Kymera Therapeutics Inc (KYMR) 2025 Q2 法說會逐字稿

Good day, everyone. My name is Olivia, and I will be your conference operator today. At this time, I would like to welcome you to the Kymera Therapeutics second quarter 2025 results call. (Operator Instructions)

大家好。我叫奧莉維亞，今天我將擔任您的會議主持人。現在，我歡迎您參加 Kymera Therapeutics 2025 年第二季業績電話會議。（操作員指示）

At this time, I would like to turn the call over to Bruce Jacobs, Chief Financial Officer.

現在，我想將電話轉給財務長布魯斯·雅各布斯 (Bruce Jacobs)。

Good morning. I'm Bruce Jacobs, and I'm kicking off this in place of Justine Koenigsberg, our Head of IR, who is out today. Joining me this morning are Nello Mainolfi, Founder, President and CEO; and Jared Gollob, our Chief Medical Officer.

早安.我是布魯斯·雅各布斯 (Bruce Jacobs)，我將代替今天缺席的投資者關係主管賈斯汀·柯尼斯堡 (Justine Koenigsberg) 開始這次會議。今天早上與我一起出席的還有創辦人、總裁兼執行長 Nello Mainolfi 和首席醫療官 Jared Gollob。

Following our prepared remarks, we'll open the call to questions from our publishing analysts. (Event Instructions)

在我們準備好發言之後，我們將開始回答出版分析師的問題。（活動須知）

Before we begin, I'd 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. The 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.

在我們開始之前，我想提醒大家，今天的討論將包括關於我們未來期望、計劃和前景的前瞻性陳述。這些聲明受風險和不確定性的影響，可能導致實際結果與預測結果有重大差異。這些風險的描述可以在我們向美國證券交易委員會提交的最新 10-Q 報告中找到。任何前瞻性陳述僅代表截至今日的觀點，我們不承擔更新今日電話會議所作任何前瞻性陳述的義務。

With that, I'll turn the call over to Nello.

說完這些，我會把電話轉給 Nello。

Thanks, Bruce, and thank you for joining us this morning. As I mentioned at the beginning of the year, we set ourselves up for a very productive and exciting 2025 and we’re delivering on that promise. The updates we’ve shared in the first half of the year represent a powerful validation of Kymera’s innovative and disciplined approach to drug development within the biopharma industry, while paving the way for our future progress across our high-impact immunology pipeline.

謝謝，布魯斯，感謝您今天早上加入我們。正如我在年初提到的那樣，我們為富有成效和令人興奮的 2025 年做好了準備，我們正在兌現這一承諾。我們在上半年分享的最新消息有力地驗證了 Kymera 在生物製藥行業內對藥物開發的創新和嚴謹方法，同時也為我們未來在高影響力免疫學管道方面的進展鋪平了道路。

We’re committed to leveraging the unique capabilities we have developed to unlock disease biology and deliver groundbreaking oral degrader medicines for areas not served well by existing technologies. Today’s immunology treatment landscape still leaves millions of patients without adequate options, forcing difficult trade-offs between efficacy, safety, cost, and convenience.

我們致力於利用我們開發的獨特能力來揭示疾病生物學，並為現有技術無法很好服務的領域提供突破性的口服降解藥物。當今的免疫治療領域仍然讓數百萬患者沒有足夠的選擇，不得不在療效、安全性、成本和便利性之間做出艱難的權衡。

Millions of patients with life altering immune-inflammatory diseases don’t have access to advanced systemic therapies, mostly injectable biologics. This is true if we look across countries with extremely diverse systems on how they prescribe, reimburse and deliver these highly effective medicines. The issue is clearly more fundamental than the inefficiencies of the healthcare ecosystems around the world. Simply put, well-tolerated, oral drugs that can be as effective as these difficult to access injectable biologics have the potential to transform the treatment landscape and in doing so impact lives of millions of patients.

數百萬患有改變生活的免疫發炎疾病的患者無法獲得先進的全身性治療，主要是注射生物製劑。如果我們觀察一下各國在開立、報銷和提供這些高效藥物方面的製度差異極大的話，就會發現事實確實如此。這個問題顯然比全球醫療保健生態系統的低效率更為根本。簡而言之，耐受性良好、效果與這些難以獲得的注射生物製劑一樣有效的口服藥物有可能改變治療格局，從而影響數百萬患者的生活。

This is what we are set to do at Kymera. It’s an exciting time for the company and I want to take a moment to briefly recap some of the key accomplishments of the first half of 2025.Starting with our first-in-class STAT6 program. We completed the first KT-621 trial in healthy volunteers and reported positive results that exceeded even our highest expectations, surpassing our target product profile.

這就是我們在 Kymera 要做的事。對於公司來說，這是一個激動人心的時刻，我想花點時間簡要回顧一下 2025 年上半年的一些主要成就。首先從我們一流的 STAT6 計畫開始。我們在健康志願者中完成了首次 KT-621 試驗，並報告了超出我們最高預期的積極結果，超出了我們的目標產品概況。

Importantly, the data further derisks our path forward and highlights the possibility of KT-621’s dupilumab-in-a-pill profile. As potential first-in-class treatment, we believe KT-621 has the ability to be a broadly accessible oral option for many dermatologic and respiratory diseases like AD and asthma.

重要的是，這些數據進一步降低了我們前進的風險，並凸顯了 KT-621 作為 dupilumab 片劑產品的可能性。作為潛在的同類首創治療方法，我們相信 KT-621 能夠成為治療多種皮膚病和呼吸系統疾病（如阿茲海默症和氣喘）的廣泛可用的口服藥物。

In addition, for Japanese regulatory purposes, we recently completed a second, small healthy volunteer study in Japanese subjects with results that were consistent with the US study. You can expect that we’ll present these findings at a future medical meeting.

此外，出於日本監管目的，我們最近完成了第二次針對日本受試者的小規模健康志願者研究，其結果與美國的研究一致。您可以期待我們將在未來的醫學會議上展示這些發現。

We also wanted to share a few updates regarding the KT-621 Phase 1b BroADen study in moderate to severe AD patients. As noted in the release, the patient data we plan to share will include data from two different dose groups. While we initially set out to explore a single dose, the speed at which the trial enrolled allowed us to evaluate the translation from healthy volunteers into patients more broadly, which we believe gives us an even richer data set to inform our Phase 2b dose choices, which was an important goal of this study.

我們也想分享一些針對中度至重度 AD 患者的 KT-621 1b 期 BroADen 研究的最新消息。如新聞稿中所述，我們計劃共享的患者數據將包括來自兩個不同劑量組的數據。雖然我們最初打算探索單劑量，但試驗招募的速度使我們能夠更廣泛地評估從健康志願者到患者的轉化，我們相信這為我們提供了更豐富的數據集，可以為我們的 2b 期劑量選擇提供參考，這是本研究的一個重要目標。

The Phase 1b was designed with a flexible protocol that contemplated this scenario, allowing us to make this choice without impacting timelines, and as a result we are well-positioned to report results in the fourth quarter, as planned.

第 1b 階段採用了靈活的協議來設計，考慮到了這種情況，使我們能夠在不影響時間表的情況下做出這一選擇，因此我們能夠按照計劃在第四季度報告結果。

I am also happy to share that we have selected and finalized the three doses that will be included in the two Phase 2b studies as well as completed long-term toxicity studies. These were really the final important pieces for our planning to start the studies beginning later this year.

我也很高興地告訴大家，我們已經選定並確定了將納入兩項 2b 期研究的三種劑量，並且已經完成了長期毒性研究。這些確實是我們計劃在今年稍後開始研究的最後的重要部分。

Given we are moving into the data collection and analysis mode soon, we are going to limit our comments around the study to what we have said previously until we are able to share the full results in the fourth quarter. But we can certainly say that we are pleased with the speed at which this trial has enrolled, very excited about the trajectory of the program, and we look forward to sharing the full data set when it’s available.

鑑於我們很快就會進入資料收集和分析模式，我們將把對研究的評論限制在我們之前所說的內容上，直到我們能夠在第四季度分享完整的結果。但我們可以肯定地說，我們對這次試驗的招募速度感到滿意，對該計劃的發展軌跡感到非常興奮，我們期待在完整數據集可用時與其分享。

The additional piece of news to share is that we have selected a follow-on STAT6 degrader to KT-621, with a strong potency, selectivity, and safety profile, and have advanced it through all required IND-enabling studies. The degrader is IND-ready should we decide to further advance it into the clinic in the future.

另外要分享的消息是，我們已經選擇了 KT-621 的後續 STAT6 降解劑，它具有強大的效力、選擇性和安全性，並且已經通過了所有必需的 IND 支持研究。如果我們決定在未來進一步推進此降解劑的臨床研究，那麼它已經準備好進行 IND 了。

More broadly, we’re building what we believe is the best in industry oral immunology pipeline, and beyond STAT6, we’re also very excited about what’s next. Earlier this year, we’ve unveiled our oral IRF5 program, which is moving through IND-enabling studies. The compelling preclinical data we have generated showcases that targeting IRF5 can lead to correcting immune dysregulation across multiple disease pathologies while generally sparing normal cells.

更廣泛地說，我們正在建立我們認為是業內最好的口服免疫學管道，除了 STAT6 之外，我們對下一步的發展也感到非常興奮。今年早些時候，我們推出了口服 IRF5 項目，該項目正在進行 IND 支持研究。我們產生的令人信服的臨床前數據顯示，針對 IRF5 可以糾正多種疾病病理中的免疫失調，同時通常保留正常細胞。

And it remains our goal to progress our early discovery pipeline of novel immunology programs, unveiling one new program per year, to expand access to oral systemic advanced therapies for broad patient populations in the space. We hope to share more about this next year.

我們的目標仍然是推進新型免疫學計畫的早期發現，每年推出一個新項目，以擴大該領域廣大患者群體獲得口服系統性先進療法的機會。我們希望明年能分享更多相關資訊。

Additionally, we announced two important partnership updates in June. First, we were very excited to announce our first oral molecular glue degrader program, targeting CDK2, will be developed under our collaboration agreement with Gilead. We have a highly innovative research engine and the CDK2 program is a great example of this given the challenges of existing technologies to address this high value target.

此外，我們在六月宣布了兩項重要的合作夥伴關係更新。首先，我們非常高興地宣布，我們的第一個口服分子膠降解劑項目，針對 CDK2，將根據我們與 Gilead 的合作協議進行開發。我們擁有高度創新的研究引擎，而 CDK2 計畫就是一個很好的例子，因為它證明了現有技術在解決這個高價值目標方面所面臨的挑戰。

With our focus in immunology, this program was an ideal candidate for partnering. We and Gilead believe that a highly specific, safe and effective CDK2 degrader has exciting potential to meaningfully improve treatment for patients living with breast cancer and other solid tumors that are inadequately treated today.

由於我們專注於免疫學，因此該計畫是合作的理想候選者。我們和吉利德相信，高度特異性、安全有效的 CDK2 降解劑具有令人興奮的潛力，可以顯著改善目前未充分治療的乳癌和其他實體腫瘤患者的治療。

Secondly, Sanofi announced that they officially opted in into the IRAK4 program and will assume full responsibility for development activities of KT-485, our second generation oral IRAK4 degrader, which we expect to advance into Phase 1 testing next year. Based on our preclinical results, KT-485 has greater potency, broader distribution, and a generally improved overall profile than KT-474, our first-generation degrader.

其次，賽諾菲宣布正式加入IRAK4項目，並將全權負責我們第二代口服IRAK4降解劑KT-485的開發活動，預計該藥物將於明年進入第一階段測試。根據我們的臨床前結果，KT-485 比我們的第一代降解劑 KT-474 具有更強的效力、更廣泛的分佈和整體改善的整體特性。

As a result, Sanofi made the decision not to advance ‘474 in further development as KT-485 has the greatest potential benefit for patients. Both these collaborations have the potential to realize significant milestones for Kymera, which Bruce will cover later in the call, and we’re very happy to collaborate with two industry leaders on these novel programs.

因此，賽諾菲決定不再進一步開發 474，因為 KT-485 對患者的潛在益處最大。這兩次合作都有可能為 Kymera 實現重要的里程碑，Bruce 將在稍後的電話會議中介紹，我們非常高興與兩位行業領袖合作開展這些新穎的項目。

Finally, to support all we have ahead of us, we’ve extended our cash runway into the second half of 2028. We raised approximately $288 million in a follow-on offering that we launched at the end of June, and received the upfront payment from Gilead, increasing our cash position to $1 billion as of the end of July. Our well-capitalized balance sheet should allow us not only to take KT-621 through the planned Phase 2b studies in AD and asthma but also to prepare for and initiate several Phase 3 studies across multiple indications, while also progressing our earlier stage pipeline.

最後，為了支持我們未來的一切，我們將現金流延長至 2028 年下半年。我們在 6 月底啟動的後續發行中籌集了約 2.88 億美元，並收到了吉利德的預付款，使我們的現金頭寸截至 7 月底增加到 10 億美元。我們資本充足的資產負債表不僅使我們能夠將 KT-621 推進到計劃中的 AD 和氣喘 2b 期研究，而且還能夠準備和啟動多個適應症的幾項 3 期研究，同時推進我們早期的研發管線。

As you have heard me say before, our strategy centers on combining the unique power of targeted protein degradation with carefully selected targets and pathways to create a transformative new class of medicines. By focusing on immunology, we’re not only addressing large patient populations, but also meeting a significant unmet need to create effective, safe, oral therapies. We believe our approach has the potential to deliver, for the first time in our industry, biologics-like efficacy with the ease and convenience of an oral pill.

正如您之前聽我說過的那樣，我們的策略是將靶向蛋白質降解的獨特能力與精心選擇的目標和途徑相結合，以創造出一種變革性的新型藥物。透過專注於免疫學，我們不僅解決了大量患者的問題，而且還滿足了創造有效、安全的口服療法這一重大未滿足需求。我們相信，我們的方法有可能在我們行業中首次實現類似生物製劑的功效，同時又具有口服藥丸的簡單性和便利性。

Again, I couldn’t be more excited about the foundation we built and where we are going. I am looking forward to the Q&A discussion but let me pause here for Jared to discuss KT-621 and our pipeline. Jared?

再說一次，我對我們所建立的基礎和我們的發展方向感到無比興奮。我期待問答討論，但請允許我在這裡暫停一下，讓 Jared 討論一下 KT-621 和我們的管道。賈里德？

Thanks, Nello. Looking back on the last quarter, we were excited to share the first KT-621 clinical data, which we believe greatly derisks the next stage of development. We identified clear goals for the Phase 1 healthy volunteer study and the data not only hit the mark, but in many instances exceeded our expectations with compelling translation from preclinical studies to humans.

謝謝，尼洛。回顧上個季度，我們很高興分享第一批 KT-621 臨床數據，我們相信這大大降低了下一階段開發的風險。我們為第一階段健康志願者研究確定了明確的目標，數據不僅達到了目標，而且在許多情況下超出了我們的預期，從臨床前研究到人體的轉化效果令人信服。

The primary objective in the healthy volunteer study was to show that we can robustly degrade STAT6 in blood and skin, which we define as a reduction of 90% or more, at doses that are safe and well tolerated. As shown here, the results exceeded our expectations across every measure.

健康志願者研究的主要目標是證明我們能夠在安全且耐受性良好的劑量下，強力降解血液和皮膚中的 STAT6，我們將其定義為減少 90% 或更多。如圖所示，結果在各方面都超出了我們的預期。

We showed more than 95% degradation in both skin and blood at very low doses. The safety profile was undifferentiated from placebo. And we are encouraged by the biomarker profile which we believe is at least comparable to what dupilumab showed in healthy volunteers or patients and in some cases is superior.

我們發現，在極低劑量下，皮膚和血液中的降解率均超過 95%。安全性與安慰劑無異。我們對生物標記概況感到鼓舞，我們相信它至少與 dupilumab 在健康志願者或患者身上表現出的情況相當，並且在某些情況下更為優越。

That said, I’d like to take a few minutes this morning to recap the results and next steps with KT-621, which we believe has the potential to profoundly alter how TH2 diseases are treated by delivering an oral drug with a biologics-like profile. For the full data set, please reference the slides presented in early June, which are available on our website.

話雖如此，今天早上我想花幾分鐘時間回顧 KT-621 的結果和後續步驟，我們相信，透過提供具有類似生物製劑特性的口服藥物，它有可能徹底改變 TH2 疾病的治療方式。如需完整資料集，請參閱我們網站上六月初提供的幻燈片。

As a reminder, we enrolled 118 volunteers in a randomized, double-blind, placebo-controlled study to assess single- and multiple-ascending doses of KT-621 across a range of doses from 6.25 margin to 800 mg in SAD and from 1.5 margin to 200 mg in MAD. In all SAD cohorts, including the lowest dose of 6.25 mg, KT-621 degraded STAT6 by 90% or more, and at doses of 75 mg or greater achieved complete degradation, with greater than 95% mean STAT6 reduction and STAT6 levels below the lower limit of quantification in multiple subjects after just a single dose.

提醒一下，我們招募了 118 名志願者參加一項隨機、雙盲、安慰劑對照研究，以評估 KT-621 的單次和多次遞增劑量，SAD 中的劑量範圍為 6.25 邊緣至 800 毫克，MAD 中的劑量範圍為 1.5 邊緣至 200 毫克。在所有 SAD 隊列中，包括最低劑量 6.25 毫克，KT-621 使 STAT6 降解了 90% 或更多，並且在 75 毫克或更高劑量下實現完全降解，僅一次劑量後，平均 STAT6 減少量超過 95%，並且多個受試者的 STAT6 水平低於量化下限。

In MAD, where volunteers were dosed daily over two weeks, we were able to completely degrade STAT6 in both blood and skin at doses of 50 mg and above. In fact, to establish the lower end of the dose response curve, we had to go back aIer the initial cohorts and add the 1.5 mg MAD cohort given none of the initially planned doses had less than 90% degradation.

在 MAD 中，志願者在兩週內每天接受劑量治療，我們能夠在 50 毫克及以上的劑量下完全降解血液和皮膚中的 STAT6。事實上，為了確定劑量反應曲線的下端，我們必須回到初始隊列之後，並添加 1.5 毫克 MAD 隊列，因為最初計劃的劑量都沒有低於 90% 的降解。

The robust degradation of STAT6 led to functional inhibition of the IL-4/13 pathway as demonstrated by median reductions of up to 37% for TARC and up to 63% for Eotaxin-3 at Day 14, a result that was comparable or superior to what has been observed for dupilumab either in healthy volunteers or in patients with TH2 diseases.

STAT6 的強烈降解導致 IL-4/13 路徑的功能性抑制，表現為第 14 天 TARC 的中位數減少量高達 37%，Eotaxin-3 的中位數減少量高達 63%，這一結果與在健康志願者或 TH2 疾病患者中觀察到的 dupilumab 的結果相當或更好。

Importantly, whether treated at the lowest or highest dose, or anywhere in between, the safety profile was undifferentiated from placebo. There were no serious adverse events, very few treatment-related adverse events that were mild, no treatment-related discontinuations, and no clinically relevant changes in vital signs, laboratory tests or ECGs with daily dosing up to 200 mg, which is 16-fold above the lowest MAD dose with greater than 90% degradation.

重要的是，無論是以最低劑量還是最高劑量，還是介於兩者之間的任何劑量進行治療，其安全性與安慰劑沒有區別。在每日劑量高達 200 毫克（比最低 MAD 劑量高出 16 倍且降解率超過 90%）的情況下，未出現嚴重不良事件，治療相關不良事件極少且較為輕微，未出現治療相關停藥，生命徵象、實驗室檢查或心電圖也未出現臨床相關變化。

As many of you have asked, we are also happy to share that we recently completed our four-month GLP toxicology study and, consistent with our earlier non-GLP and GLP tox studies, we did not see any adverse events of any type at all of the doses tested. This study completes the necessary preclinical work to allow us to initiate the Phase 2b trials planned to start later this year and early next.

正如許多人所問，我們也很高興地告訴大家，我們最近完成了為期四個月的 GLP 毒理學研究，與我們先前的非 GLP 和 GLP 毒理學研究一致，我們在所有測試劑量下均未發現任何類型的不良事件。這項研究完成了必要的臨床前工作，使我們能夠啟動計劃於今年稍後和明年年初開始的 2b 期試驗。

Prior to reporting the healthy volunteer data, we initiated a 28-day Phase 1b trial, named BroADen, which was designed to enroll approximately 20 moderate to severe atopic dermatitis patients. We’ve had a high level of engagement from sites on the trial and are pleased to report that we are on track to share data in the fourth quarter.

在報告健康志願者數據之前，我們啟動了一項為期 28 天的 1b 期試驗，名為 BroADen，旨在招募約 20 名中度至重度異位性皮膚炎患者。我們從試驗站點獲得了高度參與，並很高興地報告，我們將在第四季度共享數據。

As a reminder, the key study aim is to show that robust STAT6 degradation in blood and skin lesions by KT-621 has a dupilumab-like effect on multiple TH2 biomarkers in the blood, TARC being the most relevant in AD patients, as well as on the TH2 transcriptome of active AD skin lesions. We will also assess KT-621's effect on clinical endpoints, such as EASI and pruritus NRS.

提醒一下，關鍵研究目的是證明 KT-621 導致血液和皮膚病變中的 STAT6 強烈降解，對血液中的多種 TH2 生物標記具有類似 dupilumab 的作用，其中 TARC 與 AD 患者最為相關，並且對活動性 AD 皮膚病變的 TH2 轉錄組也具有類似作用。我們也將評估 KT-621 對 EASI 和搔癢 NRS 等臨床終點的影響。

Beyond the Phase 1b BroADen study which, again, is designed as a streamlined biomarker-focused study, we are planning parallel Phase 2b dose range-finding trials to enable subsequent registrational Phase 3 studies across multiple indications.

除了 1b 期 BroADen 研究（該研究同樣被設計為一項簡化的以生物標記為重點的研究）之外，我們還計劃進行平行的 2b 期劑量範圍探索試驗，以便隨後針對多種適應症進行註冊 3 期研究。

As Nello mentioned, we have selected the three doses for the studies, and our STAT6 team has done a remarkable job keeping this program moving at a rapid pace, including all the necessary work to initiate two global Phase 2b trials. The AD Phase 2b trial will begin in the fourth quarter this year and the asthma study is expected to initiate in the first quarter of 2026.

正如 Nello 所提到的，我們已經選擇了三種劑量進行研究，我們的 STAT6 團隊出色地完成了這項工作，使該計畫保持快速進展，包括啟動兩項全球 2b 期試驗所需的所有工作。AD 2b 期試驗將於今年第四季開始，氣喘研究預計將於 2026 年第一季啟動。

And quickly on the IRF5 program. Historically an undrugged transcription factor and genetically validated target, IRF5 is a master regulator of innate and adaptive immune response pathways involving pro-inflammatory cytokines, B cell activation and autoantibody production, and Type I Interferons. We believe IRF5 degradation has the potential to be the first broad anti-inflammatory mechanism that effectively addresses immune dysregulation while sparing normal cell function.

並快速啟動IRF5程式。IRF5 歷來是一種未經藥物治療的轉錄因子和經過基因驗證的靶點，它是涉及促炎細胞因子、B 細胞活化和自身抗體產生以及 I 型乾擾素的先天性和適應性免疫反應途徑的主要調節器。我們相信 IRF5 降解有可能成為第一個有效解決免疫失調同時保留正常細胞功能的廣泛抗發炎機制。

KT-579, our potent, selective and oral degrader, has the potential to be the first IRF5-targeted therapy to deliver a completely novel and potentially transformative treatment option, in many cases superior to pathway biologics, in a range of autoimmune and rheumatic indications such as lupus, RA, Sjogren’s and others.

KT-579 是我們強效、選擇性和口服降解劑，有可能成為第一個針對 IRF5 的療法，為一系列自體免疫和風濕病（如狼瘡、類風濕性關節炎、乾燥綜合徵等）提供全新且具有變革性的治療選擇，在許多情況下優於通路生物製劑。

This program is progressing in IND-enabling studies, and we expect to advance KT-579 into Phase 1 testing in early 2026 with what we believe will be the first oral IRF5 degrader to enter the clinic.

該計畫正在 IND 支持研究中取得進展，我們預計將於 2026 年初將 KT-579 推進到第 1 階段測試，我們相信這將是第一個進入臨床的口服 IRF5 降解劑。

Across our portfolio, we see strong potential to advance multiple first-in-class oral degraders that address major market opportunities in immunology. Our STAT6 and IRF5 programs represent significant advancements, not only for our pipeline, but for the industry and patients, as we look to deliver the first oral therapies with biologics-like profiles in immunology.

在我們的產品組合中，我們看到了推進多種一流口服降解劑的巨大潛力，這些降解劑可以解決免疫學領域的主要市場機會。我們的 STAT6 和 IRF5 計畫代表著重大進步，不僅對我們的產品線而言，而且對整個產業和患者而言，因為我們希望提供第一種在免疫學方面具有類似生物製劑特性的口服療法。

We’re excited about their continued progress and remain focused on our goal of expanding access to transformative treatments for millions of patients. So let me pause here and Bruce will review our second quarter financial results and provide a collaboration overview. Bruce?

我們對他們不斷取得的進步感到興奮，並將繼續專注於我們的目標，即讓數百萬患者能夠獲得變革性的治療。所以請允許我在這裡暫停一下，布魯斯將回顧我們第二季度的財務表現並提供合作概述。布魯斯？

Thanks, Jared. I will quickly run through our results for the quarter. Also, because this past quarter has been busy with collaboration and financing activity, I wanted to provide a brief summary of our recent news as well. As I walk through the second quarter results, please reference the tables found in today’s press release and 10-Q, which was filed this morning.

謝謝，賈里德。我將快速回顧本季的業績。此外，由於過去一個季度一直忙於合作和融資活動，所以我想簡要概述我們的最新消息。當我介紹第二季的業績時，請參考今天的新聞稿和今天早上提交的 10-Q 表中的表格。

Revenue in the second quarter of 2025 was $11.5 million, all of which was attributable to the Sanofi collaboration. With respect to operating expenses, R&D for the quarter was $78.4 million. Of that, approximately $8.0 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $70.4 million, which excludes that stock-based comp, reflects a 3% decrease from the comparable amount in the first quarter of 2025.

2025 年第二季的營收為 1,150 萬美元，全部歸功於與賽諾菲的合作。就營運費用而言，本季研發費用為 7,840 萬美元。其中約 800 萬美元為非現金股票薪酬。調整後的現金研發支出為 7,040 萬美元（不包括股票補償），較 2025 年第一季的可比金額下降 3%。

On the G&A side, our spending for the quarter was $17.6 million, of which $7.4 million was non-cash stock-based comp. The adjusted cash G&A spend of $10.2 million, again, excluding that stock-based compensation, reflects a 6% increase from the comparable amount in the prior quarter.

在一般及行政費用方面，我們本季的支出為 1,760 萬美元，其中 740 萬美元為非現金股票補償。調整後的現金 G&A 支出為 1,020 萬美元，同樣不包括股票薪酬，比上一季的可比金額增加了 6%。

Overall, adjusted operating expenses were down slightly from the prior sequential quarter. We ended June with a cash balance of $963 million. Our quarter-end cash balance included the base proceeds from our $250 million follow-on offering that closed at the end of June. The June total does not include either the additional proceeds from the underwriters’ overallotment option, which was fully exercised in July, or the first payment that we received from Gilead as part of our recently signed CDK2 partnership, both of which were received in July.

整體而言，調整後的營運費用較上一季略有下降。截至 6 月底，我們的現金餘額為 9.63 億美元。我們的季度末現金餘額包括 6 月底結束的 2.5 億美元後續發行的基本收益。6 月的總金額不包括承銷商超額配售選擇權的額外收益（該收益已於 7 月全部行使）或我們作為最近簽署的 CDK2 合作夥伴關係的一部分從吉利德收到的第一筆付款，這兩項款項均於 7 月收到。

As a result, we ended the month of July with a cash balance of approximately $1 billion, providing a cash runway into the second half of 2028. Just a quick reminder that our runway calculations exclude any unearned milestones. And with that in mind, I'd like to take you briefly through the key financial terms of our two collaboration agreements.

因此，截至 7 月底，我們的現金餘額約為 10 億美元，為 2028 年下半年提供了現金儲備。只需快速提醒一下，我們的跑道計算不包括任何未達到的里程碑。考慮到這一點，我想向您簡要介紹我們兩項合作協議的主要財務條款。

Starting with Gilead. Under our collaboration, we are eligible to receive up to $750 million in total payments, in addition to tiered royalties on net product sales that range from the high single digits to the mid-teens. This $750 million includes $85 million related to the upfront payment, which was received in July, and you can see on our balance sheet shown as deferred revenue, and the potential option exercise.

從吉利德開始。根據我們的合作，我們有資格獲得高達 7.5 億美元的總額付款，此外還可獲得從高個位數到十幾歲的中等淨產品銷售額的分級特許權使用費。這 7.5 億美元包括 7 月收到的 8,500 萬美元預付款，您可以在我們的資產負債表上看到它顯示為遞延收入和潛在的選擇權行使。

If Gilead chooses to exercise its option for an exclusive license, they will assume global rights to develop, manufacture, and commercialize all products arising from the collaboration.

如果吉利德選擇行使其獨家許可權，他們將獲得開發、製造和商業化合作產生的所有產品的全球權利。

Turning to Sanofi and the development of KT-485. Under the existing collaboration, we could earn up to $975 million in clinical, regulatory, and commercial milestones for KT-485. We retain the right to opt into a 50/50 cost and profit share in the US prior to the first Phase 3 trial, in addition to international royalties. If we decide not to opt-in, we would instead be entitled to worldwide royalties ranging from the low double digits up to the high teens.

談到賽諾菲和 KT-485 的開發。根據現有的合作，我們可以在 KT-485 的臨床、監管和商業里程碑中賺取高達 9.75 億美元的收入。除國際特許權使用費外，我們還保留在第一次 3 期試驗之前在美國選擇 50/50 成本和利潤分成的權利。如果我們決定不加入，我們將有權獲得從兩位數低點到十幾位高位不等的全球版稅。

To conclude, as you’ve heard today, there’s a great deal of momentum across our programs. And, importantly, we have the resources in place to continue executing on our development strategy and the progression of our earlier stage pipeline. With that, we’ll pause here so we can convene in our main conference room, at which point we will open the call for questions. Thank you.

總而言之，正如大家今天所聽到的，我們的各項計畫都呈現出強勁的發展動能。而且，重要的是，我們擁有足夠的資源來繼續執行我們的發展策略和早期階段的管道進展。說到這裡，我們將在這裡暫停一下，以便我們可以在主會議室召開會議，屆時我們將開始提問。謝謝。

(Operator Instructions)

（操作員指示）

Michael Schmidt, Guggenheim.

古根漢美術館的麥可·施密特。

It's Paul on for Michael. I had one on the dose levels that you're exploring for '621. Maybe first, could you provide some color on that decision to add the second dose in the Phase Ib study, I think it's probably safe to assume that both the doses fall within the broad range that achieved complete STAT6 degradation, but just wondering how you're thinking about exploring both the high and the low dose, which is perhaps two doses in the higher range?

保羅替換邁克爾。我有一個關於你正在探索的‘621’劑量水平的信息。首先，您能否解釋一下在 Ib 期研究中添加第二劑的決定，我認為可以安全地假設這兩種劑量都屬於實現完全 STAT6 降解的廣泛範圍，但我只是想了解您是如何考慮探索高劑量和低劑量的，這可能是較高範圍內的兩種劑量？

Yes. Thanks, Michael. We want to make sure we're -- you can hear us. So as we said today, so the doses -- both doses are within the range that we explored in the Phase I healthy volunteer study. And as we've also said, as you're aware, we had initially decided to explore one dose, thinking that roughly 20 patients will be enough to give us the data to speak to what is the profile of that one dose.

是的。謝謝，麥可。我們希望確保──你們能聽到我們的聲音。正如我們今天所說的，兩種劑量都在我們在第一階段健康志願者研究中探索的範圍內。正如我們所說，如您所知，我們最初決定探索一種劑量，認為大約 20 名患者就足以為我們提供數據來說明該劑量的特性。

And then obviously, as we were moving along with the enrollment and given how quickly it was going and given that we were able to assess the performance in the one dose, we decided to explore an additional dose so that we'll get even robust translation from healthy volunteer to patients of STAT6 degradation.

然後顯然，隨著我們進行招募，考慮到進展速度如此之快，並且我們能夠評估單劑量的效果，我們決定探索額外的劑量，以便從健康志願者到 STAT6 降解患者獲得更穩健的轉化。

I think it's important to keep in mind that in the healthy volunteer data, we had multiple doses. I would say, almost all those doses besides one met our target product profile. And so we wanted to confirm that the really, really robust profile could be translated into patients with the same level of fidelity. And so I think we're happy that we did that.

我認為重要的是要記住，在健康志願者的數據中，我們有多次劑量。我想說，除了一種劑量之外，幾乎所有劑量都符合我們的目標產品特性。因此，我們想確認，這個非常、非常強大的配置文件是否可以轉化為具有相同保真度的患者。所以我認為我們很高興我們這樣做了。

Obviously, I'm not going to speak too high, low, medium, et cetera. Rest assured that the main goal was really to refine the Phase IIb dose selection. And so all that happened so quickly that now between the healthy volunteer data and whatever data we have access from this study, we're able to firm up and select the Phase IIb doses even in the absence of completing the Phase Ib study.

顯然，我不會說得太高、太低、太中等等。請放心，主要目標實際上是改進 IIb 期劑量選擇。所以這一切都發生得如此之快，現在透過健康志願者的數據和我們從這項研究中獲得的任何數據，即使沒有完成 Ib 期研究，我們也能夠確定並選擇 IIb 期劑量。

Great. And if I kind of a quick follow-up on that point. And mostly on just what back into the dose selection for the Phase II studies? Was it predominantly the healthy volunteer data you presented? Was there anything emerging from the Japanese studies or GLP tox? Can you say if there's a different range of doses being explored between the AD and the asthma studies.

偉大的。如果我對這一點進行快速跟進。主要是關於第二階段研究的劑量選擇嗎？您提供的主要是健康志工的數據嗎？日本研究或 GLP 毒理學研究有什麼新發現嗎？您能否說說 AD 和氣喘研究之間是否探討了不同的劑量範圍。

Yes. So great question actually. So as you saw, it was a very, very busy Q2. I don't think we've had a busier Q2 in the history of the company, given everything that we've accomplished. So I will say that if you look back at the healthy volunteer data, there was a dose selection based on this data. Everything else that we've done confirm, was able to confirm our initial instinct.

是的。這實際上是一個好問題。正如您所看到的，第二季度非常非常繁忙。考慮到我們所取得的成就，我認為在公司歷史上，我們從未經歷過如此忙碌的第二季。所以我想說，如果你回顧健康志願者的數據，你會發現劑量的選擇是基於這些數據的。我們所做的其他一切都證實了我們最初的直覺。

We didn't learn, to be honest, anything new that made us change the initial instinct, let's say, on dose selection, but it was highly encouraging that everything that we've seen in healthy volunteer was supported by, obviously, the four-month tox, which we said was completely clean. The Japanese study, which was very much in line with the US study and the early -- let's call it, early data for the Phase Ib.

說實話，我們並沒有學到任何新的東西讓我們改變最初的直覺，例如劑量選擇，但令人鼓舞的是，我們在健康志願者身上看到的一切都得到了四個月毒性實驗的支持，我們說這是完全乾淨的。日本的研究與美國的研究以及早期（我們稱之為 Ib 期的早期數據）非常一致。

Derek Archila, Wells Fargo.

德里克·阿奇拉，富國銀行。

Congrats on the progress here. So just one and a follow-up. So basically, I just want to understand maybe following up on this line of questioning just in terms of what you would expect to see at these additional doses that you're looking at in the Phase IIb? Ultimately, like we saw very good degradation and pretty quick. So I guess how do you think some of the doses will differentiate?

恭喜你在這裡的進展。因此，僅一個，然後跟進。所以基本上，我只是想了解一下，也許可以繼續問這個問題，就您期望在 IIb 階段看到的這些額外劑量而言，會發生什麼？最終，我們看到了非常好的退化，而且相當快。那麼我猜您認為不同劑量之間會有什麼區別呢？

And then just a follow-up to that, what do you actually expect to see with the follow-on STAT6 that you're developing? And what sort of optionality are you really looking for with that molecule?

然後接下來的問題是，您對正在開發的後續 STAT6 有什麼期望？您真正尋求的是該分子的什麼可選性？

Great question, Derek. So the first one, I just want to confirm we're talking about the dose for the Phase IIb. So I think the important thing for a drive, obviously, is to find a dose that has the best risk-reward profile. And so I think what we want to ask in a 16 -- let's say, for AD, a 16-week study, is what is the maximal or we believe close to maximal at that point, level of clinical activity that we will see and what is the safety profile at different levels of degradation.

好問題，德瑞克。所以第一個問題，我只想確認我們正在討論 IIb 期的劑量。因此，我認為，對於驅動器來說，重要的顯然是找到具有最佳風險回報特徵的劑量。因此，我認為，在一項為期 16 週的研究中，我們想問的是，對於 AD 來說，最大或我們認為接近最大值的水平是多少，我們將看到的臨床活動水平以及不同退化水平下的安全性概況是什麼。

Obviously, we will explore maximum degradation, which we call complete, which, again, is where really we see in most subjects STAT6 level be below the lower limit of quantitation. So we want to ask that question, what is the clinical profile of maximal degradation? And then obviously, we want to ask the question at a couple of lower doses just to again, at the end of the study, being sure that we're taking into Phase III, the profile that we believe has the best risk reward.

顯然，我們將探索最大程度的降解，我們稱之為完全降解，這也是我們在大多數受試者中看到的 STAT6 水平低於定量下限的情況。所以我們想問這個問題，最大程度退化的臨床特徵是什麼？然後顯然，我們想在幾個較低的劑量下提出這個問題，只是為了在研究結束時再次確保我們進入第三階段，我們認為該方案具有最佳風險回報。

So it's obviously a necessary step that we need to take as a company to fulfill regulatory requirements to do dose ranging studies before selecting a Phase III dose. I think we have bets in the company where the Phase III dose will be already, but we got to run the studies and make sure that we do all the right steps to derisk the program.

因此，作為一家公司，在選擇 III 期劑量之前進行劑量範圍研究顯然是我們需要採取的必要步驟，以滿足監管要求。我認為我們已經對該公司第三階段的劑量下了賭注，但我們必須進行研究並確保我們採取所有正確的步驟來降低該計劃的風險。

With regard to the follow-on molecules. So that's something many of you that has followed us for years know that every program, we always have a next-generation molecule. As you saw for IRAK4, Sanofi decided to focus the efforts on the follow-on, and we call it the next-generation molecule KT-485.

關於後續分子。因此，許多關注我們多年的人都知道，在每個專案中，我們總是會有下一代分子。正如您在 IRAK4 中看到的，賽諾菲決定將精力集中在後續產品上，我們稱之為下一代分子 KT-485。

For STAT6, to be honest, we didn't really have a particular goal with the next-generation compound given how well KT-621 has performed. And this is the reason why we've advanced a very good molecule that, in many ways, looks at least in terms of profile very much like KT-621. It's potent, extremely well tolerated, very active in vivo.

對於 STAT6，說實話，考慮到 KT-621 的出色表現，我們對下一代化合物並沒有特別的目標。這就是我們發展出一個非常好的分子的原因，這種分子在許多方面至少在外形上與 KT-621 非常相似。它功效強大，耐受性極佳，在體內非常活躍。

And the principle is to support the franchise for one is, for the eventual likely scenario that we need another molecule or for a strategic choice of eventually advancing another molecule should we choose to do for different severities or different indications. I think given how well KT-621 is doing, we have decided for now to keep this follow-on molecule IND ready, meaning that we have everything we need to file an IND, but we're not planning to file an IND in the short term.

原則是支持特許經營，一方面，對於最終可能需要另一種分子的情況，或者對於最終推進另一種分子的戰略選擇，我們應該選擇針對不同的嚴重程度或不同的適應症進行治療。我認為，鑑於 KT-621 的良好表現，我們目前決定讓這個後續分子 IND 準備就緒，這意味著我們擁有提交 IND 所需的一切，但我們不打算在短期內提交 IND。

I think another important point in this highly competitive space is STAT6 is becoming, having a molecule line be ready, probably ahead of any other, let's call it, a competitor that is behind us. So we have two molecules ahead of every other competitor. I think he also sends a message how committed the company is to this franchise and to the potential of this franchise.

我認為在這個競爭激烈的領域中另一個重要的點是 STAT6 正在成為一條分子線，可能領先於任何其他人，我們稱之為落後於我們的競爭對手。因此，我們比其他競爭對手領先兩個分子。我認為他也傳達了公司對這個特許經營權以及這個特許經營權的潛力有多麼的承諾。

Andrew Newkirk, Goldman.

高盛的安德魯紐柯克。

Two for me as well. Maybe the first, recognizing the primary objective of the Phase Ib data, is to show a dupi-like profile here on biomarkers, but I was hoping you might be willing to frame your expectations on what you'd like to see on the clinical efficacy measures, particularly EASI-75 as well as NRS.

我也有兩個。也許首先，認識到 Ib 期數據的主要目標是在生物標記上顯示類似 dupi 的概況，但我希望您可能願意根據您希望在臨床療效指標上看到的內容來製定您的期望，特別是 EASI-75 和 NRS。

And then secondly, just noting the completion of the GLP tox studies that you mentioned. And obviously, your Phase I healthy volunteer also looked really clean, but if you could just speak to the potential safety risk of degrading STAT6 completely, what type of signals are you most looking for in the Phase Ib to really feel comfortable here with the safety profile as you move forward?

其次，請注意您提到的 GLP 毒理研究的完成情況。顯然，您的 I 期健康志願者看起來也非常乾淨，但如果您可以談論完全降解 STAT6 的潛在安全風險，那麼在 Ib 期您最希望看到什麼類型的信號，以便在前進的過程中對安全性感到真正放心？

Thanks. Great question. Jared, I thought maybe you could take at least the first one, if not both.

謝謝。好問題。賈里德，我想你至少可以選第一個，即使不能兩個都選。

Yes. In terms of on the clinical expectations, I think we emphasize always that the primary objective here is to show a robust STAT6 degradation in the blood and an active AD skin lesions and to show that, that results in a dupi-like biomarker, in fact, both in blood and skin were -- and skin, we're looking at the TH2 transcriptome and we don't want to see a dupi-like effect there.

是的。就臨床預期而言，我認為我們始終強調，這裡的主要目標是顯示血液中 STAT6 的強烈降解和活躍的 AD 皮膚病變，並顯示這會導致類似 dupi 的生物標誌物，事實上，無論是在血液中還是在皮膚中 - 以及皮膚中，我們正在研究 TH2 轉錄組，我們不希望在那裡看到類似 dupi 的效果。

We sort of have set of expectations around biomarkers, I think TARC is the most important blood biomarker probably in AD, where dupi studies have shown even at 28 days, about a 70-plus percent reduction in dupilumab. So that's a general ballpark that we would expect to see in patients who like in those dupi-AD studies had greatly elevated TARC levels at baseline. We'll be looking at other biomarkers in the blood as well as these various transcriptional biomarkers in the skin.

我們對生物標記有一定的期望，我認為 TARC 可能是 AD 中最重要的血液生物標記物，dupi 研究表明，即使在 28 天時，dupilumab 也減少了約 70% 以上。因此，這是我們預計在 dupi-AD 研究中基線 TARC 水平大幅升高的患者中看到的大致情況。我們將研究血液中的其他生物標記以及皮膚中的各種轉錄生物標記。

In terms of clinical endpoints, again, we've always emphasized that in the absence of a placebo control, these are more exploratory. However, we think we do have an opportunity to look at end points like EASI and pruritus, NRS and IGA because we know from dupi that you can see impact on those biomarkers as early as 28 days.

就臨床終點而言，我們一直強調，在沒有安慰劑對照的情況下，這些終點更具探索性。然而，我們認為我們確實有機會研究 EASI 和搔癢、NRS 和 IGA 等終點，因為我們從 dupi 得知，最早可以在 28 天看到這些生物標記的影響。

And we're not really giving specific numbers where that bar would be set. I think the published data are out there with dupi and one can look at those published data at 28 days and get a sense for what we mean by sort of being in the ballpark with regard to those clinical endpoints.

我們實際上並沒有給出設定該標準的具體數字。我認為已發布的數據已經透過 dupi 公佈，人們可以查看 28 天的已發布數據，並了解我們所說的大致符合這些臨床終點的含義。

In terms of your second question around safety risk, as you noted, we've been very pleased with what we've seen in our GLP tox studies. We've now completed our four-month tox studies as now indicated, and we've seen no safety signals whatsoever. That's very in line with our four-week GLP tox in our prior non-GLP tox studies.

關於安全風險的第二個問題，正如您所說，我們對 GLP 毒理研究的結果非常滿意。正如現在所示，我們現在已經完成了為期四個月的毒性研究，但沒有看到任何安全訊號。這與我們先前的非 GLP 毒性研究中的四週 GLP 毒性非常一致。

We are very encouraged by the fact that our safety profile was undifferentiated from placebo in healthy volunteers with two weeks of dosing. So that's very encouraging. And now we'll be looking at safety with four weeks of dosing, of course, in the Phase Ib.

我們感到非常鼓舞的是，在健康志願者服用兩週後，我們的安全性與安慰劑沒有區別。這非常令人鼓舞。現在我們將透過 Ib 階段的四周給藥來觀察安全性。

I think overall, this is in line with our expectations based on our mechanism of action and based on the fact that it appears that STAT6 is highly selective for the IL-4/IL-13 pathways and human genetics. I have pointed not just to the phenotype of abnormalities of STAT6, but also to the safety of knocking down STAT6 have mouse knockout studies. And so this is all in line with what we expected for a transcription factor that is very specific for IL-4 and IL-13, and for a drug like ours, and it's highly selective just for STAT6.

我認為總體而言，這符合我們基於作用機制的預期，並且基於 STAT6 對 IL-4/IL-13 路徑和人類遺傳學具有高度選擇性的事實。我不僅指出了 STAT6 異常的表型，還指出了敲除 STAT6 的安全性，並進行了小鼠敲除研究。因此，這一切都符合我們對 IL-4 和 IL-13 非常特異的轉錄因子以及像我們這樣的藥物的預期，它對 STAT6 具有高度選擇性。

I would only -- thanks, Jared. I wouldn't say anything differently. I will only add one thing, just to be clear, again, as Jared said, on the clinical endpoints, it's difficult to compare -- it's also difficult to compare placebo-control randomized study, like the industries followed these arguments over comparing placebo-controlled studies. So it's even more difficult to compare non-controlled study.

我只會——謝謝，賈里德。我不會說任何不同的話。我只想補充一點，只是為了更清楚，正如賈里德所說，在臨床終點方面，很難比較——也很難比較安慰劑對照隨機研究，就像業界在比較安慰劑對照研究時遵循這些論點一樣。因此，比較非對照研究就更加困難了。

But I just want to say our expectations are that we will have a very active drug. I don't want to hide behind the impossibility to compare. We expect that this mechanism is going to be on par with what dupilumab has shown and that's the bar for us without talking about numbers.

但我只想說，我們期望我們能夠擁有一種非常有效的藥物。我不想躲在無法比較的背後。我們預計這種機制將與 dupilumab 所展示的效果相當，這就是我們的標準，無需談論數字。

Faisal Khurshid, Leerink.

費薩爾·庫爾希德（Faisal Khurshid），Leerink。

Just wanted to ask on the doses for the Phase Ib and the Phase IIb. Are you able to confirm if the dose that you added to the Phase Ib is higher or lower than the dose that you originally went in with. And could you also confirm if like either or both of these doses are part of like the three that you've selected for Phase IIb?

只是想問 Ib 期和 IIb 期的劑量。您能否確認您添加到 Ib 階段的劑量是否高於或低於您最初的劑量。您能否確認其中一個劑量或兩個劑量是否屬於您為 IIb 期選擇的三個劑量的一部分？

So I don't want to get into the higher or lower, because I think whatever I say, it's going to be viewed one way or the other. What I can say is that both doses have been tested in the healthy volunteer studies. I don't want to talk about what our doses are for the IIb because I think we might choose to keep that, as I've said in other venues, to keep that close to the vest for as long as we can, only for competitive reasons. All I can say that we have several doses in the healthy volunteers that performed really well.

所以我不想討論高低，因為我認為無論我說什麼，都會被這樣或那樣地看待。我可以說的是，這兩種劑量都已經在健康志願者研究中進行了測試。我不想談論我們對 IIb 的劑量是多少，因為我認為我們可能會選擇保留這個信息，就像我在其他場合所說的那樣，盡可能長時間地保密，只是出於競爭的原因。我只能說，我們在健康志願者身上進行了幾次劑量試驗，結果表現非常好。

And so really, the main driver here are these doses going to perform as well in patients given that -- I actually don't remember the number, Bruce will know better, but we're spending tens, if not 100-plus millions of dollars in these two studies.

因此，實際上，這裡的主要驅動力是這些劑量在患者身上也能發揮同樣的作用——我實際上不記得具體數字了，布魯斯會更清楚，但我們在這兩項研究中花費了數千萬甚至數億美元。

And we're not going to optimize over -- for these studies on making or thinking that we selected the right doses. These are consequential decisions. And so given that we had the time to do it, we said, let's make sure. So that's really what's behind these. And I think once we'll share the data we can add a bit more color to work in first.

我們不會對這些研究進行過度優化，或認為我們選擇了正確的劑量。這些都是重要的決定。因此，既然我們有時間去做這件事，我們就說，讓我們確保一下。這就是背後的真正原因。我認為，一旦我們共享數據，我們就可以先添加更多顏色來工作。

Got it. Makes sense. And then could you confirm if it's still 20 patients for the Phase Ib? And then also like between the two doses, would you like to or do you have to see a dose response between those two doses?

知道了。有道理。那麼，您能否確認 Ib 期是否仍需要 20 位患者？然後，在兩次劑量之間，您是否想或必須觀察兩次劑量之間的劑量反應？

Great question. So I think what we said that the goal of the Ib was approximately 20 patients, and that's still the case. I don't want to get into the dose response. I think we will talk about it once we share the data.

好問題。所以我認為我們所說的 Ib 的目標是約 20 名患者，現在仍然如此。我不想討論劑量反應。我認為一旦我們共享數據我們就會討論這個問題。

Alex Thomson, Stifel.

亞歷克斯·湯姆森（Alex Thomson），Stifel。

I guess another question on the next-gen STAT6. How different is the scaffold binding to STAT6 than '621? Is that a key part of this decision making? And when might you consider potentially splitting indications here? Is that a near-term decision? Or are you going to wait quite a while before that comes down?

我猜還有另一個關於下一代 STAT6 的問題。支架與 STAT6 的結合與 '621 的結合有何不同？這是決策的關鍵部分嗎？您什麼時候會考慮在這裡進行潛在的分割指示？這是近期的決定嗎？或者您要等一段時間才能實現？

Yes. So what I can say -- that's a great question, Alex. So we have several scaffolds, let's call it, across actually all binding [ivies], whether it's E3 ligase or it's STAT6. We have plenty of chemistry, some patterns are published from us as many have seen, there is plenty they haven't yet. So we have a plethora of chemistry in this program that covers everything that you can imagine. So maybe I'll leave at that.

是的。所以我可以說——這是一個很好的問題，亞歷克斯。因此，我們有幾個支架，我們稱之為，實際上跨越所有結合[ivies]，無論是 E3 連接酶還是 STAT6。我們擁有大量的化學知識，正如許多人所見，我們已經發表了一些模式，但還有很多他們還沒有發表。因此，我們在這個專案中涵蓋了大量的化學知識，涵蓋了你能想到的所有內容。所以也許我會就此離開。

On the indication splitting, it's a bit obviously challenging to think about that particular end game given kind of the evolving landscape right now in terms of pricing and reimbursement and global versus US. So I think we want to keep maximum optionality and that kind of the goal behind everything that we're doing.

關於適應症分割，考慮到目前定價、報銷以及全球與美國的不斷變化的情況，思考特定的最終結果顯然有點困難。所以我認為我們希望保持最大程度的可選性，這是我們所做的一切事情背後的目標。

But it's difficult for us right now to at least disclose what's the latest thinking on that. But as we get closer to Phase III, which actually with the recent raise, hopefully was clear from our remarks earlier. Now with the money we have in hand, we can actually initiate multiple Phase III studies. So I think as we get closer to those, we'll be able to disclose more about what our indication sequence and strategy will be.

但目前我們很難至少透露對此的最新想法。但隨著我們越來越接近第三階段，實際上隨著最近的升息，希望從我們先前的評論中可以清楚地看出這一點。現在，憑藉手頭上的資金，我們實際上可以啟動多個第三階段研究。因此我認為，隨著我們越來越接近這些目標，我們將能夠更多地揭露我們的指示順序和策略。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

Going back to the data that you're going to have by year-end, I just wanted to ask, you talked about your expectations for what data you're going to show. Should we assume that you're also going to be able to show some level of itch data? I ask because some doctors have indicated that in addition to, let's say, EASI scores, that is something that they feel is important when they're going to make a decision in a real-world setting about what potential options they might choose.

回到您年底將要獲得的數據，我只是想問一下，您談到了您對將要展示的數據的期望。我們是否應該假設您也能夠顯示一定程度的搔癢數據？我之所以問這個問題，是因為有些醫生表示，除了 EASI 分數之外，他們認為在現實環境中決定可能選擇哪些潛在選項時，這一點也很重要。

Yes. Tazeen, it's a great question. And as Jared said, yes, we will show EASI, pruritus, NRS. And so itch is going to be an important factor. As you know, itch is -- probably has the biggest impact on quality of life of these patients and so it's something that we're watching very closely. So we will share that data as well.

是的。Tazeen，這是一個很好的問題。正如賈里德所說，是的，我們將展示 EASI、搔癢症、NRS。因此搔癢將是重要因素。如您所知，搔癢可能是對這些患者的生活品質影響最大的問題，因此我們正在密切關注。因此我們也將分享這些數據。

And will that be for all the patients that you're going to show or it'll be a subset?

這適用於您要展示的所有患者嗎？還是只適用於其中一部分？

Well, I mean if we have collected the data, yes, so we'll share it. So yes, it should be all patients.

嗯，我的意思是，如果我們已經收集了數據，是的，那麼我們就會分享它。所以是的，應該是所有患者。

Kelly Shi, Jefferies.

Kelly Shi，傑富瑞集團。

Congrats on the quarter. So one question on STAT6. Conjunctivitis is believed to be an on-target AE for DUPIXENT. So do you expect to see a similar level of conjunctivitis in KT-621 Phase Ib trial like in one or two patients, and also could a daily oral drug differentiator in safety profile versus injectables due to a potentially more flat PK curve?

恭喜本季取得佳績。關於 STAT6 有一個問題。結膜炎被認為是 DUPIXENT 的目標不良事件。那麼，您是否預計在 KT-621 Ib 期試驗中會看到與一兩名患者類似的結膜炎水平，並且由於 PK 曲線可能更平坦，每日口服藥物與注射劑在安全性方面是否存在差異？

Maybe I'll start, and then I'll pass it to Jared, that can speak more to the medical part. I mean our view with Kymera is that STAT6 and hopefully, it's not just here at Kymera, STAT6 is the selected transcription factor of IL-4 and IL-13, and we've shown pre-clinically, early-clinically and hopefully, will show in Q4 that if you block STAT6, you can phenocopy dupilumab.

也許我會開始，然後我會把它傳給賈里德，他可以更多地談論醫療部分。我的意思是，我們對 Kymera 的看法是 STAT6，希望它不僅僅是在 Kymera 這裡，STAT6 是 IL-4 和 IL-13 的選定轉錄因子，我們已經在臨床前、早期臨床中證明，並且希望在第四季度證明，如果你阻斷 STAT6，你就可以表型複製 dupilumab。

So if conjunctivitis, which is actually mostly if not only seen in atopic dermatitis patients, so it's really a feature of the disease and these IL-4 and IL-13 biologics. So again, if conjunctivitis is an on-mechanism event -- adverse event for IL-4 and IL-13 biology, then we expect to see. If it's to do with the receptor or the cytokines, then we wouldn't see it. So it's hard for us to know.

因此，如果結膜炎實際上主要（甚至不僅僅）見於異位性皮膚炎患者，那麼它實際上是該疾病和這些 IL-4 和 IL-13 生物製劑的一個特徵。因此，如果結膜炎是一種機制事件——IL-4 和 IL-13 生物學的不良事件，那麼我們期望看到。如果它與受體或細胞因子有關，那麼我們就不會看到它。所以我們很難知道。

Maybe, Jared, you can speak to also, is it seen after only four weeks. I don't know --

也許，賈里德，你也可以說一下，僅四周後就可以看到效果。我不知道--

Yes. I mean, mechanistically, it's not really know why some patients, especially AD patients do develop conjunctivitis. If you look at the dupilumab studies, when you do see conjunctivitis, oftentimes, you'll see it within the first, say, four- to eight weeks or so of treatment. And then over time, it actually tends to diminish. It is an adverse event that one does see with dupi, it's not a dose-limiting adverse event and most of the case of dupi are sort of in the mild-to-moderate range.

是的。我的意思是，從機制上講，我們並不清楚為什麼有些患者，尤其是 AD 患者會患上結膜炎。如果你看一下度普利尤單抗的研究，你會發現，當你發現結膜炎時，通常會在治療後的前四到八週左右發現它。隨著時間的推移，這種現象實際上會逐漸減少。這是使用 dupi 時確實會出現的不良事件，它不是劑量限制性不良事件，大多數 dupi 病例都處於輕度至中度範圍內。

I think importantly, we haven't seen it preclinically in our tox studies, we haven't seen in healthy volunteers, and we really wouldn't expect to see it there in healthy volunteers since this appears to be something unique to AD patients. But as Nello said, we don't have any reason to believe that we'd see either less or more AD patients compared to what dupilumab has seen.

我認為重要的是，我們在毒理學研究中沒有在臨床前看到它，我們也沒有在健康志願者中看到它，我們真的不希望在健康志願者中看到它，因為這似乎是 AD 患者獨有的。但正如 Nello 所說，我們沒有任何理由相信與 dupilumab 相比，我們會看到更少或更多的 AD 患者。

Yes, we're watching it because it's an interesting -- obviously, feature of many of these drugs, right? It's not only dupilumab, all the IL-13 drugs have it. So we're watching that very closely and see if we see it in our four-week studies. And we'll -- obviously, we'll share all the data in 4Q.

是的，我們正在關注它，因為它是一個有趣的——顯然，許多此類藥物都有這個特點，對吧？不僅 dupilumab 有這種成分，所有 IL-13 藥物都有這種成分。因此，我們正在密切關注這一點，看看我們是否能在四周的研究中發現這一點。顯然，我們將在第四季度分享所有數據。

And then you talked about the safety difference between once oral daily and biologics. I mean from what we have both understood and what we've empirically derived in our preclinical studies, dupilumab has a very, very robust pathway blockade.

然後您談到了每日一次口服藥物和生物製劑之間的安全性差異。我的意思是，根據我們所了解的情況以及我們在臨床前研究中所獲得的經驗，dupilumab 具有非常非常強大的路徑阻斷作用。

I would compare the dupilumab pathway blockade pretty much in line with the level of pathway blockade we see from our 50 mg, 100 mg dose, 200 -- the complete degradation type of pathway blockade. I would put it on that kind of level of pathway blockade. So if that's the case, then I don't see why pathway blockade coming from STAT6 degradation should look different from pathway blockade from an IL-4 receptor -- IL-4 blockade.

我會將 dupilumab 通路阻斷與我們從 50 毫克、100 毫克劑量、200 毫克劑量（完全降解型通路阻斷）中看到的通路阻斷水平進行比較。我會把它放在那種等級的通路阻塞上。因此，如果情況確實如此，那麼我不明白為什麼來自 STAT6 降解的路徑阻斷應該與來自 IL-4 受體的路徑阻斷（IL-4 阻斷）有所不同。

So anyway, I think that's another feature and another part of the analysis that we will do again. I'll repeat in our preclinical study, in our adding the four-month tox, K-621 has been exceptionally well tolerated. So we'll continue to, again, watch everything that happens in the clinic.

所以無論如何，我認為這是另一個特徵，也是我們將再次進行的分析的另一部分。我要重複我們的臨床前研究，當我們添加四個月的毒性時，K-621 的耐受性非常好。因此，我們將繼續關注診所內發生的一切。

Judah Frommer, Morgan Stanley.

猶大‧弗洛默，摩根士丹利。

Just one for us. I guess can you comment a little bit further on enrollment progress and the success you're having there and maybe what feedback is from investigators. Is the oral administration of the drug resonating? I'm curious if you think you'd have similar success if there were a placebo arm in the trial?

對我們來說只有一個。我想您能否進一步評論一下招生進展和您取得的成功以及研究人員的回饋。藥物口服有共振嗎？我很好奇，您是否認為如果試驗中有安慰劑組，您會取得類似的成功？

Yes, it's a great question. So the challenge of a 28-day study, remember, is that the patients are not going to be on the drug beyond day 28. We don't have an extension arm to the study. So it's -- I would say before we started the study, we were nervous because there are a huge amount of incentives for patients to come on to the study besides knowing they'll be on an active drug. And that's part of the reason why we decided not to have placebo, we thought it would have had an impact on our enrollment rate.

是的，這是一個很好的問題。因此請記住，28 天研究的挑戰在於患者不會在 28 天後繼續服用該藥物。我們沒有這項研究的延伸部分。所以——我想說，在我們開始這項研究之前，我們很緊張，因為除了知道他們將使用一種活性藥物之外，還有大量的激勵措施來激勵患者參與這項研究。這就是我們決定不使用安慰劑的原因之一，我們認為這會對我們的入學率產生影響。

As we expect -- part of us or our expectation was that patients do want an oral drug. And so I think we are seeing that in our study and this has allowed us to meet our enrollment goal, I would say, even exceed our enrollment goal for sure. And maybe that's where I'm going to leave it.

正如我們所預料的——我們的部分預期是患者確實想要一種口服藥物。所以我認為我們在研究中看到了這一點，這使我們能夠實現我們的招生目標，甚至可以肯定超過我們的招生目標。也許這就是我要離開的地方。

I think once we start seeing more differentiation, it's probably going to be in the Phase IIb study where now you're offering 16-week, potentially OLE, so that would be interesting to see our enrollment versus biologics and whether it's telling us also something about what patients are also looking for in the market.

我認為，一旦我們開始看到更多的差異化，它可能會進入 IIb 期研究，現在您提供 16 週的、潛在的 OLE，因此看看我們的招生情況與生物製劑相比會很有趣，以及它是否也告訴我們患者在市場上尋找什麼。

Kripa Devarakonda, Truist.

Kripa Devarakonda，Truist。

Congrats on the progress through the quarter. So I'll ask one non-STAT6 question. So congrats on your CDK partnership with Gilead. I know this diversifies your pipeline into oncology, where you've been focused a little bit more on I&I in the recent past.

恭喜本季取得的進展。所以我想問一個非 STAT6 問題。恭喜您與 Gilead 建立 CDK 合作夥伴關係。我知道這會使您的研究領域多樣化，進入腫瘤學領域，最近您在腫瘤學領域更加專注於免疫與免疫療法 (I&I)。

But given the data we've seen so far with CDK2 inhibitors, can you talk a little bit about how you think the degrader could be differentiated based on the data that you have? And what the strategy of development is? And then I have a follow-up.

但是，根據我們目前看到的有關 CDK2 抑制劑的數據，您能否談談您認為如何根據現有數據來區分降解劑？發展戰略是什麼？然後我有一個後續問題。

Yes. Thank you. So just to be clear, our discovery engine has been also very focused on immunology. We have programs that we were working on from the earlier days and one of our program wasn't CDK2. And so with our strategy shift to focus on developing immunology drug, we decided that it was best to place a very exciting CDK2 program from a development standpoint in the hands of a partner that was committed to that space. So that's a bit to the strategy.

是的。謝謝。因此需要明確的是，我們的發現引擎也非常關注免疫學。我們有一些早期開發的程序，其中一個程序不是 CDK2。因此，隨著我們的策略轉向專注於開發免疫學藥物，我們決定最好將從開發角度來看非常令人興奮的 CDK2 專案交給致力於該領域的合作夥伴。這就是一點策略。

The reason why we have that program because we firmly believe that small molecule inhibitors of CDK2 are really not able to selectively target CDK2. They all inhibit to a large extent, CDK1 that pharmacologically active doses to different degrees. And that it leads to clinical doses that are probably not optimally blocking CDK2, again for the risk of hitting CDK1.

我們之所以開展該項目，是因為我們堅信 CDK2 的小分子抑制劑無法真正選擇性地靶向 CDK2。它們均在不同程度上抑制了藥理活性劑​​量的CDK1。這會導致臨床劑量無法最佳地阻斷 CDK2，從而再次存在打擊 CDK1 的風險。

Another important aspect for us to develop this drug was to have a brain-penetrant asset so that we would also address potential brain secondary tumor metastasis from breast cancer. And so our degraded program -- molecular degrader program is highly specific CDK2 also reaches the CNS.

我們開發這種藥物的另一個重要方面是擁有一種腦滲透性資產，這樣我們還可以解決乳癌潛在的腦繼發性腫瘤轉移。因此，我們的降解程序－分子降解程序具有高度特異性，CDK2 也能到達中樞神經系統。

And we believe it's going to -- has the potential to be best in class. If I look at the small molecules out there, it's by far superior. Obviously, I'm not aware of other programs that are in early discovery, early development. So I can say obviously, for sure, but with regards to the development, that's a question you have to ask Gilead. We can't speak for them on that particular front.

我們相信它有潛力成為同類產品中最好的。如果我觀察一下那裡的小分子，它就更加優越了。顯然，我不知道還有哪些項目處於早期探索和早期開發階段。所以我當然可以說，但關於開發，這個問題你必須問吉利德。我們不能就這一特定方面代表他們發言。

Okay. And just following up on Tazeen's question about itch relief, and this is something that we've heard from KOLs too that it's really important to see rapid itch relief. Will we get a sense of that when we see the data, the rapidity of response in the fourth quarter?

好的。讓我們來回答 Tazeen 關於止癢的問題，我們也從 KOL 那裡聽說，快速止癢非常重要。當我們看到第四季的數據和反應速度時，我們是否會有這種感覺？

Yes, we will. I mean, as Nello already mentioned, looking at pruritus NRS is a key part of the sort of suite of clinical endpoints. And we'll be looking at it fairly regularly as we'll be looking at EASI. So we'll have a good sense of the kinetics of impact on itch as well as on EASI, that will be certainly part of the profile that we share once we have those data in Q4.

是的，我們會的。我的意思是，正如 Nello 已經提到的，觀察搔癢症 NRS 是一系列臨床終點事件的關鍵部分。我們會定期查看它，就像我們查看 EASI 一樣。因此，我們將很好地了解對搔癢和 EASI 的影響動力學，這肯定會成為我們在第四季度獲得這些數據後分享的概況的一部分。

Yes. I think you'll see, hopefully, that will be the case. But it would be like we'll show day 7, day 14, then 21, day 28. So you'll be able to see the kinetics of all of these parameters.

是的。我想你會看到，希望情況確實如此。但我們會顯示第 7 天、第 14 天、第 21 天、第 28 天。因此您將能夠看到所有這些參數的動力學。

(Operator Instructions)

（操作員指示）

Mayank Mamtani, B. Riley.

Mayank Mamtani，B. Riley。

Congrats on the progress team. Any color you're able to provide on the baseline EASI scores of the patients you're enrolling or have enrolled? And I wonder always about the screen failure rate for atopic derm trial sites. And maybe just remind us how you're measuring degradation in skin tissue. There's obviously a couple of ways to do that. And lastly, anything you've learned on the degradation from the four-months GLP tox studies you completed?

祝賀團隊取得進步。您能否提供您正在招募或已經招募的患者的基線 EASI 評分的詳細資訊？我一直對過敏性皮膚病試驗點的篩檢失敗率感到疑惑。也許只是提醒我們您是如何測量皮膚組織的退化。顯然有幾種方法可以做到這一點。最後，您從所完成的為期四個月的 GLP 毒理學研究中了解到了什麼有關降解的情況？

So you asked four questions in there. So that's a way to (multiple speakers)

所以你在那裡問了四個問題。所以這是一種（多位發言者）

I will not ask a follow up. I promise no follow up.

我不會問後續情況。我保證不會再有後續行動。

Yes, but you asked four. Let's see if I remember. So the first one was -- the EASI -- yes, we're not going to comment on the baseline EASI, but I will refer you to our entry. So the baseline criteria for entering the studies EASI above 16 -- 16 or above. There is obviously itch as well. There is PSA more than 10%. So we have a strict criteria that really overlap with what has been done with dupilumab.

是的，但是你問了四個。看看我是否記得。所以第一個是 - EASI - 是的，我們不會對基線 EASI 進行評論，但我會讓你參考我們的條目。因此，進入研究的基準標準是 EASI 16 以上——16 或以上。顯然還有癢的感覺。PSA 超過 10%。因此，我們有一個嚴格的標準，實際上與 dupilumab 的標準重疊。

On the -- again, on the failure rate, again, I don't know if we'll speak when we released the data. All I can say is that our team is watching the study very closely. And we've worked very, very hard to make sure that patients that enter a study actually have atopic dermatitis, which would be shock that, that could be possible if you don't watch the study closely that their disease is active.

關於——再次，關於失敗率，我不知道我們是否會在發布數據時談論這個問題。我只能說我們的團隊正在密切關注這項研究。我們非常努力地確保參與研究的患者確實患有異位性皮膚炎，如果您不密切關注研究，他們的疾病可能處於活躍狀態，這令人震驚。

And obviously, that their lab work is in line with making sure we're not taking sick patients on our study. So I think when you take all of that, that results into obviously screen failures that, again, I'm not able to comment on today.

顯然，他們的實驗室工作是為了確保我們不會在研究中招募病人。所以我認為，當你把所有這些都考慮進去時，顯然會導致螢幕故障，對此我今天無法發表評論。

On the degradation in the skin, as we've done in many of our studies, we are fortunate enough to have patients on our study be willing to take biopsies, which, as you know, it does add an additional layer. That's why we're so impressed on how we were able to enroll patients again quickly because we ask patients to undergo biopsy at baseline and day 28 to measure STAT6 with the mass spec. So that's how we're going to measure it.

關於皮膚退化，正如我們在許多研究中所做的那樣，我們很幸運，研究中的患者願意接受活檢，正如你所知，這確實增加了額外的一層。這就是為什麼我們對能夠再次快速招募患者感到如此印象深刻，因為我們要求患者在基線和第 28 天進行活檢以使用質譜測量 STAT6。這就是我們要測量的方法。

Anything you learned from the GLP tox study on degradation?

您從 GLP 毒性降解研究中了解到了什麼？

I mean, all we learned in these studies is that we -- obviously, at this tox doses there is no STAT6 anywhere to be found that we degraded completely, that's maybe all I can say. Yes, if the question is, does the STAT6 degradation wanes off after sometimes? Obviously, the answer is no. We see STAT6 degradation all throughout the study.

我的意思是，我們在這些研究中了解到的是——顯然，在這種毒性劑量下，我們找不到任何 STAT6，我們已經完全降解了，這也許就是我能說的全部。是的，如果問題是，STAT6 降解是否會在一段時間後逐漸減弱？顯然，答案是否定的。我們在整個研究過程中都看到了 STAT6 的退化。

Jeet Mukherjee, BTIG.

Jeet Mukherjee，BTIG。

I know we're a long ways out, but can you speak to payer willingness to cover therapies in the dermatology space that given alternative administration format like an oral option with DUPIXENT-like efficacy for KT-621? Or is there a bar truly superior efficacy versus standard of care options?

我知道我們還有很長的路要走，但您能否談談付款人是否願意承擔皮膚病學領域的治療費用，並提供替代給藥方式，例如具有與 DUPIXENT 類似療效的口服藥物，用於 KT-621？或是有比標準治療方案更優異的療效？

Well, no, it's a great question. We believe that when you make the case for an oral option, first, you will hear from prescribers that actually you don't even need to have dupilumab-like activity for expecting a substantial adoption in the market. It just speaks to the fact that there is a need of flexible, easy to prescribe, reimbursed and take medicines. So the reason why we see dupi-like in appeal is because all the data we've seen so far speaks to that. And so that's why our bar has always been there and hopefully will continue to be there.

嗯，不，這是一個很好的問題。我們相信，當您提出口服選擇時，首先，您會從處方醫生那裡聽到，實際上您甚至不需要具有類似 dupilumab 的活性就可以預期市場會大量採用。這只是說明我們需要靈活、易於開處方、報銷和服用的藥物。因此，我們之所以認為 dupi 具有如此高的吸引力，是因為我們迄今為止所看到的所有數據都證明了這一點。這就是為什麼我們的酒吧一直在那裡，並且希望能夠繼續在那裡。

Again, I think when you make the case for having a therapy even with the same activity, you're telling actually insurance companies and prescribers and patients that this drug has a much bigger impact on their quality of life and asking for a lot less, right, in terms of visit to the doctors, testing, needing or lack thereof of cold storage of the drug, needles, injection site reactions. So I think that's the value case that a drug like this will have.

再說一次，我認為，當你提出即使作用相同的治療方法時，你實際上是在告訴保險公司、處方醫生和患者，這種藥物對他們的生活品質有更大的影響，並且在就診、檢測、是否需要冷藏藥物、針頭、注射部位反應等方面的要求要少得多。所以我認為這就是這種藥物的價值所在。

And especially if you compare it to -- for example, the only drug there right now is approved in AD, it's a drug with a black box. And that drug actually is doing quite well. I think that speaks -- and then it's a drug that requires testing before you start the therapy. And so it speaks to the hunger that this market has for an oral drug. And I think you've seen in all markets, oral drugs and multiple effective therapies are needed to expand access and penetration.

尤其是如果你將它與——例如，目前唯一在 AD 中獲得批准的藥物——進行比較，它是一種帶有黑框的藥物。而且這種藥物的效果確實很好。我認為這說明——這是一種在開始治療之前需要進行測試的藥物。這顯示市場對口服藥物的需求。我想你已經看到，在所有市場中，都需要口服藥物和多種有效療法來擴大獲取途徑和滲透率。

Now the -- especially atopic dermatitis market is really dominated by a single player, I would say, mostly with dupilumab, but it still has less than 15% penetration. I would say, if you look at all moderate-to-severe, it's less than 10%. And so I think we need this option to expand access dramatically in the US and all over the world.

現在，尤其是異位性皮膚炎市場實際上由單一參與者主導，我想說，主要是dupilumab，但其滲透率仍然不到15％。我想說，如果你看所有中度至重度病例，這個比例還不到 10%。因此我認為我們需要這個選項來大幅擴大美國乃至全世界的訪問範圍。

Jeff Jones, Op Co.

傑夫瓊斯，Op Co.

One question from us on IRAK4. Can you provide any additional detail behind what drove the exchange of '474 for the '485 candidate, given the specificity differences, was there something that was being seen with '474 that was concerning?

我們對 IRAK4 有一個問題。您能否提供更多細節，說明是什麼原因導致 '474 簽證換成 '485 簽證？考慮到特異性差異，'474 簽證是否存在令人擔憂的問題？

Great question, Jeff. Thanks for asking about this. So just to remind everybody, the decision was made by Sanofi to focus all the resources of the IRAK4 collaboration on KT-485. Based on preclinical data, KT-485 seems to be superior to '474 on both potency distribution, and we demonstrated also lack -- complete lack of the subclinical QT filing that we have seen with '474 in our clinical studies.

很好的問題，傑夫。感謝您詢問這個問題。因此，提醒大家，賽諾菲決定將 IRAK4 合作的所有資源集中在 KT-485 上。根據臨床前數據，KT-485 在效力分佈方面似乎優於 '474，我們也證明它缺乏——完全缺乏我們在臨床研究中看到的 '474 的亞臨床 QT 歸檔。

I will also reiterate that particular finding was self-resolving with continued dosing, meaning that it will go away as you continue to dose. And we didn't learn anything even in the ongoing Phase II studies that spoke negatively with regards to the safety of the drug beyond what we've already shared. So I think it was really focus on the fact that '485 overall seem to add a better profile, and we believe both clinically and maybe commercially more competitive.

我還要重申，特定發現會隨著持續服藥而自行解決，這意味著隨著您繼續服藥，它就會消失。除了我們已經分享的資訊之外，即使在正在進行的第二階段研究中，我們也沒有了解到任何對該藥物安全性產生負面影響的資訊。因此，我認為真正關注的是「485」總體上似乎增加了更好的形象，我們相信在臨床和商業上都更具競爭力。

But since you asked me about actually IRAK4, I thought it's also interesting to see how the landscape is evolving. I don't know if you guys have seen AstraZeneca starting -- about to start the big Phase II study in COPD after they've run a small earlier study, which we haven't seen data for, but they have shared that they're going to share their data for their IRAK4 inhibitor in COPD.

但既然您實際上問我有關 IRAK4 的問題，我認為看看景觀如何演變也很有趣。我不知道你們是否看到阿斯特捷利康在進行一項小型早期研究後，即將開始針對 COPD 的大型 II 期研究，我們還沒有看到相關數據，但他們表示將分享其 IRAK4 抑製劑在 COPD 治療中的數據。

So that's another indication that we at Kymera thought IRAK4 could be well positioned for. So it's exciting that a big company is -- I think it's 400 patients. No, it's more than 100 that, 1000 patient study.

因此，這再次表明我們 Kymera 認為 IRAK4 可能處於有利地位。因此，一家大公司能擁有 400 名患者，這真是令人興奮。不，這需要超過 100 名，1000 名患者的研究。

So anyway, just the field continues to learn and evolve. And we're excited to have a great asset out there that hopefully could also go towards that direction. But that's something that we need to obviously discuss with Sanofi.

所以無論如何，這個領域都在繼續學習和發展。我們很高興能擁有如此優秀的資產，希望它也能朝著這個方向發展。但這顯然是我們需要與賽諾菲討論的事情。

Andy Chen, Wolfe Research.

安迪‧陳 (Andy Chen)，沃爾夫研究公司 (Wolfe Research)。

On IRF5, is there a reason for degradation in cytokine reduction and all that would not translate into humans? It looks like your STAT6 degrader has more than translated? Wouldn't all of that read through to IRF5? Or is there still something special about that molecule that makes you think that you're still maybe semi-concerned and maybe the de-risking steps are still ahead of you? And also what are the top two-, three safety signals that you'll be watching for in humans?

對於 IRF5 來說，細胞因子減少的退化以及所有這些都不會轉化為人類的原因是什麼？看起來你的 STAT6 降解劑已經翻譯完了？所有這些難道不會讀到 IRF5 嗎？或者該分子是否仍然具有某些特殊性，讓您認為您可能仍然有點擔心，也許降低風險的步驟仍在您面前？另外，您在人類身上需要注意的最重要的兩到三個安全訊號是什麼？

Yes. Great question. So for IRF5, I mean, we're at this stage, to be honest, we've been here for a while where all of our programs have translated really well. You can argue whether you like the target and the biology that translate, but all of our programs have translated really well in the clinic. So we expect IRF5 to translate just as well as KT-621.

是的。好問題。所以對於 IRF5，我的意思是，我們正處於這個階段，說實話，我們已經在這裡待了一段時間，我們所有的程式都翻譯得非常好。您可以爭論是否喜歡該目標和轉化的生物學，但我們所有的程序在臨床上都轉化得非常好。因此我們預期 IRF5 的翻譯效果與 KT-621 一樣好。

Also for IRF5, KT-579 in non-GLP tox, we've seen no adverse event of any type, and we went up to 200-fold above the expected 90% degradation human exposure. We are in the midst of buying the enabling studies. I'm confident we'll continue to see an exceptionally well-tolerated drug.

此外，對於非 GLP 毒性中的 IRF5、KT-579，我們沒有看到任何類型的不良事件，我們的研究結果比預期的 90% 人體暴露降解率高出 200 倍。我們正在購買支持性研究。我相信我們將繼續看到一種耐受性極好的藥物。

So we're excited about that drug. We're working already, really hard not only to prepare for the healthy volunteer study that will start early next year, but the team has been spending in the past few months working on and planning our patient study that will start soon after the healthy volunteer study and we're prioritizing indications. We're talking to KOLs and refining protocol. So yes, we are working under the assumption that the translation will be happening just as well as it did for '621.

所以我們對這種藥物感到很興奮。我們已經非常努力地工作，不僅為明年年初開始的健康志願者研究做準備，而且團隊在過去的幾個月裡一直在致力於和規劃將在健康志願者研究後不久開始的患者研究，我們正在優先考慮適應症。我們正在與 KOL 溝通並完善協議。所以是的，我們假設翻譯將會像 621 一樣順利。

So we're just about up against time, operator. We'll try to just move really quickly through these last few.

所以，我們只是在與時間賽跑，操作員。我們將嘗試快速瀏覽最後幾個內容。

(Operator Instructions)

（操作員指示）

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）。

Just another one on IRAK4. I guess can you elaborate a little bit on what we've seen clinically with the first-generation IRAK4. And I guess, what gives you the confidence in the efficacy of this target in AD and HS. And I mean, I heard your comments on AstraZeneca. I mean any difference now in terms of how you might be thinking about the opportunity set across indications now for IRAK4.

這只是 IRAK4 上的另一個。我想您能否詳細說明一下我們在第一代 IRAK4 上臨床觀察到的情況。我想，是什麼讓您對這個目標在 AD 和 HS 方面的功效充滿信心。我的意思是，我聽到了您對阿斯特捷利康的評論。我的意思是，就您現在如何看待 IRAK4 的各種適應症中的機會集而言，是否存在任何差異。

And then also just a follow-up on CDK2. Can you elaborate on some of the learnings on working with molecular glues versus heterobifunctional degraders, and your confidence in the selectivity for CDK2 with these programs?

然後也只是 CDK2 的後續行動。您能否詳細說明使用分子膠與異雙功能降解劑的一些經驗教訓，以及您對這些程序對 CDK2 的選擇性的信心？

Yes. So on IRAK4 quickly, we can't speak to what we've seen or not seen in these studies. Unfortunately, that is Sanofi's guidance on that. On the indications, again, this is again another question for Sanofi, but asthma and COPD have always been on the high priority list for that biology.

是的。因此，對於 IRAK4，我們無法快速說出在這些研究中我們看到了什麼或沒看到什麼。不幸的是，這是賽諾菲對此的指導。關於適應症，這又是賽諾菲面臨的另一個問題，但氣喘和慢性阻塞性肺病一直是該生物學領域的高優先研究對象。

Obviously, we're talking about non-eosinophilic COPD, which is a huge patient population. And with CDK2, so we -- again, we've historically said that these two, the heterobifunctional degrader molecular glue are two complementary technology and they're not one, the next generation of the other, although many companies seem to go in that direction.

顯然，我們談論的是非嗜酸性 COPD，這是一個龐大的患者群體。有了 CDK2，我們——再說一次，我們過去曾說過，這兩種異雙功能降解分子膠是兩種互補的技術，它們並不是其中一種的下一代，儘管許多公司似乎都朝著這個方向發展。

We use molecular glues where we believe that binding site and ability to bind to the target is either not feasible or not with the selectivity, if you use binding -- specific binding to CDK2, it's really difficult to find selectivity against CDK1 and that's why we built our CDK2 degrader, which does not have any kind of cross finding with CDK1. That's why we went in that direction.

我們使用分子膠，因為我們認為結合位點和結合目標的能力要么不可行，要么不具有選擇性，如果使用結合 - 特定結合 CDK2，則很難找到針對 CDK1 的選擇性，這就是我們構建 CDK2 降解劑的原因，它與 CDK1 沒有任何交叉發現。這就是我們朝這個方向努力的原因。

There are no more questions at this time. I would now like to turn the call over to Nello Mainolfi, for closing remarks.

目前沒有其他問題。現在我想把發言時間交給 Nello Mainolfi，請他做最後發言。

Well, thanks, everybody. Sorry, we went a bit too long today. Another exciting quarter. We're here for any follow-up questions. You know where to find us, and thanks again for joining. Have a great day.

好的，謝謝大家。抱歉，今天我們講的時間有點長。又一個令人興奮的季度。我們隨時準備好解答您的任何後續問題。您知道在哪裡可以找到我們，再次感謝您的加入。祝你有美好的一天。