Kymera Therapeutics Inc (KYMR) 2024 Q3 法說會逐字稿

Good day and welcome to the Kymera Therapeutics third-quarter 2024 results conference call. (Operator Instructions) Please note this event is being recorded. I would like now to turn the conference over to Justine Koenigsberg, Head of Investor Relations. Please go ahead.

美好的一天，歡迎參加 Kymera Therapeutics 2024 年第三季業績電話會議。（操作員說明）請注意此事件正在被記錄。我現在想把會議交給投資者關係主管賈斯汀·科尼斯堡 (Justine Koenigsberg)。請繼續。

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

謝謝。早安，歡迎收聽 Kymera 的季度更新電話。今天早上和我一起來的有創辦人、總裁兼執行長 Nello Mainolfi； Jared Gollob，我們的首席醫療官；和我們的財務長布魯斯·雅各布斯。

Please note that during Jared's remarks, we intend to reference data from slides in our corporate presentation, which is available within the IR section of our website at kymeratx.com. Following our prepared remarks, we will open the call to questions. (Event Instructions)

請注意，在 Jared 的講話中，我們打算引用公司簡報中幻燈片中的數據，這些數據可在我們網站 kymeratx.com 的 IR 部分中找到。在我們準備好的發言之後，我們將開始提問。（活動須知）

Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected.

在我們開始之前，我想提醒您，今天的討論將包括有關我們未來期望、計劃和前景的前瞻性陳述。這些陳述存在風險和不確定性，可能導致實際結果與預測有重大差異。

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.

這些風險的描述可以在我們最近向 SEC 提交的 10-Q 中找到。任何前瞻性陳述僅代表今天的情況，我們不承擔更新今天電話會議上所做的任何前瞻性陳述的義務。

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

現在，我將把電話轉給尼洛。

Thank you, Justine, and good morning everybody. We have a lot of important updates today. So let's jump right in. First and foremost, we're extremely excited that we have started the Phase 1 study of KT-621, a first in class oral STAT6 degrader, and the first STAT6 medicine to ever enter clinical development.

謝謝賈斯汀，大家早安。今天我們有很多重要的更新。那麼就讓我們直接開始吧。首先，我們非常興奮，我們已經開始了 KT-621 的 1 期研究，KT-621 是一流的口服 STAT6 降解劑，也是第一個進入臨床開發的 STAT6 藥物。

It's important to highlight that we were able to accelerate the path to the clinic given our recent increased focus of resources and capital that were directed towards our growing immunology pipeline. I believe this is also an important moment for the whole industry.

需要強調的是，鑑於我們最近更加關注資源和資本，這些資源和資本都用於我們不斷增長的免疫學管道，因此我們能夠加快臨床之路。我相信這對整個產業來說也是一個重要的時刻。

We have shown in preclinical species that a STAT6 degrader like KT-621 can block IL-4 and 13 similarly, or even more potently than in upstream biologics like the (inaudible) in both cellular and in-vivo models. We've also shown that KT-621 was well tolerated in all safety studies that we have run in a wide variety of preclinical species.

我們在臨床前物種中證明，在細胞和體內模型中，像KT-621 這樣的STAT6 降解劑可以類似地阻斷IL-4 和13，甚至比上游生物製劑（例如（聽不清楚））更有效。我們還表明，在我們對多種臨床前物種進行的所有安全性研究中，KT-621 具有良好的耐受性。

In summary, we have an investigational drug that has the potential to have a dupilumab like profile in a daily oral pill. Many of you know there are more than 150 million patients just in the US, Europe, and Japan, who suffer from diseases associated with TH2 inflammation.

總之，我們有一種研究藥物，有可能在每日口服藥丸中具有類似 dupilumab 的特性。你們很多人都知道，光是在美國、歐洲和日本就有超過 1.5 億患者患有與 TH2 發炎相關的疾病。

And according to market data, less than a million of those patients received dupilumab. While one could focus on the roughly millions of patients currently on dupilumab, Kymera is focused on expanding access across the tens of millions of patients that are waiting for a convenient, safe and effective oral pill, one that doesn't require needles, refrigeration, syringes, and frequent trips to the doctor's office.

根據市場數據，其中不到 100 萬名患者接受了 dupilumab 治療。雖然人們可以關注目前正在使用dupilumab 的大約數百萬患者，但Kymera 專注於擴大數以千萬計的患者的可及性，這些患者正在等待一種方便、安全和有效的口服藥，這種藥不需要針頭、冷藏、注射器，以及經常去醫生辦公室。

We believe KT-621 is a medicine that has the potential to transform treatment paradigms in many diseases that affect millions of patients such as atopic dermatitis, asthma, COPD, EoE, just to name a few. In addition, given that TH2 diseases are highly prevalent in children, we believe this has the potential to be a drug that will change quality of life for many families in the future.

我們相信 KT-621 是一種有潛力改變影響數百萬患者的許多疾病治療模式的藥物，例如異位性皮膚炎、氣喘、慢性阻塞性肺病、EoE 等。此外，鑑於 TH2 疾病在兒童中非常普遍，我們相信這有可能成為一種藥物，在未來改變許多家庭的生活品質。

Our next STAT6 update is expected to be upon completion of the healthy volunteer study in the first half of 2025, at which point we will share the full results. Following the completion of the Phase 1 study, our plan is to move quickly into patients.

我們的下一次 STAT6 更新預計將在 2025 年上半年完成健康志願者研究後進行，屆時我們將分享完整的結果。第一階段研究完成後，我們的計畫是迅速進入患者體內。

We have those plans well established, and we expect to provide guidance on the next stage of 621 clinical development next year. Jared will share more details around the ongoing Phase 1 study later in the call.

我們已經制定了這些計劃，預計明年將為下一階段的 621 臨床開發提供指導。賈里德將在稍後的電話會議中分享有關正在進行的第一階段研究的更多細節。

I also wanted to briefly highlight another important update on KT-474, our first in class IRAK4 degrader. This is another program where Kymera was first to clinic and a success has influenced the industry with several companies following our lead with other IRAK4 directed assets.

我還想簡單強調一下 KT-474 的另一個重要更新，KT-474 是我們的首款 IRAK4 降解器。這是 Kymera 率先投入臨床的另一個項目，其成功影響了整個行業，多家公司紛紛效仿我們的其他 IRAK4 定向資產。

We're finally able to share more information on the expanded Phase 2 studies that are being run by our partner Sanofi. As I'm sure you have read in our press release earlier today, the program is transitioning from a proof of concept like Phase 2 studies to fully powered Phase 2b studies with those ranging as a means of accelerating our path to registration of Phase 3 studies right at the conclusion of the ongoing studies.

我們終於能夠分享更多有關我們的合作夥伴賽諾菲正在進行的第二階段擴展研究的資訊。我確信您已經在今天早些時候閱讀了我們的新聞稿，該計劃正在從第 2 階段研究等概念驗證過渡到全面的第 2b 階段研究，其中包括加速我們註冊第 3 階段研究的途徑就在正在進行的研究結束時。

In terms of the specific trial changes, we basically added one dose group to each study, to have enough information to being able to select the dose for the subsequent registrational Phase 3 studies. We're thankful to our partner Sanofi for the increased confidence in and commitment to this important program.

就具體的試驗變化而言，我們基本上在每項研究中增加了一個劑量組，以便有足夠的資訊能夠為後續註冊3期研究選擇劑量。我們感謝我們的合作夥伴賽諾菲對這項重要計劃的信心和承諾。

Turning to TYK2, we have exciting progress to report as well. At our R&D day in January of this year, we introduced our TYK2 program in our lead molecule KT-294. Similar to all of our programs, as KT-294 was being advanced through preclinical development, we had parallel work ongoing on other promising compounds.

談到 TYK2，我們也有令人興奮的進展要報告。在今年 1 月的研發日上，我們在先導分子 KT-294 中推出了 TYK2 計畫。與我們所有的項目類似，隨著 KT-294 正在透過臨床前開發進行推進，我們也在其他有前景的化合物上進行並行工作。

One of the compounds we were evaluating demonstrated an even more compelling profile than KT-294, highlighted by greater in-vivo activity and with a similar selectivity and safety profile. As a result, we have decided to advance the new compound KT-295 as our lead clinical candidate. Importantly, we believe we can do that without impacting our previously stated TYK2 development timelines, which assume the Phase 1 trial start in the first half of '25.

我們正在評估的一種化合物表現出比 KT-294 更引人注目的特性，突顯了更高的體內活性以及相似的選擇性和安全性。因此，我們決定將新化合物 KT-295 作為我們的主要臨床候選藥物。重要的是，我們相信我們可以在不影響之前規定的 TYK2 開發時間表的情況下做到這一點，該時間表假設第一階段試驗於 25 年上半年開始。

Finally, I just wanted to provide everyone with a broad strategic update and specifically as it pertains to our oncology program. As many of you recall, it was around this time last year, we first shared that we had increased our focus in immunology.

最後，我只是想向每個人提供廣泛的策略更新，特別是與我們的腫瘤學計劃相關的更新。正如你們許多人所記得的那樣，大約在去年的這個時候，我們第一次分享我們增加了對免疫學的關注。

The rationale was driven by the profoundly impactful profiles. We believe we could generate an immunology with oral degraders that could compete with injectable biologics in terms of adequacy and safety. As shown with KT-474 in the clinic and with our STAT6 and TYK2 efforts pre-clinically, we think we're positioned to develop a potential best in industry portfolio of oral immunology assets, with opportunities to impact millions of patients.

其基本原理是由具有深遠影響力的個人資料所驅動的。我們相信，我們可以用口服降解劑產生一種免疫學，在充分性和安全性方面可以與注射生物製劑競爭。正如臨床中的 KT-474 以及我們在臨床前的 STAT6 和 TYK2 努力所顯示的那樣，我們認為我們有能力開發潛在的行業最佳口腔免疫學資產組合，並有機會影響數百萬患者。

Even more today, with KT-474 in multiple Phase 2b trials, KT-621 in the clinic, and KT-295 close to the clinic, and other exciting immunology programs that we would be unveiling starting from next year, we believe that now is the time to focus even more of our resources into this space, where we believe we can create outsized value.

如今，隨著 KT-474 處於多個 2b 期試驗、KT-621 進入臨床、KT-295 接近臨床，以及其他我們將從明年開始推出的令人興奮的免疫學項目，我們相信現在是現在是時候將我們更多的資源集中到這個領域了，我們相信我們可以在這個領域創造巨大的價值。

As a result, while we made some encouraging progress with our clinical oncology pipeline, demonstrating promising clinical activity in a variety of tumor types, as we have completed Phase 1 enrollment, we have made the decision that we will only advance KT-333, our STAT3 degrader; and KT-253, our MDM2 degrader beyond Phase 1 with their partner. You can expect they will share more on this if and when it makes sense to do so.

因此，雖然我們在臨床腫瘤學管線方面取得了一些令人鼓舞的進展，在多種腫瘤類型中表現出了有希望的臨床活性，但隨著我們已經完成了1 期註冊，我們決定只推進KT -333，我們的STAT3 降解器；以及 KT-253，我們與合作夥伴一起完成第一階段的 MDM2 降解器。您可以預期，如果有意義的話，他們會就此分享更多資訊。

While there are many considerations that contributed to this decision, ultimately, we believe our internal resources, both capital and people are best focused on our expanding immunology pipeline. It should be noted that we did not take this decision lightly, or made it without thinking about the potential impact on patients. We are in fact grateful to patients, families and investigators, and the Kymera team who support their studies and these programs.

儘管做出這項決定有很多考慮因素，但最終，我們相信我們的內部資源（資本和人員）最好專注於我們不斷擴大的免疫學產品線。應該指出的是，我們做出這個決定並不是輕易做出的，或者說沒有考慮到對患者的潛在影響就做出了這個決定。事實上，我們感謝患者、家屬和研究人員以及支持他們的研究和這些計畫的 Kymera 團隊。

In conclusion, as we approach year-end, it is quite exciting to see the trajectory that Kymera had in 2024 especially within our immunology pipeline. We've advanced in the clinic KT-621 with what could become one of the biggest programs in our industry.

總之，隨著年底的臨近，看到 Kymera 在 2024 年的發展軌跡非常令人興奮，尤其是在我們的免疫學管道中。我們在 KT-621 診所取得了進展，這可能成為我們行業最大的項目之一。

We have supported Sanofi to advance KT-474 in expanding the Phase 2 studies. We've developed a TYK2 degrader with a compelling profile and are closer to the clinic. And we have raised a total of approximately $600 million in just 2024, that has enabled us to have cash into mid-2027 and through several inflection points across our pipeline.

我們支持賽諾菲推進 KT-474 擴大 2 期研究。我們開發了一款 TYK2 降解劑，具有引人注目的外形並且更接近臨床。僅在 2024 年，我們就籌集了總計約 6 億美元的資金，這使我們能夠在 2027 年中期之前擁有現金，並度過我們管道中的幾個拐點。

I will pause here and let Jared share more details on our programs, and Bruce will walk you through the third quarter financial results. I'm looking forward to the Q&A session at the end of our prepared remarks. Jared?

我將在此暫停，讓賈里德分享有關我們計劃的更多詳細信息，布魯斯將向您介紹第三季度的財務業績。我期待著我們準備好的發言結束後的問答環節。賈里德？

Thanks Nello. As it relates to immunology, I'd like to first recognize our KT-621 team for the rapid progression to advance this first in class program through IND enabling studies, culminating in the I&D clearance and the initiation of the Phase 1 healthy volunteer study earlier this month.

謝謝尼洛。由於它與免疫學相關，我首先要感謝我們的 KT-621 團隊，他們透過 IND 支持研究快速推進了這一一流項目，最終獲得了 I&D 許可並提前啟動了 1 期健康志願者研究本月。

As we have not shared many details on the trial design, I wanted to take the opportunity now to provide a quick overview of the Phase 1 design. The SAD, MAD healthy volunteer trial includes single and multiple ascending dose cohorts evaluating KT-621 as compared to placebo.

由於我們還沒有分享許多有關試驗設計的細節，我現在想藉此機會快速概述第一階段的設計。SAD、MAD 健康志願者試驗包括單次和多次遞增劑量隊列，評估 KT-621 與安慰劑的比較。

In the SAD component, each subject receives a single dose of either KT-621 or placebo. In the MAD component, each subject receives a daily dose of either KT-621 or placebo over 14 days. In terms of data, we plan to share the main objective of the trial is to demonstrate that we can robustly degrade STAT6 in blood and skin at doses that are safe and well tolerated.

在 SAD 部分中，每位受試者接受單劑量的 KT-621 或安慰劑。在 MAD 部分中，每位受試者在 14 天內每天接受 KT-621 或安慰劑劑量。就數據而言，我們計劃分享該試驗的主要目標是證明我們可以以安全且耐受性良好的劑量強力降解血液和皮膚中的 STAT6。

Based on our pre-clinical work, we are targeting statistics degradation of 90% or more, which is the level at which we saw strong biologics like activity in our preclinical models. In fact, levels of pathway blockade in this case measured by STAT6 levels are the data that we have shown to be translatable to patient efficacy. As we have said, STAT6 degradation and safety and tolerability are the key readouts from this study.

根據我們的臨床前工作，我們的目標是統計降解率達到 90% 或更高，這是我們在臨床前模型中看到強生物製劑活性的水平。事實上，在這種情況下，透過 STAT6 水平測量的通路阻斷水平是我們已證明可轉化為患者療效的數據。如我們所說，STAT6 降解以及安全性和耐受性是本研究的關鍵讀數。

Additionally, as many of you know, we plan to measure certain TH2 biomarkers, specifically IgE and TARC, and the healthy volunteers on our study. We fully expect KT-621 to have an impact on these biomarkers. However, we believe the impact is likely to be much more robust and relevant in patients, as is also true for dupilumab.

此外，正如你們許多人所知，我們計劃測量某些 TH2 生物標記物，特別是 IgE 和 TARC，以及我們研究中的健康志願者。我們完全預期 KT-621 會對這些生物標記產生影響。然而，我們相信對患者的影響可能更加強烈和相關，dupilumab 也是如此。

With enrollment underway, we continue to expect to report the full SAD and MAD Phase 1 results for KT-621 in the first half of 2025. At or before that time, we will also share our plans for the next stage of KT-621's development.

隨著註冊的進行，我們繼續預計在 2025 年上半年報告 KT-621 的完整 SAD 和 MAD 第一階段結果。屆時或之前，我們也將分享 KT-621 下一階段的開發計畫。

I'll now turn to our TYK2 program. As Nello mentioned, we made the decision to advance a new development candidate KT-295 into the clinic, which we believe we can do without impacting our stated timelines of the first half of 2025 for the start of the Phase 1 study.

我現在談談我們的 TYK2 計劃。正如 Nello 所提到的，我們決定將新的開發候選藥物 KT-295 推進臨床，我們相信我們可以在不影響我們規定的 2025 年上半年一期研究開始的時間表的情況下做到這一點。

I thought it would take a few minutes to share some details around KT-295, particularly a comparison to KT-294 that influenced our decision. You can also reference the TYK2 program slides in our corporate presentation, which is available on our website.

我認為需要花幾分鐘時間來分享有關 KT-295 的一些細節，特別是與影響我們決定的 KT-294 的比較。您也可以在我們的公司簡報中參考 TYK2 程式投影片，該投影片可在我們的網站上找到。

Slides 48 and 49 of our corporate deck, you can see that in preclinical testing, KT-295 demonstrated picomolar degradation potency and potent inhibition of the IL-23, IL-12, and Type I interferon pathways, showing its potential to recapitulate the biology of human TYK2 loss of function mutations.

在我們公司的幻燈片48 和49 中，您可以看到，在臨床前測試中，KT-295 表現出皮摩爾降解效力以及對IL-23、IL-12 和I 型乾擾素途徑的有效抑制，顯示其重現生物學特性的潛力人類 TYK2 功能喪失突變。

Like KT-294, on slide 50, KT-295 did not impact any of the other jack proteins, and spared IL-10 signaling, a feature important in the treatment of inflammatory bowel disease. Importantly, KT-295 had greater in-vivo activity compared to KT-294 as shown back on slide 48.

與第 50 張投影片上的 KT-294 一樣，KT-295 不會影響任何其他 Jack 蛋白，也不會影響 IL-10 訊號傳導，而 IL-10 訊號傳導是治療發炎性腸道疾病的重要特徵。重要的是，與 KT-294 相比，KT-295 具有更高的體內活性，如幻燈片 48 所示。

Through this profile, KT-295 has the potential to replicate the TYK2 loss of function profile and achieve biologics like activity at lower doses than what was predicted for KT-294. To round out our I&I franchise, I will cover IRAK4.

透過這項特徵，KT-295 有可能複製 TYK2 功能喪失特徵，並以比 KT-294 預測的劑量更低的劑量實現生物製劑樣活性。為了完善我們的《I&I》系列，我將報導《IRAK4》。

We are pleased that Sanofi has taken steps to accelerate the overall KT-474 development program. And as a reminder, the goal of the previously announced decision to expand the Phase 2 program was to structure the hidradenitis suppurativa and atopic dermatitis trials with the necessary regulatory perspective to enable dose selection and advancement directly to pivotal Phase 3 studies, ultimately, with a meaningfully shorter timeline.

我們很高興賽諾菲已採取措施加速整個 KT-474 開發計畫。提醒一下，先前宣布的擴大第二階段計劃的決定的目標是從必要的監管角度構建化膿性汗腺炎和特應性皮膚炎試驗，以便能夠進行劑量選擇並直接推進關鍵的第三階段研究，最終，有意義地更短的時間。

To support this strategy, the size of the studies has increased with additional doses being evaluated in both trials. There are no changes to study endpoints. Specifically, the HS Phase 2 trial has been expanded from 99 to 156 patients, and will evaluate two doses of KT-474 versus placebo versus just one active dose previously.

為了支持此策略，研究規模增加，兩項試驗都評估了額外的劑量。研究終點沒有變化。具體來說，HS 2 期試驗已從 99 名患者擴大到 156 名患者，並將評估兩劑 KT-474 與安慰劑以及先前僅一劑活性劑量的情況。

The AD Phase 2 trial has increased from 115 to 200 patients, and will evaluate three doses of KT-474 compared to placebo versus just two active doses previously. These changes drive the primary completion dates to the first half of 2026 and mid-2026 for HS and AD respectively.

AD 2 期試驗已從 115 名患者增加到 200 名患者，並將評估三劑 KT-474 與安慰劑相比，而先前僅評估兩劑活性劑量。這些變更使得 HS 和 AD 的主要竣工日期分別為 2026 年上半年和 2026 年中期。

While that obviously extends the time before the complete Phase 2 data readout, we expect that it will meaningfully reduce overall development timelines for the KT-474 program by allowing a faster path to pivotal studies.

雖然這顯然延長了完整的第 2 階段資料讀出之前的時間，但我們預計，它將透過更快地進行關鍵研究，從而有意義地縮短 KT-474 專案的整體開發時間。

We're energized by the progress and potential impact of our immunology programs, each representing pipeline product opportunities. And we believe that our oral degraders are uniquely positioned to have both the efficacy and safety of biologics with multiple development opportunities and large high met need indications.

我們對免疫學計畫的進展和潛在影響感到振奮，每個計畫都代表著管道產品的機會。我們相信，我們的口服降解劑具有獨特的優勢，具有生物製劑的功效和安全性，具有多種開發機會和大量高滿足的需求適應症。

Finishing up on oncology, I will not add too much more to what Nello said earlier, but I did want to remind everyone that we will be sharing the totality of the Phase 1 data for our STAT3 degrader, KT-333 at Ash in December.

結束了腫瘤學，我不會對 Nello 之前所說的內容添加太多內容，但我確實想提醒大家，我們將於 12 月在 Ash 分享 STAT3 降解劑 KT-333 的全部 1 期數據。

As a reminder, our latest enrollment was focused on Hodgkin's lymphoma patients given the promising responses we observed in that population, and those results will be included in the poster presentation.

提醒一下，我們最新的招募重點是霍奇金淋巴瘤患者，因為我們在該族群中觀察到了有希望的反應，這些結果將包含在海報演示中。

I'll stop here, and ask Bruce to review the third quarter financial results. Bruce?

我就講到這裡，請布魯斯回顧一下第三季的財務表現。布魯斯？

Thanks Jared. As we have a lot to cover on this call, and I'm sure you all have many questions, I'm going to provide a quicker than normal overview of our financials, and then refer you to the financial statements in the press release and our 10-Q which we filed this morning.

謝謝賈里德。由於我們在這次電話會議上要講很多內容，而且我相信你們都有很多問題，因此我將比平常更快地概述我們的財務狀況，然後請您參閱新聞稿中的財務報表和我們今天早上提交的10-Q。

In the quarter, we recognized $3.7 million of revenue that was all attributable to Sanofi and their collaboration. A combined spending of R&D and SG&A excluding cash based, non-cash stock based compensation was $61 million in the quarter, and that's down about 2% sequentially from the June quarter. And then finally, we ended the quarter with $911 million of cash on our balance sheet, providing a cash runway to mid-2027.

在本季度，我們確認了 370 萬美元的收入，這全部歸功於賽諾菲及其合作。本季研發和銷售、管理、行政費用（不包括基於現金和非現金股票的薪酬）的合計支出為 6,100 萬美元，比 6 月季度環比下降約 2%。最後，本季結束時，我們的資產負債表上有 9.11 億美元的現金，為 2027 年中期提供了現金跑道。

I'll now turn the call back to Nello.

我現在將電話轉回給尼洛。

Thanks Bruce and Jared. Before we open the call to questions, I just want to reiterate that we're more enthusiastic than ever about the opportunities in front of us. Advancing KT-621 in the clinic is a significant milestone for Kymera and the industry.

謝謝布魯斯和賈里德。在我們開始提問之前，我只想重申，我們對眼前的機會比以往任何時候都更加熱情。在臨床上推進 KT-621 對於 Kymera 和整個產業來說是一個重要的里程碑。

And we're doing so with a very exciting drug profile based on our preclinical finding. We're executing on the rest of our immunology pipeline, and we look forward to sharing updates on TYK2 and providing more visibility on other pipeline programs which we have yet to disclose likely next year.

基於我們的臨床前發現，我們正在利用非常令人興奮的藥物概況來實現這一目標。我們正在執行免疫學管道的其餘部分，我們期待分享 TYK2 的更新，並提供更多我們尚未在明年披露的管道項目的可見性。

We're well-resourced to plant our best in industry pipeline of degraded therapeutics, and look forward to keeping you updated with our progress. The next 6 to 12 months will provide multiple value creating catalysts and we look forward to sharing these with you.

我們擁有充足的資源來建立業界最好的降解療法管道，並期待向您通報我們的最新進展。未來 6 至 12 個月將提供多種價值創造催化劑，我們期待與您分享這些催化劑。

Finally, I wanted to thank the Kymera team and our collaborators for continuing to deliver on very ambitious goals and first in industry endeavors. I'll pause here, and ask the operator to open the call to questions.

最後，我要感謝 Kymera 團隊和我們的合作者繼續實現非常雄心勃勃的目標和業界第一的努力。我將在這裡暫停，並要求接線員開始提問。

(Operator Instructions) Marc Frahm, TD Cowen.

（操作員說明）Marc Frahm，TD Cowen。

Thanks for taking my questions. Maybe thinking to the 621 healthy volunteer data. And thanks for the kind of clarity on exactly kind of where the target profile is. But maybe thinking through to the TH2 biomarkers, investors seem to be really trying to comp this to what was seen with dupi as you alluded to.

感謝您回答我的問題。也許想想621名健康志願者的數據。感謝您對目標設定檔的確切位置的清晰了解。但也許仔細考慮 TH2 生物標誌物，投資者似乎真的在嘗試將其與您提到的 dupi 所看到的情況進行比較。

How reliable do you think those changes, this percent changes in IgE and TARC from the healthy volunteer study, almost a decade ago, really are how comparable and how tight of a range do you think you need to get to?

您認為這些變化有多可靠，即近十年前健康志願者研究中 IgE 和 TARC 變化的百分比，您認為您需要達到的可比性和範圍有多窄？

Yes, maybe I'll start, and Jared, please free to jump in. So first, I mean, Jared, I think explained, the main goal of the Phase 1 study for any program, but especially for us is first to demonstrate that we have predictable PK and the safety translating from the amazingly well tolerated profile that we've seen pre-clinically.

是的，也許我會開始，賈里德，請隨意加入。所以，首先，我的意思是，賈里德，我想解釋了，任何專案的第一階段研究的主要目標，但特別是對我們來說，首先是證明我們具有可預測的PK 和安全性，這些目標來自我們令人驚訝的良好耐受性。

Now with a degree there, as we've done it multiple times, we have this unique opportunity to access a direct biomarker. So don't forget lots of other modalities and companies use downstream biomarkers because they're not able to have a proximal biomarker.

現在，我們已經獲得了那裡的學位，正如我們多次這樣做的那樣，我們有這個獨特的機會來獲取直接的生物標記。因此，不要忘記許多其他模式和公司使用下游生物標誌物，因為他們無法擁有近端生物標記。

So we have the most proximal biomarker, which is STAT6 protein levels. So we can look at STAT6 protein levels in blood and skin to show that we're able to block IL-4 and 13 pathway fully. And that's the goal of the study. That is the only biomarker that has been correlated to disease impact, again, blocking the pathway is being correlated to disease impact.

所以我們有最接近的生物標誌物，即 STAT6 蛋白質水平。因此，我們可以觀察血液和皮膚中的 STAT6 蛋白質水平，以表明我們能夠完全阻斷 IL-4 和 13 路徑。這就是研究的目標。這是唯一與疾病影響相關的生物標記物，同樣，阻斷該途徑與疾病影響有關。

In fact, actually, there was a recent paper, sorry if I'm digressing a bit, where actually there were humans where they found partial loss of function variant of STAT6 that was protected against TH2 asthma. So that's actually now for the first time even correlating protein function, protein levels, to protection in TH2.

事實上，最近有一篇論文，抱歉我有點離題了，其中實際上有人發現了 STAT6 部分功能喪失的變體，可以預防 TH2 氣喘。因此，這實際上是第一次將蛋白質功能、蛋白質水平與 TH2 的保護聯繫起來。

So now many companies including Regeneron back in the day, and you also saw in other companies with this long acting biologics, obviously look at downstream levels, again because you can't really measure your direct biomarkers.

因此，現在包括再生元在內的許多公司，以及您在其他擁有這種長效生物製劑的公司中也看到，顯然會關注下游水平，同樣是因為您無法真正測量直接生物標誌物。

As you know, people have looked at IgE and TARC, I feel like IgE has been mostly detected by the dupilumab data. And I think it's from recent publication from other companies, I actually haven't seen IgE data out there, but mostly TARC and (inaudible) other companies.

如您所知，人們已經研究過 IgE 和 TARC，我覺得 IgE 大部分是透過 dupilumab 數據檢測到的。我認為這是來自其他公司最近發布的數據，實際上我還沒有看到 IgE 數據，但主要是 TARC 和（聽不清楚）其他公司。

So it's important to understand that they're modestly elevated in healthy volunteers, right? You're trying to measure something that is just around the baseline. There is intersubject variability, so it makes it difficult to predict the degree of reduction.

因此，重要的是要了解它們在健康志願者中的水平略有升高，對吧？您正在嘗試測量基線附近的一些東西。存在個體間差異，因此很難預測減少的程度。

So if you look at, for example, if you look at the published paper of the dupilumab that you were referring to in healthy volunteers, you see IgE is impacted between 10% and 30%. Actually, if you look at the subcu dose actually up to 15%, and there is quite a bit of variability, and TARC between 15% and 35% which is actually in line with the data also from the long acting IL-13 biologics that is being evaluated in Phase 1.

因此，例如，如果您查看您在健康志願者中提到的 dupilumab 發表的論文，您會發現 IgE 受到 10% 至 30% 的影響。實際上，如果你觀察 subcu 劑量實際上高達 15%，並且存在相當大的可變性，並且 TARC 在 15% 到 35% 之間，這實際上也與長效 IL-13 生物製劑的數據一致正在第一階段進行評估。

So I think, that kind of sets the range. I would just discourage people because from trying to understand the exposure to biomarker relationship because this data, at least in other endeavors are very noisy. So that's why we say what we know is critical is obviously safety PK but levels of STAT3 degradation, because they tell us ability to suppress pathways signaling.

所以我認為，這設定了範圍。我只是阻止人們嘗試了解生物標記關係的暴露，因為這些數據，至少在其他努力中是非常吵雜的。因此，這就是為什麼我們說我們所知道的關鍵顯然是安全性 PK，但 STAT3 降解水平，因為它們告訴我們抑制路徑訊號傳導的能力。

Then again, we have confidence it will change the biomarkers, and I'm sure they will be in the range of what has been seen for these agents that have been in the clinic. Sorry long answer.

話又說回來，我們有信心它會改變生物標誌物，而且我確信它們將在臨床上這些藥物所見的範圍內。抱歉，答案很長。

Long, but very helpful. Then maybe just more on the model with Bruce, just talk through with the kind of continuing prioritization of the immunology side. Are there kind of any savings of that from the oncology or it's all going to be redeployed into immunology?

很長，但很有幫助。然後也許只是與布魯斯更多地討論模型，只是討論免疫學方面的持續優先順序。腫瘤學方面是否有任何節省，或全部將被重新部署到免疫學領域？

Yeah, thanks, Marc. It's a good question. So I mean, there are savings, yes, in aggregate, because of the fact that obviously the some of the clinical development plans that we contemplated, we won't be undertaking on our own.

是的，謝謝，馬克。這是一個好問題。所以我的意思是，是的，總的來說，是有節省的，因為顯然我們考慮的一些臨床開發計劃，我們不會自己進行。

However, we do imagine that a meaningful part of that if not all would be invested in our immunology pipeline, both the clinical development of the programs you know about, and the ones that we haven't yet disclosed but will in the future.

然而，我們確實認為，其中有意義的一部分（如果不是全部）將投資於我們的免疫學管道，包括您了解的項目的臨床開發，以及我們尚未披露但將來會披露的項目。

So while there might be a modest change in the ultimate cash runway, not enough to change the guidance. I think most of it you should assume will be reinvested in our immunology programs.

因此，儘管最終現金跑道可能會發生適度變化，但不足以改變指導。我認為你應該假設其中大部分將重新投資於我們的免疫學計畫。

Kalpit Patel, B. Riley.

卡爾皮特·帕特爾，B.萊利。

Yeah. Hey, good morning and thanks for taking the question. Maybe just one on the STAT6 program here. I'm curious if you've made comparisons to dupi, pre-clinically if you've looked at the change in ear thickness and the atopic derm model, the MC930. And as a follow up, I think the 32 milligrams per kilogram showed the most reductions in IgE, so I'm curious what that dose translates into humans? Thank you.

是的。嘿，早上好，感謝您提出問題。也許這裡只是 STAT6 程式中的一個。我很好奇您是否在臨床前與 dupi 進行過比較，是否觀察過耳朵厚度的變化和特應性皮膚模型 MC930。作為後續研究，我認為每公斤 32 毫克的 IgE 降低幅度最大，所以我很好奇這個劑量對人類來說意味著什麼？謝謝。

Yes, thanks, Kalpit, great question. So let's start with the second. So if you look at the slides that have been out for now, close to 12 months. So in the mouse to reach 90% degradation, because that's really what we're looking at, we use basically what you said 30, 32 mg per kg dose.

是的，謝謝，卡爾皮特，很好的問題。那麼讓我們從第二個開始。如果你看看現在已經發布的幻燈片，你會發現已經有將近 12 個月的時間了。因此，要在小鼠中達到 90% 的降解，因為這確實是我們所關注的，我們基本上使用您所說的每公斤 30、32 毫克的劑量。

In monkeys or in dogs, you actually need a much lower dose in the single digit milligrams per kilogram. So the reason why in mouse you need a larger dose is because actually plasma protein binding in mouse is higher than it is in dogs, in monkeys, and in humans.

對於猴子或狗來說，實際上需要的劑量要低得多，僅為每公斤個位數毫克。因此，在小鼠中需要更大劑量的原因是因為實際上小鼠的血漿蛋白結合率高於狗、猴子和人類。

So when you do dose projections, you should look at maybe more the dog, the monkey data, I would say the dog will show more data than use the mouse. So we don't talk about dose projections. What we said in the past is that the doses that we've explored in the IRAK4 programs broadly are probably again, broadly what we would be exploring in this program as well. So it's pretty relatively low doses.

因此，當您進行劑量預測時，您應該更多地查看狗、猴子的數據，我想說狗會顯示比使用老鼠更多的數據。所以我們不談劑量預測。我們過去所說的是，我們在 IRAK4 專案中廣泛探索的劑量可能也是我們在這個專案中廣泛探索的劑量。所以它的劑量相對較低。

With regards to your first question, so when we run these models, we focus on TH2 biomarkers and TH2 driven disease outcomes. And so that's why we looked at again in those models IgE and other TARC and other measures of TH2 inflammation.

關於你的第一個問題，所以當我們運行這些模型時，我們專注於 TH2 生物標記和 TH2 驅動的疾病結果。這就是為什麼我們再次研究這些模型中的 IgE 和其他 TARC 以及 TH2 發炎的其他指標。

And for disease outcome, we look more at the asthma model where we can look at both lung and the infiltrate of cells in the lungs as well as other TH2 biomarker. That model is not only TH2, so ear thickness is not something we kind of monitor either for dupi or for our degrader just because it's a more composite outcome that is non-TH2 as well.

對於疾病結果，我們更關注氣喘模型，在該模型中我們可以觀察肺部和肺部細胞的浸潤以及其他 TH2 生物標記。這個模型不僅是 TH2，因此耳朵厚度不是我們為 dupi 或我們的 degrader 監控的東西，因為它是一個更複合的結果，也不是 TH2。

Okay. Got it. Thanks for taking the questions.

好的。知道了。感謝您提出問題。

Yeah. Operator, next question.

是的。接線員，下一個問題。

Kripa Devarakonda, Truist Securities.

Kripa Devarakonda，Truist 證券公司。

This is [Alex Sanagasan] for Kripa. A question on the TYK2 asset. We had some conversations with investors about what they would describe as a slow launch for TYK2, citing some efficacy, good efficacy, and indications like psoriasis and maybe some challenges and others like IBD.

我是 Kripa 的 [Alex Sanagasan]。關於 TYK2 資產的問題。我們與投資者進行了一些對話，討論了他們所描述的 TYK2 的緩慢推出，並指出了一些功效、良好的功效以及銀屑病等適應症，也許還有一些挑戰和 IBD 等其他適應症。

Do you think that a degrader could address these issues and provide additional benefit? And when you think about future enrollments for the studies, would you consider enrolling in TYK2 inhibitor experienced patients in the trial as an expanded opportunity? Thanks.

您認為降級器可以解決這些問題並提供額外的好處嗎？當您考慮未來的研究招募時，您是否會考慮招募有 TYK2 抑制劑經驗的患者參加試驗作為擴大的機會？謝謝。

Yeah, maybe I'll address the first one, and I'll let Jared address the recruitment one. So, I mean, you obviously bring the point of the current commercial success of TYK2 inhibitors. I'm going to answer it a bit differently but hopefully still addressing your point.

是的，也許我會解決第一個問題，然後我會讓賈里德解決招募問題。所以，我的意思是，您顯然提出了 TYK2 抑制劑目前商業成功的觀點。我會以不同的方式回答這個問題，但希望仍然能解決你的觀點。

So what we have right now in the industry, we have a genetically validated target TYK2 that has been dragged by multiple molecules from different companies. One has been approved by BMS, and there are at least two or three other companies in different stages of development.

因此，我們現在在行業中擁有一個經過基因驗證的目標 TYK2，它已被來自不同公司的多個分子拖曳。一家已獲得BMS批准，另外至少還有兩到三家公司處於不同的發展階段。

We believe strongly at Kymera, and I think people that understand TYK2 biology would tend to agree with us that all these inhibitors are going to be difficult to be differentiated because they don't -- they address only partial function of TYK2. TYK2 has a well characterized scaffolding function, that actually is important in receptor signaling, IL-23, IL-12, Type I interferon.

我們在 Kymera 堅信，並且我認為了解 TYK2 生物學的人會傾向於同意我們的觀點，即所有這些抑製劑都將很難區分，因為它們不 - 它們只解決 TYK2 的部分功能。TYK2 具有明確的支架功能，實際上在受體訊號傳導、IL-23、IL-12、I 型乾擾素中很重要。

By removing the protein, we are going to completely block TYK2 signaling, and we're able to near complete block three of these pathways. So obviously, if the profile of our degrader looked like the inhibitor, we would obviously have failed, that's not the type of profile that we're looking for.

通過去除該蛋白質，我們將完全阻斷 TYK2 訊號傳導，並且我們能夠接近完全阻斷其中的三個途徑。顯然，如果我們的降解劑的概況看起來像抑制劑，我們顯然會失敗，這不是我們正在尋找的概況類型。

We're looking for something that can compete with biologics in many of those indications. And I actually believe that if we're able to translate the preclinical profile, we have even a more active molecule with 295, because again, full target degradation is the name of the game in this particular program.

我們正在尋找在許多適應症上可以與生物製劑競爭的藥物。我實際上相信，如果我們能夠轉化臨床前概況，我們甚至會得到更活躍的 295 分子，因為再次強調，完全目標降解是這個特定程序中的遊戲名稱。

I think that we're going to have a really transformative drug. And I think at this point is being missed right now because there is a bit of general, maybe fatigue in the TYK2 space. But Jared there's a comment about recruitment.

我認為我們將擁有一種真正具有變革性的藥物。我認為現在人們正在錯過這一點，因為 TYK2 領域存在一些普遍的、可能是疲勞的情況。但賈里德有一個關於招聘的評論。

Yeah I think for the initial proof of concept study in patients, we would likely not put on patients who had been on prior TYK2 and had progressed. Whereas we might include patients who have been on a prior TYK2 inhibitor, but have come off due to tolerability issues.

是的，我認為對於患者的初步概念驗證研究，我們可能不會讓先前接受過 TYK2 治療並取得進展的患者接受治療。而我們可能會納入先前使用過 TYK2 抑制劑但因耐受性問題而停止使用的患者。

Further down the road, once we've gone through initial proof of concept, we might be interested in understanding the activity of our drug even in those patients who have progressed after prior TYK2 inhibitors, but we probably wouldn't do that in the first study.

下一步，一旦我們完成了初步的概念驗證，我們可能有興趣了解我們的藥物的活性，即使是在那些在先前使用TYK2 抑制劑後病情出現進展的患者中，但我們可能不會一開始就這樣做學習。

Next question, operator.

下一個問題，操作員。

Brad Canino, Stifel.

布拉德·卡尼諾，斯蒂菲爾。

Hi, good morning. I know you stated in the prepared remarks that the next steps for STAT6 will be shared after the SAD, MAD results, and hitting that 90% plus degradation safely. But dupilumab replication in TH2 patients is the major question.

嗨，早安。我知道您在準備好的評論中說過，STAT6 的後續步驟將在 SAD、MAD 結果以及安全達到 90% 以上的退化之後共享。但 dupilumab 在 TH2 患者中的複製是主要問題。

Is there a particular type of TH2 disease where this test is best to conduct? I guess how much duration of testing is likely needed. And do you need hard clinical endpoints or will biomarkers in patients be sufficient to accelerate mid to late stage development? Thank you.

是否存在最適合進行該測試的特定類型 TH2 疾病？我猜想可能需要多長時間的測試。您是否需要硬性臨床終點，或者患者的生物標記足以加速中後期開發？謝謝。

Yeah, Brad, great question. So I would kind of say it this way. I think the goal of the Phase 1 study is to demonstrate that you can reach STAT6 degradation levels that we believe are therapeutically relevant, which as you said, actually, anywhere between 70%, 90% we've shown that is therapeutically relevant. But 90% is where we see maximal activity in a safe manner.

是的，布拉德，好問題。所以我會這樣說。我認為 1 期研究的目標是證明您可以達到我們認為具有治療相關性的 STAT6 降解水平，正如您所說，實際上，我們已經證明 70% 到 90% 之間的水平具有治療相關性。但 90% 是我們以安全方式看到最大活動的地方。

I believe that Regeneron and Sanofi have done an excellent job actually doing studies of what does dupilumab do in the blood and skin, especially of AD patients with regards to biomarker signature. And I think there's a really well established dupi signature, especially in the skin of AD patients.

我相信再生元和賽諾菲實際上在 dupilumab 在血液和皮膚中的作用研究方面做得非常出色，特別是在 AD 患者的生物標記特徵方面。我認為 dupi 特徵確實很明確，尤其是在 AD 患者的皮膚中。

And I think that one could actually very briefly get into that type of context and demonstrate that you're able to have a relevant biomarker signature that shows that STAT6 degradation blocks the pathway at least as well as an IL-4 receptor antagonist. So you could imagine a biomarker study in patients to be exceptionally telling of the profile of the drug.

我認為實際上可以非常簡單地了解這種類型的背景，並證明您能夠擁有相關的生物標記特徵，表明 STAT6 降解至少與 IL-4 受體拮抗劑一樣阻斷該途徑。因此，您可以想像對患者進行的生物標記研究能夠特別說明藥物的概況。

And that will probably allow you to move into large studies in all the important relevant population. So I think that could be an interesting sequence of events. I think we're not quite ready to share what our plans are, but those are important opportunities to validate these mechanisms.

這可能會讓你進入所有重要相關人群的大型研究。所以我認為這可能是一系列有趣的事件。我認為我們還沒有準備好分享我們的計劃，但這些是驗證這些機制的重要機會。

Appreciate it.

欣賞它。

Vikram Purohit, Morgan Stanley.

維克拉姆‧普羅希特，摩根士丹利。

Good morning, everyone. This is Gospel on for Vikram. We have one question on KT-253 and KT-323. What would an ideal partnership look like? And our discussions with potential partners currently under way< and should a partnership be something we expect in the near term? Thank you.

大家早安。這對維克拉姆來說是個福音。我們有一個關於 KT-253 和 KT-323 的問題。理想的合作關係是什麼樣的？我們目前正在與潛在合作夥伴進行討論<，我們是否應該在短期內期望建立合作夥伴關係？謝謝。

Yeah, great question. So we're not going to comment on the ongoing or hypothetical conversations that obviously happen at any time in the lifetime of companies. But what I will say is, we know we've shown across our oncology pipeline that we've been able to demonstrate a really impeccable translation of our PK, PD and safety into the clinic across the different programs.

是的，很好的問題。因此，我們不會對公司生命週期中任何時候明顯發生的正在進行的或假設的對話發表評論。但我要說的是，我們知道我們已經在整個腫瘤學管道中證明了我們能夠在不同的項目中將我們的 PK、PD 和安全性真正完美地轉化為臨床。

And we've shown some exciting early clinical activity across different indications. And Jared mentioned, we have an Ash poster on 323 which I encourage people to look out for. And so these are the activity we've shown has been in many cases in (inaudible) indication.

我們已經在不同的適應症中展示了一些令人興奮的早期臨床活動。Jared 提到，我們在 323 有一張 Ash 海報，我鼓勵人們留意它。因此，這些是我們在許多情況下（聽不清楚）指示中顯示的活動。

So in order to maximize value in those patient populations, I think a partner that has franchise both clinical and commercial in those areas, I think would be able to create most values. And for us, it's really how do we have patients in the most effective way, and that's what's going to drive some of our decision making, given that our focus will be again or our internal resources in immunology.

因此，為了在這些患者群體中實現價值最大化，我認為在這些領域擁有臨床和商業特許經營權的合作夥伴將能夠創造最大的價值。對我們來說，這實際上是我們如何以最有效的方式接待患者，這將推動我們做出一些決策，因為我們的重點將再次放在免疫學的內部資源上。

Kelly Shi, Jefferies.

施凱莉，傑弗里斯。

Congrats on the progress, and thank you for taking my questions. I would appreciate your insights on what are the major differentiations of targeting STAT6 compared to targeting IRAKIMID-413, or like a OX-40 from biology perspective.

恭喜您的進展，並感謝您回答我的問題。我非常感謝您對靶向 STAT6 與靶向 IRAKIMID-413 或從生物學角度看像 OX-40 的主要區別有何見解。

For example, STAT6 is also known involved in innate immunity besides IL-4/13 signaling. So what do you see the breadth of indications that the STAT6 program could pursue based on its MoA? Thank you.

例如，除了 IL-4/13 訊號傳導之外，STAT6 還參與先天免疫。那麼，您認為 STAT6 計畫基於其 MoA 可以追求哪些廣泛的跡象？謝謝。

Yeah, Jared. I'll take a bit of a bit but maybe you can help me. So, yeah, great question. So what we've shown in our studies pre-clinically that the activity that we see of STAT6 in immune cells is really almost all if not all driven from IL-4 receptor signaling, so IL-4 and 13.

是的，賈里德。我會花一點時間，但也許你可以幫助我。所以，是的，很好的問題。因此，我們在臨床前的研究中表明，我們在免疫細胞中看到的 STAT6 活性實際上幾乎全部（如果不是全部）由 IL-4 受體訊號傳導驅動，即 IL-4 和 13。

And we've shown that if you block IL-4/13, as others have shown you, you reduce (inaudible) STAT6 levels. If you reduce STAT6, you reduce IL-4 receptor level. Again, I don't want to keep quoting this recent paper. But if you read this recent paper on the partial loss of function variant of STAT6, that actually shows the same that there is reduction of IL-4 receptor signaling.

我們已經證明，如果您阻斷 IL-4/13，正如其他人向您展示的那樣，您就會降低（聽不清楚）STAT6 水平。如果減少 STAT6，就會降低 IL-4 受體水準。再說一次，我不想繼續引用這篇最近的論文。但如果你閱讀最近這篇關於 STAT6 功能變體部分喪失的論文，實際上表明 IL-4 受體訊號傳導減少。

If you look at gain of function in humans, again, I'm talking about human people, humans, sorry, also there the STAT6 gain of functions have severe allergic diseases, TH2 biology. So we kind of expect to be TH2 biology that the mechanism we're eliciting. So biologically, we feel like it's really on pathway to IL-4 receptor.

如果你看看人類的功能獲得，我再說一遍，我說的是人類，人類，對不起，STAT6 的功能獲得也有嚴重的過敏性疾病，TH2 生物學。所以我們有點期望我們所引出的機制是 TH2 生物學。因此，從生物學角度來看，我們認為它確實處於通往 IL-4 受體的途徑中。

Jared, is there anything you want on or [Ken]?

Jared，有什麼想穿的嗎？[肯]？

No. I think that covers it. I mean, we expect STAT6 degradation to phenocopy what's been seen with drugs like dupilumab that are resulting in a full blockade of IL4, IL-13. And we've seen that impact both in our in-vivo models where we see efficacy that's comparable to dupi in the asthma and AD models.

不。我認為這涵蓋了它。我的意思是，我們預期 STAT6 降解的表型與 dupilumab 等藥物所觀察到的情況相同，這些藥物會導致 IL4、IL-13 的完全阻斷。我們已經在我們的體內模型中看到了這種影響，在氣喘和 AD 模型中我們看到了與 dupi 相當的功效。

And we've seen it in multiple cell types, even in a recent (inaudible) presentation where we looked at STAT6 degradation and human sensory neurons, we saw that it was able to block IL-13 induced up regulation of transcripts involved in itch and pain, which are key symptoms in AD.

我們已經在多種細胞類型中看到了它，甚至在最近（聽不清楚）的演示中，我們研究了STAT6 降解和人類感覺神經元，我們發現它能夠阻止IL-13 誘導的與瘙癢和瘙癢有關的轉錄本的上調。

So we think STAT6 targeting really has an advantage in addition to the unique pharmacology of being able to degrade STAT6 by over 90% sort of 24/7, could give us pharmacology that may be unique and differentiated from what can be achieved with the upstream (inaudible) antibody biologics.

因此，我們認為STAT6 標靶確實具有優勢，除了能夠24/7 降解90% 以上的STAT6 的獨特藥理學之外，還可以為我們提供可能是獨特的、與上游可以實現的藥理學不同的藥理學（聽不清楚）抗體生物製劑。

Great. Thanks.

偉大的。謝謝。

Jeff Jones, Oppenheimer.

傑夫瓊斯，奧本海默。

Good morning guys, and thanks for taking the question. I guess we'll stay on 621 and STAT6. Clearly you guys aren't the only ones targeting STAT6 and your IRAK4 partners to know if he's working with both Recludix and Neurax.

早上好，夥計們，感謝您提出問題。我想我們會繼續使用 621 和 STAT6。顯然，你們並不是唯一針對 STAT6 和你們的 IRAK4 合作夥伴知道他是否同時與 Recludix 和 Neurax 合作的人。

Could you comment on the differentiation between a degrader approach here for STAT6 versus the small molecule approach? And maybe any differentiation between your degrader platform and Neurax? Thank you.

您能否評論一下 STAT6 降解劑方法與小分子方法之間的差異？也許您的降級器平台和 Neurax 之間有什麼區別？謝謝。

Yeah, so great question. So first, I would say that we're the only company that has actually generated a wealth of data comparing 621 and STAT6 degradation to approved medicines. And while all the data so far has been pre-clinical, so there's always the caveat of pre-clinical.

是的，很好的問題。首先，我想說我們是唯一一家實際上產生了大量數據將 621 和 STAT6 降解與已批准藥物進行比較的公司。雖然到目前為止所有的數據都是臨床前的，所以總是有臨床前的警告。

We've shown that STAT6 degradation can penocopy in a variety of models what dupilumab does, both in that's the breadth of activity. And some would argue that we've seen even more activity than dupilumab in some of these models, but so that's that.

我們已經證明，STAT6 降解可以在多種模型中模仿 dupilumab 的作用，無論是在活性廣度上。有些人會爭辯說，我們在其中一些模型中看到了比 dupilumab 更多的活性，但事實就是這樣。

I think what we believe is that degrading STAT6 is the only pharmacological way to block this pathway as fully as the saturating dose of an IL-4 receptor alpha antibody. You can (inaudible) use a small molecule inhibitor to block STAT6.

我認為我們相信降解 STAT6 是像 IL-4 受體 α 抗體的飽和劑量一樣完全阻斷該途徑的唯一藥理方法。您可以（聽不清楚）使用小分子抑制劑來阻斷 STAT6。

But blocking the path we given these occupancy base that there is the challenge of PK and PD correlation, we believe that the degrader there is both highly potent and catalytic that doesn't require the correlation between PK and PD, has a much more profound impact in terms of pathway blockade.

但是，鑑於這些佔用基礎存在 PK 和 PD 相關性的挑戰，我們認為，那裡的降解劑既具有高效性又具有催化作用，不需要 PK 和 PD 之間的相關性，具有更深遠的影響在通路封鎖方面。

And I will also encourage you to be patient as well you'll hear more from us on this particular topic in the near future. With regards to us and other companies, it's hard for me to have again, I think no other company has shown any data, no other company has a compound even in from what we understand that has made past or a development candidates.

我也鼓勵您保持耐心，在不久的將來您會聽到我們關於這個特定主題的更多資訊。對於我們和其他公司來說，我很難再有這樣的情況，我認為沒有其他公司顯示過任何數據，沒有其他公司擁有一種化合物，甚至從我們了解的情況來看，已經成為過去或正在開發的候選者。

So, I mean, the two companies (inaudible) just two out of many that are doing pre-clinical work in STAT6. I think since we shared our data, I've heard of many other companies that are attempting to do what we've done. Again, I'll encourage you to continue to follow us. You'll hear more about our efforts in STAT6, even beyond 621 as we progress this program.

所以，我的意思是，這兩家公司（聽不清楚）只是在 STAT6 中進行臨床前工作的眾多公司中的兩家。我認為自從我們共享數據以來，我聽說許多其他公司正在嘗試做我們所做的事情。我再次鼓勵您繼續關注我們。隨著我們推進該計劃，您將更多地了解我們在 STAT6 中所做的努力，甚至超越 621。

Appreciate the update guys. Thank you.

感謝各位的更新。謝謝。

Thanks.

謝謝。

Eric Joseph, JPMorgan.

艾瑞克‧約瑟夫，摩根大通。

Hi, good morning. Just picking up on the Phase 1 trial with 621. Could you -- I'm sorry if I missed it, but can you give us a sense of sort of the number of those cohorts and patient numbers that you're evaluating and the SAD, MAD.

嗨，早安。剛開始 621 的第一階段試驗。如果我錯過了，我很抱歉，但是您能否讓我們了解一下您正在評估的隊列數量和患者數量以及 SAD、MAD。

And whether the read out in the first half would include both SAD and MAD components or maybe a partial read out thereof. And yeah, and the extent of which sort of the prior Phase 1 with the IRAK4 is a useful road map here.

以及前半部的讀出是否包括SAD和MAD分量，或者可能是其中的部分讀出。是的，IRAK4 的前期第一階段的範圍是一個有用的路線圖。

On the good side, you didn't miss anything, Eric. So Jared can tell you more about at least what we can at this point by your question.

從好的方面來說，你沒有錯過任何事情，埃里克。所以賈里德至少可以透過你的問題告訴你更多關於我們現在能做什麼的資訊。

I mean, we can't provide you a whole lot of color around the actual number of those cohorts. But I think your comparison to the IRAK4 Phase 1, SAD, MAD, probably is within the ballpark in terms of how we plan to interrogate both the SAD and MAD portions.

我的意思是，我們無法為您提供有關這些群體實際數量的大量資訊。但我認為，就我們計劃如何詢問 SAD 和 MAD 部分而言，您與 IRAK4 第 1 階段、SAD、MAD 的比較可能在大致範圍內。

And just as a reminder that these are placebo controlled cohorts of healthy volunteers with the MAD being 14 days of dosing and the SAD obviously being single doses. So I think we'll generate a very robust data set going across a full range of doses in both SAD and MAD.

提醒一下，這些是安慰劑對照的健康志願者隊列，MAD 是 14 天的給藥時間，SAD 顯然是單次給藥。因此，我認為我們將產生一個非常可靠的數據集，涵蓋 SAD 和 MAD 的全部劑量範圍。

And we plan on doing that sufficiently with healthy volunteers. And as we mentioned, the data read out in the first half of next year will include both the SAD and MAD portions. So it will be the full data set from the healthy volunteer, SAD, MAD, that we revealed in the first half of next year.

我們計劃與健康的志工一起充分做到這一點。正如我們所提到的，明年上半年讀出的數據將包括 SAD 和 MAD 部分。因此，這將是我們在明年上半年公佈的健康志工、SAD、MAD 的完整數據集。

(multiple speakers) Sorry Eric, just to add because it's going to show up on clinicaltrial.gov in a few days, any time. I think we say there that the total number of patients in SAD and MAD is roughly 120 or up to 120. So that's the additional piece of piece of the info we can share today. Go ahead. Do you have to follow-up?

（多名演講者）抱歉，埃里克，我只是補充一下，因為它將在幾天內隨時出現在 ClinicalTrial.gov 上。我認為我們在那裡說 SAD 和 MAD 患者的總數大約是 120 人或最多 120 人。這就是我們今天可以分享的額外資訊。前進。有必要跟進嗎？

Yes. Thanks for that detail. And yes, we were looking for the trial entry, couldn't find it. But anyway, thank you. Follow-up just with the kind of the focus going forward here in I&I, any, I guess we should be anticipating additional targets programs here in that space over the next year or so.

是的。謝謝你的詳細資料。是的，我們正在尋找試用條目，但找不到。但無論如何，謝謝你。跟進 I&I 中未來的重點，我想我們應該預計在未來一年左右的時間裡，該領域將有更多的目標計劃。

Yeah, I mean, it's for sure. So we've been three plus years that we have focused our research, and now development effort in immunology. We're working on many, many programs. We have multiple development candidates that are being nominated in the past few -- in the next few months.

是的，我的意思是，這是肯定的。因此，我們已經花了三年多的時間專注於免疫學的研究和開發工作。我們正在開發很多很多的專案。我們有多名開發候選人在過去幾個月和未來幾個月內被提名。

So we'll be happy to share as, again, as we've done in the past when we're close to the clinic. We're happy to share next targets. I think we've also learned from our previous experiences that maybe we should wait a bit longer before sharing our target and data package for competitive reason. So maybe we'll share when we're a bit closer to the clinic than in the past, but you should expect next year at least one disclosure.

因此，我們很樂意再次分享，就像我們過去在靠近診所時所做的那樣。我們很高興分享下一個目標。我認為我們也從先前的經驗中了解到，出於競爭原因，我們可能應該等待更長的時間才能共享我們的目標和資料包。因此，當我們比過去更接近診所時，也許我們會分享，但你應該期待明年至少有一項披露。

Ellie Murrell, UBS.

艾莉‧默雷爾，瑞銀集團。

Hey, it's Sam on for Ellie. I guess, can you just touch on a little bit your level of confidence for IRAK4 efficacy and HS versus atopic derm heading into those seats to read out in '26. And then second on STAT6, how quickly do you expect to move into patients following this SAD, MAD portion, and any expectations for timing on that? Thanks.

嘿，艾莉是山姆。我想，您能談談您對 IRAK4 功效以及 HS 與特應性皮膚的信心程度嗎？其次是關於 STAT6，您預計在 SAD、MAD 部分之後多快進入患者，以及對此時間的任何期望？謝謝。

So maybe I'll take the second and I'll let Jared take the first one. So as we said, I think we've said it today that we expect to go into patients soon after the Phase 1. To be honest, mostly for competitive reasons, we're not sharing those plans yet.

所以也許我會選擇第二個，而我會讓賈里德選擇第一個。正如我們所說，我想我們今天已經說過，我們希望在第一階段之後很快進入患者階段。老實說，主要是出於競爭原因，我們還沒有分享這些計劃。

We have them, we've had them for months, if not, for years. But we'll be to share as we're closer to those studies, what the plans are, both in terms of near term development and eventually long term development.

我們擁有它們，我們已經擁有它們幾個月了，甚至幾年了。但隨著這些研究的臨近，我們將分享近期發展和最終長期發展的計劃。

Jared, on IRAK4?

賈里德，在伊拉克4號嗎？

Yeah, I think in terms of your question around our level of confidence and being active in HS versus AD, I think we have and Sanofi as well, have a high level of confidence, and potentially being active in both of these indications. And mechanistically, for example, HS, we know is driven by IL-36, IL-1, total like receptor activation AD, we know there's an important component of IL-1, IL-33, and (inaudible) like receptors.

是的，我認為就你關於我們對 HS 與 AD 的信心水平和積極程度的問題而言，我認為我們和賽諾菲也有很高的信心，並且有可能積極參與這兩個適應症。從機制上講，例如，我們知道HS 是由IL-36、IL-1、總樣受體激活AD 驅動的，我們知道有IL-1、IL-33 和（聽不清楚）樣受體的重要組成部分。

And so I think there's a mechanistic basis for believing that IRAK4 targeting should be effective there. And I think also if you look at our Phase 1 study where we did have experience with both HS and AD patients, we did see impact both on skin lesions and importantly on symptoms in both of those diseases, impacting pain significantly in HS, and pruritis in AD, these being the number one symptoms that affect quality of life in these patients.

因此，我認為有一個機制基礎可以相信，針對 IRAK4 的目標應該在那裡有效。我想，如果你看一下我們的1 期研究，我們確實對HS 和AD 患者都有經驗，我們確實看到了對皮膚損傷的影響，而且重要的是對這兩種疾病的症狀的影響，對HS的疼痛和搔癢有顯著影響在 AD 中，這些是影響這些患者生活品質的首要症狀。

And so I think in addition to that Phase 1 study, we showed modulation of pro-inflammatory pathways and skin biopsies from both of those patients. So I think we have confidence in both, and look forward ultimately to the clinical readouts from the Phase 2b trials, which will ultimately answer that question.

因此，我認為除了第一階段研究之外，我們還對這兩位患者進行了促發炎途徑和皮膚切片的調節。因此，我認為我們對兩者都有信心，並最終期待 2b 期試驗的臨床結果，這將最終回答這個問題。

Thank you.

謝謝。

Michael Schmidt, Guggenheim.

邁克爾·施密特，古根漢。

Hey, good morning. Thanks for taking my question. Another one on 621. Nello, so degraders as a modality have obviously been very safe so far. But based on the mechanism and perhaps preclinical data, what are potential on target or perhaps off target AEs that one might expect to see in the study at high 621 doses in the clinic, and what our learnings from STAT6 knockout animal models. Thanks so much.

嘿，早安。感謝您提出我的問題。621 上的另一張。尼洛，所以到目前為止，降級器作為一種方式顯然是非常安全的。但根據機制和可能的臨床前數據，人們可能期望在臨床高 621 劑量的研究中看到哪些潛在的目標或脫靶 AE，以及我們從 STAT6 敲除動物模型中學到的知識。非常感謝。

Yeah, thanks Mike. So in terms of what we know is that STAT6 degradation and even (inaudible) above the exposure in which we reach the full STAT6 degradation, we have not seen in pre-clinical species, any adverse events.

是的，謝謝邁克。因此，就我們所知，STAT6 降解，甚至（聽不清楚）高於我們達到 STAT6 完全降解的暴露水平，我們在臨床前物種中沒有看到任何不良事件。

Our molecule as you've seen 621 is an exceptionally selective molecule, in both proteomics as well as any other biological testing that we've done. So we do not expect to have any off target activity. So I don't have an answer for you what we expect to see in terms of safety flag.

正如您所看到的，我們的分子 621 是一種具有極高選擇性的分子，無論是在蛋白質體學還是我們所做的任何其他生物測試中。因此，我們預計不會有任何偏離目標的活動。因此，我無法為您提供我們期望在安全標誌方面看到的答案。

The reality is that so far, we haven't seen anything, we hope not to see anything in the clinic also. In terms of what we know from genetics, so we know that knockout mice or are normal and fertile, we know gain of function STAT6 people have severe atopic diseases, which again tells you that STAT6 is really only signaling through the IL-4 receptor alpha pathway.

現實是，到目前為止，我們還沒有看到任何東西，我們希望在診所也不會看到任何東西。就我們從遺傳學中了解到的情況而言，我們知道敲除小鼠或是正常且有生育能力的，我們知道功能獲得STAT6 的人患有嚴重的特應性疾病，這再次告訴您STAT6 實際上僅透過IL-4 受體α 發出訊號途徑。

Again, I mentioned already twice, this is also this partial loss of function humans which also are protected, they don't have any phenotype. So I would say that if we look at the totality of our data, this is the perfect target, and we hope we're right.

再次，我已經提到過兩次，這也是人類的部分功能喪失，它們也受到保護，他們沒有任何表型。所以我想說，如果我們查看全部數據，這是一個完美的目標，我們希望我們是對的。

Great and just a quick follow up. So, in terms of subsequent studies, how do you think about prioritizing potential indications? Would you move into AD first perhaps I know there's a lot of work on STAT6 out there in lung inflammation. So asthma is that top of the list, or how do you how do you plan on prioritizing potential opportunities?

很好，只是快速跟進。那麼，就後續研究而言，您如何考慮優先考慮潛在適應症？你會先進入 AD 嗎？那麼氣喘是最重要的，或者您如何計劃如何優先考慮潛在的機會？

I mean, look again, as I mentioned earlier, we were not going to disclose our clinical development plan, not because we don't have it, it's just it's premature at this point. But I can say that we believe this is a TH2 drug, this is not an AD drug or an asthma drug, this is a TH2 drug.

我的意思是，再看看，正如我之前提到的，我們不會透露我們的臨床開發計劃，不是因為我們沒有它，只是現在還為時過早。但我可以說，我們相信這是一種 TH2 藥物，這不是 AD 藥物或氣喘藥物，這是 TH2 藥物。

So this drug has the opportunity to work in all these indications that dupilumab has worked in. So we're talking now seven, eight indications with also the most recent data. Our approach would be to prioritize the larger indications for obvious reasons.

因此，該藥物有機會在 dupilumab 已發揮作用的所有這些適應症中發揮作用。所以我們現在談論的是七、八個跡像以及最新的數據。出於顯而易見的原因，我們的方法是優先考慮較大的適應症。

So AD, asthma, COPD would likely be the primary indications, but we are committed to helping all patients of all ages of all severity of diseases. That's our mission and vision for this program, for this franchise, I should say. And so we are going to do as much as possible to help as many people as possible, unlike the biologics that are now on the market or soon to be on the market.

因此，AD、氣喘、慢性阻塞性肺病可能是主要適應症，但我們致力於幫助所有年齡、所有嚴重疾病的所有患者。我應該說，這就是我們對這個計畫、這個系列的使命和願景。因此，我們將盡最大努力幫助盡可能多的人，這與現在市場上或即將上市的生物製劑不同。

Faisal Khurshid, Leerink Partners.

費薩爾‧庫希德 (Faisal Khurshid)，Leerink 合夥人。

Hey guys, thanks for taking the question. I realize this might be premature but wanted to ask anyways. So how are you thinking about partnership opportunities on KT-621? And when do you think the best time for that would be?

嘿夥計們，感謝您提出問題。我意識到這可能為時過早，但無論如何還是想問一下。那麼您如何看待 KT-621 的合作機會？您認為最佳時機是什麼時候？

One answer would be we're not thinking about that, but to answer, it is a good question, it's not pretty much pre-mature actually, not because we're planning to do so, but it's good to discuss. So we believe we're best positioned to develop KT-621 and our franchise through the next inflection point.

一個答案是我們沒有考慮這個問題，但要回答的是，這是一個很好的問題，實際上並不是太不成熟，不是因為我們計劃這樣做，而是討論一下是件好事。因此，我們相信我們最有能力開發 KT-621 和我們的特許經營權，度過下一個拐點。

We believe it will be except -- I believe personally will be exceptionally premature to have these discussions in the near future. I think we have a great development plan that will take us through some compelling hopefully Phase 2b studies.

我們相信，我個人認為，在不久的將來進行這些討論還為時過早。我認為我們有一個偉大的發展計劃，它將帶領我們完成一些令人信服的 2b 期研究。

I think as we're nearing commercialization and Phase 3 and commercialization, the questions will be based on our cost of capital, our pipeline, what is the best way to create value and impact patients? One part would be to go all in, and become these amazing companies that commercializes this product everywhere.

我認為，隨著我們接近商業化、第三階段和商業化，問題將基於我們的資本成本、我們的管道，創造價值和影響患者的最佳方式是什麼？其中一部分就是全力以赴，成為這些令人驚嘆的公司，將這種產品商業化到世界各地。

Another part will be to find a partner that helps us commercialize this drug in particular regions. But it's going to be an extremely high bar for us to partner STAT6, and we've been asked multiple times, it's probably an understatement.

另一部分是尋找合作夥伴，幫助我們在特定地區將這種藥物商業化。但對我們來說，與 STAT6 合作的門檻非常高，而且我們已經被多次詢問過，這可能是輕描淡寫的說法。

Great. Thank you.

偉大的。謝謝。

Andy Chen, Wolfe Research.

安迪陳，沃爾夫研究中心。

Hey guys, it's [Chuka] here for Andy. Thanks for the clarification on IRAK4 trial design changes. So Santa Fe is deciding to add an additional dose to both HS and AD. Are they adding a dose because they think the previous doses are too safe or too unsafe. Our guess is that the previous doses are very safe. So is it safe for us to assume that these new doses or these new higher doses in both trials?

嘿夥計們，我是安迪的[Chuka]。感謝您對 IRAK4 試驗設計變更的澄清。因此，Santa Fe 決定在 HS 和 AD 中增加額外劑量。他們增加劑量是否是因為他們認為之前的劑量太安全或太不安全。我們的猜測是之前的劑量非常安全。那麼我們在這兩項試驗中假設這些新劑量或這些新的更高劑量是否安全？

Can you guys hear me?

你們聽得到我說話嗎？

Yeah. Yeah, I think we got to. Yeah. Did you have anything else? I think it's --

是的。是的，我想我們必須這麼做。是的。你還有別的事嗎？我認為是--

Yeah, it sounds like it cut off for a second. So let's say for us to assume that the new doses are higher in both trials because the efficacy can go higher or are we thinking of this wrong?

是的，聽起來好像中斷了一秒鐘。那麼，讓我們假設這兩項試驗中的新劑量都更高，因為療效可以更高，還是我們認為這是錯誤的？

So it's a great question actually. So let's take a step back because actually maybe we -- because we talked about this for so many times we didn't today. So I will remind everybody that how we got to this point, that Santa Fe decided elected to do in a safety advocacy, early in the year, to look at the profile of the drug to that point, and decided to use that data set to make an investment decision or not actually.

所以這實際上是一個很好的問題。因此，讓我們退後一步，因為實際上也許我們 - 因為我們已經多次討論過這個問題，但今天卻沒有。因此，我要提醒大家，我們是如何走到這一步的，聖達菲決定在今年年初進行安全宣傳，以研究該藥物到那時的概況，並決定使用該數據集來是否實際做出投資決定。

And the data and again, early data in both safety and efficacy was supportive of an increased investment to accelerate the overall development timeline. And so what we haven't said publicly whether it's a lower or higher dose.

這些數據再次表明，安全性和有效性方面的早期數據支持增加投資以加快整體開發時間表。所以我們還沒有公開說明劑量是更低還是更高。

I think you can speculate 1,000 things. I think what we've said publicly is that the need or the desire to add another dose was driven from regulatory needs to conduct those ranging studies before selecting the dose for Phase 3.

我認為你可以推測 1,000 件事。我認為我們公開表示的是，添加另一種劑量的需要或願望是出於監管需要，在選擇第三階段劑量之前進行這些範圍研究。

And so it's probably neither of your hypothesis is more, they wanted to add another dose so that you've checked that box in order to move into late development into Phase 3 studies, and maybe less about, was it not safe or too safe? I think the data that we both saw was compelling enough that it was about accelerating the study.

因此，您的假設可能都不是更多，他們想添加另一個劑量，以便您選中該框，以便進入第三階段研究的後期開發，也許更少的是，它是否不安全或太安全？我認為我們都看到的數據足夠令人信服，足以加速研究。

Got you, got you. Makes sense. Thank you.

得到你了，得到你了。有道理。謝謝。

So I think this was the last question. I wanted to thank everybody for joining our call. As you all know, we're easily reachable if there is any follow up questions from our stakeholders externally. I want to thank our team again because they continue to do some amazing work.

所以我認為這是最後一個問題。我想感謝大家加入我們的電話會議。眾所周知，如果外部利害關係人有任何後續問題，可以輕鬆聯繫我們。我想再次感謝我們的團隊，因為他們繼續做了一些令人驚嘆的工作。

And looking forward to an exciting year-end and early next year. We've probably never been busier at Kymera. And so I think everybody says busy is good, so looking forward to the next update.

並期待著激動人心的年底和明年初。我們在 Kymera 可能從未如此忙碌過。所以我想每個人都說忙碌是好事，所以期待下次更新。

This concludes today's presentation. You may now disconnect.

今天的演講到此結束。您現在可以斷開連線。