的認可。這就是我可以告訴你的。

Great. Appreciate it, guys. Thank you.

偉大的。非常感謝，夥計們。謝謝。

Thank you. This concludes our question-and-answer session. I would like to turn the conference back over to Justine Koenigsberg for closing remarks.

謝謝。我們的問答環節到此結束。我想將會議轉回賈斯汀·柯尼斯堡 (Justine Koenigsberg) 致閉幕詞。

Thank you. We'd like to thank everyone for joining us this morning and look forward to keeping you updated on our progress. Later this month, we'll be participating at the BofA Conference and hope to see many of you there. In the meantime, please don't hesitate to reach out if there are additional questions following today's call. Thank you. That concludes today's call.

謝謝。我們要感謝大家今天早上加入我們，並期待向您通報我們的最新進展。本月晚些時候，我們將參加美國銀行會議，希望在那裡見到你們。同時，如果在今天的電話會議後還有其他問題，請隨時與我們聯繫。謝謝。今天的電話會議到此結束。

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

謝謝。會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。