Kymera Therapeutics Inc (KYMR) 2025 Q1 法說會逐字稿

Good morning, and welcome to Kymera's Immunology Innovation Day, our virtual event to introduce our next immunology program, IRF5. I'm Justine Koenigsberg, Kymera's Head of Investor Relations.

早安，歡迎參加 Kymera 的免疫學創新日，這是我們的虛擬活動，旨在介紹我們的下一個免疫學計畫 IRF5。我是 Kymera 投資者關係主管 Justine Koenigsberg。

Please note that we are hosting today's event in lieu of our regularly scheduled quarterly update call. However, we have reported our results and filed our 10-Q this morning. For additional details on our Q1 results, please reference our press release issued this morning, which is available in the IR section of our website.

請注意，我們舉辦今天的活動是為了取代定期舉行的季度更新電話會議。不過，我們今天早上已經報告了我們的業績並提交了 10-Q 表。有關我們第一季業績的更多詳細信息，請參閱我們今天上午發布的新聞稿，該新聞稿可在我們網站的 IR 部分找到。

During today's presentation, you'll hear from our team about our strategy, our pipeline advancements, and our next high-value immunology program. Joining me this morning are Nello Mainolfi, our Founder, President and CEO; Jared Gollob, our Chief Medical Officer; and Veronica Campbell, our Senior Director of Immunology and Project Team Leader of our newly introduced program, IRF5.

在今天的演講中，您將聽到我們的團隊介紹我們的策略、我們的管道進展以及我們的下一個高價值免疫學計劃。今天早上與我一起出席的有我們的創始人、總裁兼首席執行官 Nello Mainolfi、我們的首席醫療官 Jared Gollob 以及我們的免疫學高級主任兼新推出的項目 IRF5 的項目團隊負責人 Veronica Campbell。

Here's a snapshot of today's agenda. Nello will begin with an overview of our strategy and the opportunity with small molecule degraders. Then Jared will provide a high-level overview of our STAT6 program, and we'll conclude with our prepared remarks with a discussion of our newly introduced IRF5 program before we open the call to questions.

以下是今天議程的概要。Nello 將首先概述我們的策略以及小分子降解劑的機會。然後，Jared 將對我們的 STAT6 計劃進行高層概述，在開始提問之前，我們將根據準備好的發言討論我們新推出的 IRF5 計劃。

(Event Instructions) A replay of today's event, including a copy of our corresponding presentation, will be available soon after the call concludes in the Investors section of our website.

（活動說明）今天活動的重播，包括我們相應簡報的副本，將在電話會議結束後不久在我們網站的投資者部分提供。

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

但在開始之前，我想提醒大家，今天的演示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, let's begin. Nello?

好了，讓我們開始吧。尼洛？

So thanks, Justine. Very exciting to be here today to share not only a pipeline update, but also our new program, IRF5, which Veronica will do in a few minutes. I thought I'd take a few minutes here to just give you an update on our strategy, where we're going, some important decisions we're making and upcoming milestones.

所以謝謝你，賈斯汀。今天能夠在這裡不僅分享管道更新，而且分享我們的新程式 IRF5，這非常令人興奮，Veronica 將在幾分鐘內完成。我想花幾分鐘時間向大家介紹我們的策略、我們的發展方向、我們正在做出的一些重要決定以及即將到來的里程碑。

So just to remind you, Kymera was founded about -- actually just very recently nine years ago with the goal of building an industry-leading pipeline of medicines using a novel modality called targeted protein degradation. We believe, with this modality, we can give rise to a series of new programs and medicines that can overcome the challenges that the industry has faced for the past 20 years. In order to do so, we've built some unique capabilities. I will start with the fact that we have become a key leader in the space of targeted protein degradation.

所以提醒一下，Kymera 成立於——實際上就在九年前，其目標是使用一種稱為靶向蛋白質降解的新方式來建立行業領先的藥物管道。我們相信，透過這種方式，我們可以推出一系列新項目和新藥物，以克服該行業過去 20 年來面臨的挑戰。為了做到這一點，我們建立了一些獨特的功能。首先我要說的是，我們已經成為標靶蛋白質降解領域的關鍵領導者。

In doing so, we built some really unique capabilities of hit finding and optimization of oral degraders. We have -- we've always had and continue to refine a unique target selection strategy based on pursuing traditionally undrugged targets in highly qualified and validated pathways. And that has allowed us to build a portfolio that is poised to really disrupt treatment paradigms.

在這樣做的過程中，我們建立了一些真正獨特的命中查找和口服降解劑優化能力。我們始終擁有並將繼續完善獨特的目標選擇策略，該策略基於以高度合格和經過驗證的途徑追求傳統上未用藥物治療的目標。這使我們能夠建立一個真正顛覆治療模式的產品組合。

We have made a conscious choice a few years ago to focus in immunology. And the main reason has been, as I'll explain in a few slides, that in that particular space, in this place and time, we've been able to combine really the right target with the disruptive potential of targeted protein degradation, delivering for the first time in industry, oral drugs with biologics-like efficacy. And this is really a unique opportunity for Kymera and for patients.

幾年前，我們有意識地選擇專注於免疫學。主要原因是，正如我將在幾張幻燈片中解釋的那樣，在那個特定的空間、地點和時間，我們能夠將正確的目標與靶向蛋白質降解的顛覆性潛力結合起來，在業界首次推出具有類似生物製劑功效的口服藥物。這對 Kymera 和患者來說確實是一個獨特的機會。

So Kymera is founded and continues to thrive on three key pillars. One is a clear vision. So we have always believed that with the new technology, not only you have an opportunity, but you have a responsibility to building a fully integrated company. So we are now building deep development capabilities to advance our programs into Phase 2 and Phase 3 studies with an eye of becoming a commercial-stage company.

因此，Kymera 成立並繼續依靠三大支柱蓬勃發展。一是清晰的願景。因此，我們始終相信，有了新技術，你不僅有機會，而且有責任建立一家完全整合的公司。因此，我們現在正在建立深度開發能力，以將我們的專案推進到第二階段和第三階段的研究，並專注於成為商業階段的公司。

We've been fortunate to always be well capitalized. We now have, as of the end of Q1, $775 million with now an extended runway into the first half of '28. We have brought five new molecules in the clinic since 2020, and we are on path to being able to deliver 10 molecules in the clinic by 2026.

我們很幸運，一直擁有充足的資金。截至第一季末，我們目前擁有 7.75 億美元，並且預計將延續到 28 年上半年。自 2020 年以來，我們已在臨床上推出了 5 種新分子，並預計在 2026 年之前在臨床上推出 10 種新分子。

We have dosed at this point way more than 300 between healthy volunteer patients across our pipeline. And one thing that we're very proud of is our ability to continue to demonstrate impeccable translation from our pre-clinical studies into the clinic with achieving in all of our programs, more than 90% degradation with the desired efficacy and safety profile.

目前，我們已經為超過 300 名健康志願者患者進行了給藥。我們非常自豪的一件事是，我們能夠繼續展示從臨床前研究到臨床的完美轉化，並在所有項目中實現超過 90% 的降解率，同時達到預期的功效和安全性。

So just a quick summary about targeted protein degradation. So the main feature of the technology is the ability to use small molecules to remove protein. So you have almost a genetic-like knockdown or knockout effect with the flexibility and the convenience of oral small molecules. So we're able to go after proteins that have not been drugged or drugged fully for the past decades with a simple oral drug that we're able to design, synthesize, and develop here at Kymera.

以上只是關於目標蛋白質降解的簡要總結。所以該技術的主要特點是能夠利用小分子去除蛋白質。因此，您可以獲得幾乎類似基因敲除或基因敲除的效果，同時又具有口服小分子的靈活性和便利性。因此，我們能夠利用我們在 Kymera 設計、合成和開發的簡單口服藥物來研究過去幾十年來未被藥物治療或完全藥物治療的蛋白質。

So why immunology? Why is this such a unique opportunity for us, and I would say, for patients? So the team did a work in the past year or so looking at the most common -- the 10 most common immune inflammatory diseases. And those are AD, asthma, COPD, as you can see from the slide, HS, multiple sclerosis. And if you look at the seven major markets, that's about 160 million patients that are impacted by these diseases.

那為什麼是免疫學呢？為什麼這對我們，以及我想說對病人來說，是一個如此獨特的機會？因此，該團隊在過去一年左右的時間裡做了一項工作，研究最常見的 10 種免疫發炎疾病。這些疾病包括 AD、氣喘、COPD（如您在幻燈片中看到的）、HS、多發性硬化症。如果你看看七大主要市場，你會發現大約有 1.6 億患者受到這些疾病的影響。

And if you look at the number of patients that are right now are accessing advanced systemic therapies, it's really around 5 million. So we basically have a 3% penetration of advanced systemic therapy into this wide variety of immune-inflammatory diseases, again, in the seven major markets.

如果你看看現在接受先進全身治療的患者數量，你會發現大約有 500 萬人。因此，我們在七大主要市場中，對各種免疫發炎疾病的先進全身性治療滲透率基本上達到 3%。

So I don't think we have a problem of innovation in immunology. There is plenty of great drugs in many disease areas. We have a problem of aligning patients to accessing these highly effective drugs. In fact, of these 5 million patients, two-thirds of these patients access biologics. So only one-third access oral drugs and these oral drugs often are not able to deliver the type of efficacy that biologics can.

所以我不認為我們在免疫學方面有創新問題。許多疾病領域都有很多優秀的藥物。我們面臨的問題是讓患者能夠獲得這些高效能藥物。事實上，在這 500 萬名患者中，三分之二的患者使用生物製劑。因此，只有三分之一的人可以使用口服藥物，而這些口服藥物通常無法達到生物製劑那樣的療效。

So we have an opportunity to expand access and expand the reach of highly innovative drugs with oral degraders that have the efficacy of these advanced systemic therapies. And so when you try to put a number on that market, obviously, it's really hard to do.

因此，我們有機會擴大獲取途徑並擴大具有這些先進全身療法功效的口服降解劑高度創新藥物的覆蓋範圍。因此，當你嘗試對該市場進行量化時，顯然這很難做到。

If you look at the 3%, the $5 million, it's a $100 billion market or more than $100 billion market. So we're talking about 90%-plus of patients that we believe could be poised to receive our novel oral systemic therapies, and that's a very large number that, obviously, it's even hard for us to quantify.

如果你看一下3％，即500萬美元，那麼這是一個1000億美元的市場，或超過1000億美元的市場。因此，我們認為 90% 以上的患者可以接受我們的新型口服全身療法，這是一個非常大的數字，顯然，我們甚至很難量化。

But our job here at Kymera is to develop, again, as I said, oral drugs that can not only displace biologics -- because they ideally and hopefully will have a similar efficacy, safety profile and the convenience of oral drugs -- but more importantly, we can now offer a convenient, highly effective advanced therapy to the 90% of patients that right now are not treated, whether it's for access, whether it's for pricing, whether it's for convenience.

但正如我所說，我們 Kymera 的工作是開發口服藥物，這些藥物不僅可以取代生物製劑 - 因為理想情況下，它們有望具有與口服藥物類似的功效、安全性和便利性 - 但更重要的是，我們現在可以為目前未接受治療的 90％ 患者提供方便、高效的先進療法，無論是為了獲得治療，為了定價，還是方便還是。

And so here in this slide is really highlighting what are the challenges and the opportunities. So biologics, as we all know, have transformed treatment paradigms. They have transformed many diseases and how doctors treat diseases. But the challenge that come with them is obviously they can be very expensive. They can be complex and expensive to manufacture and as well as to prescribe and reimburse.

這張投影片真正強調了我們所面臨的挑戰和機會。眾所周知，生物製劑已經改變了治療模式。它們改變了許多疾病以及醫生治療疾病的方式。但隨之而來的挑戰顯然是它們可能非常昂貴。它們的製造、處方和報銷都很複雜且昂貴。

They have often, not always, immunogenicity issue. They have cold storage issues. So if you're taking a biologic with you on a vacation, you have to think about cold storage. And obviously, they bring the inconvenience route of administration, often painful and again, inconvenient.

它們經常（但並非總是）存在免疫原性問題。他們有冷藏問題。因此，如果您在度假時攜帶生物製劑，則必須考慮冷藏。顯然，它們帶來了不方便的給藥途徑，常常很痛苦，而且不方便。

In an industry survey that was done, I think, as recently as, I believe, 1.5 years, a few hundred patients were asked, if you had an option to switch from a biologics to an oral drug with the same profile, would you make that switch? And 75% of patients said yes. So there's clearly not only an opportunity, but there is a clear unmet need for patients to access oral therapies that will have a biologics-like profile.

在一項行業調查中，我記得就在一年半前，有數百名患者被問及，如果可以選擇從生物製劑轉換為具有相同特性的口服藥物，你會選擇轉換嗎？75% 的患者表示同意。因此，這顯然不僅是一個機遇，而且患者對具有類似生物製劑特性的口服療法的需求也明顯尚未得到滿足。

So the question would be why wouldn't traditional small molecule oral drug capture that need? And the answer that we try to depict here is in the bottom of the slide. A traditional oral small molecules follow a traditional PK/PD profile. So the efficacy is driven by the ability of the drug to block that pathway 24/7. And because the PK and the PD of a small molecule drug is really connected, you see a sigmoidal curve mostly that depicts that correlation. So you're not able to block the pathway constantly 24/7, but you have a peak to trough PD effect.

那麼問題是，為什麼傳統的小分子口服藥物無法滿足這種需求？我們試圖在此描述的答案就在幻燈片的底部。傳統的口服小分子遵循傳統的 PK/PD 曲線。因此，藥物的療效取決於其全天候阻斷該通路的能力。由於小分子藥物的 PK 和 PD 確實存在關聯，因此您會看到一條主要描述這種相關性的 S 形曲線。因此，您無法全天候持續阻斷通路，但您能夠獲得從峰值到谷的 PD 效應。

And this is very evident when you look at targets, for example, like TYK2, where while you're blocking the IL-23 pathway in principle well, you're not able to deliver the type of activity seen with an injectable IL-23 antibody. And that's really because of small molecules' inability to block the pathway fully.

當你觀察目標時，這一點非常明顯，例如，像 TYK2 這樣的目標，雖然你在原則上很好地阻斷了 IL-23 通路，但你無法提供注射 IL-23 抗體所見的那種活性。這其實是因為小分子無法完全阻斷該路徑。

With a degrader that we've shown extensively, both preclinically and clinically, we can block the pathway fully at steady state, maintaining that degradation consistent. And that, as we've shown, can mimic biologics like pathway blockade.

利用我們在臨床前和臨床上廣泛展示的降解劑，我們可以在穩定狀態下完全阻斷該途徑，並保持降解的一致性。正如我們所展示的，這可以模擬通路阻斷等生物製劑。

So there is -- in the next couple of slides, I just wanted to share with you two key features of Kymera that I believe has made us a leader in developing unique programs, especially now in immunology. One is really around the capabilities that we've built. I believe we're the best company today at finding small molecule ligands to undrugged or difficult-to-drug protein. We're some of the best structural biology capabilities, and we've published on this extensively in peer-reviewed journals on understanding ternary complex interactions of our drugs with the proteins and the E3 ligases. And we've shown consistently our ability to translate in the clinic, our deep understanding of PK/PD in different tissues in preclinical species and then in humans, which really de-risks the translation into patients and hopefully into disease outcome.

因此，在接下來的幾張投影片中，我只想與大家分享 Kymera 的兩個主要特點，我相信這兩個特點使我們成為開發獨特專案的領導者，尤其是在免疫學領域。一個是圍繞著我們已經建立的能力。我相信我們是當今在尋找未用藥或難以用藥的蛋白質的小分子配體方面最好的公司。我們擁有最好的結構生物學能力，並且在同行評審期刊上廣泛發表了有關理解我們的藥物與蛋白質和 E3 連接酶的三元複合物相互作用的文章。我們始終如一地展示了我們在臨床上轉化的能力，我們對臨床前物種以及人類不同組織中的 PK/PD 有著深入的了解，這真正降低了轉化到患者身上的風險，並有望降低疾病結果的風險。

And all of these capabilities have resulted in some really important accomplishments in the past few years. We've delivered, at this point, I believe, more than nine development candidates, four against our undrugged transcription factors. We've shown now extensively that our degraders are very potent, very specific, orally bioavailable with a great and even distribution across tissues. And we've shown over and over again, as I mentioned, our ability to translate these profiles effectively into the clinic.

所有這些能力在過去幾年裡已經取得了一些非常重要的成就。我相信，目前我們已經推出了 9 種以上的候選藥物，其中 4 種是針對我們未開發的轉錄因子的。我們現在已經廣泛證明，我們的降解劑非常有效、非常特異、口服生物利用度高，並且在組織中分佈均勻。正如我所提到的，我們已經一次又一次地證明了我們有能力將這些資料有效地應用到臨床上。

So another key feature. So we've talked about capabilities, another key feature of Kymera's strategy is how we think about target selection. And we have these key four pillars that have been the same since day one. We go after targets that have not been drugged or drugged well before, where there is strong human genetics for the target, and importantly, where the pathway has been validated with other agents, usually upstream of our targets. We usually, if not always, have a clear path to show clinical differentiation early in our development strategy as well as now we're very, very keen on programs that have access to large clinical and commercial opportunities.

另一個關鍵特徵是。我們已經討論了能力，Kymera 策略的另一個關鍵特徵是我們如何考慮目標選擇。我們從第一天起就擁有這四大支柱。我們尋找那些以前沒有使用過藥物或用過很久的靶點，這些靶點具有強大的人類遺傳學特性，而且重要的是，這些途徑已經通過其他藥物進行了驗證，通常位於我們靶點的上游。我們通常（如果不是總是）在開發策略的早期就有一個清晰的路徑來展示臨床差異化，而且現在我們非常熱衷於那些能夠獲得大型臨床和商業機會的專案。

So if you look at our targets today that we're actively pursuing, STAT6 and IRF5, two undrugged transcription factors where Kymera has delivered the first development candidate -- or for STAT6, actually the first clinical entry and soon the first clinical data, these have been targets that have been pursued for decades and really the technology has been missing. And here, we have first-in-class drug with targets with strong genetic validation. IRAK4, the target that has been drugged but not well, with traditional small molecules.

因此，如果您看看我們今天正在積極追求的目標，STAT6 和 IRF5，這兩個未經藥物治療的轉錄因子，Kymera 已經提供了第一個開發候選藥物 - 或者對於 STAT6，實際上是第一個臨床條目，很快就會有第一個臨床數據，這些是幾十年來一直追求的目標，但實際上技術一直缺失。在這裡，我們擁有一流的藥物，其標靶經過強有力的基因驗證。IRAK4 是已經使用傳統小分子藥物治療但效果不佳的標靶。

The beauty about our strategy is also that we're going after these pathways that have been -- that have complementarity. So not only these are standalone important programs after IL-4 and IL-13, Type I interferon cytokines, B cells, autoantibodies, IL-1/TLR pathways, but also you can imagine that eventually these pathways can be synergistic in how we think about further development in combination, et cetera.

我們的策略的優點還在於，我們走的是具有互補性的路徑。因此，這些不僅是 IL-4 和 IL-13、I 型乾擾素細胞因子、B 細胞、自體抗體、IL-1/TLR 路徑之後的獨立重要程序，而且您還可以想像，這些路徑最終可以在我們如何考慮組合進一步發展等方面發揮協同作用。

And this is probably even more appreciatable if you look at the slide 13 here, where we're looking at where we're developing these assets in which not only disease area, but also in which indications. So you see, for example, for STAT6, we have a big effort in atopic diseases, which are more often in dermatology and respiratory. And here, you see seven or eight different diseases, for IRF5, which I would say is more traditional immunology, rheumatology, you see more in GI and rheumatology, RA, lupus, et cetera, while IRAK4 has places in each of these disease areas.

如果你看這裡的第 13 張投影片，你可能會更明白這一點，我們不僅了解了我們在哪些疾病領域開發這些資產，還了解了它們在哪些適應症中發揮作用。例如，對於 STAT6，我們在過敏性疾病方面做出了巨大努力，這些疾病更常見於皮膚病學和呼吸系統疾病。在這裡，你可以看到七、八種不同的疾病，對於 IRF5 來說，我認為它是更傳統的免疫學、風濕病學，在胃腸道和風濕病學、類風濕性關節炎、狼瘡等方面更常見，而 IRAK4 在這些疾病領域都有一席之地。

So not only we can actually capture almost the totality of potential immune-inflammatory indications, but then you can imagine when there is overlap, a potential strategy down the road could be a combination of these assets.

因此，我們不僅可以真正捕捉到幾乎所有潛在的免疫發炎指徵，而且你可以想像，當存在重疊時，未來的潛在策略可能是這些資產的組合。

This is a slide that captures the concept that was made before about the unmet need in the space. And this actually puts a number to the concept. We can use STAT6 and the concept can be applied to the other programs. Again, if you look at the seven major market, we have more than 100 million patients that are diagnosed with Th2 diseases. And you can see the most prevalent there, AD, asthma, COPD, chronic [rhiniitis], et cetera.

這張投影片概括了先前提出的有關該領域未滿足需求的概念。這實際上為這個概念賦予了一個數字。我們可以使用 STAT6，並且該概念可以應用於其他程式。再說一次，如果你看看七大市場，我們有超過 1 億被診斷出患有 Th2 疾病的患者。您可以看到那裡最常見的疾病是阿茲海默症、氣喘、慢性阻塞性肺病、慢性鼻炎等等。

The number of patients that have access to advanced systemic therapy, right now dominated by dupilumab, is really around 1 million patients. So we have almost 100 million patients, if not more, that I believe we strongly believe would benefit from an oral drug that has the efficacy and the safety of an injectable biologics. So an oral drug that can change how doctors prescribe medicines for patients with these diseases.

目前，能夠接受以度普利尤單抗為主的先進全身治療的患者數量約為 100 萬人。因此，我相信，我們有近 1 億甚至更多的患者，他們將受益於一種具有註射生物製劑的功效和安全性的口服藥物。因此，口服藥物可以改變醫生為這些疾病患者開藥的方式。

And so that's really what we're trying to do not only for STAT6, but also for IRF5 in diseases that are, as we said, complementary to the STAT6 diseases. This is really around SLE, RA, Crohn's disease, UC, et cetera, and both Veronica and Jared will share more. And then IRAK4 with, again, the more traditional IL-1/TLR-driven diseases.

因此，我們實際上不僅要針對 STAT6 進行研究，還要針對 IRF5 進行研究，因為 IRF5 所致的疾病，正如我們所說，是與 STAT6 疾病互補的。這其實是關於 SLE、RA、克隆氏症、UC 等等，Veronica 和 Jared 都會分享更多內容。然後 IRAK4 再次與更傳統的 IL-1/TLR 驅動疾病有關。

So hopefully, this slide gives you a sense of the opportunities we have in front of us with oral drugs that are really best in pathway, combine the convenience of oral drug and the efficacy of a biologic. So in this slide, I just -- we will actually go through the upcoming milestones soon. And so I don't want to spend too much time going through the details of the slide. I just want to say we have the next 18 months with the reach of milestones.

所以希望這張投影片能讓您了解我們面臨的機遇，即口服藥物在途徑上確實是最好的，結合了口服藥物的便利性和生物製劑的功效。因此，在這張幻燈片中，我們很快就會經歷即將到來的里程碑。所以我不想花太多時間去講解幻燈片的細節。我只想說，在接下來的 18 個月裡，我們將實現里程碑。

We have STAT6 upcoming data in June, which we're very excited to finally get there. We have Phase 1b data at the end of the year. We have 2 Phase 2b studies to start. Veronica will tell you about IRF5. So maybe I'll give you an update on a couple of programs that will not be the subject of the later presentation.

我們將在六月獲得 STAT6 數據，我們非常高興終於能夠獲得這些數據。我們在年底有 1b 階段的數據。我們有 2 個 2b 期研究即將開始。維羅妮卡將向您介紹 IRF5。因此，也許我會向你們介紹一些不會成為後續演示主題的程序的最新情況。

So first, on IRAK4. As you know, Sanofi is progressing KT-474 in 2 parallel Phase 2b studies in both HS and AD. We continue to expect these studies to be completed in 2026, in first half, mid-2026 with data shortly thereafter. As you know, IRAK4 was our first immunology target and early success in that program has allowed us and has actually given us the impetus to invest even more in immunology and allowed us to build what we believe to be one of the best, if not the best, oral immunology pipeline in this industry.

首先，關於 IRAK4。如您所知，賽諾菲正在推進KT-474在HS和AD兩個疾病領域的兩個平行2b期臨床試驗。我們預計這些研究將於2026年上半年或中期完成，並在隨後不久獲得數據。如您所知，IRAK4 是我們的第一個免疫學目標，該計畫的早期成功使我們能夠並且實際上給了我們在免疫學方面進行更多投資的動力，並使我們能夠建立我們認為是業內最好的口服免疫學管道之一（如果不是最好的話）。

And so while Sanofi has been advancing 474, we've had additional ongoing effort at Kymera under the collaboration. We said that in the past. As a result of these efforts, we're pleased to announce today that we have recently achieved the preclinical milestones, resulting in $20 million payment that we expect to receive in the second quarter. So a validation of both the strategy and the work that both teams have been doing in the past few years.

因此，在賽諾菲不斷推進 474 的同時，我們也在合作下對 Kymera 做出了額外的持續努力。我們過去就說過這句話。由於這些努力，我們今天很高興地宣布，我們最近已經實現了臨床前的里程碑，預計將在第二季度收到 2000 萬美元的付款。因此，這既是對兩個團隊過去幾年所採取的策略的驗證，也是對這兩個團隊所做工作的驗證。

Secondly, I'd like to touch on the disclosure that we released this morning in the press release around our decision around TYK2. So first, I'll say that it's, I think, widely accepted that we're in a very volatile market period, not only biotechnology, but I would say the broader market. And with that, we believe that Kymera is exceptionally well positioned to navigate this uncertain environment.

其次，我想談談我們今天早上在新聞稿中發布的有關 TYK2 決定的披露內容。首先，我想說的是，我認為大家普遍認為我們正處於一個非常動盪的市場時期，不僅是生物技術領域，我想說整個市場都是如此。因此，我們相信 Kymera 完全有能力應對這種不確定的環境。

We have what we believe, as I just said, probably the best oral immunology pipeline in the industry. We have multiple upcoming catalysts that we'll go through later in the presentation. We have an incredible research team that continues to deliver novel programs. You've seen IRF5; you'll see more in the near future. And we have a strong balance sheet of $775 million as of the end of Q1.

正如我剛才所說，我們相信，我們擁有業內最好的口腔免疫學管道。我們有多個即將出現的催化劑，我們將在稍後的演示中討論。我們擁有一支出色的研究團隊，不斷推出新穎的專案。您已經看到了 IRF5；不久的將來您將看到更多。截至第一季末，我們的資產負債表強勁，達到 7.75 億美元。

But obviously, we can't just sit and be complacent. We continue to look for opportunities to ensure that our human as well as our capital resources are always prioritized towards the highest return activities. And in fact, with this philosophy that we've continued to optimize our resource allocation strategy. You've seen changes that we made in the past around our oncology investments.

但顯然，我們不能就此安心自滿。我們不斷尋找機會，確保我們的人力和資本資源始終優先用於最高回報的活動。事實上，我們秉持著這個理念，不斷優化我們的資源配置策略。您已經看到我們過去在腫瘤學投資方面所做的改變。

And so it's really with this spirit of prioritizing and funding the highest return activities that we are announcing today our strategic decision not to advance our TYK2 degrader, KT-295, into clinical development. Now I just want to take a moment to explain that well.

因此，正是本著優先考慮和資助最高回報活動的精神，我們今天宣布了我們的策略決定，不再將我們的 TYK2 降解劑 KT-295 推進到臨床開發階段。現在我只想花一點時間來好好解釋一下。

First, I would like to say that we have completed IND-enabling studies with this drug, and we have seen no adverse events in any of our studies in any of our doses. So this was as a successful IND-enabling campaign as you wish. And we continue to be a strong believer in the differentiated case for a degrader in this highly validated pathway.

首先，我想說我們已經完成了該藥物的 IND 支持研究，並且在我們任何劑量的任何研究中都沒有發現不良事件。因此，正如您所希望的那樣，這是一個成功的 IND 支援活動。我們仍然堅信，在這個經過高度驗證的途徑中，降解劑具有差異化的情況。

At the same time, in this current environment, resource allocation is very important. And we believe resource allocation, and particularly our people, to programs with the highest probability of success is paramount. So at this point, we've decided to pause on our TYK2 efforts and redirect those resources.

同時，在目前環境下，資源配置非常重要。我們相信，將資源（尤其是我們的人員）分配給成功機率最高的專案至關重要。因此，我們決定暫停 TYK2 工作並重新分配這些資源。

So this decision will allow us to address two important points. One, we're able now to dedicate more human capital as well as our finances to what I believe it to be one of the largest -- potentially one of the largest programs in the industry, our STAT6 programs and 621, I would say the STAT6 franchise and 621, that is really at the cusp of key inflection points. We also can use some of these both human and financial capital to fund IRF5 and other efforts that we have in other areas.

因此，這項決定將使我們能夠解決兩個重要問題。首先，我們現在能夠將更多的人力資本和資金投入到我認為是業內最大的項目之一，即我們的 STAT6 項目和 621，我想說 STAT6 特許經營和 621，這確實處於關鍵轉折點的邊緣。我們還可以利用這些人力和財力資本來資助 IRF5 以及我們在其他領域的努力。

And then secondly, what this decision has allowed us to do is to extend our cash runway from mid-2027 to the first half of 2028. So this is very important because now our cash runway is well beyond important inflection points, especially, I would say, well beyond the Phase 2b readouts for 621.

其次，這項決定使我們能夠將現金流從 2027 年中期延長至 2028 年上半年。所以這非常重要，因為現在我們的現金流已經遠遠超出了重要的轉折點，特別是，我想說，遠遠超出了 621 第 2b 階段的讀數。

So you all know it's never easy when we make this resource allocation decision. But I hope I was able to convey our strategic thinking around this decision and then happy for myself and the team to take questions in the Q&A at the end.

所以大家都知道，當我們做出這個資源分配決定時，這絕非易事。但我希望我能夠傳達我們圍繞這一決定的戰略思想，然後很高興自己和團隊在最後的問答環節中回答問題。

So I thought I'll pause here now and pass it on to Jared for him to go through our STAT6 program.

所以我想我現在就在這裡停下來並將其傳遞給 Jared，讓他了解我們的 STAT6 程式。

Thanks, Nello. This is a very exciting time for Kymera from a development perspective. We are well positioned to achieve multiple clinical data readouts that we believe will further validate our approach and strategy. Before we formally introduce our IRF5 program, I'd like to give you a brief update on our ongoing and planned clinical trials for KT-621, our first-in-class oral STAT6 degrader program and the first STAT6-targeted medicine to enter clinical development.

謝謝，尼洛。從發展角度來看，這對 Kymera 來說是一個非常令人興奮的時刻。我們已做好準備，實現多項臨床數據讀數，我們相信這將進一步驗證我們的方法和策略。在我們正式介紹我們的 IRF5 項目之前，我想向您簡要介紹我們正在進行和計劃進行的 KT-621 臨床試驗，這是我們一流的口服 STAT6 降解劑項目，也是第一個進入臨床開發的針對 STAT6 的藥物。

The IL-4/IL-13 pathway drives Th2 inflammation and is highly validated by dupilumab, an injectable biologic targeting IL-4 receptor alpha that inhibits IL-4 and IL-13 signaling and is approved for the treatment of multiple different Th2 allergic diseases, including atopic dermatitis and asthma. STAT6 is the obligate and specific transcription factor in the IL-4/13 pathway and is, therefore, the critical signaling node controlling Th2 inflammation. For this reason, blocking the function of STAT6 is expected to phenocopy IL-4/IL-13 targeting.

IL-4/IL-13 路徑驅動 Th2 炎症，並已得到 dupilumab 的高度驗證，dupilumab 是一種針對 IL-4 受體 alpha 的注射生物製劑，可抑制 IL-4 和 IL-13 信號傳導，並被批准用於治療多種不同的 Th2 過敏性疾病，包括異位性皮膚炎和氣喘。STAT6 是 IL-4/13 路徑中的強制性和特異性轉錄因子，因此是控制 Th2 發炎的關鍵訊號節點。因此，阻斷 STAT6 的功能有望實現 IL-4/IL-13 標靶表型複製。

There is also compelling genetic validation for the criticality of STAT6 in driving Th2 allergic diseases and the safety of reducing its expression, including the following. First, the pathogenic role of STAT6 is supported by human genetics showing that gain of function mutations of STAT6 cause severe early onset allergic disease in humans. Second, a recent publication found that human heterozygous STAT6 loss of function mutations protected against severe Th2 asthma, showing for the first time how decreased STAT6 protein levels can be protective against Th2 diseases.

還有令人信服的基因驗證證明 STAT6 在驅動 Th2 過敏疾病中的重要性以及降低其表現的安全性，包括以下內容。首先，STAT6 的致病作用得到了人類遺傳學的支持，顯示 STAT6 的功能獲得性突變會導致人類嚴重的早發性過敏性疾病。其次，最近的一份出版物發現，人類雜合的 STAT6 功能喪失突變可以預防嚴重的 Th2 氣喘，首次顯示 STAT6 蛋白質水平降低如何可以預防 Th2 疾病。

Additionally, STAT6 knockout in mice is protective in multiple allergic disease models and STAT6 knockout mice developed normally, are viable, and are fertile. So the human and mouse genetics tell us that STAT6 is a compelling target for treating IL-4/IL-13-driven allergic diseases and suggests it can be safely knocked down.

此外，小鼠 STAT6 敲除在多種過敏性疾病模型中具有保護作用，且 STAT6 敲除小鼠發育正常、具有生存能力和生育能力。因此，人類和小鼠遺傳學告訴我們，STAT6 是治療 IL-4/IL-13 驅動的過敏性疾病的一個有力靶點，並表明它可以被安全地抑制。

Only the unique pharmacology of STAT6 degradation has the potential to fully block IL-4/13 signaling with an oral daily drug and thereby phenocopy the activity and safety of an upstream biologic like dupilumab. Historically, the development challenge has been to design oral small molecules that can fully block STAT6 round the clock and thereby inhibit the IL-4/13 pathway to the same extent as biologics. We believe the only modality that can do this are degraders. Furthermore, if an oral STAT6 degrader can truly block the IL-4/13 pathway to the same extent as, say, dupilumab, this has the potential to transform the treatment paradigm for all of the different Th2 allergic indications that have already been de-risked by dupilumab.

只有 STAT6 降解的獨特藥理學才有可能透過每日口服藥物完全阻斷 IL-4/13 訊號傳導，從而模擬 dupilumab 等上游生物製劑的活性和安全性。從歷史上看，開發的挑戰是設計能夠全天候完全阻斷 STAT6 的口服小分子，從而像生物製劑一樣抑制 IL-4/13 路徑。我們相信唯一能做到這一點的方式是降解劑。此外，如果口服 STAT6 降解劑能夠真正阻斷 IL-4/13 通路，達到與度普利尤單抗相同的程度，那麼這有可能改變所有不同 Th2 過敏適應症的治療模式，而這些適應症已經透過度普利尤單抗降低了風險。

Dupilumab has transformed the lives of patients with dermatologic, respiratory, and gastrointestinal Th2 diseases and has become one of the largest drugs in this industry. We think we can change the treatment paradigm and reach an even broader patient population with an oral drug targeting STAT6 across all the indications de-risked by dupilumab and perhaps open up new opportunities in additional allergic indications beyond these. We have a robust preclinical data set to support this program, and I'll walk you through this at a high level.

Dupilumab改變了皮膚病、呼吸系統和胃腸道Th2疾病患者的生活，並成為該行業最大的藥物之一。我們認為，我們可以改變治療模式，利用針對 STAT6 的口服藥物覆蓋更廣泛的患者群體，涵蓋所有透過 dupilumab 降低風險的適應症，甚至可能為除此之外的其他過敏適應症開闢新的機會。我們擁有強大的臨床前數據集來支持該計劃，我將向您詳細介紹該計劃。

Preclinically, KT-621 was shown to be exquisitely selective for STAT6 and shows no functional inhibition of other STATs. It degrades STAT6 at low picomolar concentrations across all disease-relevant human primary cell types evaluated, including lymphocytes, myeloid cells, epithelial cells, and smooth muscle cells, among others.

臨床前研究表明，KT-621 對 STAT6 具有極好的選擇性，並且對其他 STAT 沒有功能性抑制。它可以在評估的所有與疾病相關的人類原代細胞類型中以低皮摩爾濃度降解 STAT6，包括淋巴細胞、髓細胞、上皮細胞和平滑肌細胞等。

We've shown preclinically that KT-621 is more potent than dupilumab at blocking IL-4 and IL-13 pathway functions relevant to Th2 disease manifestations in cell systems and is equal or superior to dupilumab at blocking Th2 inflammation in preclinical disease models. This was demonstrated in the mouse house dust mite asthma model at doses achieving 90% or greater STAT6 degradation. Overall, the preclinical data generated highlight the best-in-pathway potential of KT-621 given its dupilumab-like activity and the convenience of an oral pill.

我們在臨床前已證明，KT-621 在阻斷細胞系統中與 Th2 疾病表現相關的 IL-4 和 IL-13 通路功能方面比 dupilumab 更有效，並且在阻斷臨床前疾病模型中的 Th2 炎症方面與 dupilumab 相同或優於 dupilumab。在小鼠屋塵蟎氣喘模型中，當劑量達到 90% 或更高時，STAT6 降解就得到了證實。整體而言，鑑於 KT-621 類似度普利尤單抗的活性和口服藥的便利性，所產生的臨床前數據凸顯了其最佳途徑的潛力。

In higher species, including dogs and monkeys, we have shown with oral daily dosing that we can fully degrade STAT6 at steady state in all relevant tissue types, and we did not observe any adverse safety findings in 4-week GLP tox studies in non-human primates and rodents.

在包括狗和猴子在內的高等物種中，我們已證明，透過每日口服給藥，我們可以在所有相關組織類型中完全降解穩定狀態下的 STAT6，並且我們在非人類靈長類動物和囓齒動物的 4 週 GLP 毒性研究中未觀察到任何不良安全性發現。

In light of the enormous potential for KT-621 to transform the treatment paradigm for patients with Th2- allergic diseases, we have adopted an accelerated development strategy that begins with Phase 1 studies in healthy volunteers and AD patients to quickly enable demonstration of clinical proof of concept and inform dose selection for Phase 2b dose range finding studies. Our plan is to run two sentinel Phase 2b trials in AD and asthma, starting in Q4 2025 and Q1 2026, respectively, that will enable dose selection for subsequent Phase 3 registrational studies, not just in AD and asthma, but also across multiple other dermatologic, respiratory, and gastrointestinal indications de-risked by dupilumab.

鑑於 KT-621 在改變 Th2 過敏性疾病患者治療模式方面具有巨大潛力，我們採取了加速開發策略，從健康志願者和 AD 患者中的 1 期研究開始，以快速證明臨床概念驗證並為 2b 期劑量範圍探索研究提供劑量選擇資訊。我們的計劃是分別於 2025 年第四季和 2026 年第一季開始針對 AD 和氣喘進行兩項哨兵 2b 期試驗，這將為後續 3 期註冊研究選擇劑量，不僅針對 AD 和氣喘，還針對 dupilumab 降低風險的多種其他皮膚病、呼吸系統和胃腸道適應症。

The Phase 1a healthy volunteer SAD/MAD study has been completed, and we're on track to report data next month. The primary objective is to show 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. Given the extensive clinical pathway validation by dupilumab, all the human STAT6 genetics data and the preclinical data we generated showing dupilumab-like activity with 90% STAT6 degradation in disease models of asthma and AD, we believe that if we can achieve this study objective, it will largely de-risk the program and meaningfully increase the probability of success as we move into patient studies.

階段 1a 健康志願者 SAD/MAD 研究已經完成，我們將於下個月報告數據。主要目標是證明我們可以強力降解血液和皮膚中的 STAT6，我們將其定義為在安全且耐受性良好的劑量下減少 90% 或更多。鑑於 dupilumab 的廣泛臨床途徑驗證、所有人類 STAT6 遺傳學數據以及我們生成的臨床前數據顯示在哮喘和 AD 疾病模型中 90% 的 STAT6 降解具有 dupilumab 樣活性，我們相信，如果我們能夠實現這一研究目標，它將在很大程度上降低該計劃的風險，並在我們進入患者研究時顯著提高成功的可能性。

We're also looking at how KT-621 impacts several circulating Th2 biomarkers, including TARC and IgE. Our expectation entering the trial was that the effect would likely be comparable to what has been reported in healthy volunteers for dupilumab. Though as we have said, we believe the best opportunity to show a significant effect on Th2 biomarkers will come in patient studies where baseline levels are greatly elevated due to IL-4/13 pathway activation.

我們也正在研究 KT-621 如何影響幾種循環 Th2 生物標記物，包括 TARC 和 IgE。我們進入試驗的預期是，其效果可能與健康志願者使用 dupilumab 所報告的效果相當。但正如我們所說，我們相信，展示對 Th2 生物標記的顯著影響的最佳機會將出現在由於 IL-4/13 通路激活而導致基線水平大幅升高的患者研究中。

Importantly, while completing the Phase 1 healthy volunteer study, we were able to initiate the first KT-621 trial in AD patients well ahead of what we had initially planned. The ongoing Phase 1b trial named BroADen is a single-arm, open-label trial that will enroll about 20 moderate to severe atopic dermatitis patients. Patients will be administered KT-621 once daily for four weeks.

重要的是，在完成第一階段健康志願者研究的同時，我們能夠提前於最初的計劃啟動 AD 患者的首次 KT-621 試驗。正在進行的 1b 期試驗名為 BroADen，是一項單臂開放標籤試驗，將招募約 20 名中度至重度異位性皮膚炎患者。患者將每天接受一次 KT-621 治療，持續四週。

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 and on the transcriptome of active AD skin lesions. The study will also assess KT-621's effect on clinical endpoints such as EASI and pruritus NRS. We expect to report the Phase 1b data in the fourth quarter.

研究的主要目的是證明 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 生物標記和活動性 AD 皮膚病變的轉錄組具有類似 dupilumab 的作用。該研究還將評估 KT-621 對 EASI 和搔癢 NRS 等臨床終點的影響。我們預計將在第四季度報告第 1b 階段的數據。

So in summary, we believe that targeting STAT6 for degradation with KT-621 is the only oral small molecule approach with the potential to achieve a dupilumab-like profile with once-daily dosing and are approaching KT-621 development with a strong sense of urgency and focus on execution. This program has enormous potential to dramatically change the way we can treat patients with inflammatory diseases and expand their access to transformative drugs.

總而言之，我們認為，以 KT-621 為目標降解 STAT6 是唯一有可能透過每日一次給藥來實現類似 dupilumab 療效的口服小分子方法，並且我們正以強烈的緊迫感和對執行的關注來推進 KT-621 的開發。該計畫具有巨大的潛力，可以徹底改變我們治療發炎疾病患者的方式，並擴大他們獲得轉化藥物的機會。

We're excited by the progress we've made in completing our Phase 1a healthy volunteer trial and initiating our Phase 1b trial in AD patients and look forward to sharing data next month for healthy volunteers and later this year for AD patients and gearing up for the start of Phase 2b trials in AD and asthma.

我們對完成 1a 期健康志願者試驗和啟動 AD 患者 1b 期試驗所取得的進展感到非常興奮，並期待下個月為健康志願者分享數據，今年晚些時候為 AD 患者分享數據，並為開始 AD 和哮喘的 2b 期試驗做好準備。

I'd like to pause here and introduce Veronica Campbell, the research lead on the IRF5 program. With her team, she's done a terrific job advancing this exciting program to development candidate and into IND-enabling studies, and we are excited to share the details with you now.

我想在這裡停下來介紹 IRF5 計畫的研究負責人維羅妮卡坎貝爾 (Veronica Campbell)。她和她的團隊出色地完成了這個令人興奮的項目，將其推進到開發候選項目並進入 IND 支援研究，我們現在很高興與您分享細節。

Thanks, Jared. I'm Veronica Campbell, Senior Director of Immunology at Kymera. I've worked at Kymera for eight years, and I'm proud to be part of this pioneering team working to develop transformative treatments for chronic immunological diseases. As the project team lead, I'm very excited to share with you the story of our first-in-class IRF5 degrader, KT-579, and why we believe it has the potential to be the first IRF5 targeted oral therapy to deliver transformative activity in several rheumatic and autoimmune diseases, superior to standard of care drugs, including several biologics.

謝謝，賈里德。我是 Kymera 免疫學高級主任 Veronica Campbell。我在 Kymera 工作了八年，我很自豪能夠成為這個致力於開發慢性免疫疾病變革性治療方法的先鋒團隊的一員。作為專案團隊負責人，我很高興與大家分享我們一流的 IRF5 降解劑 KT-579 的故事，以及為什麼我們相信它有可能成為第一個針對 IRF5 的口服療法，在幾種風濕病和自身免疫性疾病中發揮轉化作用，優於包括幾種生物製劑在內的標準護理藥物。

Today, I will cover, first, how Kymera's TPD approach has a unique opportunity to provide a novel oral therapy against what has been historically undrugged transcription factor. From there, I will describe the well-established biological function of IRF5 and the genetic and clinical pathway validation, next, the clinical development and commercial opportunities IRF5 presents. Then I'll describe the exciting preclinical data package for our development candidate, KT-579, and finally, the expected time lines and next steps for the program.

今天，我將首先介紹 Kymera 的 TPD 方法如何為歷史上未用藥物治療的轉錄因子提供獨特的新型口服療法。從那裡，我將描述 IRF5 已確定的生物學功能以及遺傳和臨床途徑驗證，接下來介紹 IRF5 提供的臨床開發和商業機會。然後，我將描述我們開發候選藥物 KT-579 的令人興奮的臨床前資料包，最後介紹該計劃的預期時間表和後續步驟。

I'd like to start by introducing our latest first-in-class oral development candidate, KT-579. KT-579 is a highly potent selective oral degrader of IRF5, which is an essential signaling node in genetically and clinically validated immune pathways, driving inflammation in multiple autoimmune diseases with significant unmet patient need. I'll share details in the coming slides on the robust activity of KT-579 in primary cell systems, including patient donor cells and preclinical efficacy models of RA and lupus. In addition, KT-579 has a highly encouraging safety profile in preclinical tox studies where it was well tolerated at up to 200 fold above the predicted human efficacious dose.

首先，我想介紹我們最新的同類首創口服候選藥物 KT-579。KT-579 是一種強效的 IRF5 選擇性口服降解劑，IRF5 是經基因和臨床驗證的免疫途徑中的重要訊號節點，可引發多種自體免疫疾病的炎症，且患者的需求尚未得到滿足。我將在接下來的幻燈片中分享有關 KT-579 在原代細胞系統中的強大活性的詳細信息，包括患者供體細胞和 RA 和狼瘡的臨床前療效模型。此外，KT-579 在臨床前毒性研究中表現出令人鼓舞的安全性，在比預期的人類有效劑量高出 200 倍的情況下仍具有良好的耐受性。

Our compelling preclinical characterization of KT-579 is consistent with the innovative science we've shared across our immunology pipeline and positions this program well on the path to development. The program is currently in IND-enabling studies, and we're on track to initiate Phase 1 testing in early 2026.

我們對 KT-579 的引人注目的臨床前表徵與我們在免疫學管道中分享的創新科學一致，並使該計畫在發展道路上處於良好的位置。該計畫目前處於 IND 支持研究階段，我們預計在 2026 年初啟動第一階段測試。

Consistent with Nello and Jared's discussion of our rigorous approach to target selection, IRF5 meets all our criteria of what we think makes a compelling target for oral TPD approach. IRF5 is an undrugged target with strong human genetic validation and supporting biological functional data within pathways that have been clinically validated.

與 Nello 和 Jared 對我們嚴格的目標選擇方法的討論一致，IRF5 滿足我們認為成為口服 TPD 方法引人注目的目標的所有標準。IRF5 是一個未經藥物治療的靶點，具有強大的人類基因驗證和支持經過臨床驗證的途徑內的生物功能數據。

As seen in the pathway image on the right, IRF5 is a central node activated downstream of pattern recognition receptors that can recognize foreign or self-antigens and is critical for mounting a pro-inflammatory response. For example, downstream of endosomal TLR7, TLR8, and TLR9 activation, IRF5 regulates Type I interferon responses, pro-inflammatory cytokines such as IL-12, TNF, and IL-6 and antibody production. Its expression is cell and activation specific, making IRF5 an attractive target with potential to block immune dysregulation while sparing normal cell function.

如右側通路圖所示，IRF5 是一個在模式識別受體下游激活的中心節點，可以識別外來或自身抗原，對激發促炎反應至關重要。例如，在內體 TLR7、TLR8 和 TLR9 活化的下游，IRF5 調節 I 型乾擾素反應、促發炎細胞因子（如 IL-12、TNF 和 IL-6）以及抗體產生。它的表達具有細胞和活化特異性，這使得 IRF5 成為一個有吸引力的靶點，有可能阻止免疫失調，同時保留正常細胞功能。

IRF5 is a highly validated target through human genetics in clinically pathway validation. IRF5 functional risk variants that have been identified associate with increased susceptibility to lupus, Sjogren's, RA, IBD and systemic sclerosis. For clinical validation, the IRF5 regulated pathways have been validated by multiple cytokine biologics and B-cell-targeting agents, highlighting the importance of pro-inflammatory mediators like Type I interferons, TNF-alpha, IL-12, and IL-23 in autoimmune disease pathogenesis. I will expand on these two points in subsequent slides.

IRF5 是經過人類遺傳學在臨床途徑驗證中高度證實的標靶。已鑑定的 IRF5 功能風險變異與狼瘡、乾燥症、類風濕性關節炎、發炎性腸道疾病和系統性硬化症的易感性增加有關。對於臨床驗證，IRF5 調節路徑已透過多種細胞激素生物製劑和 B 細胞標靶劑得到驗證，突顯了 I 型乾擾素、TNF-alpha、IL-12 和 IL-23 等促發炎介質在自體免疫疾病發病機制中的重要性。我將在後續的幻燈片中詳細闡述這兩點。

IRF5 has been challenging to drug to date, likely due to its multiple complex activation steps, splicing isoforms and high degree of IRF family member homology. As previously reported, TPD is well suited to deplete undrugged transcription factor targets like IRF5, where a single and specific binding event drives molecule activity and can disrupt all IRF5 signaling.

迄今為止，IRF5 一直難以用藥，可能是因為其具有多個複雜的活化步驟、剪接異構體以及高度的 IRF 家族成員同源性。如先前報導的，TPD 非常適合消耗未用藥的轉錄因子靶點，如 IRF5，其中單一特定的結合事件可驅動分子活性並可破壞所有 IRF5 訊號傳導。

Let's discuss IRF5 more in disease context and as a master regulator of innate and adaptive response. IRF5 is selectively expressed in dendritic cells, monocytes, macrophages, and B cells. Pathway-specific IRF5 dysregulation is cell and stimulant dependent. In autoimmunity, it is activated by pattern recognition receptors that can recognize nuclear self-antigens in the body to initiate and amplify both innate and adaptive immune responses by increasing pro-inflammatory cytokines like TNF-alpha, IL-6, IL-12, IL-23, Type I interferons and pathogenic autoantibodies. This can lead to immune complex formation and propagate subsequent inflammation in autoimmune diseases such as lupus, systemic sclerosis and dermatomyositis, among others. Therefore, targeting IRF5 offers the opportunity for a transformative and multi-pronged approach to treat these complex and heterogeneous diseases.

讓我們在疾病背景下進一步討論 IRF5，並將其作為先天和適應性反應的主要調節劑。IRF5 選擇性地在樹突狀細胞、單核細胞、巨噬細胞和 B 細胞中表現。通路特異性的 IRF5 失調依賴細胞和刺激物。在自體免疫中，它由模式識別受體激活，該受體可以識別體內的核自身抗原，透過增加促炎細胞因子（如 TNF-alpha、IL-6、IL-12、IL-23、I 型乾擾素和致病自身抗體）來啟動和放大先天性和適應性免疫反應。這會導致免疫複合物的形成，並在狼瘡、系統性硬化症和皮肌炎等自體免疫疾病中引發發炎。因此，針對 IRF5 為治療這些複雜且異質性的疾病提供了變革性和多管齊下的方法的機會。

Now let's look further into the genetics associated with IRF5. Literature shows the pathogenic role of IRF5 is supported by human genetics, where multiple genome-wide association studies identify IRF5 as an autoimmune susceptibility gene. Specifically, if you look at the bottom left chart, meta-analysis of GWAS studies have shown IRF5 to be a strong risk focus in lupus with risk haplotypes and functional variants identified in patients that associate with high serum interferon alpha levels, anti-double-stranded DNA autoantibodies or anti-RNA-1 binding protein antibodies. Beyond lupus, genetic associations of functional variants have also been identified in RA, IBD, systemic sclerosis, and multiple sclerosis.

現在讓我們進一步了解與 IRF5 相關的遺傳學。文獻顯示，IRF5 的致病作用得到了人類遺傳學的支持，其中多項全基因組關聯研究將 IRF5 確定為自體免疫易感基因。具體來說，如果您查看左下角的圖表，GWAS 研究的薈萃分析表明 IRF5 是狼瘡的一個主要風險焦點，在與高血清幹擾素 α 水平、抗雙鏈 DNA 自身抗體或抗 RNA-1 結合蛋白抗體相關的患者中發現了風險單倍型和功能變異。除了狼瘡之外，在 RA、IBD、系統性硬化症和多發性硬化症中也發現了功能變異的遺傳關聯。

Looking at mouse knockout studies, IRF5 knockout mice are viable and fertile with normal B cell development. In the bottom chart showing a mouse model of lupus, IRF5 plays an essential role in lupus development in pathogenesis that is interestingly independent of Type I interferon pathways. As shown in the survival curves below where Richez et al. knocked out IRF5 and showed increased protection versus the knockout of interferon A receptor that results in modest protection against lupus. Additionally, knockout studies demonstrated attenuated disease in other mouse models of lupus, RA, and IBD, showing biological functionality and supporting the therapeutic potential of IRF5 degradation.

從小鼠基因敲除研究來看，IRF5 基因敲除小鼠具有生存能力和生育能力，B 細胞發育正常。下圖顯示了狼瘡小鼠模型，IRF5 在狼瘡發病機制中起著至關重要的作用，有趣的是，它與 I 型乾擾素路徑無關。如下面的生存曲線所示，Richez 等人敲除了 IRF5 後，與敲除乾擾素 A 受體相比，保護作用增強，而敲除乾擾素 A 受體則對狼瘡具有適度的保護作用。此外，敲除研究表明，其他小鼠狼瘡、類風濕性關節炎和發炎性腸道疾病模型中的疾病有所減輕，顯示出生物學功能並支持 IRF5 降解的治療潛力。

As previously mentioned, IRF5 is only expressed in a limited number of cell types and only activated by specific stimuli. This indicates that IRF5 degradation has the potential to selectively block inflammation to restore immune regulation. Dendritic cells, monocytes and macrophages, when activated by members of the TLR family or other pattern recognition receptors like Dectin, mediate a pathogenic immune response via many pro-inflammatory cytokines, including TNF-alpha, IL-6 and Type I interferons.

如前所述，IRF5 僅在有限數量的細胞類型中表達，並且僅由特定刺激激活。這表明IRF5降解具有選擇性阻斷發炎以恢復免疫調節的潛力。當樹突細胞、單核細胞和巨噬細胞被 TLR 家族成員或其他模式識別受體（如 Dectin）活化時，它們會透過許多促發炎細胞因子（包括 TNF-alpha、IL-6 和 I 型乾擾素）介導致病免疫反應。

In addition, IRF5 is activated by endosomal toll-like receptors and B cells, resulting in pathogenic autoantibody production. There are many agents which are approved in targeting some of these pro-inflammatory mediators like anti-TNF-alpha, anti-IL-12/23, anti-interferon alpha and some which target B cells directly, further validating the target. The multi-faceted functions of IRF5, which occur in specific cell context and upon specific stimuli point to superior efficacy and tolerability profiles compared to current agents for autoimmune disease with the potential to be best-in-class to treat complex diseases like lupus, Sjogren's, and RA, IBD and others.

此外，IRF5 被內體 Toll 樣受體和 B 細胞激活，導致致病自體抗體的產生。有許多藥物被批准用於針對這些促發炎介質，如抗 TNF-alpha、抗 IL-12/23、抗干擾素 alpha，還有一些藥物直接針對 B 細胞，進一步驗證了目標。IRF5 的多方面功能發生在特定的細胞環境和特定的刺激下，與目前的自體免疫疾病藥物相比，它具有更優異的療效和耐受性，有可能成為治療狼瘡、乾燥症、類風濕性關節炎、發炎性腸道疾病等複雜疾病的最佳藥物。

The development opportunity for targeting IRF5 is vast, and there are numerous potential indications across multiple immunological therapeutic areas with a total potential patient impact of more than 10 million patients. KT-579, our oral IRF5 degrader, is designed to block the source of multiple pro-inflammatory mechanisms and improve on effectiveness, durability, and tolerability over currently approved agents in diseases such as RA, lupus, Sjogren's, systemic sclerosis, IBD, among others listed on this slide. Our IRF5 degrader has the potential to be a transformative oral therapy superior to oral and biologics standard of care across all indications on this slide as a result of its broad but cell-specific mechanism.

針對 IRF5 的開發機會龐大，在多個免疫治療領域有許多潛在適應症，總潛在患者影響可能超過 1,000 萬人。我們的口服 IRF5 降解劑 KT-579 旨在阻斷多種促炎機制的源頭，並提高療效、持久性和耐受性，優於目前已獲批准的用於治療 RA、狼瘡、乾燥綜合徵、系統性硬化症、IBD 等疾病的藥物，這些疾病在本幻燈片中列出。由於其廣泛但細胞特異性的機制，我們的 IRF5 降解劑有可能成為一種變革性的口服療法，優於此幻燈片上所有適應症的口服和生物製劑護理標準。

Now let's look at the exciting profile of KT-579, and its impact across the biological mechanisms and pathways just discussed. We have an incredible opportunity with KT-579, given its potential to have an enormous impact on the treatment of autoimmune and rheumatic diseases. As we walk through the preclinical characterization, we hope you will share our enthusiasm for what we believe is another high-value target to emerge in our pipeline. I will show you the potent selective activity of KT-579 in normal human primary cells, donor cells from lupus patients and in vivo disease models of lupus and RA.

現在讓我們來看看 KT-579 令人興奮的概況，以及它對剛才討論過的生物機制和途徑的影響。KT-579 為我們帶來了難以置信的機遇，因為它有可能對自體免疫疾病和風濕病的治療產生巨大影響。當我們進行臨床前表徵時，我們希望您能與我們分享我們的熱情，因為我們相信我們的管道中會出現另一個高價值目標。我將向您展示 KT-579 在正常人類原代細胞、狼瘡患者供體細胞以及狼瘡和 RA 體內疾病模型中的強效選擇性活性。

I'll start with KT-579's effects in human primary cells from healthy donors. KT-579 is an exquisitely selective degrader. As you have seen from our programs over and over, we look at concentrations well above that achieving maximal degradation of our intended target. IRF5 is the only protein degraded out of the 10,000 or so proteins that were detected by mass spec. No other IRF family proteins were degraded to any extent. Looking at specific cell-based assay degradation of IRF3 and IRF7, which are IRF5's closest family members, again, we see no degradation even at concentrations as high as 10 micromole.

我將從 KT-579 對健康捐贈者的人類原代細胞的影響開始。KT-579 是一種選擇性極強的降解劑。正如您從我們的計劃中反覆看到的那樣，我們關注的是遠高於實現預期目標最大降解程度的濃度。在質譜檢測出的約 10,000 種蛋白質中，IRF5 是唯一降解的蛋白質。其他 IRF 家族蛋白均未發生任何程度的降解。透過對 IRF3 和 IRF7（IRF5 的近親）進行特定細胞降解分析，我們再次發現，即使濃度高達 10 微摩爾，也沒有出現降解。

Additionally, as seen on the right, KT-579 is a very potent degrader of IRF5. KT-579 demonstrated picomolar to nanomolar potencies across functionally relevant human cell types evaluated, including B cells, dendritic cells, macrophages, and monocytes, all key players in the pathogenesis of inflammation associated with IRF5. As seen with our other degrader programs, it is critical for us to understand degradation across all relevant human cell types in preclinical settings to build the right translational package to predict our human efficacious doses.

此外，如右圖所示，KT-579 是一種非常有效的 IRF5 降解劑。KT-579 在評估的功能相關人類細胞類型中表現出皮摩爾至納摩爾的效力，包括 B 細胞、樹突狀細胞、巨噬細胞和單核細胞，它們都是與 IRF5 相關的發炎發病機制中的關鍵參與者。正如我們在其他降解程序中所看到的，對於我們來說，了解臨床前環境中所有相關人類細胞類型的降解情況至關重要，這樣才能建立正確的轉化包來預測人類有效劑量。

Next, we wanted to demonstrate selectivity not only through proteomics, but also through downstream pathway activated biology and IRF5 cellular mobilization. KT-579 selectively depletes IRF5 over other key transcription factors within the same pathway axes and downstream of TLR7 and TLR8 activation. This is an important aspect of KT-579 given the high sequence homology between IRF5, IRF3, and IRF7.

接下來，我們不僅想透過蛋白質體學來證明選擇性，還想透過下游路徑活化生物學和 IRF5 細胞動員來證明選擇性。KT-579 選擇性地消耗 IRF5 而不是同一通路軸內的其他關鍵轉錄因子以及 TLR7 和 TLR8 活化的下游。鑑於 IRF5、IRF3 和 IRF7 之間的高度序列同源性，這是 KT-579 的一個重要面向。

As seen in the [standing] on the slide, depleting IRF5 with low nanomolar concentration of KT-579 leaves these other critical transcription factors completely intact. These data provide additional evidence that the functional inhibition we've observed in subsequent slides is driven through IRF5 depletion only and highlights how selective the compound is. In addition, we show we can degrade IRF5 both in the cytoplasm and nucleus as shown in the bottom panel.

如幻燈片上的[站立]所示，用低納摩爾濃度的 KT-579 消耗 IRF5 會使其他關鍵轉錄因子完全完好無損。這些數據提供了額外的證據，證明我們在後續幻燈片中觀察到的功能抑制僅透過 IRF5 消耗來驅動，並強調了該化合物的選擇性。此外，我們表明我們可以在細胞質和細胞核中降解 IRF5，如下圖所示。

Here, we see that KT-579 demonstrated potent inhibition of key pro-inflammatory cytokines and Type I interferon production downstream of TLR4, TLR7, and TLR8, and 9 activation in primary cellular assays shown in the table in graphs. For example, we show KT-579 can block IL-12 and interferon beta production in monocytes and block the production of TNF-alpha and IL-23 in PBMCs. These data highlight KT-579's broad and potent activity that is both cell and stimuli dependent.

在這裡，我們看到 KT-579 表現出對關鍵促炎細胞因子和 TLR4、TLR7 和 TLR8 下游的 I 型乾擾素產生以及表格中所示的原代細胞測定中的 9 激活的強效抑製作用。例如，我們表明 KT-579 可以阻斷單核細胞中 IL-12 和乾擾素 β 的產生，並阻斷 PBMCs 中 TNF-alpha 和 IL-23 的產生。這些數據凸顯了 KT-579 的廣泛而強大的活性，它既依賴細胞，也依賴刺激。

Additionally, transcriptomics analysis demonstrates that KT-579 dampens Type I interferon response and select interferon stimulated genes that are reported to be elevated in systemic autoimmune diseases such as lupus and Sjogren's. Type I interferon responses can be induced by endosomal TLR7 and TLR8 activation via single-stranded RNA nuclear self-antigens.

此外，轉錄組學分析表明，KT-579 可抑制 I 型乾擾素反應並選擇據報道在狼瘡和乾燥綜合徵等系統性自體免疫疾病中升高的干擾素刺激基因。I 型乾擾素反應可透過單股 RNA 核自身抗原活化內體 TLR7 和 TLR8 來誘導。

On the left, differential gene analysis demonstrates that KT-579 can block the Type I interferon at least as effectively as an anti-TLR7/8 inhibitor, afimetoran, at concentrations predicted to be clinically active. On the right, we see that KT-579 can achieve comparable inhibition to afimetoran of select ISGs that have been associated with increased disease activity in lupus.

左側差異基因分析表明，在預測臨床活性的濃度下，KT-579 可以至少與抗 TLR7/8 抑制劑阿菲美托倫一樣有效地阻斷 I 型乾擾素。在右側，我們看到 KT-579 可以對與狼瘡疾病活動增加相關的特定 ISG 實現與阿美托崙相當的抑制。

Turning now to KT-579's activity in patient-derived donor cells. We examined KT-579's impact on lupus patient-derived PBMCs. Endosomal TLR7/8 activation can be IRF5 dependent and KT-579 effectively block TLR 7/8 induced pro-inflammatory cytokines and interferon beta production. These data include some patients with IRF5 common functional variants where we observed similar activity on both IRF5 degradation and downstream functional effects.

現在來談談 KT-579 在患者來源的供體細胞中的活性。我們檢查了 KT-579 對狼瘡患者來源的 PBMCs 的影響。內體 TLR7/8 活化可以依賴 IRF5，而 KT-579 可有效阻斷 TLR 7/8 誘導的促發炎細胞因子和乾擾素 β 的產生。這些數據包括一些具有 IRF5 常見功能變異的患者，我們觀察到 IRF5 降解和下游功能效應具有相似的活動。

By inhibiting pro-inflammatory cytokines in Type I interferon, we hope to reduce inflammation, suppress the development of autoantibodies and ultimately mitigate the progression of autoimmune diseases like lupus, independent of IRF5 genotype. We plan to share more of these data in subsequent presentations.

透過抑制 I 型乾擾素中的促炎細胞因子，我們希望減少炎症，抑制自身抗體的發展，並最終減輕狼瘡等自體免疫疾病的進展，而無需考慮 IRF5 基因型。我們計劃在後續的演示中分享更多這些數據。

Continuing with the lupus patient samples, on this slide, you can see how KT-579 significantly inhibits IgG production in B cells cultured with CGB with or without KT-579 for seven days. In lupus, double-stranded DNA nuclear self-antigens or anti-double-stranded DNA complexes can activate endosomal TLR9 and B cells, leading to B-cell activation, differentiation, and pathogenic autoantibody production. This data really shows the promise of an IRF5-directed treatment to reduce the B-cell-mediated inflammatory cascade in lupus patients.

繼續使用狼瘡患者樣本，在這張投影片上，您可以看到 KT-579 如何顯著抑制在有或沒有 KT-579 的情況下用 CGB 培養七天的 B 細胞中的 IgG 產生。在狼瘡中，雙股 DNA 核自體抗原或抗雙股 DNA 複合物可以活化內體 TLR9 和 B 細胞，導致 B 細胞活化、分化和致病性自體抗體的產生。這些數據確實顯示了 IRF5 導向治療在減少狼瘡患者 B 細胞介導的發炎級聯方面的前景。

And finally, let's turn to the in-vivo preclinical data. In the first model shown here, we evaluated KT-579's activity in mouse acute TLR models that elicit a potent inflammatory cytokine response. In these studies, KT-579 dosed orally once a day for 4 days, achieved deep degradation of IRF5 here measured in the spleen. Importantly, as we discussed with other programs in our pipeline, degraders require higher doses in mouse models compared to other species due to higher plasma protein binding and lower affinity, while in higher species like NHP, which is more translatable to humans, we can achieve full degradation at much lower doses.

最後，讓我們來看看體內臨床前數據。在這裡顯示的第一個模型中，我們評估了 KT-579 在引發強烈發炎細胞因子反應的小鼠急性 TLR 模型中的活性。在這些研究中，每天口服一次 KT-579，持續 4 天，實現了脾臟中測量的 IRF5 深度降解。重要的是，正如我們在與管道中的其他項目討論的那樣，由於更高的血漿蛋白結合率和更低的親和力，降解劑在小鼠模型中需要的劑量比其他物種更高，而在更適合人類的高等物種如 NHP 中，我們可以在更低的劑量下實現完全降解。

Then on the fourth day, TLR7 or TLR9 stimulants were administered systemically and KT-579 activity was compared to a TLR7/8 inhibitor, M5049, as shown on the charts to the right. As expected, only KT-579 led to dose-dependent inhibition of cytokines in both models, blocking both TLR7 and TLR9 induced cytokines, including TNF alpha and also IL-6, IL-12 and interferon beta, which are not shown here.

然後在第四天，全身施用 TLR7 或 TLR9 興奮劑，並將 KT-579 活性與 TLR7/8 抑制劑 M5049 進行比較，如右側圖表所示。如預期的那樣，只有 KT-579 在兩種模型中導致劑量依賴性細胞因子抑制，阻斷 TLR7 和 TLR9 誘導的細胞因子，包括 TNF α 以及 IL-6、IL-12 和乾擾素 β，這些細胞因子未在此處顯示。

This demonstrates KT-579's advantage in blocking both TLR7 and TLR9 activities, which should translate to greater efficacy in several autoimmune diseases. This potential advantage is further supported by mouse TLR knockout studies where TLR7 and TLR9 double knockout led to greater impact on disease onset and severity in mouse models of lupus, for example. In addition, these acute studies allowed us to select active doses for use in chronic mouse models of lupus and RA.

這證明了 KT-579 在阻斷 TLR7 和 TLR9 活性方面​​的優勢，這將轉化為對多種自體免疫疾病的更大療效。小鼠 TLR 敲除研究進一步證實了這一潛在優勢，例如，在小鼠狼瘡模型中，TLR7 和 TLR9 雙敲除對疾病的發生和嚴重程度產生了更大的影響。此外，這些急性研究使我們能夠選擇用於慢性狼瘡和 RA 小鼠模型的活性劑量。

In the next few slides, we will go over our preclinical efficacy studies and show you how our IRF5 degrader, KT-579, compares to existing agents in lupus and RA models, phenocopying IRF5 knockout studies. To start, MRL/Ipr mice have a susceptible genetic background and single gene mutation in FAS, quickly developing lupus-like symptoms and manifestations. Disease biomarkers can be detected as early as 8 weeks of age.

在接下來的幾張投影片中，我們將回顧我們的臨床前功效研究，並向您展示我們的 IRF5 降解劑 KT-579 與狼瘡和 RA 模型中的現有藥物相比如何，以及表型複製 IRF5 敲除研究。首先，MRL/Ipr 小鼠具有易感的遺傳背景和 FAS 的單基因突變，很快就會出現類似狼瘡的症狀和表現。最早可在 8 週齡時檢測到疾病生物標記。

Treatment began at week 10 and ended at week 19 when mice are expected to present with extensive kidney pathology. KT-579 daily oral dosing was well tolerated at both doses of 50 mgs per kg and 200 mgs per kg for the duration of treatment.

治療從第 10 週開始，到第 19 週結束，預計小鼠屆時將出現廣泛的腎臟病理。在治療期間，KT-579 每日口服劑量（50 毫克/公斤和 200 毫克/公斤）均耐受性良好。

KT-579 demonstrated sustained and near complete reduction of proteinuria and 100% survival at both doses, achieving at least 85% degradation with activity superior to approved or clinically active drugs such as afimetoran, deucravacitinib, cyclophosphamide, and an anti-interferon A receptor mouse surrogate antibody administered at the top dose reported in the literature. Additional endpoint readouts are currently ongoing.

KT-579 在兩種劑量下均表現出持續且接近完全減少蛋白尿和 100% 存活率的效果，降解率至少達到 85%，且活性優於文獻報導的最高劑量下已獲批准或臨床活性的藥物，如阿非美托崙、德克拉伐替尼、環磷酰胺和抗干擾素 A 受體小鼠替代抗體。目前正在進行額外的端點讀數。

Next, we evaluated the impact of IRF5 degradation in the long-term NZBW1 spontaneous lupus model using an earlier potent and selective IRF5 tool degrader. This degrader was used for proof of concept in this model while characterization was ongoing for our development candidate, KT-579. NZBW1 mice have a polygenic background and spontaneously develop lupus that present with high levels of circulating anti-double-stranded DNA, anti-ANA, proteinuria, and immune complex-mediated glomerular nephritis, similar to human lupus.

接下來，我們使用早期強效且選擇性的 IRF5 工具降解劑評估了 IRF5 降解對長期 NZBW1 自發性狼瘡模型的影響。在我們對候選開發產品 KT-579 進行特性分析的同時，該降解劑也用於該模型中的概念驗證。NZBW1 小鼠具有多基因背景，會自發性罹患狼瘡，表現為高水平的循環抗雙股 DNA、抗 ANA、蛋白尿和免疫複合物介導的腎絲球腎炎，類似人類狼瘡。

Treatment was initiated at week 21 during early onset of disease. Daily oral doses of an IRF5 degrader for 4 months were well tolerated, and doses that achieved greater than 80% IRF5 degradation led to sustained reduction of proteinuria and near complete reduction of circulating serum anti-double-stranded DNA autoantibodies, generally better than standard of care, cyclophosphamide approved anti-interferon A receptor 1 surrogate, and clinical stage testing agents, afimetoran and deucravacitinib.

治療於疾病早期發作的第 21 週開始。每日口服 IRF5 降解劑 4 個月，耐受性良好，達到 80% 以上 IRF5 降解的劑量可導致蛋白尿持續減少，並且幾乎完全減少循環血清抗雙鏈 DNA 自身抗體，通常優於標準護理、環磷酰胺批准的抗干擾素 A 受體 1 替代品和臨床階段測試藥物阿菲美托崙和德克拉伐替尼。

These are really exciting results that demonstrate the ability of an oral IRF5 degrader to achieve similar activity on IRF5 to genetic depletion. We will be testing KT-579 in this model, and we expect it to look very similar to this given the similar potency of the drugs, and we plan to share the results at a subsequent presentation.

這些確實令人興奮的結果證明了口服 IRF5 降解劑能夠在 IRF5 上實現與基因耗竭類似的活性。我們將在該模型中測試 KT-579，鑑於藥物的效力相似，我們預計它看起來會與此非常相似，我們計劃在後續的演示中分享結果。

Next, in the antigen-induced arthritis mouse model of RA, daily oral dosing with KT-579 that achieved approximately 90% degradation, led to significant reduction in joint swelling comparable to tofacitinib. IRF5 degradation [fetoscopies] IRF5 knockout and leads to reduction in ankle swelling, circulating pro-inflammatory cytokines as shown here with IL-12 and infiltrating inflammatory pathogenic Th1 T cells evaluated by flow, which is also shown here on the right. These data exemplify the potential for an oral IRF5 degrader to impact multiple inflammatory biologies in autoimmune diseases.

接下來，在抗原誘發的 RA 關節炎小鼠模型中，每日口服 KT-579 可達到約 90% 的降解，導致關節腫脹顯著減少，與託法替尼相當。IRF5 降解 [胎兒鏡檢查] IRF5 敲除可減少踝關節腫脹、循環促炎細胞因子（如此處所示的 IL-12）以及透過流動評估的浸潤性發炎性致病 Th1 T 細胞（如右側所示）。這些數據證明了口服 IRF5 降解劑對自體免疫疾病中的多種發炎生物學產生影響的潛力。

As part of KT-579's preclinical characterization, we looked at degradation of IRF5 across several preclinical species. As shown on the chart to the right, with daily dosing for 7 days, we observed KT-579 can robustly deplete IRF5 at steady state with low oral doses in non-human primate. Importantly, the degradation was measured 24 hours after the last dose.

作為 KT-579 臨床前表徵的一部分，我們研究了幾種臨床前物種中 IRF5 的降解。如右圖所示，透過連續 7 天的每日給藥，我們觀察到 KT-579 可以在非人靈長類動物中以低口服劑量穩定地消耗 IRF5。重要的是，在最後一次服藥後 24 小時測量了降解情況。

KT-579 was also very well tolerated with no adverse effects or relevant findings up to 200-fold the predicted human efficacious exposure in our non-GLP toxicology studies in both non-human primate and rodents, derisking our path to human translation and proof of concept.

KT-579 的耐受性也非常好，在我們對非人靈長類動物和囓齒動物進行的非 GLP 毒理學研究中，即使劑量高達預期的人類有效暴露量的 200 倍，也沒有出現任何不良反應或相關發現，從而降低了我們進行人體轉化和概念驗證的風險。

In summary, I've shown you that, first, IRF5 has the potential to be the first broad anti-inflammatory that effectively addresses immune dysregulation while sparing normal cell function. And both human and mouse genetics, along with preclinical validation, indicate a best-in-class profile for IRF5 in treating lupus, Sjogren's, RA, and other diseases.

總而言之，我向您展示了，首先，IRF5 有可能成為第一種能夠有效解決免疫失調同時保留正常細胞功能的廣泛抗炎藥物。人類和小鼠遺傳學以及臨床前驗證均顯示 IRF5 在治療狼瘡、乾燥症、類風濕性關節炎和其他疾病方面具有最佳功效。

Next, KT-579 stands out as a highly selective potent oral IRF5 degrader. Also, our in vivo study showed that IRF5 degradation leads to robust cytokine inhibition and demonstrate superior or comparable efficacy in lupus and RA models compared to approved drugs in this space. In addition, KT-579 achieves complete degradation across multiple preclinical safety species and relevant tissues, maintaining a favorable safety profile.

其次，KT-579 作為一種高選擇性強效口服 IRF5 降解劑脫穎而出。此外，我們的體內研究表明，IRF5 降解可導致強大的細胞因子抑制，並且在狼瘡和 RA 模型中表現出比該領域已批准的藥物更優異或相當的療效。此外，KT-579在多個臨床前安全物種和相關組織中實現完全降解，並保持了良好的安全性。

At last, we're very happy that this program is progressing in IND-enabling studies. And we expect to advance KT-579 into the clinic in early 2026 as we believe the first oral IRF5 degrader.

最後，我們很高興看到該計畫在 IND 支持研究中取得進展。我們預計將於 2026 年初將 KT-579 推進至臨床，因為我們相信這是第一個口服 IRF5 降解劑。

With that, I'd like to now turn the call back to Nello for his closing remarks.

說完這些，我現在想把電話轉回內洛，請他做最後發言。

Thank you, Veronica. It's always exciting to hear these stories. Even if I've heard that multiple times internally, I think when we do this public disclosures, it's just an exciting time to put all our data out there and show how productive the team can be and more importantly, the level of sophistication that the team goes when we build these preclinical packages. So very excited to take this program in the clinic.

謝謝你，維羅妮卡。聽到這些故事總是令人興奮。即使我已經在內部多次聽到這種說法，但我認為，當我們進行公開披露時，這是一個激動人心的時刻，我們可以把所有的數據都公佈出來，展示團隊的高效性，更重要的是，展示團隊在構建這些臨床前方案時的複雜程度。我非常高興能在診所參加這個計畫。

So why don't I maybe complete this presentation today by going through our pipeline and spending a bit more time on the upcoming milestones? And then we look forward to take questions from the audience and the analysts.

那麼，為什麼我不在今天完成這次演講，透過介紹我們的流程並花更多時間討論即將到來的里程碑呢？然後我們期待回答觀眾和分析師的問題。

So first, as we've repeated now multiple times, obviously, KT-621 is moving very rapidly, as we've said, likely much more rapidly than we anticipated, which is a great problem to have. We've been able to complete our healthy volunteer study in really dosing in March. We are collecting the last small data points, and then we're really excited to being able to share our Phase 1 healthy volunteer data in June. So that's an important date on your calendar.

首先，正如我們多次重複的那樣，顯然，KT-621 的移動速度非常快，正如我們所說的那樣，可能比我們預期的要快得多，這是一個很大的問題。我們已經能夠在三月完成健康志願者的實際劑量研究。我們正在收集最後的小數據點，然後我們非常高興能夠在六月分享我們的第一階段健康志工數據。所以這是你日曆上的一個重要日期。

As you also know, we have started our Phase 1b AD study in April. And again, kudos to the team, the 621 team for being able to do that, as I said, very rapidly. We're now recruiting patients, and we expect to be able to share data from that study in the fourth quarter of the year.

如您所知，我們已於 4 月啟動 1b 期 AD 研究。再次向團隊表示敬意，621 團隊能夠非常迅速地完成這項工作，正如我所說。我們目前正在招募患者，並希望能夠在今年第四季分享研究的數據。

The team is already gearing up to initiate these two large Phase 2b studies. So we'll start the AD study in the fourth quarter of '25 and the asthma study in the first part of '26. So very busy with all these activities.

團隊已準備好啟動這兩項大型 2b 期研究。因此，我們將於 25 年第四季開始 AD 研究，並於 26 年上半年開始氣喘研究。所有這些活動讓我非常忙碌。

So important two data readouts, healthy volunteer in June, and then AD patient data in the fourth quarter of the year. And then we'll embark in these large studies that will obviously take longer than the Phase 1b study, and we'll share more details about expectations around timing and data readouts as we get closer to them.

因此，有兩個數據讀數非常重要，一個是 6 月的健康志願者數據，另一個是第四季度的 AD 患者數據。然後，我們將開始這些大型研究，這顯然會比第 1b 階段的研究花費更長的時間，隨著我們越來越接近這些研究，我們將分享有關時間和數據讀數的預期的更多細節。

For IRF5, KT-579, as Veronica said, the preclinical package, both on safety and efficacy looks extremely impressive. And so we're expecting to file an IND towards year-end, starting our Phase 1 early next year with data -- with Phase 1 data already next year. And then as we mentioned with IRAK4, we expect to have data in '26 for both HS and AD.

對於IRF5、KT-579，正如維羅妮卡所說，臨床前方案無論是在安全性還是有效性方面看起來都極為令人印象深刻。因此，我們預計將在年底前提交 IND，並在明年年初開始第一階段的研究並提供數據——明年第一階段的研究數據就已經出來了。然後，正如我們在 IRAK4 中提到的那樣，我們預計在 26 年將獲得 HS 和 AD 的數據。

So thank you, everybody, for taking the time. I know it was during the morning on a Friday, but hopefully, you'll appreciate the level of details that we shared today, and we're happy to reconvene and take questions once we get together in a couple of minutes.

所以，感謝大家抽空。我知道那是在星期五的早上，但希望您能欣賞我們今天分享的細節，我們很高興在幾分鐘後再次召開會議並回答問題。

Thank you. (Operator Instructions)

謝謝。（操作員指示）

Derek Archila, Wells Fargo.

富國銀行的德里克‧阿奇拉 (Derek Archila)。

Hi. This is Yvonne for Derek. Thanks for taking our questions. Just a quick one from us. Can you talk a bit about your confidence on targeting STAT6 in AD and showing an effect in the 4-week study? Like should we be expecting a relatively noisy data set given it's such a short study? Thanks.

你好。我是德里克的伊馮娜。感謝您回答我們的問題。我們只需簡單說一下。您能否談談您對針對 AD 中的 STAT6 並在 4 週研究中顯示效果的信心？鑑於這是一項如此短暫的研究，我們是否應該期待一個相對嘈雜的數據集？謝謝。

Yeah. Thanks for the question. So obviously, the underpinning of this program is that IL-4 and 13 mass signal through STAT6 to propagate the signal and to impact downstream Th2 cytokines. So the de-risking and the expectation that we've set on this program are purely driven by the data that's been shown in AD already by the best IL-4 and IL-13 agent, which is dupilumab, which is actually the only drug that blocks both IL-4 and IL-13.

是的。謝謝你的提問。因此顯然，該程序的基礎是 IL-4 和 13 質量訊號透過 STAT6 傳播訊號並影響下游 Th2 細胞因子。因此，我們對該計劃設定的降低風險和期望純粹是由最佳 IL-4 和 IL-13 藥物 dupilumab 在 AD 中已經顯示的數據驅動的，它實際上是唯一一種同時阻斷 IL-4 和 IL-13 的藥物。

So we know with that drug, even in 4 weeks, you can actually generate quite compelling differentiated data set. The first one is that even in 4 weeks, you can impact both circulating and skin biomarkers of Th2 inflammation very robustly. And actually, if you look at the dupilumab data at 4 weeks in terms of disease scores and other clinical endpoints, while they don't -- they do not reach maximal effect, they are quite robust.

因此我們知道，使用該藥物，即使在 4 週內，您實際上也可以產生相當引人注目的差異化資料集。第一個是，即使在 4 週內，你也可以對 Th2 發炎的循環和皮膚生物標記產生非常強烈的影響。實際上，如果你從疾病評分和其他臨床終點的角度來觀察 4 週的 dupilumab 數據，你會發現雖然它們沒有達到最大效果，但它們相當穩健。

And so we -- given all the preclinical data that we've generated on this -- on our program with KG-621 and the fact that all the models and assays that we run this compound through, we've shown a dupi-like effect, in some cases, even a dupi-better effect, we expect that we'll be able to see really robust data, but first in biomarkers because that's really what the study has been powered on but also on clinical endpoints.

因此，考慮到我們在 KG-621 計畫中獲得的所有臨床前數據，以及我們對這種化合物進行的所有模型和分析的結果，我們都看到了類似 dupi 的效果，在某些情況下，甚至是更好的效果，我們預計我們將能夠看到真正可靠的數據，但首先是在生物標誌物方面，因為這確實是這項研究的重點，但也在這項研究的終點方面。

Jeet Mukherjee, BTIG.

Jeet Mukherjee，BTIG。

Hey. Good morning. Maybe just one question around the decision not to advance the TYK2 program. You obviously talked about the decision in the context of being capital conscious in the macro backdrop. But it appears you've swapped TYK2 for perhaps IRF5. So was there anything there in terms of the molecule's profile or just the evolving competitive landscape that influenced your decision? Thanks.

嘿。早安.也許只是關於不推進 TYK2 計劃的決定的一個問題。您顯然是在宏觀背景下注重資本的背景下談論這一決定的。但看起來您已經將 TYK2 換成了 IRF5。那麼，分子特性或不斷變化的競爭格局是否影響了您的決定？謝謝。

Great question. So I think it's important to maybe spend even a bit more time as you're suggesting. So we remain, and I can say even personally, I remain confident in the TYK2 opportunity with a degrader. I think the decision is really around, today, where we are with both resources, both human and capital, we feel like being able to power up even more so our 621 program given that it's really accelerated in terms of pace.

好問題。因此我認為，正如您所建議的，花更多的時間是很重要的。因此，我們仍然對使用降解劑的 TYK2 機會充滿信心，甚至可以說就我個人而言。我認為，今天的決定實際上是圍繞著我們現有的資源、人力和資本，我們覺得能夠進一步加強我們的 621 計劃，因為它在速度上確實加快了。

And obviously, I can't speak to the data, but obviously, we have a lot of confidence going into these larger studies. Given the risk-reward in that program, we feel like that's the place where we want to go and put a lot of resources in.

顯然，我無法談論數據，但顯然，我們對這些更大規模的研究充滿信心。考慮到該計劃的風險回報，我們覺得那是我們想要去並投入大量資源的地方。

I think the IRF5 program is actually quite different from TYK2. TYK2, it is true to reflect that the TYK2 space is obviously, there is a lot of competitive intensity. We look at not just TYK2, but I always look at all the other IL-23 drugs out there, including the quite impressive J&J peptide. And obviously, the bar in that space has been raised.

我認為 IRF5 程序實際上與 TYK2 有很大不同。TYK2，確實反映出TYK2領域明顯存在很大的競爭強度。我們不僅關注 TYK2，我還一直關注所有其他 IL-23 藥物，包括令人印象深刻的 J&J 肽。顯然，該領域的標準已經提高。

We think IRF5 is a totally different program. I think that's going to be a best-in-class drug for a wider variety of diseases. And that's a program we want to go all in. We will be first -- the competitive intensity right now in that program in those pathways is close to zero. And we have an opportunity to have a highly differentiated profile.

我們認為 IRF5 是一個完全不同的程式。我認為這將成為治療多種疾病的最佳藥物。這是我們想要全心投入的計畫。我們將是第一——目前該項目在這些途徑中的競爭強度接近零。我們有機會擁有高度差異化的形象。

So that's -- again, there is obviously competitive intensity and risk-reward conversations that have happened within the company on how programs have been prioritized. I think what you're alluding to is fair. But at the same time, I would say the main driver is we have the largest program in the industry in our hands, probably, maybe if you remove the GLP-1 drugs. And we got our resources at the maximum that we can do at this point in time.

所以，再次強調，公司內部顯然已經就如何決定專案的優先順序進行了競爭強度和風險回報對話。我認為你提到的是公平的。但同時，我想說，主要的驅動力是我們手中擁有業內最大的項目，也許，如果你去除 GLP-1 藥物的話。目前我們已經盡力調配了資源。

Marc Frahm, TD Cowen.

馬克·弗拉姆（Marc Frahm），TD Cowen。

Thanks for taking my questions. On the IRF5 burn that you disclosed today. Just as you get into the clinic, what does that minimum kind of target profile in terms of degradation look like?

感謝您回答我的問題。關於您今天披露的 IRF5 燒毀事件。當您進入診所時，就退化而言，最低限度的目標概況是什麼樣的？

And as we get to clinical data, as you highlighted with your kind of intro Nello, the bar in some of these other diseases where you started going after orals, things like psoriasis, like is extremely high. There really isn't much room even there or to some extent, AD to push efficacy higher. But some of these diseases you're talking about for IRF5, there's certainly much more room for clinical -- for efficacy improvement. How important is that to ultimately show versus just kind of matching available therapies but offering oral convenience?

當我們獲得臨床數據時，正如您在介紹中所強調的那樣，Nello，您開始研究口服藥物治療的一些其他疾病，例如牛皮癬，其標準非常高。確實，即使在那裡，或者從某種程度上來說，AD 也沒有太多空間來提高功效。但是，您談到的某些 IRF5 疾病在臨床療效方面肯定還有很大的提升空間。與僅僅匹配現有療法但提供口服便利性相比，這最終有多重要？

Yeah, I think it's a great question. Maybe I can start and others can follow it. So first, I think that's very insightful question. I will start with just looking at our preclinical data. As you could appreciate, I know we've only just gone through it, and we didn't have a lot of time to digest. At least so far, it looks like once we -- at least 80% degradation and above is able to deliver some really best-in-class profile. So we're actually doing more work to understand is even less than 80% degradation is sufficient to drive the activity that we've seen.

是的，我認為這是一個很好的問題。也許我可以開始，其他人可以跟著做。首先，我認為這是一個非常有見地的問題。我先來看看我們的臨床前數據。正如你所理解的，我知道我們才剛剛經歷這一切，我們沒有太多的時間來消化。至少到目前為止，看起來一旦我們——至少 80% 及以上的退化就能提供一些真正一流的性能。因此，我們實際上正在做更多的工作來了解即使低於 80% 的退化是否足以推動我們所看到的活動。

So I guess to answer your question, there's even more work that we're doing. I think if you look at -- and just in both lupus and RA, but I would start maybe with the lupus model, clearly, targeting IRF5 in these quite translational models of lupus seems to have by far the best effect, which I think if you look at approved therapies in lupus that right now, they don't really work very well. So there is clearly unmet need on the efficacy.

所以我想回答你的問題，我們還在做更多的工作。我認為如果你觀察——並且只觀察狼瘡和 RA，但我可能會從狼瘡模型開始，顯然，在這些相當具有轉化性的狼瘡模型中針對 IRF5 似乎具有迄今為止最好的效果，我認為如果你觀察目前已批准的狼瘡療法，它們的效果並不是很好。因此，在療效方面顯然存在未滿足的需求。

So being able to deliver both efficacy and convenience that is superior to existing and even clinically active drug, I think, is really what we're trying to deliver there. So maybe even one step over some of the conversations we've been having in the past few months. And then the team with Veronica's leadership has come up with an extremely well-behaved molecule that we believe will be highly differentiated in the clinic. But I don't know, Jared or Veronica, if you guys want to add.

因此，我認為，我們真正想要實現的是能夠提供優於現有甚至臨床活性藥物的功效和便利性。因此，也許比我們過去幾個月進行的一些對話更進了一步。然後，由維羅妮卡領導的團隊開發了一種表現極為良好的分子，我們相信它在臨床上將具有高度的差異化。但我不知道，賈里德或維羅妮卡，如果你們想補充的話。

I think I'd only add that importantly, we know that, number one, we can achieve greater than 90% knockdown of IRF5 across multiple different species, including higher species like non-human primates. And that in our 14-day studies, that can be achieved with very favorable safety. So I think that's very important.

我想我只想補充一點，重要的是，我們知道，第一，我們可以在多個不同物種中實現超過 90% 的 IRF5 敲低，包括非人類靈長類動物等高等物種。在我們為期 14 天的研究中，我們可以非常安全地實現這一目標。所以我認為這非常重要。

It's also very interesting to note in terms of your question around, well, how much knockdown do we really need even if 90% or greater is safe. It's very interesting that these sort of heterozygous IRF5 knockout mice are actually fairly well protected from diseases like lupus. So it's possible we might not need that much knockdown for efficacy, but we know we can achieve that degree of knockdown, high degree of knockdown and that would be safe. So that's going to be very important for us.

關於你的問題，值得注意的是，即使 90% 或更高是安全的，我們真正需要多少擊倒率。非常有趣的是，這些雜合的 IRF5 基因敲除小鼠實際上可以很好地預防狼瘡等疾病。因此，我們可能不需要那麼高的擊倒率來實現功效，但我們知道我們可以達到那種程度的擊倒，高程度的擊倒，而且是安全的。這對我們來說非常重要。

Yeah. I think our expectation is, again, that we would see superior efficacy, and that's because of the multiple biologies that we can hit with IRF5, right, as we talked about during the presentation, being able to impact autoantibody producing cells, Type I interferon and then also pro-inflammatory cytokines that will be very important when you go after complex and heterogeneous diseases like those -- like lupus. So I think even compared to, let's say, amifrolimab, we would expect to have a lot more efficacy.

是的。我認為我們的期望是，我們會看到更好的療效，這是因為我們可以使用 IRF5 來打擊多種生物製劑，正如我們在演示過程中所討論的那樣，能夠影響自身抗體產生細胞、I 型乾擾素以及促炎細胞因子，這在治療像狼瘡這樣的複雜和異質性疾病時非常重要。因此我認為，即使與阿米弗利單抗相比，我們也期望其療效更佳。

Ellie Merle, UBS Securities.

瑞銀證券的艾莉‧梅爾 (Ellie Merle)。

Hey, guys. Just on IRF5, just a quick search. There's obviously a lot of literature showing that this plays a critical role in a lot of diseases. But curious how you're thinking about balancing the safety here. It looks like there's some data showing that IRF5 can act as a tumor suppressor. I mean, obviously, we're new to this target, and it seems like it's involved in a lot of diseases. But just can you explain why you're comfortable with the safety here?

嘿，大家好。就在 IRF5 上，只是快速搜尋一下。顯然，大量文獻表明這在許多疾病中起著關鍵作用。但很好奇您是如何考慮平衡這裡的安全的。看起來有些數據顯示 IRF5 可以充當腫瘤抑制因子。我的意思是，顯然我們對這個目標還很陌生，而且它似乎與許多疾病有關。但你能解釋為什麼你對這裡的安全感到放心嗎？

And I know in the last question, you mentioned that you can even get disease protection or modification perhaps with the 50% degradation, just from a clinical development perspective. Even if early on 90% degradation is safe, would you also explore moving forward with, say, 50% degradation, 90% with multiple dose levels and thinking about the long-term safety profile? Thanks.

我知道在最後一個問題中，您提到從臨床開發的角度來看，也許透過 50% 的降解就能獲得疾病保護或改變。即使早期 90% 的降解是安全的，您是否還會探索進一步發展，例如 50% 的降解，90% 的多種劑量水平，並考慮長期安全性？謝謝。

Yeah. So I'll let actually Veronica address kind of the first part of your question. I just want to touch a high level. So the beauty about IRF5, which will require a few days of work from everybody to kind of get up to speed, is that what Veronica has said multiple times that is cell specific. It's really only expressed in a subset of cells. And it's also really only activated in the presence of diseases.

是的。因此，我會讓維羅妮卡來回答你問題的第一部分。我只是想觸及高層次。因此，IRF5 的美妙之處在於，它需要每個人花幾天的時間才能跟上進度，正如維羅妮卡多次提到的，它是細胞特異性的。它實際上只在一部分細胞中表達。而且它實際上只有在疾病存在時才會被啟動。

There are multiple other IRFs that are contributing to, let's say, immune surveillance from a safety perspective, from an infection perspective. So it's really one of those only great targets, and that's why it's been pursued without much knowledge because with a lot of failures by the whole industry in the past 10 years, at least that we know of, because it actually combines broad anti-flammatory effect, IL-12, IL-23, IL-6, TNF, IgG, Type I interferon, but in a context-specific manner. And that's really why even in these preclinical studies, we can remove the target completely. We've gone 200-fold above that dose and have not seen any activity.

從安全角度和感染角度來看，還有多種其他 IRF 有助於免疫監視。所以它確實是那些僅有的幾個偉大目標之一，這就是為什麼人們在沒有太多了解的情況下對它進行研究，因為過去 10 年整個行業有很多失敗，至少我們知道是這樣，因為它實際上結合了廣泛的抗炎作用，IL-12、IL-23、IL-6、TNF、IgG、I 型乾擾素，但以特定於環境的方式。這就是為什麼即使在這些臨床前研究中，我們也可以完全去除目標。我們已經將劑量增加 200 倍，但沒有看到任何效果。

Veronica, do you want to take that? I know you had the answer to that question better than I do.

維羅妮卡，你想拿走這個嗎？我知道你對這個問題的答案比我更好。

Yeah. No, thank you for the question. That was part of our due diligence in the beginning, we evaluated the target, some of the studies that you mentioned. And when we looked across TCGA aggregate studies, there's actually very little evidence that loss of IRF5 associates with cancer. And in fact, when you look, it seems like gain of function is associated with cancer.

是的。不，謝謝你的提問。這是我們一開始盡職調查的一部分，我們評估了目標，以及您提到的一些研究。當我們查看 TCGA 綜合研究時，發現實際上很少有證據表明 IRF5 的缺失與癌症有關。事實上，如果你觀察一下，你會發現功能的獲得似乎與癌症有關。

And the one report that pops up is from one lab. There has been no follow-up work. And with a target that's more highly expressed in heme cells, it's sort of hard to believe that loss in a breast cancer epithelial cell will lead to cancer. So there has been really no follow-up there. And again, with our broader analysis, we don't really see a risk in that area.

彈出的一份報告來自一個實驗室。目前尚未進行後續工作。由於標靶在血紅素細胞中表達較高，因此很難相信乳癌上皮細胞的缺失會導致癌症。因此那裡確實沒有後續行動。而且，根據我們更廣泛的分析，我們確實沒有看到該地區有風險。

Sudan Loganathan, Stephens.

蘇丹·洛加納坦，史蒂芬斯。

Hi, good morning. And thank you, this morning, again for this detailed presentation and for taking my questions. My first one is on the IRF5 program. In your preclinical work or any of the literature out there, did the degradation of IRF5 trigger any feedback mechanisms that may have activated IRAK4, MYD88, [Nak1, 2] or any other IRFs that could be a means of causing like an untargetable relapse in a disease state whenever treated in humans going forward?

嗨，早安。再次感謝您今天早上的詳細演講和回答我的問題。我的第一個是關於 IRF5 程序的。在您的臨床前工作或任何文獻中，IRF5 的降解是否觸發了任何反饋機制，可能激活了 IRAK4、MYD88、[Nak1, 2] 或任何其他 IRF，而這些 IRF 可能會導致人類在今後接受治療時出現無法靶向的疾病復發？

Yeah. No, that's a great question. So this is something we pay a lot of attention to across our programs, right? Do we see either an evolving potential resistance mechanism or other pathways coming into play. We haven't seen any of that in our studies.

是的。不，這是一個很好的問題。所以這是我們在整個專案中非常關注的事情，對嗎？我們是否看到了正在演變的潛在抵抗機製或其他途徑正在發揮作用。我們在研究中沒有發現任何此類現象。

I mean, as Veronica showed, some of these are probably some of the longest studies that we've run preclinically. You see that the lupus model is a 4-month study. I think mice were dosed 106 days in a row, if I remember correctly. And with that, we haven't seen -- during the study, and obviously, the mice have taken down at the end -- but even when we -- when it's happened that we -- in other studies, we dose and then stop dosing. We have not seen any kind of flares or rebound of these inflammatory pathways.

我的意思是，正如維羅妮卡所展示的，其中一些可能是我們在臨床前進行的最長的研究。您會看到狼瘡模型是一項為期 4 個月的研究。如果我沒記錯的話，我認為老鼠連續服藥 106 天。而且，在研究過程中，我們還沒有看到這種情況，顯然，老鼠在最後已經停止了——但即使我們——當這種情況發生在我們——在其他研究中，我們給老鼠服藥然後又停止服藥。我們尚未發現這些發炎途徑有任何爆發或反彈。

The beauty about these inflammatory pathways is that these are not overexpressed or activated in inflammatory process -- or sorry, they're not overexpressed. They just signal through. There is just a signal that moves into a particular pathway. In this case, let's say, to IRF5. And so there isn't kind of an increase of protein expression that you're slowing down or removing, which will make the cell kind of react with producing some other protein.

這些發炎路徑的美妙之處在於它們在發炎過程中不會過度表達或活化——或者抱歉，它們沒有過度表達。他們只是發出訊號。只是有一個訊號進入特定的路徑。在這種情況下，假設是 IRF5。因此，你不會減慢或消除蛋白質表現的增加，這會導致細胞產生其他蛋白質的反應。

So anyway, the short answer is we haven't seen it. We don't expect to see it. We haven't seen it for any program so far.

無論如何，簡短的回答是我們還沒有看到它。我們並不期望看到它。到目前為止，我們還沒有在任何程式中看到它。

Great. I appreciate that. And just if I can squeeze in a follow-up, just in regards to the STAT6 program and the degradation. I think you've mentioned before, obviously, also achieving a pretty high level of STAT6 degradation, hopefully, in the human population as well in your trial. Between the different indications you're going after with STAT6 degradation, does the level of that degradation need to be exceeding 90% for all the indications? Or is it different between each ones to get a clinical benefit specific to each type, for instance, with AD in the skin and blood, are there kind of targets between the two different tissue types there when it comes to looking at the STAT6 degradation to form a clinical benefit?

偉大的。我很感激。如果我可以擠出時間跟進的話，就 STAT6 程序和降級而言。我想您之前提到過，顯然，在您的試驗中，也希望在人類群體中實現相當高水平的 STAT6 降解。在您所追蹤的 STAT6 降解的不同適應症中，所有適應症的降解程度是否需要超過 90%？或者每種類型之間是否有差異以獲得特定於每種類型的臨床益處，例如，對於皮膚和血液中的 AD，當觀察 STAT6 降解以形成臨床益處時，兩種不同組織類型之間是否存在目標？

Yeah. It's a great question. I think there is kind of two answers. One, -- we -- our goal of our Phase 1 study was to hopefully being able to achieve 90%-plus in blood and skin. The reason for that is -- there are two, right? One, preclinically, we've shown in mice that if we get to 90%-plus, we have a dupi-like effect.

是的。這是一個很好的問題。我認為有兩種答案。首先，我們第一階段研究的目標是希望能夠在血液和皮膚中達到 90% 以上。原因是──有兩個，對嗎？首先，在臨床前研究中，我們已經在小鼠身上證明，如果我們達到 90% 以上，就會產生類似 dupi 的效果。

The second reason is why we want to have also the same target in skin is because we don't want to be left with the question of what if we had more than 90% degradation in skin, what would the activity look like? So that's why we want to -- we would like to target a profile that has similar degradation in both blood and skin so that we maximize our probability of success.

第二個原因是，我們之所以希望在皮膚上也設定同樣的目標，是因為我們不想留下這樣的問題：如果皮膚退化超過 90%，活動會是什麼樣子？所以這就是為什麼我們想要——我們想要針對血液和皮膚都有類似退化的概況，以便最大限度地提高成功的機率。

Second part of your question, which actually was Ellie's question that I don't think I answered is what is the level of degradation needed for particular diseases for both STAT6 and in IRF5 as well. I think that's why we're so keen on running at least for STAT6 for now imminently this Phase 2b dose-ranging studies. It's the ability to correlate a degradation profile with the clinical outcome that will allow us to select the right dose for Phase 3.

你的問題的第二部分，實際上是 Ellie 的問題，我認為我沒有回答，那就是特定疾病所需的 STAT6 和 IRF5 降解程度是多少。我認為這就是為什麼我們如此熱衷於至少針對 STAT6 進行即將進行的 2b 期劑量範圍研究。將降解情況與臨床結果關聯起來的能力使我們能夠為第 3 階段選擇正確的劑量。

So right now, we are -- for STAT6, at least we're going -- based on our preclinical data, we're going into the clinic with the expectation that 90%-plus is the desired profile. But once we run a Phase 2b study where we'll be able to ask the questions of multiple doses and multiple degradation profile, we might learn that less than 90% is sufficient. I don't know if we expect that more than 90% is needed, but that's why we run the dose-ranging studies. It's really to establish those relationships.

因此現在，對於 STAT6，至少我們是根據臨床前數據進行的，我們進入臨床階段，預計 90% 以上是理想的情況。但是，一旦我們進行 2b 期研究，我們將能夠詢問多劑量和多種降解情況的問題，我們可能會發現低於 90% 就足夠了。我不知道我們是否預計需要超過 90%，但這就是我們進行劑量範圍研究的原因。這實際上是為了建立這些關係。

Vikram Purohit, Morgan Stanley.

摩根士丹利的維克拉姆·普羅希特（Vikram Purohit）。

Great, good morning. Thanks for taking the questions and for the presentation. We had a follow-up question on IRF5. I mean you've alluded to how challenging this target has been through your prepared remarks and also through the responses to the last few questions. But we were wondering if you could speak in a bit more detail about prior competitive approaches that may have been attempted for IRF5 and where specifically these approaches may have faltered and how 579 has been engineered specifically to address some of the missteps that others in the space may have faced in the past. And I have a follow-up, but I'll save that for post your response.

太好了，早安。感謝您回答問題並進行演講。我們對 IRF5 有一個後續問題。我的意思是，您在準備好的發言以及對最後幾個問題的回答中都提到了這個目標有多麼具有挑戰性。但我們想知道您是否可以更詳細地談談之前針對 IRF5 嘗試過的競爭方法，以及這些方法具體在哪些方面可能失敗，以及 579 是如何專門設計來解決該領域其他人過去可能遇到的一些失誤的。我還有一個後續問題，但我會將其保存起來以備您的回覆。

Okay. I think that's a great question. So the main challenge with IRF5 -- actually, I would say from a chemistry perspective, this has probably been the hardest program in the company. And the reason is identifying a highly specific IRF5 binder or for others has been inhibitor is extremely difficult. There is a high sequence of allergy.

好的。我認為這是一個很好的問題。因此，IRF5 面臨的主要挑戰是——實際上，我想從化學角度來看，這可能是公司中最困難的項目。原因是識別高度特異性的 IRF5 結合劑或其他抑制劑極為困難。過敏序列較高。

Veronica showed you IRF1 and 7 versus -- 3 and 7, sorry, versus 5. And we were, I would say, also lucky to find, thanks to the great team that we have, a molecule that is basically 100% specific to IRF5, does not bind to any IRFs.

維羅妮卡向您展示了 IRF1 和 7 與 3 和 7，抱歉，與 5 的對比。我想說，我們也很幸運，感謝我們優秀的團隊，我們發現了基本上 100% 針對 IRF5 的分子，它不會與任何 IRF 結合。

The other point is IRF brings this kind of complex activation. And I think you had to really inhibit all type of IRF5s have the right type of biology. And with that drug, we bind to basically degrade all types of IRF5s. And so it has been a really difficult target to drug. I think it's probably underappreciated how difficult it has been. And this is a highly -- I think this program has a lot of focus on by, I think, the external immunology community because this would be the first time that we finally hit this target selectively and well.

另一點是IRF帶來了這種複雜的活化。我認為你必須真正抑制所有類型的 IRF5 才能擁有正確的生物學類型。利用這種藥物，我們可以結合並基本上降解所有類型的 IRF5。因此，它確實是一個難以用藥物治療的目標。我認為人們可能低估了它的難度。我認為這是一個高度——這個計畫受到了外部免疫學界的高度關注，因為這是我們第一次有選擇地、很好地實現這一目標。

Great And then as a follow-up, on the development program, how broad of an initial development plan do you think you will end up pursuing for 579? Is it reasonable to expect something like 621 where you started with the two sentinel indications and then go from there? And relatedly, you mentioned a mid-2028 runway. How far in development do you think you could get with 579 through that time point? Thanks.

太好了，那麼作為後續問題，關於開發計劃，您認為您最終會為 579 制定多廣泛的初步開發計劃？從兩個哨兵指標開始，然後從那裡開始，這樣預期像 621 這樣的事合理嗎？與此相關的是，您提到了 2028 年中期的跑道。您認為到那時 579 的開發能進行到什麼程度？謝謝。

All right. So I'll answer high level. So first, I think it's a bit early for us to get into the actual development plan. But what I would say is that there is a plethora of opportunities where I think there was an earlier comment from one of your colleagues that was quite apt, which is this drug can actually really, really make a difference for many patients with these, let's call it, rheumatological immune inflammatory diseases.

好的。因此我將從高層次進行回答。所以首先，我認為我們現在開始實際的發展計畫還為時過早。但我想說的是，有很多機會，我認為您的一位同事之前的評論非常恰當，這種藥物實際上可以真正為許多患有這些疾病的患者帶來改變，我們稱之為風濕免疫發炎疾病。

And so we believe that this is going to be also a relatively broad development program with more than one indication that would be prioritized. I think the runway, just to be clear, I think we said first half of '28 -- you give us mid '28, I'll take it if you also give us the money.

因此，我們相信這也將是一個相對廣泛的發展計劃，其中有多個需要優先考慮的指標。我認為，為了清楚起見，我們說的是 28 年上半年——你給我們 28 年中期，如果你也給我們錢，我會接受。

But I think what we said is that we plan to start Phase 1 early next year. We plan to complete Phase 1 within that year. So you can expect that we'll have some meaningful clinical data within this runway.

但我認為我們所說的是我們計劃在明年年初啟動第一階段。我們計劃在那一年內完成第一階段。因此，您可以期待我們將在此跑道內獲得一些有意義的臨床數據。

Eric Joseph, JPMorgan.

摩根大通的艾瑞克‧約瑟夫。

Thanks for taking the questions. Just on IRF5, can you talk a little bit about the relative infection risk given the broader or more pan pro-inflammatory cytokine suppression profile here? To what extent are you able to model that preclinically perhaps? And then in what sounds like lupus or SLE being one of the lead -- one of the focal indications with this approach, have you preclinically looked at the comparative efficacy of 579 versus some of the B-cell depleting or modulating approaches to the extent that this is also feasible to do in mice models? Thanks.

感謝您回答這些問題。僅就 IRF5 而言，您能否談談在更廣泛或更多泛促炎細胞因子抑制概況下相對感染風險？您在臨床前階段能夠建立多程度的模型？然後，聽起來狼瘡或 SLE 是這種方法的主要適應症之一，您是否在臨床前研究過 579 與一些 B 細胞消耗或調節方法的比較療效，以至於在小鼠模型中這也是可行的？謝謝。

Great question. I'm going to let you guys answer on the infection risk. We have tons of answers. I don't want to give all the answers. Veronica, do you want to go first and then, Jared, maybe you can speak to that and some other aspects of it.

好問題。關於感染風險的問題，我請你們來回答。我們有很多答案。我不想給出所有答案。維羅妮卡，你想先說嗎？然後，賈里德，也許你可以談談這個以及其他一些方面。

Thanks for the question. We don't think that IRF5 will work like a broad immunosuppressant, right? And the reason for that is because it's really selectively expressed in very key immune cells. Those four that I listed is really where it's highly expressed. And not only that, but it's also specifically activated through certain stimuli.

謝謝你的提問。我們不認為 IRF5 會像廣譜免疫抑制劑一樣發揮作用，對嗎？原因在於它確實在關鍵的免疫細胞中選擇性表現。我列出的這四個確實是高度體現的。不僅如此，它還能透過某些刺激特別活化。

So I think that combination when we look into the certain autoimmune diseases will be an advantage because we won't have this broad immunosuppression against all stimuli, really only the ones that are elevated in those autoimmune diseases that we're going after.

因此，我認為，當我們研究某些自體免疫疾病時，這種組合將是一種優勢，因為我們不會對所有刺激進行廣泛的免疫抑制，實際上只會針對我們正在研究的自身免疫性疾病中升高的刺激。

And the immune surveillance, you can talk about the other IRF.

關於免疫監視，您可以談談其他 IRF。

Right exactly. So we will be leaving like we showed IRF3 and 7 intact, and those are really important for viral infections, right? Those are actually the transcription factors that drive high Type I interferon response. So by leaving those intact and blocking IRF5, we don't think we'll have anything as severe as, let's say, Saphnelo, anifrolumab. We probably would expect it to look less, right, because there you're blocking all Type I interferon response. So that's just an example.

完全正確。因此，我們將保持 IRF3 和 7 完好無損，而它們對於病毒感染非常重要，對嗎？這些實際上是驅動高 I 型乾擾素反應的轉錄因子。因此，透過保持這些完整性並阻斷 IRF5，我們認為不會出現像 Saphnelo、anifrolumab 那樣嚴重的問題。我們可能希望它看起來更少，對吧，因為你阻止了所有 I 型乾擾素反應。這只是一個例子。

And then Eric, I think your second question was around comparison to B-cell depleters. I mean the data that Veronica showed so far are the comparisons have not been to the B cell depleters per se, but we have looked at comparisons in those lupus models to deucra, so TYK2 and TLR7/8 inhibition; with afimetoran, alpha-interferon receptor; antibodies, we've been at least comparable, probably better actually in our activity in those models compared to all those standards of care, even cyclophosphamide.

然後埃里克，我認為你的第二個問題是關於與 B 細胞耗竭者的比較。我的意思是，到目前為止，維羅妮卡展示的數據還沒有與 B 細胞耗竭者本身進行比較，但我們已經研究了這些狼瘡模型與 deucra 的比較，因此 TYK2 和 TLR7/8 抑制；使用阿菲美托崙、α-幹擾素受體；抗體，我們在這些模型中的活性至少是相當的，甚至比環胺類藥物治療方法，我們在這些模型中實際上的活性至少是相當的，甚至是所有這些標準治療方法，我們在這些模型中實際上的活性至少是相當的，磷酰胺可能比所有這些標準治療方法。

And I think probably looking at B-cell depleters will be something that we can do in the future. I think it's important to recognize that IRF5 impacts multiple different components of inflammation. B-cell is one part of that inflammation, but there's also the dendritic cell component. There's also the T-cell component that is stimulated by macrophages and dendritic cells. So we would anticipate that we would have a broader effect and potentially could be even more active than the more sort of selective B cell depleters.

我認為研究 B 細胞耗竭者可能是我們將來可以做的事情。我認為認識到 IRF5 會影響發炎的多種不同成分非常重要。B 細胞是發炎的一部分，但也有樹突狀細胞成分。還有受巨噬細胞和樹突狀細胞刺激的 T 細胞成分。因此，我們預計我們將產生更廣泛的影響，甚至可能比選擇性 B 細胞耗竭劑更活躍。

And safer, I think. Yeah, I think also better tolerated.

而且我認為比較安全。是的，我認為耐受性也更好。

And it's actually known that anti-CD20s, as an example, don't perform very well in these lupus models.

事實上，眾所周知，抗 CD20 在這些狼瘡模型中表現不佳。

Okay. Anything else, Eric?

好的。還有什麼嗎，艾瑞克？

No. I appreciate you taking the questions. Thanks for the update.

不。感謝您回答這些問題。感謝您的更新。

Faisal Khurshid Leerink.

費薩爾·庫爾希德·李林克。

Hey, guys. Good to see you. Thanks for taking the question. So we're still early in our few days of work, I think you said now to understand the target. But I saw that there is one other kind of disclosed development program for IRF5. That's an allosteric modulator. Can you talk a little bit about how you kind of see the potential benefits of a degrader approach over an allosteric modulator?

嘿，大家好。很高興見到你。感謝您回答這個問題。所以我們這幾天的工作才剛開始，我想您現在說的是了解目標。但我看到IRF5還有另外一種公開的開發計畫。這是一種變構調節劑。您能否稍微談談您如何看待降解劑方法相對於變構調節劑的潛在優勢？

Yeah. As I mentioned earlier, yeah, there are disclosed programs. We haven't seen any data. So I always don't comment on those because they're just a word on a slide. But I think the main really challenge has been can you do it selectively? And then can you block all the functions of IRF5 including all the splicing variants?

是的。正如我之前提到的，是的，有一個公開的計劃。我們還沒有看到任何數據。所以我總是不對這些發表評論，因為它們只是幻燈片上的一個字。但我認為真正的主要挑戰是你能否有選擇地做到這一點？那你能阻止 IRF5 的所有功能，包括所有剪接變體嗎？

And I think it's really hard to do -- I'm not going to say it's impossible to do. I'm going to say we believe in our hands. It's extremely hard to do with an inhibitor. Then you put on top of it the fact that with an inhibitor, if the need is to block IRF5 at high level continuously, obviously, we made the case that degraders allow you to do once a day oral drug with a low dose with inhibitor to stay on top of that target 24/7 is going to be really difficult. But I think for this one, it's really the selective context independent inhibition is going to be hard, but we'll see.

我認為這確實很難做到——但我並不是說這不可能。我想說我們相信自己的力量。使用抑制劑很難做到這一點。然後你再考慮到這樣一個事實：如果需要使用抑制劑持續阻斷高水平的 IRF5，顯然，我們認為降解劑可以讓你每天口服一次低劑量的抑制劑，以全天候保持該目標，這將非常困難。但我認為對於這一點來說，選擇性上下文獨立抑制確實會很難，但我們會看到。

Geoff Meacham, Citi.

花旗銀行的 Geoff Meacham。

Hey, guys. This is Nishant on for Jeff. Thanks for the question and really helpful presentation. So first on IRF5. So there has been like genetic links between certain IRF5 isoforms and lupus susceptibility. So are there any concerns that 579 could exacerbate disease in subset of patients and whether you have designed this kind of degrader to target specific isoforms to avoid this effect?

嘿，大家好。這是 Nishant 代替 Jeff 上場的。感謝您的提問和非常有幫助的演講。首先是 IRF5。因此，某些 IRF5 亞型和狼瘡易感性之間存在遺傳關聯。那麼，是否有人擔心 579 可能會加劇部分患者的病情，以及您是否設計了這種降解劑來針對特定的異構體以避免這種影響？

Veronica, you want to take it? I think the second one was if we get all the isoforms.

維羅妮卡，你想拿走它嗎？我認為第二個問題是我們是否獲得了所有的異構體。

Can we selectively target certain isoforms that are expressed in these variant patients? Yeah. That's really difficult to do because the isoforms are really cell-specific expression, right? So that would be really hard to do.

我們能否選擇性地針對這些變異患者中表現的某些亞型？是的。這確實很難做到，因為異構體實際上是細胞特異性表達，對嗎？所以這真的很難做到。

What we do know is that 579 can degrade all the different isoforms that are expressed, whether it's those that are caused by the variants or not, which might actually be important in these autoimmune diseases because there are also other mechanisms besides the variants that can turn IRF5 on. So we believe that really the best is to try and block all of the different isoforms for IRF5. But we have not seen any.

我們確實知道的是，579 可以降解所有表達的不同亞型，無論這些亞型是否由變異引起，這實際上對這些自體免疫疾病可能很重要，因為除了可以開啟 IRF5 的變異之外，還有其他機制。因此我們認為最好的方法是嘗試阻斷 IRF5 的所有不同亞型。但我們還沒有看到任何跡象。

We want to get all isoforms because we want to get the broader population. And also we -- in our hands already, we know that there is biology that is -- this is relevant that has nothing to do with the splicing isoforms activation, right?

我們希望獲得所有異構體，因為我們想要獲得更廣泛的群體。而且我們已經知道，存在與剪接異構體活化無關的生物學，對嗎？

Right.

正確的。

Pathway activation.

通路活化。

Michael Schmidt, Guggenheim.

古根漢美術館的麥可·施密特。

Hey, guys. Good morning. I just wanted to come back to KT-621 and STAT6, especially sort of heading to the June update coming up here very soon. How important will be interpretation of some of the PD marker analysis in this Phase 1 healthy volunteer study, especially given that, as you mentioned earlier, the biomarkers in healthy is really very low at baseline. And also asking because there was a lot of variability, especially with TARC, in some of the Dupi studies. So how meaningful is interpretation of these biomarkers in the June data set?

嘿，大家好。早安.我只是想回到 KT-621 和 STAT6，尤其是即將發布的 6 月更新。在這個第一階段健康志願者研究中，對一些 PD 標記分析的解釋有多重要，特別是考慮到，正如您之前提到的，健康的生物標記在基線時確實非常低。之所以詢問，也是因為在一些 Dupi 研究中存在著很大的變異性，尤其是 TARC。那麼，對六月資料集中的這些生物標誌物的解釋有多大意義呢？

And perhaps then following up on your upcoming Phase 1b study in patients, so what are some of the things that you're trying to address in this study ahead of starting your randomized Phase 2 trial later this year? Are there any particular outcomes or questions you're trying to answer in patients before starting the Phase 2? Thanks.

然後也許會跟進您即將在患者身上進行的 1b 期研究，那麼在今年稍後開始隨機 2 期試驗之前，您想在這項研究中解決哪些問題？在開始第二階段之前，您是否想解答患者的某些特定結果或問題？謝謝。

Yeah. I kind of -- I think about a rapid way to give you an answer on all the questions, which is we made the case from the beginning for this program that a STAT6 degrader should perform like dupilumab. And so I would say the expectation across the studies is to perform like dupilumab. In the healthy volunteer study, obviously, dupilumab didn't look at STAT6 degradation. But whatever they saw in biomarkers, you should expect it from us. In the1b study, they did a nice 28-day study of both biomarkers and clinical endpoint, I would say we expect to see a dupi-like effect. That's probably the quickest way to answer this question.

是的。我有點——我想到一種快速的方法來回答你所有的問題，那就是我們從一開始就為這個項目證明了 STAT6 降解劑應該像 dupilumab 一樣發揮作用。因此我想說，整個研究的期望是像度普利尤單抗一樣發揮作用。在健康志願者研究中，顯然，dupilumab 沒有關注 STAT6 降解。但無論他們在生物標誌物中看到什麼，你都應該期待我們這樣做。在 1b 研究中，他們對生物標記和臨床終點進行了 28 天的良好研究，我想我們有望看到類似 dupi 的效果。這可能是回答這個問題的最快方法。

In addition to dupilumab, the beauty about working in protein degradation that if you're good, you can actually understand what's going on. You just don't look at some biomarkers after you dose the drug, but you can see, okay, what is the level of pathway blockade that we can achieve in blood and skin, and so we're going to be able to look at degradation of STAT6 in blood and skin.

除了度普利尤單抗之外，在蛋白質降解方面發揮作用的美妙之處在於，如果你很擅長，你實際上就能了解到底發生了什麼。服用藥物後，您不僅可以觀察一些生物標記物，還可以了解我們可以在血液和皮膚中達到的通路阻斷水平，因此我們將能夠觀察血液和皮膚中 STAT6 的降解情況。

Obviously, safety is going to be paramount for this drug in this environment, in this landscape. But in terms of biomarkers, I would just say that we expect to have dupi-like because that's what we've seen all along in our preclinical study. And we've been seeing for a while.

顯然，在這種環境、這種情況下，這種藥物的安全性至關重要。但就生物標記而言，我只想說我們預計會有類似 dupi 的生物標記物，因為這是我們在臨床前研究中一直看到的。我們已經看到了一段時間了。

And maybe just a quick follow-up. Can I ask a follow-up? So on dosing in particular, Dupixent is typically given at a high initial loading dose and then there's a lower maintenance dose. How do you think about that in context of the sort of KT-621 dynamics? Is that something that you're evaluating to for the Phase 2 perhaps?

也許只是一個快速的跟進。我可以問後續問題嗎？因此，具體到劑量方面，Dupixent 通常採用較高的初始負荷劑量，然後採用較低的維持劑量。在 KT-621 動態背景下，您如何看待這一點？這是否是您正在評估的第二階段的事情？

Well, obviously, I can't speak to the data. I just would go to preclinical data with the KT-621, we're able to achieve in preclinical models, the full extent of the desired degradation in hours. And so based on the data, we've never built a loading dose model preclinically, and we hope that will be the case in the clinic, too.

嗯，顯然我無法談論數據。我只是想了解 KT-621 的臨床前數據，我們能夠在臨床前模型中在數小時內實現所需的完全降解程度。因此，根據數據，我們從未在臨床前建立過負荷劑量模型，我們希望在臨床上也是如此。

Yifan Xu, Jefferies.

徐一凡，杰弗里斯。

Hi. This is Yifan from Jeffrey for Kelly. Thank you for taking my question. Maybe another question on the STAT6 program. Could you please provide some additional color on the dose level used in the Phase 1b trial because this is a single-arm trial. How does it compare to the highest dose tested in the healthy volunteer studies? And how might it relate to the potential dose that you are going to use in the upcoming Phase 2b trials? Thank you.

你好。我是 Jeffrey 為 Kelly 服務的 Yifan。感謝您回答我的問題。也許還有關於 STAT6 程序的另一個問題。由於這是一項單臂試驗，您能否提供一些有關 1b 期試驗中使用的劑量水平的更多詳細資訊。與健康志願者研究中測試的最高劑量相比如何？它與您即將在 2b 期試驗中使用的潛在劑量有何關係？謝謝。

Yeah. Thank you. It's a great question. We can't really comment on the dose. I think what we've said is we have a target in terms of degradation, and we believe that is an important target, which, as we said, 90%-plus in blood and skin. And that is the target that we'd like to explore in patients. But I'm not going to speak to the dose and the profile.

是的。謝謝。這是一個很好的問題。我們無法真正評論劑量。我認為我們已經說過，我們在降解方面有一個目標，我們認為這是一個重要的目標，正如我們所說，血液和皮膚中的降解率超過 90%。這就是我們想要在患者身上探索的目標。但我不會談論劑量和概況。

I think once we share a healthy volunteer data, we can talk a bit about the profile. But then as we share the data from 1b, we'll talk about the dose as well likely.

我認為，一旦我們分享了健康志工的數據，我們就可以談論個人資料。但當我們分享 1b 的數據時，我們也會討論劑量。

Andy Chen, Wolfe Research.

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

Hey. Thank you for taking the question. On IRF5, do you see this as a conceptual equivalent to a combo therapy, including [ipilimumab] and anifrolumab and perhaps also Humira? Is this like a dual biologic or maybe triple biologic?

嘿。感謝您回答這個問題。關於 IRF5，您是否認為它在概念上等同於聯合療法，包括 [ipilimumab] 和 anifrolumab 以及可能還包括 Humira？這像是雙重生物製劑還是三重生物製劑？

So in terms of the studies that you have done in vivo, do we have reasons to believe that your -- it would act like a dual drug or even a triple drug? So I noticed that in the mouse model, you tested deucravacitinib and if not, separately, but can you combine them in mice? And would you see better efficacy that way? Thank you.

那麼，根據您在體內進行的研究，我們是否有理由相信它的作用類似於雙重藥物甚至三重藥物？所以我注意到在小鼠模型中，您測試了 deucravacitinib，如果沒有，則單獨測試，但是您可以在小鼠身上將它們結合起來嗎？這樣的話，您會看到更好的效果嗎？謝謝。

So I'll take a quick and then maybe Jared and Veronica you guys can add. So I think as we've said, the beauty of IRF5 is that you can actually -- yes, you can imagine having a multi-asset combo in a single drug in a context-specific manner, right? Like if you think about anti-TNF or anti-23 or anti-interferon, these are antibodies that block those cytokines independently of what's going on in your body. This is why they work well, but they also have, in many cases -- in some cases, they have some side effects because you probably don't want to remove all of your Type I interferon consistently all the time.

所以我先快速說一下，然後也許 Jared 和 Veronica 你們可以加入。所以我認為，正如我們所說的，IRF5 的美妙之處在於你實際上可以 - 是的，你可以想像以特定於環境的方式在單一藥物中擁有多種資產組合，對嗎？例如，如果您考慮抗 TNF 或抗 23 或抗干擾素，這些抗體可以獨立於您體內發生的情況來阻斷這些細胞激素。這就是為什麼它們效果良好的原因，但在許多情況下，它們也有一些副作用，因為您可能不想一直持續地去除所有的 I 型乾擾素。

So the beauty about IRF5, why it's a broad anti-inflammatory agent, but also well tolerated is because we only do it in those cell types in those disease context. Maybe, Jared, do you want to comment about from a medical clinical perspective, what would that mean?

IRF5 的優點在於，它之所以是一種廣泛的抗發炎劑，而且耐受性良好，是因為我們只在那些疾病背景下的那些細胞類型中使用它。也許，賈里德，你想從醫學臨床的角度來評論一下，這代表什麼？

Yeah. No, I mean I think the fact that we can have this sort of broad effect that's context-specific and hopefully, therefore, have a safety profile that would be very favorable should allow us even as a single agent to potentially have activities that are equivalent to combining multiple different drugs.

是的。不，我的意思是，我認為我們可以產生這種針對具體情況的廣泛影響，因此希望具有非常有利的安全性，這應該使我們即使作為單一藥劑也能具有相當於結合多種不同藥物的活性。

I think with that being said, I think Nello earlier in his presentation talked about how these various pathways that are in our pipeline are complementary, right, whether it's TYK2, IRF5, now IRF5, IRAK4, and STAT6, one could think about combining these, right, across certain diseases if there are potential synergies that could be obtained, especially if a drug like IRF5 ends up being safe and well tolerated that really opens up the optionality, especially as an oral drug for combining several different oral drugs from within our pipeline or combining our oral drug with other standard of care agents that are out there.

話雖如此，我認為 Nello 在他的演講中早些時候談到了我們管道中的這些不同途徑是如何互補的，對吧，無論是 TYK2、IRF5，現在是 IRF5、IRAK4 和 STAT6，人們可以考慮將它們結合起來，對吧，在某些疾病中，如果有潛在的協同作用，特別是如果像 IRF5這樣的藥物最終是安全且耐受性良好的，這確實開闢了可選性，特別是作為口服藥物，可以結合我們管道中的幾種不同的口服藥物，或將我們的口服藥物與其他現有的標準護理藥物結合起來。

But again, I think we -- our expectation based on the data that Veronica showed in the preclinical models is that we should have substantial activity even as a single agent. So it's not as though we're obligated to combine it, but we certainly have that optionality.

但我再次認為，根據維羅妮卡在臨床前模型中展示的數據，我們的預期是，即使作為單一藥物，我們也應該具有實質的活性。因此，我們並沒有義務將其合併，但我們確實有這種選擇權。

Operator, we're smidge over time. Maybe one last question and then we'll wrap up. Thanks.

接線員，我們稍微超時了。也許還有最後一個問題，然後我們就結束了。謝謝。

Kalpit Patel, B. Riley.

卡爾皮特·帕特爾，B.萊利。

Yeah, hey. Good morning and thanks for squeezing me in here. Now, I just had one question on the degradation kinetics that you may show here with the STAT6 degrader in patients by the year-end. For the IRAK4 program, previously, in that paper that was published, there was a rebound of the protein between day 14 to day 28, which you attributed to the variability in the method used, the testing method used and the storage conditions. So I guess, going forward, what steps are you taking to ensure that the kinetics will more accurately reflect the true target knockdown rather than any measurement or sampling handling issues?

是啊，嘿。早安，感謝您抽空邀請我來這裡。現在，我只有一個問題，關於降解動力學，您可能會在年底前在這裡展示患者體內的 STAT6 降解劑。對於 IRAK4 程序，先前在發表的那篇論文中提到，在第 14 天到第 28 天之間出現了蛋白質的反彈，您將其歸因於所用方法、所用測試方法和儲存條件的變化。所以我想，展望未來，您將採取哪些措施來確保動力學更準確地反映真正的目標擊倒，而不是任何測量或採樣處理問題？

Yeah. Maybe just to -- thanks for the question. Just to kind of make sure we're all on the same page. So with IRAK4, what we've shown is -- in the healthy volunteer studies, we were able to show robust degradation using mass spec technology that would follow from obviously, day 1 to day 14.

是的。也許只是—感謝您的提問。只是為了確保我們都達成共識。因此，對於 IRAK4，我們在健康志願者研究中證明，我們能夠使用質譜技術證明從第 1 天到第 14 天會出現明顯的降解。

When you go into this broader study in the patient study, we -- it's really hard to use mass spec because the isolation procedure, it's difficult to use in multiple sites that you're using. So we ended up using flow. And in flow, what happens is, unfortunately, that the -- in some cases, the sample can deteriorate. And so it makes it more difficult to measure the effect of the degrader with time.

當您在患者研究中進行更廣泛的研究時，我們 - 使用質譜圖真的很難，因為分離程序很難在您使用的多個站點使用。因此我們最終採用了流程。不幸的是，在流動過程中，在某些情況下，樣品可能會變質。因此，測量降解劑隨時間的影響變得更加困難。

And so what we have planned for, obviously, the existing study of 621 and the Phase 1b study is that we'll have several opportunities to ensure that we can measure protein levels well. And I think I can't speak because I will speak about the data as well. But I think once we share the healthy volunteer data, it might be easier for me to comment more on your question.

因此，顯然，我們為現有的 621 研究和 1b 期研究制定的計劃是，我們將有幾次機會確保能夠很好地測量蛋白質水平。我認為我不能說，因為我也會談論數據。但我認為，一旦我們分享健康志工的數據，我可能會更容易對您的問題發表更多評論。

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

目前沒有其他問題。現在我想將發言時間交給 Nello Mainolfi 來做結束語。

Thank you. First, I wanted to thank everybody for attending our call. I want to thank the team at Kymera for putting together a great story today. Obviously, we have a lot of more opportunities ahead of us to engage further on some exciting milestones that we're reaching soon.

謝謝。首先，我要感謝大家參加我們的電話會議。我要感謝 Kymera 團隊今天創作出如此精彩的故事。顯然，我們還有更多的機會進一步參與我們即將達到的一些令人興奮的里程碑。

In the meanwhile, if you have further questions, you know where to find us. We want to make sure that the richness of the data we shared today can be appreciated with fullest. So again, thank you for everybody for attending. The slides are on our website, so you can review in your own time. And we'll see you actually soon.

同時，如果您還有其他問題，您可以知道在哪裡找到我們。我們希望確保我們今天分享的數據的豐富性能夠得到充分的重視。再次感謝大家的出席。幻燈片在我們的網站上，因此您可以隨時查看。我們很快就會見到你。