Kymera Therapeutics, Inc. (KYMR) 2026 Q1 法說會逐字稿

Good day, everyone. My name is Stefan, and I'll be your conference operator today. At this time, I'd like to welcome you to the Kymera Therapeutics first-quarter 2026 results Call. (Operator Instructions)

各位好。我的名字是Stefan，今天將擔任本次電話會議的會議操作員。此刻，我謹代表主辦方歡迎各位參加Kymera Therapeutics 2026年第一季業績電話會議。（操作員指示）

At this time, I'd like to turn the call over to Justine Koenigsberg, Vice President of Investor Relations.

此刻，我想將電話會議交給投資人關係副總裁Justine Koenigsberg。

Good morning, and welcome to Kymera Therapeutics quarterly update conference call.

各位早安，歡迎參加Kymera Therapeutics季度更新電話會議。

Joining me today are Nello Mainolfi, our Founder, President and Chief Executive Officer; Jared Gollob, our Chief Medical Officer; and Bruce Jacobs, our Chief Financial Officer. Following our prepared remarks, we will open the call for questions from our covering analysts. (Operator Instructions)

今天與我一同出席的有：我們的創辦人、總裁兼執行長Nello Mainolfi；首席醫療長Jared Gollob；以及首席財務長Bruce Jacobs。在我們完成事先準備的發言後，將開放由追蹤我們的分析師提問。（操作員指示）

But before we begin, I would like to remind you that today's discussion will include forward-looking statements subject to risks and uncertainties described in our most recent Form 10-Q filed with the SEC. Please note, any forward-looking statements speak only as of today's date, and we undertake no obligation to update them.

不過在開始之前，我想提醒各位，今天的討論將包含前瞻性陳述，並受我們最近向美國證券交易委員會（SEC）提交之Form 10-Q中所述風險與不確定性影響。請注意，任何前瞻性陳述僅截至今日有效，我們不承擔更新之義務。

With that, I will now turn the call over to Nello.

接下來，我將把電話會議交給Nello。

Thanks, Justine, and thanks, everyone, for joining us this morning. Next week marks the 10-year anniversary of Kymera's founding, and it represents more than just a milestone. We have stepped into a new chapter where we believe the strong foundation we've built over the past decades positions us to deliver transformative medicines for patients around the world. In the past 10 years, we've built unique capabilities, including our hit finding approach to identify ligands to historically undrugged proteins, building on that, creating new rules on how we identify dry-like highly specific and potent degraders, importantly, key insights to deliver high fidelity of clinical translation and finally, creative early clinical studies to derisk clinical development -- late clinical development. We have continued to refine our target selection strategies such as we believe we've built one of the most compelling oral small molecule pipeline in the industry.

謝謝你，Justine，也謝謝各位今天早上加入我們。下週是Kymera成立10週年，這不僅僅是一個里程碑。我們已邁入新篇章；我們相信，過去數十年所建立的堅實基礎，使我們具備為全球患者帶來變革性藥物的條件。在過去10年裡，我們建立了獨特能力，包括：我們的hit finding方法，用以辨識可結合於歷來難以成藥蛋白的配體；在此基礎上，建立新的規則，說明我們如何辨識具藥物樣（drug-like）、高度特異且高效的降解劑；更重要的是，取得關鍵洞見以實現高保真度的臨床轉譯；最後，透過具創意的早期臨床研究來降低臨床開發（以及後期臨床開發）的風險。我們也持續精進標的選擇策略，因此我們相信已打造出業界最具吸引力的口服小分子產品線之一。

As we look to the next decades, our guiding principles remain unchanged. We'll continue to focus on both signs, demonstrate early proof-of-concept to support our investments and build medicines that we believe can change the standard of care for many diseases. And we'll obviously be looking to make the final step becoming a fully integrated global commercial company that delivers groundbreaking medicines for patients around the world. And it's these principles that have shaped our innovative and increasingly differentiated pipeline. We're laser-focused on our wholly-owned programs such as KT-621, KT-579, where we're applying targeted protein degradation to well-validated disease-relevant pathways in immunology.

展望未來數十年，我們的指導原則不變。我們將持續聚焦於兩個面向：展示早期概念驗證（proof-of-concept）以支持投資決策，以及打造我們相信能改變多種疾病照護標準的藥物。同時，我們也將朝向最後一步邁進，成為一家完整整合、具全球商業化能力的公司，為全球患者提供突破性藥物。正是這些原則塑造了我們創新且日益差異化的產品線。我們高度聚焦於自有（wholly-owned）專案，例如KT-621、KT-579，將標靶蛋白降解應用於免疫學中已充分驗證、與疾病高度相關的路徑。

At the same time, we're extending our reach through partnership like our work with Gilead advancing KT-200, our first molecular glue program and Sanofi with IRAK4. What ties it all together is our commitment to pursuing high-value disease-driving targets with precision and to do it repeatedly across different therapeutic areas. The sharp focus and the consistency of results we've delivered is what gives us confidence not just in individual programs, but in our ability to broaden and expand our pipeline. We've done a lot of groundwork over the past few years as we sit here today, we're well-positioned to execute on our strategy and deliver on the groundbreaking promises of our programs. Our immediate priority is execution of the two KT-621 Phase 2b studies.

同時，我們也透過合作夥伴關係擴大觸角，例如與Gilead合作推進KT-200（我們第一個分子膠專案），以及與Sanofi在IRAK4上的合作。將這一切串聯起來的，是我們承諾以精準方式追求高價值、驅動疾病的標的，並能在不同治療領域中反覆成功地做到這一點。我們所展現的高度聚焦與一致的成果，使我們不僅對單一專案有信心，也對擴大與延伸產品線的能力充滿信心。過去幾年我們已完成大量基礎工作；以目前的狀態來看，我們已具備良好條件執行策略，並兌現各項專案所承諾的突破性潛力。我們當前最優先的任務，是執行兩項KT-621的2b期研究。

In atopic dermatitis, we're on track to complete enrollment this year in the BROADEN2 study, and we expect data by mid-2027. We continue to be encouraged by the level of interest from both investigators and patients, and it's clear the enthusiasm for the trial is high. We're tracking with our internal expectations for asthma as well, where the BREADTH study readout is expected by the end of 2027. As we advance these studies, we'll continue to assess a broader development strategy, including areas such as COPD, EoE, chronic rhinosinusitis and others to maximize the value of the program. Turning to IRAK5.

在異位性皮膚炎方面，我們按計畫於今年完成BROADEN2研究的受試者收案，並預期於2027年年中取得數據。我們持續受到研究者與患者高度興趣的鼓舞，顯然市場對該試驗的熱情很高。在氣喘方面，我們也符合內部預期，BREADTH研究的讀出（readout）預計在2027年底前出爐。隨著這些研究推進，我們也將持續評估更廣泛的開發策略，包括COPD、EoE、慢性鼻竇炎等領域，以最大化該專案的價值。接著談IRAK5。

We expect to report healthy volunteer data from the KT-579 Phase 1 study in the second half of 2026. The overall goal is to demonstrate that we can safely degrade the target and the biology translates in humans in a way that's consistent with what we've seen preclinically. IRAK5 has been a target of particular interest across the industry for a very long time. Jared will spend more time on the opportunity, but what's compelling here is that by selectively degrading IRAK5, we have the potential to impact multiple key drivers of disease with a single mechanism. If we think about lupus specifically, we're addressing autoantibodies, Type 1 interferon, pro-inflammatory cytokines, all through one pathway.

我們預期在2026年下半年公布KT-579 1期研究的健康受試者數據。整體目標是證明我們能夠安全地降解該標的，且其生物學效應在人體中的呈現方式與我們在臨床前所見一致。IRAK5長期以來一直是業界高度關注的標的。Jared稍後會更深入說明這個機會；但此處最具吸引力的是，透過選擇性降解IRAK5，我們有機會以單一機制影響多個關鍵致病驅動因子。以紅斑性狼瘡為例，我們可透過同一路徑同時處理自體抗體、第一型干擾素（Type 1 interferon）以及促發炎細胞激素等。

While individual drugs can address specific -- each specific pathway, we believe a single mechanism such as an IRAK5 degrader has the potential to address all pathways and potentially have greater therapeutic potential. We also have several opportunities emerging in our early research pipeline and expect to disclose the next target later this year when we reach development candidate. Before I move on, I wanted to touch briefly on our Gilead collaboration. We recently announced that Gilead has made the decision to advance KT-200, our CDK2 molecular glue, which could enter the clinic as early as next year. This program is a great example of the power of Kymera's R&D capabilities.

雖然單一藥物可以針對特定——各個特定路徑進行處理，但我們相信，像IRAK5降解劑這樣的單一機制，有潛力同時涵蓋所有路徑，並可能帶來更高的治療潛力。我們在早期研究產品線中也有數個新機會正在浮現，並預期在今年稍晚、當我們達到開發候選物（development candidate）階段時，揭露下一個標的。在我繼續之前，我想簡要提及我們與Gilead的合作。我們近期宣布，Gilead已決定推進KT-200（我們的CDK2分子膠），該專案最快可於明年進入臨床。此專案是Kymera研發能力威力的絕佳例證。

Our ability to reach a target like CDK2 with a highly selective molecular glue really speaks to the depth and reach of our capabilities. CCNE-amplified tumors need specific agents to address the underlying biology. CDK2 selective blockade has not been achieved by any investigational drugs, in my opinion. Mostly because of the homology and cross-reactivity with CDK1. We designed an absolutely selective molecular glue degrader to achieve this target product profile.

我們能以高度選擇性的分子膠觸及像CDK2這樣的標的，充分展現了我們能力的深度與廣度。CCNE擴增的腫瘤需要特定藥物來處理其底層生物學。依我看，任何研究中藥物都尚未達成對CDK2的選擇性阻斷（selective blockade），主要原因在於與CDK1的同源性與交叉反應。我們設計出一個絕對選擇性的分子膠降解劑，以達成此目標產品特性（target product profile）。

I'm thankful to Gilead for believing in this program early on and now for taking KT-200, Kymera Therapeutics discovered development candidate into development. Special thanks to our CDK2 team for delivering this molecule in record time. So everything we're doing across all this program is to build long-term value. This isn't just about incremental progress. It's about our commitment to developing medicines that we believe can change treatment paradigms and expand access to important treatment options.

我感謝Gilead在早期就相信這個專案，並且如今將KT-200——由Kymera Therapeutics發現的開發候選物——推進至開發階段。也特別感謝我們的CDK2團隊，以破紀錄的速度交付這個分子。因此，我們在所有這些專案上的努力，都是為了建立長期價值。這不只是漸進式的進展，而是我們致力於開發我們相信能改變治療典範、並擴大重要治療選項可近性的藥物。

KT-621 is the best example of our strategy in action. Our continued engagement with KOLs reinforce the growing anticipation for a therapeutic that can potentially fundamentally change the treatment paradigm in Type 2 inflammatory diseases. As you all know, we have shared compelling data sets, including most recently AAD. With that as a backdrop, I thought it was worth stepping back and framing what makes this opportunity so compelling. When it comes to treating these conditions, patients and physicians are often forced to make trade-offs.

KT-621是我們策略落地的最佳例證。我們與關鍵意見領袖（KOL）的持續互動，強化了市場對一種可能從根本上改變第二型發炎疾病治療典範之療法的期待。如各位所知，我們已分享多組具說服力的數據集，最近一次是在AAD。在此背景下，我認為值得退一步，說明為何這個機會如此引人注目。當談到治療這些疾病時，患者與醫師往往被迫做出取捨。

What they want most is simple, a safe, effective and convenient option. We believe KT-621 is well-positioned to meet that need with the potential to deliver the efficacy of biologics and the convenience of an oral pill. And that matters because patients' preference is clear. Given the option, many would choose oral therapy over the burden of injections, especially for chronic diseases that require long-term treatment. In fact, most patients are being treated with suboptimal therapies such as topical creams, which can be massive ineffective or with inhaled medicines, often because they or their prescribers are not comfortable moving to advanced systemic injectable therapies.

他們最想要的其實很簡單：安全、有效且便利的選項。我們相信KT-621具備良好條件滿足此需求，有潛力同時提供生物製劑的療效與口服藥丸的便利性。這點很重要，因為患者偏好非常明確：在有選擇的情況下，許多人會選擇口服治療，而非承受注射的負擔，尤其是需要長期治療的慢性疾病。事實上，多數患者仍在使用效果不理想的治療方式，例如外用乳膏（可能非常無效），或吸入型藥物；這往往是因為患者或開立處方者不願意升級至更進階的全身性注射治療。

KT-621 can change this dynamic completely, allow patients that are not well treated by these local therapies to access a simple, accessible, effective and trusted oral pill. So when you put it all together, the mechanism, the clinical profile and the simplicity of administration, we believe KT-621 can stand on its own has the potential to represent a true paradigm shift. As a result, our focus is to expand the market and redefine what patients and physicians should expect from treatment. When you take a broader view, the scale of opportunity really comes into focus. This is a slide you've seen before, but it's worth revisiting because it highlights just how much untapped potential still exists in Type 2 inflammatory diseases, particularly for new entrants that can expand the market.

KT-621可以徹底改變這種局面，讓那些無法從局部治療中獲得良好控制的患者，能取得一種簡單、可近、有效且值得信賴的口服藥丸。綜合來看，從作用機制、臨床特性到給藥方式的簡便性，我們相信KT-621本身就能成立，並有潛力代表真正的典範轉移。因此，我們的重點是擴大市場，並重新定義患者與醫師對治療應有的期待。從更宏觀的角度來看，機會規模就更加清晰。這張投影片各位之前看過，但值得再次回顧，因為它凸顯了第二型發炎疾病中仍存在大量尚未被開發的潛力，特別是對於能夠擴大市場的新進者而言。

Importantly, nearly 50 million patients could benefit from better therapies. This opportunity is not just about taking share from existing treatments. It's about reaching the much larger population of patients who are untreated or undertreated today. We're already doing the work to better understand the patient population, market dynamics and access landscape, and these insights are guiding our development and ultimately, our commercial strategy. If successful, KT-621 could become the preferred option and potentially shift treatment earlier in the disease course where earlier intervention can meaningfully reduce disease burden and progression. At AAD and through recent advisory board meeting, the feedback has been consistent. There is clear demand for a convenient effective oral option and strong excitement around this mechanism.

重要的是，近5,000萬名患者可能受益於更好的療法。這個機會不僅僅是從現有治療中取得市占率，而是要觸及當今更龐大、尚未接受治療或治療不足的患者族群。我們已在進行工作，以更深入了解患者族群、市場動態與可近性（access）環境，而這些洞見正引導我們的開發工作，並最終形塑我們的商業策略。若能成功，KT-621可望成為首選方案，並可能將治療時點前移至疾病進程更早期；在更早期介入可實質降低疾病負擔與進展。在AAD以及近期的諮詢委員會會議中，回饋一致：市場對便利且有效的口服選項有明確需求，且對此一作用機制抱持高度期待。

With that, I'll turn it over to Jared to discuss our clinical pipeline a bit more, including KT-579. Jared?

接下來，我把時間交給Jared，請他更進一步說明我們的臨床產品線（clinical pipeline），包括KT-579。Jared？

Thanks, Nello. Given the growing focus and attention on our IRAK5 program, I'd like to use most of my time this morning to highlight why we are enthusiastic about this program and target. There is a significant unmet need in autoimmune diseases like lupus, which are characterized by broad immune dysregulation rather than disruption of a single pathway. While biologics have successfully validated individual targets such as Type 1 interferon, pro-inflammatory cytokines and B cells, these approaches act downstream and only narrowly address the underlying disease biology. As a result, many patients continue to experience inadequate responses.

謝謝你，Nello。鑑於外界對我們IRAK5計畫的關注與重視日益增加，我想把今天上午大部分時間用來說明為何我們對這個計畫與標的感到振奮。在如狼瘡等自體免疫疾病中，存在顯著未被滿足的醫療需求；這類疾病的特徵是廣泛的免疫失衡，而非單一路徑的失調。儘管生物製劑已成功驗證了如第一型干擾素、促發炎細胞激素與B細胞等個別標的，但這些方法多在下游發揮作用，且僅能狹窄地處理疾病的根本生物學。因此，許多患者仍持續出現療效不足的反應。

This is where IRF5 becomes particularly compelling. It is a genetically and biologically validated transcription factor that functions as a master regulator and central amplifier of immune responses across multiple autoimmune diseases. When dysregulated, it drives coordinated activation of multiple inflammatory pathways, effectively locking the immune system into a persistent inflammatory state. Importantly, human genetic data connect increased IRF5 activity to these pathways that are known drivers of autoimmune disease. This biology supports our confidence that modulating IRF5 has the potential to translate into meaningful clinical benefit.

這正是IRF5特別引人注目的原因。它是一個在遺傳學與生物學上均已被驗證的轉錄因子，作為主調控因子（master regulator）與核心放大器，能在多種自體免疫疾病中調控免疫反應。當其失衡時，會驅動多條發炎路徑的協同活化，等同將免疫系統鎖定在持續發炎狀態。重要的是，人類遺傳資料將IRF5活性增加與這些已知會驅動自體免疫疾病的路徑連結起來。這些生物學證據支持我們的信心：調節IRF5有潛力轉化為具臨床意義的療效。

KT-579 is designed to selectively degrade IRF5 and thereby rebalance immune activity by simultaneously modulating multiple downstream disease-driving pathways. Our goal is to rebalance the immune system more comprehensively and deliver a durable response compared to injectable biologics that target single pathways, while also offering the convenience of oral dosing. We continue to generate compelling preclinical data demonstrating activity across multiple disease-relevant models. These results reinforce our confidence in IRF5 and support the potential for KT-579 to offer clinical benefit. We plan to present preclinical data, including new data in IBD models at DDW next month and Focus at EULAR in June.

KT-579的設計是選擇性降解IRF5，藉此同時調節多個下游致病路徑，以重新平衡免疫活性。我們的目標是更全面地重塑免疫系統，並相較於僅針對單一路徑的注射型生物製劑，提供更持久的反應，同時也具備口服給藥的便利性。我們持續產出具說服力的臨床前數據，顯示其在多個與疾病相關的模型中具有活性。這些結果強化我們對IRF5的信心，並支持KT-579可能帶來臨床效益。我們計畫在下個月的DDW發表臨床前數據（包括在IBD模型中的新數據），並於6月在EULAR的Focus會議上分享。

We have already generated a robust preclinical data package and have shown that we can effectively and selectively modulate this central node of inflammation. As you'll see here in our lupus models, KT-579 demonstrated strong and durable activity associated with deep IRF5 degradation. Importantly, the level of activity observed compares favorably to both approved therapies and other clinically active agents evaluated in similar preclinical settings. Taken together, these data further support the potential of IRF5 degradation to drive meaningful disease modification in autoimmune conditions like lupus and IBD. I should also note that from a safety perspective, IRF5 is not essential for host defense against infectious pathogens, which suggests there may be an opportunity to modulate the immune system through IRF5 targeting without the risk of bacterial or viral infections.

我們已建立一套扎實的臨床前數據組合，並證明我們能有效且選擇性地調節這個發炎的核心節點。如各位在我們的狼瘡模型中所見，KT-579在深度IRF5降解的情況下，展現強勁且持久的活性。重要的是，所觀察到的活性水準，與已核准療法以及在相似臨床前情境中評估的其他具臨床活性的藥物相比，表現相當甚至更佳。綜合而言，這些數據進一步支持：透過IRF5降解，有潛力在如狼瘡與IBD等自體免疫疾病中帶來具意義的疾病修飾效果。我也要補充，從安全性角度來看，IRF5並非宿主防禦感染性病原所必需，這表示或許有機會在不增加細菌或病毒感染風險的情況下，透過鎖定IRF5來調節免疫系統。

IRF5 knockout mice do not show any susceptibility to infections. And in our four-week GLP tox studies in nonhuman primates and rodents, we did not observe any adverse findings. We've now advanced KT-579 into the clinic. The Phase 1 healthy volunteer study is designed to evaluate single and multiple ascending oral doses with a focus on achieving greater than 90% IRF5 degradation in blood and a favorable safety profile. We will also assess pharmacodynamic activity using ex vivo stimulation assays to understand the impact of IRF5 degradation on key inflammatory pathway biomarkers upregulated by TLR7, 8 and 9 agonists, including Type 1 interferons, pro-inflammatory cytokines and inflammatory pathway gene transcripts.

IRF5基因剔除小鼠並未顯示對感染的易感性。而在我們針對非人靈長類與囓齒類所進行的四週GLP毒理研究中，也未觀察到任何不良發現。我們現已推進KT-579進入臨床。第一期健康受試者研究的設計，將評估單次與多次遞增口服劑量，重點在於達成血液中超過90%的IRF5降解，以及良好的安全性概況。我們也將使用離體（ex vivo）刺激試驗來評估藥效動力學（pharmacodynamic）活性，以了解IRF5降解對關鍵發炎路徑生物標記的影響；這些標記由TLR7、8與9致效劑上調，包括第一型干擾素、促發炎細胞激素以及發炎路徑基因轉錄本。

It's our expectation that we should see a 50% to 80% reduction in these biomarkers across the three TLR pathways assessed if we're engaging IRF5 effectively, which would suggest the potential for IRF5 degradation translating into clinical activity in subsequent patient studies with KT-579. Looking ahead, we expect to report Phase 1 healthy volunteer data in the second half of 2026. Following that, we are planning a proof-of-concept study likely in lupus where genetic and biological rationale for IRF5 targeting is particularly strong. We will share more details on the planned design later this year. Before I wrap up, I did want to touch briefly on our STAT6 program.

我們預期，若能有效作用於IRF5，則在所評估的三條TLR路徑中，這些生物標記應可下降50%至80%；這將暗示IRF5降解有潛力在後續KT-579的患者研究中轉化為臨床活性。展望未來，我們預計在2026年下半年公布第一期健康受試者數據。其後，我們規劃進行概念驗證（proof-of-concept）研究，可能會先在狼瘡中展開，因為在該適應症中，鎖定IRF5的遺傳與生物學理據特別強。我們將在今年稍晚分享更多關於研究設計的細節。在結束之前，我也想簡要提及我們的STAT6計畫。

There continues to be a lot of excitement around new mechanisms in AD and KT-621's profile continues to resonate well. Last month, we had the privilege of presenting the KT-621 Phase Ib BROADEN data at AAD during a highly attended late-breaking trial results session. In addition to the presentation, we had a strong presence at our booth at AAD and meaningful engagement with the AD patient community, including patient support groups, which reinforced the real need for new treatment options and excitement over the potential of KT-621 to provide an effective and safe oral therapy for AD. We also connected with a number of KOLs and investigators who shared their enthusiasm for KT-621 and viewed it as one of the most promising new approaches to treating AD. New in the AAD presentation was the first detailed look at impact on Body Surface Area or BSA, a measure of the extent of AD skin lesions.

在AD領域，新作用機制仍持續引發高度關注，而KT-621的產品特性也持續獲得良好共鳴。上個月，我們有幸在AAD一場備受關注的最新突破性試驗結果（late-breaking）專場中，發表KT-621第一期Ib期BROADEN研究數據。除正式發表外，我們在AAD的攤位也有強勢曝光，並與AD患者社群（包括患者支持團體）進行了有意義的互動，進一步印證市場對新治療選項的迫切需求，以及對KT-621有望提供有效且安全的AD口服療法的期待。我們也與多位KOL與研究者交流，他們分享了對KT-621的熱忱，並認為其是治療AD最具前景的新方法之一。此次AAD發表中的新內容，是首次更詳細呈現對體表面積（Body Surface Area，BSA）的影響；BSA是衡量AD皮膚病灶範圍的指標。

We saw an overall mean reduction of BSA of 49% at four weeks across the two dose groups, reflecting a substantial reduction in disease burden. This, like other key clinical efficacy endpoints included EASI and pruritus was in line with published data for dupilumab at week 4. These early data continue to highlight the potential of KT-621 in AD, and we look forward to learning more in our randomized placebo-controlled Phase 2 studies. We are actively enrolling the KT-621 Phase 2b BROADEN2 and BREADTH studies in AD and asthma and look forward to sharing data from these studies by mid-2027 and late 2027, respectively. Overall, we are highly encouraged by all the progress with both KT-621 and KT-579 and look forward to keeping you updated as these programs progress in the clinic.

我們觀察到在兩個劑量組中，四週時BSA的整體平均下降49%，反映疾病負擔顯著降低。這一結果與其他關鍵臨床療效終點（包括EASI與搔癢）一致，並與已發表的dupilumab在第4週的數據相符。這些早期數據持續凸顯KT-621在AD上的潛力，我們也期待在隨機、安慰劑對照的第二期研究中獲得更多資訊。我們正積極招募KT-621第二期b期BROADEN2與BREADTH研究（分別於AD與氣喘），並期待分別在2027年年中與2027年年底分享這些研究的數據。整體而言，我們對KT-621與KT-579兩項計畫的進展都深受鼓舞，並將在這些計畫於臨床推進的過程中持續向各位更新。

With that, I'll pause here and turn the call over to Bruce.

接下來我先在此暫停，並把電話會議交給Bruce。

Thanks, Jared. As I walk through the first quarter results, please refer to the tables found in today's press release, which was filed this morning. Collaboration revenue in the first quarter of 2026 of $34.4 million is attributable fully to our Gilead partnership. More broadly with respect to Gilead, we received an upfront payment of $40 million upon signing the licensing and option agreement last year, which now has been fully recognized in our revenue. As Gilead has exercised its option on KT-200, we are due to receive $45 million investment from Gilead, which is expected to be recognized as revenue in the second quarter of 2026.

謝謝你，Jared。在我說明第一季業績時，請各位參考今天新聞稿中的表格，我們已於今早提交。2026年第一季的合作收入為3,440萬美元，全部歸因於我們與Gilead的合作。更廣泛地談到Gilead方面，我們在去年簽署授權與選擇權協議時收到4,000萬美元的預付款，現已全數認列為收入。由於Gilead已行使其對KT-200的選擇權，我們將收到Gilead的4,500萬美元投資，預計將於2026年第二季認列為收入。

And as a reminder, under this agreement, we are eligible for approximately an additional $700 million in total milestone payments. Also on the partnering front, we continue to expect Sanofi to advance KT-485 into Phase 1 testing this year, which will include the receipt of a milestone upon dosing the first healthy volunteer. As a reminder, under the structure of the Sanofi agreement, we have the potential to realize nearly $1 billion in total milestones. Now with respect to operating expenses, R&D for the quarter was $98.2 million. Of that, approximately $8.6 million represented noncash stock-based comp.

另外提醒各位，依據該協議，我們有資格獲得總計約7億美元的額外里程碑款項。在合作夥伴方面，我們仍預期Sanofi將於今年推進KT-485進入第一期試驗，屆時在首位健康受試者完成給藥時，我們將收到一筆里程碑款。提醒各位，依Sanofi協議的架構，我們有機會實現總計近10億美元的里程碑款。接著談營運費用，本季研發費用為9,820萬美元。其中約860萬美元為非現金的股票基礎給付（stock-based comp）。

The adjusted cash R&D spend of $89.6 million, which excludes that stock-based comp, reflects an 18% increase from the comparable amount in the fourth quarter of 2025. On the G&A side, our spending for the quarter was $20.4 million, of which $7.4 million was noncash stock-based comp and the adjusted cash G&A spend of $13 million, again, excluding that stock-based comp, reflects a 30% increase from the comparable amount in the fourth quarter of 2025. I should note that this quarter's G&A growth was elevated relative to our typical run rate, primarily driven by the timing of certain expenses. And with that said, we expect G&A growth to moderate in the coming quarters. And finally, we ended March with a cash balance of $1.55 billion, providing a runway into 2029.

經調整後的研發現金支出為8,960萬美元（不含該等以股票為基礎的薪酬），較2025年第四季的可比金額增加18%。在一般及行政（G&A）方面，本季支出為2,040萬美元，其中740萬美元為非現金的以股票為基礎的薪酬；經調整後的G&A現金支出為1,300萬美元，同樣不含該等以股票為基礎的薪酬，較2025年第四季的可比金額增加30%。我想指出，本季G&A成長相較於我們典型的運行水準偏高，主要是由於部分費用認列時點所致。話雖如此，我們預期未來幾季G&A成長將趨於溫和。最後，我們在3月底的現金餘額為15.5億美元，可支撐營運至2029年。

This allows us to complete both the KT-621 Phase 2b trials in AD and asthma and to fund a large part of the first Phase 3 trial for KT-621 in AD. The runway also allows us to advance KT-579 through initial proof-of-concept testing to progress our research pipeline and to grow our organization and build our capabilities as we prepare for later-stage development and ultimately commercialization. Overall, we remain well-positioned and well-capitalized to execute on our clinical programs and pipeline.

這使我們得以完成KT-621在異位性皮膚炎（AD）與氣喘的兩項第2b期試驗，並為KT-621在AD的首項第3期試驗提供大部分資金。該資金續航期也讓我們能推進KT-579，完成初步概念驗證（proof-of-concept）測試，以推動研發管線進展，並在我們為後期開發、最終商業化做準備之際，擴大組織並建構能力。整體而言，我們仍處於有利位置且資本充足，能夠執行我們的臨床計畫與管線。

With that, we'll pause while we regroup in our conference room and assemble the queue for your questions. Thank you.

接下來，我們將先暫停一下，回到會議室重新整隊並整理各位的提問順序。謝謝。

(Operator Instructions) Ellie Merle, Barclays.

（接線員指示）Ellie Merle，巴克萊。

This is Jasmine on for Ellie. I just wanted to ask a bit more about the IRF5 data at healthy as we expect later this year. So in your remarks, I know you said you're looking for 50% to 80% modulation of the biomarker pathways in the ex vivo stimulation assays. Can you help us understand a little bit better how you get to that threshold and elaborate on what you would expect this to translate to clinically?

我是代替Ellie的Jasmine。我想再多問一些關於我們預期今年稍晚在健康受試者中取得的IRF5數據。在你們的發言中，我知道你們提到在離體（ex vivo）刺激試驗中，會尋求生物標誌物路徑達到50%到80%的調節幅度。你們能否協助我們更清楚理解為何設定這個門檻，並進一步說明你們預期這在臨床上會轉化為什麼意義？

Yes. Thank you. Maybe I'll start and then pass it to Jared to spend a bit more time on the details. So obviously, whenever we set out these expectations are always based, especially for the first human translation or our preclinical data. Just remember, this is a critical node that actually intersects three key pathways.

好的，謝謝。也許我先開始，接著再請Jared補充更多細節。顯然，每當我們提出這些預期時，尤其是首次人體轉譯（first human translation），都會以我們的臨床前數據為基礎。請記得，這是一個關鍵節點，實際上交會於三條重要路徑。

So we see that when we block this node, even not even -- we don't need to even get above 90% degradation, we're able to see modulation of a series of downstream biomarkers. Maybe, Jared, you can speak to how we come up with those numbers.

因此我們看到，當我們阻斷這個節點時，甚至不需要——我們甚至不必達到超過90%的降解，就能觀察到一系列下游生物標誌物的調節。Jared，也許你可以談談我們是如何得出那些數字的。

Yes. So the we assess these pathways, in particular, the TLR7/8/9 pathways with ex vivo stimulation of whole blood. That's how we're planning to do it in Phase 1 using agonist to the TLR7, 8 and 9 receptors. So essentially, the way we came up with 50% to 80% is that our expectation based on our preclinical in vitro data is that if we're able to degrade IRF5 by at least 90%, we should be able to see that range of blockade of these particular pathways. Now that 50% to 80% is approximate-- whether we end up seeing within that range or more than that remains to be seen.

好的。我們評估這些路徑的方法，是透過對全血進行離體刺激（ex vivo stimulation），特別是TLR7/8/9路徑。這也是我們計畫在第1期試驗中採用的方法，使用對TLR7、8與9受體的致效劑（agonist）。基本上，我們之所以提出50%到80%的範圍，是因為根據我們臨床前的體外（in vitro）數據，我們預期若能將IRF5至少降解90%，就應能在這些特定路徑上看到該範圍的阻斷效果。當然，50%到80%只是約略值——最終是否落在該範圍內或高於該範圍，仍有待觀察。

But that's an approximate level that we would expect to see of inhibition in conjunction with at least 90% degradation of the target.

但這是我們在目標至少達到90%降解的前提下，預期可觀察到的抑制程度之大致水準。

And maybe just to add, if this was a single pathway, like we've seen, for example, 621 with STAT6 and we have a downstream biomarker that is activated, obviously, we expect complete blockade of that one biomarker. But given that these are multiple pathways and this pathway is also signaled through other receptor, this is why there is a range because it depends on what pathway, what stimuli, what biomarkers. That's how -- that's why there is a bit more nuance into this biology.

另外補充一下，如果這是一條單一路徑——例如我們在621上看到的STAT6，且有一個被活化的下游生物標誌物——那麼很明顯，我們會預期能完全阻斷那一個生物標誌物。但由於這裡涉及多條路徑，而且該路徑也可透過其他受體傳遞訊號，因此才會出現一個範圍；因為結果取決於是哪一條路徑、何種刺激、以及哪些生物標誌物。這也就是——這也是為什麼這個生物學機制需要更細緻的解讀。

Okay. That's helpful. And then one quick follow-up. Should we expect enrollment completion for the 621 AD study as more of a near-term event or likely later in the year based on the trends that you're seeing?

了解，這很有幫助。再追問一個簡短問題：就你們目前看到的趨勢而言，我們應該把621的AD研究完成收案視為較近期的事件，還是更可能在今年稍晚？

Yes, great question. Look, I think we've said from the beginning of the study, we expect to complete enrollment by the end of the year. So we're going to stick with that guidance. I think the expectation will be that when we complete enrollment, we will communicate it.

是的。你問得很好。你看，我想我們從研究一開始就說過，我們預期在年底前完成收案。所以我們會維持這項指引。我想一旦完成收案，我們就會對外溝通。

Brian Cheng, JPMorgan.

Brian Cheng，摩根大通。

It's great that you have laid out the expectations for IRF5 degradations in healthy volunteers. But just kind of looking ahead into lupus patients, do you have a sense of the level of IRF5 degradations that we need to see in lupus patients where you start to see some clinical benefits? And in other words, is there a minimum threshold of IRF5 degradation that you need to hit in patients? And for this mechanism, how translatable is it from healthy volunteers to patients in terms of IRF5 degradation?

你們已經清楚說明在健康志願者中對IRF5降解的預期，這很棒。但往前看至紅斑性狼瘡患者，你們是否對需要達到何種程度的IRF5降解、才會開始看到一些臨床效益有概念？換句話說，在患者身上是否存在一個必須達到的IRF5降解最低門檻？另外，就這個機制而言，從健康志願者到患者在IRF5降解方面的可轉譯性如何？

Yes. No, thanks, Brian. So let's start with what we're trying to do here. So as we've done now, this is the sixth program, the human translation is focused on understanding key parameters, which is what is the exposure and dose needed to achieve a level of degradation X and then what level of degradation X translates in terms of clinical benefit as well as safety in patients. So we always do this in multiple steps, as you know.

是的。不，謝謝你，Brian。我們先從我們在這裡想做的事情談起。正如我們目前所做的，這是第六個專案；人體轉譯的重點在於理解關鍵參數，也就是：需要什麼樣的暴露量與劑量才能達到某個降解程度X，以及降解程度X在患者身上會如何轉化為臨床效益與安全性。你也知道，我們一向分多個步驟來做。

So right now, what we're trying to figure out is what is the dose and exposure that gives us the level of degradation that we believe is therapeutically relevant. Based on preclinical data, and as you know well, if we -- if the preclinical model -- animal model data will always translate in humans, we would have cured all diseases. So all this preclinical data has to be taken with a grain of salt. But what we've learned preclinically is that as low as, let's say, 80% degradation is sufficient to drive, let's say, efficacy benefit in this mouse model, benefits that actually are comparable, in many cases, superior to standard of care or drugs in development. So with that in mind, our goal is always to being able to demonstrate more than 90% degradation because that gives us the flexibility to then titrate pack in a dose-ranging study and establish as we're doing for 621 now, what is the level of degradation needed to achieve maximal and minimal efficacy.

因此目前我們要釐清的是：什麼樣的劑量與暴露量能帶來我們認為具有治療相關性的降解程度。根據臨床前數據，而且你也很清楚——如果臨床前模型、動物模型的數據總是能在人類身上轉譯，那我們早就治癒所有疾病了。所以所有這些臨床前數據都必須審慎看待。但我們在臨床前學到的是，低至例如80%的降解，就足以在這個小鼠模型中帶來療效上的收益；而這些收益在許多情況下可與標準治療相當，甚至優於現有標準治療或開發中的藥物。基於此，我們的目標一向是能證明超過90%的降解，因為這讓我們在劑量範圍研究中有彈性，之後就能像我們現在對621所做的一樣，建立達到最大與最小療效所需的降解程度。

So that's the same we're going to do with 579. I think we want to establish, as Jared said, robust degradation. We want to see more than 90%, knowing that that might not be necessary. But for us, I think it's important to demonstrate that. And then translation of degradation between healthy and patients, which was the second part of your question, historically, we have never seen a difference of degradation between healthy volunteers and patients.

所以我們對579也會做同樣的事。我想我們希望如Jared所說，建立強而有力的降解。我們希望看到超過90%，即便我們知道那可能不是必要條件。但對我們而言，我認為證明這一點很重要。至於你問題的第二部分——健康受試者與患者之間的降解轉譯——從歷史經驗來看，我們從未看到健康志願者與患者在降解程度上有差異。

Remember, these are catalytic molecules that do not perform depending on expression of targets, but actually perform depending on exposure of drug and thresholds of exposure. So we expect that whatever we see in healthy volunteers will translate in patients. We've shown that with 621. We've shown it with IRAK4. We've shown it also in other programs in other disease areas.

請記得，這些是具催化作用的分子，其表現並不取決於目標的表達量，而是取決於藥物暴露量以及暴露量的門檻。因此我們預期在健康志願者中看到的結果會轉譯到患者身上。我們已在621上證明過，也在IRAK4上證明過，並且在其他疾病領域的其他專案中也同樣證明過。

Faisal Khurshid, Jefferies.

Faisal Khurshid，Jefferies。

This is (inaudible) on for Faisal. Just wanted to ask about the initial enrollment in BROADEN2. Have the initial patients tracked with your expectations with respect to the baseline characteristics?

我是代替Faisal的（聽不清）。我想請問關於BROADEN2的初期收案：最初入組的患者在基線特徵方面，是否符合你們的預期？

Thank you. Great question. So I think we're not going to comment on what -- where we are with baseline characteristics. I think it's a bit of a futile exercise until we complete the study and share the data. What I would say historically, we've said that if you look at the early dupilumab studies, the baseline entry criteria in terms of severity of disease have been historically higher, meaning more severe than more recent studies.

謝謝，你問得很好。我想我們不會評論——我們目前在基線特徵方面的情況。我認為在研究完成並分享數據之前，這樣的討論有點徒勞。我能說的是，從歷史上看，我們曾提到如果你回顧早期的dupilumab研究，其入組的基線標準在疾病嚴重度方面歷來較高，也就是說，相較於較近期的研究，患者病情更為嚴重。

And that have been -- we said also historically that there are maybe two main reasons. One is that given that there are drugs on the market, more severe patients, especially in these highly advanced sophisticated clinical centers. So more severe patients have access to these therapies. And also generally, the other main reason is because of the competitive landscape and the general, again, way that sites and investigators enroll in these studies, you've seen a bit more of a less severe population in studies. And I'm not talking about our studies.

而這一直是——我們也曾從歷史角度說過，可能有兩個主要原因。其一是，鑑於市面上已有藥物，更嚴重的病患，特別是在這些高度先進、成熟的臨床中心，因此更嚴重的病患能夠取得這些治療。另一個主要原因則是競爭態勢，以及整體上——再說一次——各研究中心與研究者在這些試驗中的收案方式；你會看到在研究中出現了更多病情較不嚴重的族群。我不是在談我們的研究。

I'm talking about studies in the past, I would say, five to six years. So we continue to have this expectation that a study that is run today, a global study has a mean baseline that is in the mid-20s based on what we've seen historically, what we've seen in the Ib. But I'm not going to comment about what we're seeing in the current study. We'll do so when we release the data.

我是在談過去大概五到六年的研究。所以我們仍然預期，如今執行的一項研究——一項全球性研究——其基線平均值會落在二十多分的中段，這是基於我們歷史上看到的情況，以及我們在 Ib 期所看到的。但我不會評論我們在目前研究中看到的狀況；我們會在公布數據時再談。

Our next question will come from Brad Canino from Guggenheim. Brad is just asking this question, we'll just move on to Biren Amin with Piper Sandler.

我們下一個問題原本會來自 Guggenheim 的 Brad Canino。Brad 只是提出這個問題，我們就先往下進行到 Piper Sandler 的 Biren Amin。

Can you hear me now?

你現在聽得到我嗎？

Not great.

不太清楚。

(technical difficulty)

（技術問題）

Biren, it's not working. Maybe you can try again in a bit or I don't know if you're underground. Give it a shot in a couple of minutes, we'll circle back.

Biren，現在不行。也許你可以稍後再試一次，或者我不知道你是不是在地下。過幾分鐘再試試看，我們再回來。

Brad Canino, Guggenheim.

Brad Canino，Guggenheim。

Good developments with Gilead and the molecular glue for the CDK2. I'm wondering if you could just discuss what technology advances the Kymera scientists have been able to unlock for this technology and how to achieve the needed protein-protein interactions. And should we expect more named pipeline molecules to emerge as glues over the next few years?

你們與 Gilead 在 CDK2 的分子膠方面有不錯的進展。我想請你談談，Kymera 的科學家在這項技術上解鎖了哪些技術進展，以及如何達成所需的蛋白質—蛋白質交互作用。另外，未來幾年我們是否應該預期會有更多具名的研發管線分子以「分子膠」的形式出現？

Yes. Thanks, Brad. And you know -- I think you know Kymera well enough to know that we've always looked at the technology as a mean to unlock value for patients through going after difficult to drug or undrugged targets. And so we always look at what is the right technology for the right target. So CDK2 is a very interesting problem, right?

是的。謝謝你，Brad。你也知道——我想你對 Kymera 夠了解，我們一直把技術視為一種手段，透過鎖定難以成藥或尚未被藥物化的標的，為病患創造價值。因此我們總是在看：對於正確的標的，什麼是正確的技術。那麼 CDK2 是一個非常有意思的問題，對吧？

We know that if you have CCNE amplified tumors, there is a mechanism of resistance to 4/6 that goes to CDK2. If you can get to CDK2 either alone or probably more excitingly in combination, you can really have profound effect in breast cancer and other type of solid tumors that unfortunately affect lots of women. And so what has been the challenge with CDK2 has been that there is a high structural homology between CDK2 and CDK1. And CDK1 doesn't actually bring any benefit to efficacy and actually only brings safety issues. And the comment I made earlier, which I'm really comfortable standing by, I don't believe there are absolutely selective CDK2 agents out there, at least in our hands.

我們知道，如果你有 CCNE 擴增的腫瘤，對 4/6 的抗藥機制會轉向 CDK2。若能觸及 CDK2，不論是單獨或——更令人興奮的——合併治療，你就能在乳癌及其他不幸影響許多女性的實體腫瘤中產生非常深遠的效果。而 CDK2 的挑戰在於 CDK2 與 CDK1 之間具有高度結構同源性。CDK1 實際上對療效沒有任何助益，反而只帶來安全性問題。我先前提到的那點——我非常有信心堅持——至少以我們的經驗來看，我不相信市面上存在絕對選擇性的 CDK2 藥物。

And so you're going to run into dose-limiting toxicity. I'm sorry if I'm going too long here. We're going to run into dose-limiting toxicity because CDK1 comes in play, and you actually do not exploit fully the power of CDK2, either mono or in combination. So why we're using molecular glues for this target is because in the traditional binding site that people use for CDK2, which is the ATP binding pocket, there is just a high structural homology. We have published on an ATP binding site based heterobifunctional degrader and while we were able to have enough selectivity, it wasn't good enough for us.

因此你會遇到劑量限制性毒性。抱歉我講得有點長。我們會遇到劑量限制性毒性，因為 CDK1 會介入，而你其實無法充分發揮 CDK2 的威力，不論是單藥或合併治療。所以我們之所以對這個標的採用分子膠，是因為在傳統上大家用於 CDK2 的結合位點——也就是 ATP 結合口袋——其結構同源性實在太高。我們曾發表過一個以 ATP 結合位點為基礎的異雙功能降解劑（heterobifunctional degrader），雖然我們能做到足夠的選擇性，但對我們而言仍不夠好。

So we moved on from that effort. And so we said, how do we get absolute CDK1 selectivity. We did it through a protein-protein interaction enabled molecular glue that is outside of the ATP binding pocket. So this is the kind of the premise to my answer, which is, yes, I mean, you should expect Kymera to have other programs from our pipeline that will use this concept because this is just a continuation of protein degradation. It's just, again, solving a different problem with a slightly different solution.

所以我們就從那個方向轉移。接著我們說：要如何達到對 CDK1 的絕對選擇性。我們是透過一種由蛋白質—蛋白質交互作用所促成的分子膠來做到，而且是在 ATP 結合口袋之外。這就是我回答的前提：是的，我的意思是，你應該預期 Kymera 的研發管線中還會有其他專案採用這個概念，因為這只是蛋白質降解的延伸；只是——再一次——用稍微不同的解法去解決不同的問題。

And yes, we expect to see more from there in any therapeutic areas. This is not just relegated, let's say, to oncology.

而且是的，我們預期在任何治療領域都會看到更多這類成果。這不僅僅局限於腫瘤學。

Geoff Meacham, Citi.

Geoff Meacham，Citi。

This is Nishant on for Geoff. I want to go back to the data you presented at AAD. So in terms of the body surface area, you saw higher reduction at 100 milligram versus 200 milligram. So you didn't see much dose response. Is this simply like a small sample noise or is there like a pharmacological explanation such as like maximal degradation plateau effects?

我是 Nishant，代 Geoff 發問。我想回到你們在 AAD 上呈現的數據。就體表面積（BSA）而言，你們在 100 毫克看到的下降幅度比 200 毫克更高，所以沒有看到明顯的劑量反應。這只是小樣本造成的雜訊，還是有藥理學上的解釋，例如達到最大降解後的平臺效應？

Yes. Actually, I'll let Jared actually speak to the data. I just want to remind you and everybody that 100 milligrams and 200 milligrams gave the same degradation. Hence, we expect to see similar activity. But Jared, maybe you can speak to BSA, which I actually don't remember.

是的。其實我先讓 Jared 來談數據。我只想提醒你以及大家，100 毫克與 200 毫克帶來相同的降解，因此我們預期會看到相似的活性。不過 Jared，也許你可以談談 BSA，因為我其實不太記得了。

Yes. If you look at the error bars on those graphs, they're actually overlapping. And so the differences between 100 milligrams and 200 milligrams are really not significant differences, and it's probably a function of the small ends. I think whether you look at BSA or EASI or the other clinical endpoints that we looked at through four weeks in that study, you don't always see complete overlap of the curves, but you do see overlap of the error bars. So I think that tells us that we're seeing comparable activity across doses across multiple different endpoints.

是的。如果你看那些圖上的誤差棒，其實是重疊的。所以 100 毫克與 200 毫克之間的差異並不顯著，這很可能是小樣本所致。我認為不論你看 BSA、EASI，或我們在該研究四週內觀察的其他臨床終點，你不一定會看到曲線完全重疊，但你會看到誤差棒重疊。我想這告訴我們的是：在多個不同終點上、跨不同劑量，我們看到的是可比的活性。

Got it. And then just a follow-up on that. In terms of EASI versus BSA, you see like a gapping magnitude, again, given like it's a small sample size. Is this expected given that EASI captures both extent and severity while BSA measures just extend alone. Does this suggest to you that there is deeper severity improvement with this molecule versus surface area clearance at four weeks?

了解。那再追問一下。就 EASI 相對於 BSA 而言，你會看到幅度上有落差——同樣地，考量到樣本數很小。這是否符合預期，因為 EASI 同時涵蓋範圍與嚴重度，而 BSA 只衡量範圍本身？這是否讓你認為，在四週時，這個分子在嚴重度改善上更深，而不是僅僅是表面積的清除？

Can I just jump into this, Jared? I'm not going to actually address the specific question. I just want to say that we've said -- I've said multiple times, let's try not to overinterpret the individual numbers in such a small study with, as Jared said, the confidence interval between the two doses were almost completely overlapping. I think the important take home from the study is that all these measures showed a robust effect, consistent across all measures and consistent with upstream biologics. But Jared, if you want to add on the particular topic.

Jared，我可以插一句嗎？我不會直接回答這個具體問題。我只想說，我已經——我也多次說過——在這麼小的研究中，請盡量不要過度解讀個別數字；如 Jared 所說，兩個劑量之間的信賴區間幾乎完全重疊。我認為這項研究最重要的重點是：所有這些衡量指標都顯示出強勁效果、在各項指標間一致，且與上游生物製劑的結果一致。不過 Jared，如果你想就這個主題補充。

No, I think your point is the main one. I think BSA and EASI, there are overlapping but sort of distinct measures, right? As you said, BSA is looking more at the extent of disease. EASI is taking into account both the sort of severity of individual lesions as well as the extent of disease. So there's an overlap there.

不，我覺得你的重點就是主要結論。我認為 BSA 和 EASI 是有重疊但又略有不同的衡量方式，對吧？如你所說，BSA 更看疾病的範圍；EASI 則同時考量單一病灶的嚴重度以及疾病範圍。所以兩者之間是有重疊的。

But the bottom line is that we're seeing a comparable robust effect on both of those endpoints with KT-621.

但總結來說，我們在 KT-621 上看到的是：在這兩個終點上都有可比且強勁的效果。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B. Riley Securities。

Congrats on the progress. So on STAT6, there's a lot of activity in the inhibitor landscape, for example. So I was just curious what questions, Nello, you have for some of these highly potent claim to be selective approaches emerging. From the preclinical data, KT-621 does stand out based on whatever is available, but we'll probably get some clinical data next year from you and others. So just curious, how do you expect the clinical data here to maintain your leadership?

恭喜進展。關於 STAT6，目前抑制劑的競爭版圖很活躍，例如有不少方案。因此我想請教，Nello，對於一些新出現、宣稱高度強效且具選擇性的策略，你有哪些疑問？從現有的臨床前數據來看，KT-621 確實很突出，但明年你們和其他公司可能都會有一些臨床數據出來。你預期這裡的臨床數據要如何維持你們的領先地位？

And then just quickly on the 621 physician excitement maybe between AD and asthma and recognize you are yet to present your data at ATS next month. Any thoughts on between the two indications, the importance of oral versus maybe less frequent injectable? Like if you've teased out what matters more to the different set of clinicians?

另外再快速問一下，關於 621 在醫師端的興奮點，可能介於異位性皮膚炎（AD）與氣喘之間；也理解你們下個月才會在 ATS 發表數據。你對兩個適應症之間，口服相較於可能較低頻率的注射，其重要性有什麼想法嗎？例如你們是否已經釐清，對不同臨床醫師族群而言，什麼因素更重要？

Okay. Well, those are two robust questions. So on the first one -- thank you. So on the first one, small molecules, degraders, we've touched on this also extensively in the past. So first of all, recognize that STAT6 has been seen as a key difficult undrug target by huge potential for more than a decade.

好的。嗯，這是兩個很扎實的問題。先回答第一個——謝謝。第一個關於小分子、降解劑，我們過去也已經相當深入地討論過。首先要認知到，STAT6 長期以來一直被視為一個關鍵且難以成藥（undruggable）的標的，但其潛力巨大，這個觀點已經存在十多年。

So it's actually quite exciting to see so many companies, large and small, pouring hundreds of millions of dollars into this mechanism, mostly, I would say, following the exciting data that we started to share as early as January of '24, but obviously, we've been working on these targets for multiple years. So I think it's great, first of all, that there is a lot of enthusiasm around this target. The reason why we believe that degraders are going to be highly differentiated is because we are so fortunate that while obviously, technology requires a level of understanding that is not easily commoditized yet. So these molecules, though, with obviously, the challenge that it takes to make highly specific component degraders, the upside is that they are catalytic in nature and require exceptionally low exposures. We're talking about nanomolar to picomolar to completely remove STAT6, which allows us to have complete degradation at very low doses and importantly, at very low exposures so that we can deliver a drug once a day.

因此，看到這麼多大大小小的公司投入數億美元在這個機制上，其實相當令人振奮；多數我會說，是在追隨我們最早於 2024 年 1 月開始分享的令人興奮的數據，當然，我們在這些標的上已經耕耘了好幾年。我認為首先很棒的一點是，市場對這個標的有很高的熱情。我們之所以相信降解劑會高度差異化，是因為我們很幸運地擁有——雖然技術本身需要一定程度的理解，而這種理解目前還不容易被商品化。這些分子在開發上確實有挑戰，因為要做出高度特異性的組件型降解劑並不容易；但其優勢在於它們具有催化特性，所需暴露量極低。我們談的是奈莫耳到皮莫耳的濃度就能完全移除 STAT6，這讓我們能在非常低的劑量、且更重要的是在非常低的暴露下達到完全降解，因此可以做到每日一次給藥。

And actually, technically, you could probably deliver a drug less frequently than once a day. With a small molecule inhibitor, as you know, you're inhibiting stoichiometrically the target. So one molecule blocks one protein. So for this type of protein, you require a large amount of molecules in the body, in all tissues for 24 hours. And this becomes a challenge with regards to PK exposure, safety, safety therapeutic index.

而且從技術上講，你甚至可能可以比每日一次更低頻率給藥。使用小分子抑制劑時，如你所知，你是以化學計量方式抑制標的：一個分子阻斷一個蛋白。因此對於這類蛋白，你需要在體內、在所有組織中維持大量分子達 24 小時。這在藥物動力學（PK）暴露、安全性以及治療指數方面就會變成一個挑戰。

And so in our experience, and I think we've said this publicly, we've invested actually quite heavily in small molecule inhibitors to actually answer the question, do we need a degrader if an inhibitor is good enough? Our answer is, yes, you need a degrader because inhibitor can't quite reach the level of pathway blockade that a catalytic degrader can. So I think the beautiful thing about drug development is at the end of the day, I can spend the next hour trying to convince you that I'm right. But the best thing is that we'll generate data soon enough. And I think that will be the final nail on the cockpit on this argument for us, I hope.

因此依我們的經驗——而且我想我們也公開說過——我們其實在小分子抑制劑上投入了相當多資源，目的就是要回答一個問題：如果抑制劑已經夠好，我們還需要降解劑嗎？我們的答案是：是的，你需要降解劑，因為抑制劑無法達到催化型降解劑所能提供的那種路徑阻斷程度。我覺得藥物開發最美的地方在於，說到底，我可以花接下來一小時試著說服你我說得對；但最好的方式是我們很快就會產出數據。我想那將會成為我們在這個論點上的最終定論——希望如此。

With regards to your second question, so we've had the fortune and hopefully, we did also something good about generating and importantly, presenting our data in many medical conferences. We were fortunate to be selected at the podium at [EADP], which I believe was probably the first time for healthy volunteer data, I might not be sure. And then we presented at AAD. We presented [ATS/T] preclinical data we'll present later. So there is a very high appreciation from the medical community, both AD and asthma, about the potential of an oral drug in this space.

至於你的第二個問題，我們很幸運——也希望我們確實做得不錯——在許多醫學會議上產生並且更重要的是呈現我們的數據。我們很榮幸在 [EADP] 被選為口頭報告，我相信那可能是首次呈現健康受試者數據（我不太確定）。之後我們也在 AAD 發表。我們也發表了 [ATS/T] 的臨床前數據，之後還會再呈現。因此，醫學界對於在這個領域推出口服藥的潛力，不論是 AD 或氣喘，都有非常高的認同。

I just want to remind you, whether it's AD or asthma, the majority of patients are not controlled well or not treated well with either local therapy like inhalers or topicals and not enough of them are on advanced systemic biologics. So our goal is actually -- our goal is not to compete with less frequent dosing. That might come in place. It's just the market dynamics. But we're actually trying to mobilize the millions of patients that are sitting on the sidelines because they feel or their prescribers feel they're not ready for an injectable biologics, and we offer that biologics like oral pill that would change their lives.

我想提醒的是，不論是 AD 或氣喘，多數患者不是控制得很好，就是沒有被好好治療；他們要嘛只用局部治療（例如吸入器或外用藥），而且接受進階全身性生物製劑的人數也不夠多。所以我們的目標其實——我們的目標不是去和更低頻率給藥競爭。那可能會發生，這是市場動態的一部分。但我們真正想做的是動員那數以百萬計仍在觀望的患者，因為他們或他們的處方醫師覺得他們還沒準備好使用可注射的生物製劑；而我們提供的是一種「像生物製劑一樣有效的口服藥丸」，能改變他們的生活。

And so I think what we're seeing in other disease areas, it's a complete different paradigm shift. And that's really what we're focused on. I think this obviously resonates with investigators and more importantly, resonates with patients based on our experience.

因此我認為，我們在其他疾病領域看到的是一個完全不同的典範轉移，而這正是我們聚焦的方向。我想這顯然能引起研究者共鳴，更重要的是，依我們的經驗，也能引起患者共鳴。

(Operator Instructions) Judah Frommer, Morgan Stanley.

（接線員指示）Morgan Stanley 的 Judah Frommer。

Maybe just building on the last one, I think it's fair to say you've established a sort of playbook for Phase 1 studies in AD. So just curious to get your take on that excitement for 621 on the oral aspect versus the mechanism aspect. There are others going after oral drugs, but maybe in more novel targets. So the level of excitement for the oral nature of the drug, but also the fact that you're hitting IL-4/13, which is so well understood by docs. And then just within the landscape, curious specifically maybe on anything around IL-18 that you see as interesting within AD or more broadly and how that could apply to the IRAK4 program.

也許延續上一題，我覺得可以說你們已經為 AD 的第一期研究建立了一套某種「作戰手冊」。所以想請教你對 621 的看法：市場的興奮點更多是在口服這個層面，還是在機制層面？也有其他公司在做口服藥，但可能是更新穎的標的。所以大家對於藥物「口服」特性的興奮程度，以及你們同時打到 IL-4/13——這是醫師非常熟悉、理解很深的路徑——這兩者的相對重要性。然後在整體競爭版圖中，也想特別問一下你們對 IL-18 在 AD 或更廣泛領域中是否看到有趣之處，以及這可能如何應用到 IRAK4 計畫上。

Yes. Thanks, Judah. I like your 90 years in your backdrop. You're 80 years older than Kymera at Morgan Stanley. So yes, to answer your question, I think you put it exactly right.

是的。謝謝你，Judah。我喜歡你背景裡那個「90 年」的元素。你在 Morgan Stanley 的資歷比 Kymera 還多 80 年。所以，是的，回答你的問題，我覺得你說得非常到位。

The reason for the excitement for 621 is not just about the oral drug. I think it's the combination of oral, which is needed in this still early market, but combine it with the sense of understanding and comfort of a well-validated pathways like IL-4 and 13. And I think that's really what's making this drug and this program very unique in the space. I mean, as you know well, there are several other potential oral mechanisms out there, which, to be honest, I hope that they have a path forward beyond early Phase 1 data. I think, obviously, what the burden approved for a mechanism in the IL-4 and 13 pathway, I assume, is a bit less than it is for completely new pathways with completely unproven efficacy and safety.

對 621 的興奮不只是因為它是口服藥。我認為是口服（在這個仍屬早期的市場中確實需要）再加上大家對 IL-4 與 IL-13 這類高度驗證路徑的理解與信心的結合。我想這正是讓這個藥物與這個計畫在同領域中非常獨特的原因。你也很清楚，外面還有幾種其他可能的口服機制；老實說，我希望它們在早期第一期數據之後仍能走得下去。但我認為，若機制是在 IL-4/13 路徑上，取得核准所需承擔的機制風險門檻，我猜會比全新路徑、且療效與安全性完全未被證實的路徑來得低一些。

So I don't know, Jared, if there was anything to add to the second part.

我不知道，Jared，你對第二部分是否有什麼要補充的？

Yes. And the only thing I would add to the first part, too, is just around -- because you talked about mechanism, Judah. And I think there is an appreciation that the unique PPD mechanism, that catalytic mechanism of action that can lead to durable, maintained complete target suppression and pathway suppression that equals what you can get with upstream injectable biologics. I think that's a big selling point here with regard to degraders versus small molecule inhibitors. You asked about IL-18.

有的。我對第一部分也只想再補充一點——因為你提到機制，Judah。我認為大家也很認同這個獨特的 PPD 機制，也就是那種催化式作用機轉，能帶來持久、可維持的完全標的抑制與路徑抑制，其效果可達到上游可注射生物製劑所能提供的程度。我想這是相較於小分子抑制劑，降解劑的一個重要賣點。你問到 IL-18。

I mean, IL-18, some of those initial data coming out of [autoimmune] are interesting, right? And I think it sort of speaks to the fact that AD does not have this one flavor of inflammation, right? Obviously, Th2 is one of the main drivers of the pathophysiology, but other types of inflammation, whether it be Th1, Th17 driven, probably have some contribution as well and seeing activity with the drug targeting IL-18 probably speaks to that. Again, it was not as well validated a pathway here in AD. It's interesting to see the results coming out of that.

我的意思是，IL-18，從 [autoimmune] 出來的一些初步數據很有意思，對吧？我想這也某種程度說明 AD 並不是只有單一型態的發炎，對吧？很明顯 Th2 是病理生理的主要驅動因素之一，但其他型態的發炎——不論是 Th1 或 Th17 驅動——可能也有一定貢獻；而看到針對 IL-18 的藥物出現活性，可能就反映了這一點。再次強調，IL-18 在 AD 這裡並不是那麼被充分驗證的路徑；看到那樣的結果很有趣。

And it makes one think of interesting possibilities down the road maybe for combination therapies by bringing on other drugs that are hitting other types of inflammation in addition to Type 2 inflammation.

這也讓人想到未來可能會有一些有趣的可能性，例如透過合併療法，引入其他藥物去打擊除第二型發炎之外的其他發炎型態。

Biren Amin, Piper Sandler.

Piper Sandler 的 Biren Amin。

Can you hear me? All right. So on BROADEN2, I noticed in the press release that you're also including adolescents in addition to adults in the trial. But I think more recently, there was some inclusion criteria changes in the trial where you're now requiring, I think, adult patients needing at least three years of chronic disease, whereas with adolescent, it's a requirement of at least one year. Can you just maybe talk about the implications of that change?

你聽得到我嗎？好。關於 BROADEN2，我注意到新聞稿中提到你們在試驗中除了成人之外也納入青少年。不過我想更近期試驗的納入條件有一些變更：你們現在要求成人患者需要至少三年的慢性病程，而青少年則要求至少一年。你能否談談這個變更可能帶來的影響？

Yes. So I mean, the addition is the inclusion of adolescents to the study. Again, this is part of our overall strategy to change treatment paradigm for adult and more importantly, I would say, for young children and adolescence is step one, right? This is a disease of young children usually diagnosed in the first probably six years of life. And a drug like 621 could have a huge potential in children.

可以。我的意思是，新增之處在於把青少年納入研究。同樣地，這是我們整體策略的一部分，目的是改變成人、而且更重要的是我會說改變幼兒與青少年的治療典範；這是第一步，對吧？這通常是一種幼兒疾病，多半在生命最初大概六年內被診斷出來。而像 621 這樣的藥物在兒童族群中可能具有巨大的潛力。

So that's the main reason why we want to study this drug in younger population as early as possible. Jared, I don't know if you want to comment to the inclusion/exclusion criteria.

所以，這就是我們希望盡可能早、在更年輕族群中研究這款藥物的主要原因。Jared，我不確定你是否想就納入／排除標準補充說明。

Yes. I think in terms of exclusion, the Hanifin and Rajka criteria, right, for AD, like you want to make sure that your patients have AD. So one element of that to make sure you're getting patients with that diagnosis is they need to have a diagnosis for a certain number of years. So for adults, obviously, because they're older, the cutoff there is at least three years. With adolescents because they're younger, had the disease for a shorter period of time, there's a one-year cutoff.

是的。我想就排除條件而言，Hanifin 和 Rajka 的標準，對吧，用於 AD（異位性皮膚炎），你會想確保你的受試者確實是 AD。因此其中一個要素、用來確保你納入的是具有該診斷的患者，就是他們需要有被診斷一定年數。對成人而言，顯然因為年齡較大，門檻是至少三年。青少年因為較年輕、罹病時間較短，門檻是一年。

And again, the reason for both of those is to give you increased certainty that these patients truly have a diagnosis of AD.

而且再次強調，這兩者的原因都是為了提高我們對這些患者確實罹患 AD 的確定性。

Got it. And then maybe just one question on IRF. There's clearly IR translocation in naive B cells, plasma blasts and monocytes in patients with lupus. I know translocation in healthy volunteers as well, but is there anything you could do ex vivo to evaluate the impact of IRF degradation on translocation?

了解。那再問一個關於 IRF 的問題。顯然在狼瘡患者的初始（naive）B 細胞、漿母細胞（plasmablast）以及單核球中都有 IR 轉位。我也知道在健康受試者中也有轉位，但是否有任何你們可以在離體（ex vivo）條件下做的事情，來評估 IRF 降解對轉位的影響？

Yes. It's unlikely that we're going to see activation or translocation of IRAK5 in healthy volunteers. So I don't think that's what we're going to be looking for. We're going to be, as Jared said, looking at ex vivo stimulation of the blood with or without translocation. Again, I think there's probably close to 0% chance we'll find that in healthy volunteers, but we'll interrogate the pathway regardless of that.

是的。我們不太可能在健康受試者中看到 IRAK5 的活化或轉位。所以我不認為那會是我們要觀察的重點。我們會如 Jared 所說，觀察在離體條件下對血液進行刺激，並評估在有或沒有轉位的情況下的反應。再次強調，我認為在健康受試者中找到那種現象的機率大概接近 0%，但無論如何我們都會去解析該訊號路徑。

Alex Thompson, Stifel.

Alex Thompson，Stifel。

Maybe again on the ongoing AD and asthma studies, can you talk a little bit about kind of more color on enrollment progress, site activation, your level of oversight of these sites? And then maybe could you tell us how many patients have been dosed at this point across both studies that would be helpful.

再回到正在進行的 AD 與氣喘研究，你們能否多談一些招募進度、試驗中心啟動情況、以及你們對這些中心的監督程度？另外，也能否告訴我們截至目前兩項研究合計已給藥了多少名患者？這會很有幫助。

Yes. No, obviously, great question. As I said, we're trying not to comment on these things, not because we want to be secretive. I think it's only productive to do it at the end. I think what I can say is that the studies are on track, both in terms of site activations and patient enrollment.

是的。不，這確實是個好問題。如我所說，我們盡量不對這些事情發表評論，並不是因為我們想保密。我認為只有在最後再談才更有建設性。我能說的是，這些研究都在按計畫進行，無論是試驗中心啟動或患者招募方面。

And so the time lines that we put out are obviously still relevant. As I said, I think the best way to manage this particular question is as soon as we complete enrollment, we will communicate and then maybe then we can answer more specific questions about what we've seen and pace of enrollment, activation, et cetera.

因此，我們先前公布的時間表顯然仍然適用。如我所說，我認為管理這個問題的最佳方式是：一旦完成招募，我們就會對外溝通；到那時我們也許就能回答更具體的問題，例如我們看到的情況、招募速度、中心啟動等。

Marc Frahm, TD Cowen.

Marc Frahm，TD Cowen。

Maybe just back to prior comments about the attractiveness of oral options and the enthusiasm also for the mechanism. Maybe can you contrast 621 with the IL-23 space because we're seeing that launch just starting now in the psoriasis space. And just how much should we view the success, hopefully, of that product as a proxy for 621 versus how different do you think these markets are in terms of their eagerness for an oral therapy?

回到先前關於口服選項吸引力以及對該機制的熱情。你能否把 621 與 IL-23 領域做個對比？因為我們看到那個產品現在才剛開始在乾癬市場上市。你認為那個產品（希望）成功在多大程度上可作為 621 的代理指標？或者你覺得這些市場在對口服治療的渴望程度上有多不同？

Yes. Thanks, Marc. I don't want to hitch our wagon on to any other mechanism or drugs because we don't control those. But it is a fair point that I think we're seeing finally something we've been saying for a while, which is novel oral mechanisms that can deliver, in some cases, close to biologics like activity having a ton of enthusiasm. Obviously, the psoriasis market is very mature.

是的，謝謝你，Marc。我不想把我們的命運綁在任何其他機制或藥物上，因為那些不是我們能控制的。但你提出的點是合理的：我們終於看到一些我們講了好一陣子的事情，也就是能帶來、在某些情況下接近生物製劑療效的新型口服機制，正獲得大量熱情。顯然，乾癬市場非常成熟。

There are drugs that you can dose every three months or even less in some cases that are extremely effective. We're seeing even less frequent dosing. Obviously, you start to wonder what's the driver for that, but that's likely is not what we're working on. And so the question is very mature market, can an oral drug with good efficacy and safety even impact the landscape? And it looks like it will.

有些藥物可以每三個月甚至更久才給藥一次，而且效果非常好。我們甚至看到給藥頻率更低。顯然你會開始思考其驅動因素是什麼，但那很可能不是我們正在做的事情。因此問題在於：在一個非常成熟的市場中，一款具有良好療效與安全性的口服藥，是否仍能改變競爭格局？看起來是可以的。

I mean I was at AAD and lots of -- not to advertise for J&J, our friend at J&J, but lots of dermatologists were super excited about that drug. So clearly, even in a well-established, super mature market where there are already multiple blockbuster drugs, a drug like that seems to be highly differentiated. So we're talking in AD where there is no oral drug with good safety and efficacy. There is really only like two category of drugs approved, and IL-4, 13 and then all these other IL-13s that are not differentiated and JAK inhibitors. So this is where psoriasis was 10 years ago.

我的意思是，我在 AAD 上看到很多——不是要替 J&J 打廣告，我們在 J&J 的朋友——但很多皮膚科醫師對那款藥非常興奮。所以很明顯，即便在一個已經非常成熟、且已有多款重磅藥物的市場，一款那樣的藥似乎仍然高度差異化。相較之下，我們談的是 AD：目前沒有一款同時具備良好安全性與療效的口服藥。真正獲批的基本只有兩大類：IL-4/13（以及其他沒有差異化的 IL-13 類）和 JAK 抑制劑。這正是乾癬在 10 年前的狀態。

So bringing to the market something that is so differentiated, so early in the treatment in the market evolution, I think will have a much bigger effect than what we might be seeing IL-23 in psoriasis. So I think it validates, but more importantly, I think our opportunity is probably much more impactful given the -- again, the maturity of that market. One could point to the obesity space, but that's a whole different market dynamics. But you're seeing also there, these new orals are activating all new patients, mostly new patients, right? And that's really what our -- I think what many of these oral drugs are there to do is to really serve the millions of patients that are not on these advanced therapies.

因此，把一個如此差異化的產品帶到市場、而且是在治療與市場演進的早期階段，我認為其影響會遠大於我們在乾癬 IL-23 可能看到的情況。所以我認為它確實是一種驗證，但更重要的是，考量到——再次強調——那個市場的成熟度，我們的機會可能更具影響力。有人可能會拿肥胖領域來類比，但那是完全不同的市場動態。不過你也看到，在那裡這些新的口服藥正在啟動大量新患者，主要是新患者，對吧？而這正是——我認為許多這類口服藥的目的——去服務數以百萬計尚未使用這些進階治療的患者。

Joe Catanzaro, Mizuho.

Joe Catanzaro，Mizuho。

A quick one for me on along the lines of 579's preclinical data at DDW and maybe also your comments on mechanism earlier. But there seems to be a growing effort towards developing combination therapies in IBD. So I wanted to ask about IRF5's mechanism and where you see it as most orthogonal or complementary with existing mechanisms in IBE like alpha-4 beta-7, IL-23, TL1A.

我這邊快速問一個，延續 579 在 DDW 的臨床前數據以及你們先前對機制的評論。看起來 IBD 領域正越來越努力發展聯合療法。我想問 IRF5 的作用機制，以及你認為它在 IBD 現有機制（例如 α4β7、IL-23、TL1A）中，最「正交」或最具互補性的地方在哪裡？

Yes. Fortunately, I'll let Jared answer this one. So Jared, I'll give you 30 seconds to come up with an answer why I say what I'm going to say. So fortunately, I think what we're trying to do here at Kymera is bringing a completely new mechanism to the IBD space, hopefully. Obviously, we haven't committed to developing in that space yet, but versus obviously combining existing mechanism or other things.

是的。幸好，這題我讓 Jared 來回答。所以 Jared，我給你 30 秒想一下答案，因為我要先說我接下來要說的。幸好，我認為我們在 Kymera 想做的是把一個全新的機制帶進 IBD 領域（希望如此）。當然，我們還沒有承諾一定會在那個領域開發，但這與把既有機制做組合或其他做法不同。

But Jared, maybe you can speak to the science.

不過 Jared，也許你可以從科學角度談談。

Yes. I mean I think one of the great aspects of IRF5 is that it really controls signaling through multiple different pathways. We talked about Type 1 interferon. We talked about B cells and autoantibodies, but also myeloid cells, monocytes, potentially neutrophils, also dendritic cells. And when it comes to inflammatory bowel disease, the myeloid component, in particular is very important in diseases like ulcerative colitis, for example, where you have cytokines like IL-12, TNF, IL-6 and others that are driving that inflammation.

是的。我想 IRF5 很棒的一點是，它確實能調控多條不同路徑的訊號傳導。我們談過第一型干擾素（Type 1 interferon）。我們談過 B 細胞與自體抗體，但也包括髓系細胞、單核球，可能還有嗜中性球，以及樹突細胞。而談到發炎性腸道疾病時，髓系成分尤其重要，特別是在例如潰瘍性結腸炎這類疾病中，你會看到像 IL-12、TNF、IL-6 等細胞激素在驅動發炎。

And so I think being able to target IRF5 in IBD really helps get at that particular component of inflammation that's really important in ulcerative colitis and will lend itself to potentially combining with other mechanisms that go beyond those particular pro-inflammatory cytokines if you want to be able to tackle multiple different aspects of the pathophysiology of a disease like UC or Crohn's. So I think that's the beauty of it. I think the other aspect is the potential safety profile of IRF5 and being able to knock IRF5 down hard and not really having to be risk of infectious complications that also will lend itself to combinations.

因此，我認為在 IBD 中靶向 IRF5，確實有助於切入潰瘍性結腸炎中非常重要的那一部分發炎機制，並且可能適合與其他機制聯合使用——如果你希望能同時處理超出這些特定促發炎細胞激素之外的機制，以便攻克像 UC 或克隆氏症這類疾病的多個病理生理面向。我認為這就是它的美妙之處。另一個面向是 IRF5 潛在的安全性特徵：能夠大幅降低 IRF5，而不太需要擔心感染併發症的風險，這也會讓它更適合做聯合治療。

Jeet Mukherjee, BTIG.

Jeet Mukherjee，BTIG。

Maybe coming back to the market opportunity for KT-621. Nello, before you mentioned you're looking to mobilize patients on the sidelines because they aren't ready for an injectable. Could you maybe put some numbers or quantification around how big that population is on the sidelines due to needle aversion or phobias around that, particularly in atopic dermatitis?

回到 KT-621 的市場機會。Nello，你先前提到你們希望動員那些在觀望的患者，因為他們還沒準備好接受注射。你能否用一些數字或量化方式說明：因為害怕針頭或對注射有恐懼而處於觀望狀態的人群有多大，特別是在異位性皮膚炎方面？

Yes. Yes. I mean -- and to be clear, I don't think what's driving that is needle phobia. I mean there is a percentage of it. I think it's probably relatively a small percentage.

是的。是的。我的意思是——而且要說清楚，我不認為驅動這件事的是對打針的恐懼。我是說，確實有一部分是。我認為那可能相對只是很小的一部分。

I think most of it is, again, it's the barrier to an advanced systemic injectable therapy that both prescribers and patients have for just accepting or feeling like there is a need of having a protein injected in your body for a disease like atopic dermatitis. I think that's really what's blocking people for transitioning from topicals into advanced systemic therapies. And the numbers are out there, we talk about -- there's probably 40 -- if you just talk about AD, there's probably 40 million patients with moderate to severe AD. But maybe it's easier to do -- we have the number of 50 million that includes also other Type 2 inflammatory diseases. So only -- really only almost less than 2 million patients have received dupi-lebri, Nivo, RINVOQ in these diseases.

我認為大部分原因是——再說一次——無論是處方醫師還是病患，對於接受一種進階的全身性注射治療都存在門檻：也就是要接受或覺得有必要為了像異位性皮膚炎這樣的疾病，把一種蛋白質注射進體內。我認為這才是真正阻礙人們從外用藥轉向進階全身性治療的因素。相關數字也都在那裡，我們常談到——如果只談 AD，可能有約 4,000 萬名中重度 AD 病患。但也許用另一種方式更容易——我們有一個 5,000 萬的數字，還包含其他第二型發炎性疾病。所以只有——真的只有不到 200 萬名病患在這些疾病中接受過 dupi-lebri、Nivo、RINVOQ。

So some companies do the math differently, but those are the numbers. If you look at diagnosed moderate to severe patients, we're talking about tens of millions of patients. If you look about treated patients with this advanced systemic therapy, we're talking about less than 2 million. So that's the opportunity, and that's far greater than, for example, the opportunity in psoriasis these days. So I think it's really hard actually to put the value on 6:1 right now.

所以有些公司用不同方式計算，但大致就是這些數字。若看已診斷的中重度病患，我們談的是數千萬人；若看接受這類進階全身性治療的病患，我們談的是不到 200 萬人。所以這就是機會所在，而且這個機會遠大於例如目前乾癬領域的機會。因此我認為，現在其實很難把 6:1 的價值量化出來。

I think a lot of us are being quite conservative for a good reason. We're still relatively early in the development of the drug. But I believe strongly that post this Phase 2b data, we need to get much more, I think, aggressive with what we're really talking about. And I think maybe that would be a good time to talk about more discrete numbers.

我認為我們很多人基於充分理由都相當保守。我們在這個藥物的開發上仍相對早期。但我堅信，在這份 2b 期數據之後，我們需要在我們真正談論的內容上更——我認為——更積極一些。我想也許那會是個好時機，來談更具體的數字。

Sudan Loganathan, Stephens.

Sudan Loganathan，Stephens。

My question is on the 621 program for asthma and related downstream indications. As we get our first look at asthma data in the late 2027, does that outcome dictate read-through and investment in going forward with COPD and other related indications? And also, are there any other go/no-go decisions much like this coming in the next 12 months as we start seeing more data for 621?

我的問題是關於 621 計畫在氣喘及其相關下游適應症。當我們在 2027 年底首次看到氣喘數據時，那個結果是否會決定我們是否要繼續推進 COPD 及其他相關適應症的延伸解讀與投資？另外，在接下來 12 個月內，隨著我們開始看到更多 621 的數據，是否還會有其他類似的 go/no-go（繼續/停止）決策點？

Yes. No, I think as we said, thank you multiple times, it's really about dose selection. We hope to be able to take the Phase 3 dose that we'll use in asthma in other diseases. We have absolute confidence that this drug will work in all Type 2 diseases. So we're really waiting for the Phase 3 dose that will come out from the Phase 2b asthma study.

是的。不，我認為如同我們多次說過的，真的重點在於劑量選擇。我們希望能把在氣喘中使用的 3 期劑量帶到其他疾病。我們對這個藥在所有第二型疾病中都會有效有絕對信心。所以我們真正是在等待 2b 期氣喘研究所產出的 3 期劑量。

Kripa Devarakonda, Truist.

Kripa Devarakonda，Truist。

This is Anna on for Kripa. Just one question on 621. I know you haven't disclosed the doses that you're going to be pursuing, but I was just wondering if you could give us a sense of the dose response range you're hoping to show with the three doses.

我是代 Kripa 發問的 Anna。關於 621 只有一個問題。我知道你們尚未揭露將要推進的劑量，但我想請問你們是否能讓我們了解一下，你們希望用這三個劑量呈現的劑量反應範圍大概是什麼？

Yes. So I don't think we're going to get into it. I think we always think about the opportunity to explore a lower dose in which you'll see less activity for both kind of mechanistic and regulatory reasons. And then obviously, a dose that would be optimal to move forward within the three doses. And so that's how we're thinking about the dose selection.

是的。所以我想我們不會深入談這個。我們一向會考慮探索一個較低劑量的機會，在那個劑量下你會看到較少的活性，這同時出於機轉與法規方面的原因。然後很明顯地，也會有一個在這三個劑量中最適合往前推進的最佳劑量。所以我們就是這樣在思考劑量選擇。

Brian Abrahams, RBC.

Brian Abrahams，RBC。

So on 579, as you think about optimizing its therapeutic window, you mentioned you'll be looking at degradation and some of the biomarkers. Anything specific that you're going to be looking out for on the side effect side there, just based on the mechanistic or preclinical data? Is it just over-suppression of the immune system or any other things that IRF5 or the other IRFs may be involved in metabolism, epithelial cells, et cetera? Thank you.

關於 579，當你們在思考如何最佳化其治療窗時，你提到會觀察降解以及一些生物標記。就副作用面向而言，基於機轉或臨床前數據，你們會特別留意哪些具體事項嗎？是單純免疫系統過度抑制，還是 IRF5 或其他 IRFs 可能也參與代謝、上皮細胞等其他面向？謝謝。

So based on preclinical data, we really haven't seen in animals at least adverse events of meaningful impact. And so -- or any actually. And so the question is always this theoretical infection risk. We know that all the IRFs are contributing to pathogen surveillance. And so we believe that removing only one should not have an impact on that.

所以基於臨床前數據，至少在動物中我們確實沒有看到具有實質影響的不良事件。也就是——或者其實根本沒有看到任何不良事件。所以問題總是落在這個理論上的感染風險。我們知道所有 IRFs 都有助於病原體監測。因此我們相信，只移除其中一個不應該會對此造成影響。

So I think that's -- we'll see, obviously, as things progress. But we don't expect any particular adverse event here with this drug of note.

所以我想就是——當然，隨著進展我們會看到結果。但我們不預期這個藥會出現任何特別值得注意的不良事件。

Our next question will come from Tazeen Ahmad with Bank of America.

我們的下一個問題來自美國銀行（Bank of America）的 Tazeen Ahmad。

My apologies. We now have Derek Archila from Wells Fargo.

抱歉。我們現在有 Wells Fargo 的 Derek Archila。

This is Hao calling in for Derek, thank you for the question. So we were at AAD and we hear also KOL noting KT-621 as the most promising candidates in AD. A question on the efficacy. I think they wanted perfect safety. On the efficacy side, I think we are hearing that even if it's less effective as to -- some of them point to 70% as effective, others using Otezla as an example, they will still be very excited.

我是代 Derek 來電的 Hao，謝謝讓我提問。所以我們在 AAD，也聽到 KOL 提到 KT-621 是 AD 領域最有前景的候選藥之一。關於療效我有個問題。我想他們希望安全性要完美。在療效方面，我們聽到的是，即使它的效果不如——有些人指向 70% 的有效性，另一些人以 Otezla 為例——他們仍然會非常興奮。

So I guess my question is like what you are hearing on what's enough to kind of really mobilizing those patients with not on biology, but be open to this oral option.

所以我想問的是，你們聽到的門檻是什麼：什麼樣的效果才足以真正動員那些目前未使用生物製劑的病患，並讓他們願意接受這個口服選項？

Yes. I mean you said it. I think I agree with you. And obviously, we've heard the same things. which is you don't need to have biologics like efficacy to mobilize millions of patients from topical therapy.

是的。我的意思是，你已經說中了。我想我同意你。而且很明顯，我們也聽到相同的看法：你不需要達到生物製劑等級的療效，就能把數百萬名病患從外用治療動員起來。

Again, the only reason why we keep pointing to a dupi-like profile is because this is the data we've seen so far. But if we end up seeing less, I think this could still be a huge drug in the space.

再說一次，我們之所以一直指向類似 dupi 的特徵，只是因為那是我們目前看到的數據。但如果最後看到的效果更低，我認為它在這個領域仍可能是一個非常重磅的藥物。

Thank you. Well, that's all we have time for questions for now. So I'd now like to turn the call over to Nello Mainolfi for closing remarks.

謝謝。好的，我們目前的提問時間就到這裡。接下來我想把電話交給 Nello Mainolfi 做結語。

Well, thanks, everybody. I'm sorry, we kind of ran out of time, and hopefully, we didn't leave anybody behind. But we're always available to take more questions offline. Thanks again for following us and for all the engaging questions, and see you soon on the next one.

好的，謝謝各位。很抱歉，我們時間有點不夠了，希望沒有漏掉任何人。不過我們隨時都可以在會後再回答更多問題。再次感謝大家關注我們、提出這麼多有深度的問題，我們下次再見。