Aclaris Therapeutics Inc (ACRS) 2024 Q1 法說會逐字稿

Good day, and thank you for standing by, and welcome to the Aclaris Therapeutics First Quarter 2024 conference call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question and answer session and to ask a question during the session, you will need to press star one one on your telephone and You will then hear an automated message advising her hand this race. To withdraw your question, please press star one one. Again, please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today. Kevin Bob, is there please go ahead.

美好的一天，感謝您的耐心等待，歡迎參加 Aclaris Therapeutics 2024 年第一季電話會議。此時，所有參與者都處於只聽模式。演講者演講結束後，將進行問答環節，要在會議期間提出問題，您需要在電話上按星號一一，然後您將聽到一條自動訊息，建議她參加這場比賽。若要撤回您的問題，請按星號一一。再次請注意，今天的會議正在錄製中。我現在想把會議交給今天的發言者。凱文·鮑勃，在嗎，請繼續。

Thank you. I am Kevin Bolton-Weiser, Chief Financial Officer for Aclaris. Please note that earlier today, we issued a press release highlighting our first quarter 2024 financial results and other business matters. For those of you who have not yet seen it, you will find the release posted under the Press Releases page of the Investors section of our website at w. w. w. dot Aclaris Tx.com. In addition, we will be referring to a slide deck entitled ITK. portfolio, which can be found on the Investor Presentations page of the Investors section of our website and furnished as an exhibit to our Form eight K that we filed with the SEC earlier today. Joining me today for the call are Neil Walker, our Interim Chief Executive Officer, and Joe Monahan, our Chief Scientific Officer, Wally Smith, our scientific and business development consultant will also be available for the Q&A portion of the call.

謝謝。我是 Kevin Bolton-Weiser，Aclaris 財務長。請注意，今天早些時候，我們發布了一份新聞稿，重點介紹了 2024 年第一季的財務業績和其他業務事項。對於那些還沒有看過的人，您可以在我們網站的投資者部分的新聞稿頁面下找到發布的新聞稿，網址為：w。 w。 w。點 Aclaris Tx.com。此外，我們將參考名為 ITK 的幻燈片。投資組合，可以在我們網站投資者部分的投資者演示頁面上找到，並作為我們今天早些時候向 SEC 提交的 8 K 表格的附件提供。今天與我一起參加電話會議的有我們的臨時首席執行官尼爾·沃克(Neil Walker) 和首席科學官喬·莫納漢(Joe Monahan)，我們的科學和業務發展顧問沃利·史密斯(Wally Smith) 也將參加電話會議的問答部分。

Before we begin our prepared remarks, I would like to remind you that various statements we make during this call about the Company's future results of operations and financial position, business strategy and plans and objectives for classes. Future operations are considered forward-looking statements within the meaning of the federal securities laws. Our forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties that could cause actual results to differ materially from those reflected in such statements. These risks are described in the Risk Factors section of Aclaris Form 10 K for the year ended December 31st, 2023, and other filings Aclaris makes with the SEC from time to time. These documents are available under the SEC Filings page of the Investors section of our website at w. w. w. dot Aclaris Tx.com. All the information we provide on this conference call is provided as of today, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events or otherwise. Please be advised that today's call is being recorded and webcast. A link to the webcast can be accessed under the Events page of the Investors section of our website.

在我們開始準備好的發言之前，我想提醒您，我們在本次電話會議中就公司未來的營運業績和財務狀況、業務策略以及課程計劃和目標發表了各種聲明。未來營運被視為聯邦證券法意義內的前瞻性陳述。我們的前瞻性陳述是基於目前的預期，其中涉及風險、情況變化、假設和不確定性，可能導致實際結果與此類陳述中反映的結果有重大差異。截至 2023 年 12 月 31 日的年度 Aclaris 表格 10 K 的風險因素部分以及 Aclaris 不時向 SEC 提交的其他文件中描述了這些風險。這些文件可在我們網站「投資者」部分的 SEC 文件頁面下獲取，網址為：w. w。 w。點 Aclaris Tx.com。我們在本次電話會議上提供的所有資訊均截至今天，我們沒有義務更新我們在本次電話會議上因新資訊、未來事件或其他原因可能做出的任何前瞻性陳述。請注意，今天的電話會議正在錄音並進行網路直播。您可以在我們網站投資者部分的活動頁面下存取網路廣播的連結。

I'll now turn the call over to Neil.

我現在將把電話轉給尼爾。

Thank you, Kevin, and good afternoon, everyone. Last quarter we announced that in addition to various cost-cutting measures and an overall review of our business strategy. We are also reevaluating the indication selection for ATI. 2138, which is our oral small molecule ITKJAK. three inhibitor. Today, I'm pleased to announce that we have decided to move ATI 2138 forward any proof of concept study in moderate to severe atopic dermatitis. Atopic dermatitis is a Th two cell driven disease and ITK. inhibition blocks, T cell differentiation, activation and production of IL-4 and IL-13.

謝謝你，凱文，大家下午好。上季我們宣布了除了各種成本削減措施以及對我們的業務策略的全面審查之外。我們也正在重新評估 ATI 的適應症選擇。 2138，這是我們的口服小分子ITKJAK。三抑制劑。今天，我很高興地宣布，我們決定進行 ATI 2138 中度至重度異位性皮膚炎的概念驗證研究。異位性皮膚炎是一種 Th 2 細胞驅動的疾病和 ITK。抑製作用可阻斷 T 細胞分化、IL-4 和 IL-13 的活化和產生。

In fact, there is extensive literature on the role that ITK. plays in regulating the signaling pathways that are central to the production of various cytokines by both Th two cells and mast cells today, we will provide an overview of ATI. 2138 and the data we have generated thus far, Joe.

事實上，有大量關於 ITK 作用的文獻。 ATI 在調節訊號通路中發揮著重要作用，而訊號通路對於 Th 2 細胞和肥大細胞產生各種細胞因子至關重要。第2138章

The new ATI 2138 is a covalent inhibitor that targets the T cell kinase ITK. as well as Jack three ITK. is a kinase downstream of the T cell receptor and is important for the regulation of T cell function. While Jack Therese required for the signaling of cytokine that utilize the gamma common receptor such as IL-2, IL-4 and IL-13, ATI 2138 through effective targeting of these two critical T cell and cytokine associated pathways provides the potential to treat a broad set of autoimmune diseases. Ati 2138 was generated from our proprietary Connect drug discovery platform using structure-based drug design, focusing on molecules with high reversible affinity containing electrify the target, the ATP. site 15 positions. Similarly in ITK. injectors, as shown in slide 5, Kobayashi and engagement of six four four two was demonstrated from the proprietary crystal structure of the ATI 2138 ITK. complex ATI 2138 also binds to and engages has nine oh nine injector and the only Jack isoform with this residue in the ATP site, the cystine Jack three has also been effectively targeted by the drug lucitanib, which is Pfizer's recently approved therapy for alopecia areata. Ati 2138, differentiates from both realistic nib and reversible Jack inhibitors, thereby demonstrating unique pharmacology and best in class potential.

新型 ATI 2138 是一種針對 T 細胞激酶 ITK 的共價抑制劑。以及傑克三ITK。是 T 細胞受體下游的激酶，對於 T 細胞功能的調節很重要。雖然Jack Therese 需要利用γ 共同受體（如IL-2、IL-4 和IL-13）的細胞激素訊號傳導，但ATI 2138 透過有效靶向這兩個關鍵T 細胞和細胞因子相關途徑，提供了治療細胞激素的潛力。 Ati 2138 是透過我們專有的 Connect 藥物發現平台使用基於結構的藥物設計生成的，重點關注具有高可逆親和力的分子，其中包含使目標 ATP 通電的分子。站點15個職位。 ITK 中也是如此。噴射器，如幻燈片 5 所示，小林和六四四二的接合是透過 ATI 2138 ITK 的專有晶體結構演示的。複合物ATI 2138 也結合併接合九歐九注射器，並且是唯一在ATP 位點具有此殘基的Jack 亞型，胱氨酸Jack 3 也已被藥物lucitanib 有效靶向，這是輝瑞最近批准的治療斑禿的療法。 Ati 2138 不同於現實 nib 和可逆 Jack 抑制劑，從而展現出獨特的藥理學和同類最佳的潛力。

As shown on slide 6, ATI 21, 38 has similar high potency for inhibiting both ITKJAK. three signaling in contrast to route lucitanib, which is less potent on both pathways and demonstrates Jack three biased pharmacology. Ati 2138 is select selective project three with no meaningful crossover to other Jack isoforms. The restricted expression of JAG three to hematopoietic cells, coupled with the lack of crossover to other jacks, may result in an improved safety profile for ATI 2138 relative to broad spectrum, reversible Jack inhibitors, clear differentiation from the prevailed inhibitor. Implicitly is demonstrated in human whole blood studies shown on slide 7, panel on the left compares ATI 2138 and limitless fitness in ITK. dependent anti CD. three stimulated interferon gamma production. While the right-hand panel compares two compounds in Jack three dependent I/O to stimulated interferon gamma release. Ati 2138 is 44.4 times more potent than replacing nib and blocking ITK. dependent cytokine production and 5.4 fold more potent in the Jack three dependent readout comparable whole blood potencies of 2138 on ITK. inject three translated to similar impact on the respective PD readouts in the human SAD and MAD studies. In contrast, at the FDA recommended 50 milligram QD dose of Reverset known for alopecia areata exposures would be expected to inhibit Jack three, but have little impact on the ITK. pathway.

如投影片 6 所示，ATI 21、38 具有相似的抑制 ITKJAK 的高效力。與途徑lucitanib相反，Lucitanib在這兩種途徑上的效力均較弱，並且證明了Jack 3偏向藥理學。 Ati 2138 是精選項目三，與其他 Jack 同工型沒有有意義的交叉。 JAG 3 對造血細胞的限製表達，加上缺乏與其他 Jack 的交叉，可能會導致 ATI 2138 相對於廣譜、可逆 Jack 抑制劑的安全性得到改善，與主流抑制劑有明顯區別。第 7 張投影片中所顯示的人類全血研究隱含地證明了這一點，左側面板比較了 ATI 2138 和 ITK 中的無限適應性。依賴性抗CD。三刺激幹擾素γ的產生。右側面板比較了傑克三依賴性 I/O 中的兩種化合物刺激幹擾素伽馬釋放的情況。 Ati 2138 的效力比替換筆尖和阻斷 ITK 強 44.4 倍。依賴的細胞激素產生，並且在傑克三依賴讀數中與 ITK 上的 2138 的全血效力相比，效力高出 5.4 倍。在人類 SAD 和 MAD 研究中，注射三種藥物對各自的 PD 讀數有類似的影響。相較之下，FDA 建議的 50 毫克 QD 劑量的 Reverset（因斑禿暴露而聞名）預計會抑制傑克三號，但對 ITK 影響不大。途徑。

Now why is ITK. an important target? Slide 8 demonstrates the current understanding of the role of ITK. T & T helper cell differentiation and activation of the tech kinases. Itk alone is required for the differentiation and activation of Th two and Th 17 cells and ITK. knockdown or inhibition results in skewing of T helper cells from the Th two Th 17 phenotype to the Th one to replicate that type ITK. inhibitors have the potential as effective oral drugs to treat diseases driven by Th two and or Th 17 cells such as atopic dermatitis. Ati 2138 has demonstrated activity in a number of preclinical immune inflammatory disease models, oral activity at various doses of 20 ATI 21, 38 in rat adjuvant induced arthritis is shown on slide 9, evaluating ankle swelling on the left and histology on the right similar, strong activity is observed with doses of five and 15 milligram per kilogram, BID. as well as 30 milligrams per kilogram to date activity was also observed in the adoptive T cell transfer model of colitis in the mouse.

現在為什麼是ITK。一個重要目標？幻燈片 8 展示了目前對 ITK 角色的理解。 T & T 輔助細胞分化與技術激酶活化。 Th 2 和 Th 17 細胞以及 ITK 的分化和活化僅需要 Itk。敲除或抑制會導致 T 輔助細胞從 Th 2 Th 17 表型偏向 Th 1 表型，以複製該類型的 ITK。抑制劑有潛力作為有效的口服藥物來治療由 Th 2 和/或 Th 17 細胞驅動的疾病，例如異位性皮膚炎。 Ati 2138 在多種臨床前免疫發炎疾病模型中表現出活性，幻燈片9 顯示了不同劑量的20 ATI 21、38 口服對大鼠佐劑誘導關節炎的活性，評估了左側踝關節腫脹和右側相似的組織學，每公斤 5 毫克和 15 毫克劑量（BID）觀察到較強的活性。迄今為止，在小鼠結腸炎過繼性 T 細胞轉移模型中也觀察到了 30 毫克/公斤的活性。

As shown on slide 10, ATI 21, 38 formulated in Ciao protected proximal and distal colon as well as the ileum from inflammation to a greater extent than the anti IL 12 p. 40 antibody preclinical studies supported the advancement of ATI 2138 into Phase one SAD and MAD clinical studies.

如幻燈片 10 所示，Ciao 中配製的 ATI 21、38 比抗 IL 12 p 更大程度地保護近端和遠端結腸以及迴腸免受發炎影響。 40 項抗體臨床前研究支持 ATI 2138 進入一期 SAD 和 MAD 臨床研究。

As summarized on slide 11, the drug was generally well tolerated at favorable PK characteristics and demonstrated dose-dependent modulation of ITK. and Jack three pharmacodynamic readouts.

正如幻燈片 11 所總結的，該藥物在有利的 PK 特性下通常具有良好的耐受性，並且顯示出 ITK 的劑量依賴性調節。和傑克三個藥效學讀數。

Slide 12 shows the PK characteristics of ATI 2138 from the MAD study exposures following the final dose on day 15 of the MAD study are shown on the left and dose proportionality shown on the right linear PK is observed with ATI 2138 following two weeks of dosing with steady-state dose proportionality observed for both C-max and AUC.

幻燈片 12 顯示了 MAD 研究第 15 天最終劑量後的 ATI 2138 PK 特徵，右側顯示了劑量比例，在服用兩週後觀察到 ATI 2138 的線性 PK。比例。

Slide 13 shows the pharmacodynamic results across the two week dosing period in the MAD study. The left panel is measuring the inhibition of ITK. dependent I/O to mRNA following ex vivo stimulation and blood, the middle panel, Jack three dependent interferon gamma production and the right panel, interferon gamma production following dual stimulation of the TCR inject three pathways, ATI 2138 demonstrated dose and time-dependent inhibition under all stimulation conditions. 50% to 90% inhibition of the PD readouts was observed with doses from five to 40 milligrams BID.

幻燈片 13 顯示了 MAD 研究中兩週給藥期的藥效學結果。左圖測量 ITK 的抑制。離體刺激和血液後對mRNA 的依賴性I/O，中間圖，傑克三依賴性幹擾素γ 產生和右圖，TCR 注射三種途徑雙重刺激後幹擾素γ 產生，ATI 2138 表現出劑量和時間依賴性抑制在所有刺激條件下。使用 5 至 40 毫克 BID 的劑量觀察到 PD 讀數的 50% 至 90% 抑制。

Slide 14 shows exposure response analysis from the three PD. readouts in comparison to translation from preclinical human whole blood analysis These data demonstrate a strong concentration dependent correspondence between EC 50s from both the SAD and MAD clinical studies and In Vitro human whole blood studies across the three stimuli as expected similar potency as observed for the ITK. pathway, Jack three and dual stimulation inhibition. Finally, exposures generator from five milligrams to 40 milligrams BID. dosing were sufficient to provide blockade of both pathways. Successful completion of the Phase one studies effectively positioned ATI 2138 to advance into Phase two, the first indication, which ATI 2138 will be evaluated as a atopic dermatitis.

投影片 14 顯示了三個 PD 的暴露反應分析。與臨床前人類全血分析的翻譯結果相比這些數據表明，SAD 和MAD 臨床研究以及體外人類全血研究的EC 50 之間存在強烈的濃度依賴性對應關係，這三種刺激物與預期的ITK觀察到的類似效力相同。途徑，傑克三和雙重刺激抑制。最後，曝光產生器從 5 毫克 BID 到 40 毫克。劑量足以阻斷兩條途徑。第一階段研究的成功完成，有效地使 ATI 2138 進入第二階段，即第一個適應症，ATI 2138 將被評估為異位性皮膚炎。

The rationale for which is shown on slide 15, the dual TCR directory specificity of ATI 2138, effectively positions it for treatment of atopic dermatitis, the important role of ITK. Th two cell differentiation and activation, coupled with the efficacy observed with the biologics targeting the Th two cytokine, IL-4 and IL-13 supports the potential for ATI 2138 as an oral alternative to these biologic. Additionally, inhibiting Jack three should and complementary efficacy through blockade of IL-2 and IL-4 signaling as evidenced by the efficacy of a number of JAK inhibitors in atopic dermatitis.

其基本原理如幻燈片 15 所示，ATI 2138 的雙重 TCR 目錄特異性，有效定位了其在異位性皮膚炎治療中的重要作用，即 ITK 的重要作用。 Th 2 細胞分化和激活，加上針對 Th 2 細胞因子、IL-4 和 IL-13 的生物製劑觀察到的功效，支持 ATI 2138 作為這些生物製劑的口服替代品的潛力。此外，抑制 Jack 3 應該透過阻斷 IL-2 和 IL-4 訊號傳導來補充功效，許多 JAK 抑制劑對異位性皮膚炎的功效證明了這一點。

The design of the atopic dermatitis study is summarized on Slide 16. This study will be an open label 12 week 15 patient study to examine the safety, PK and early signs of efficacy of ATI 2138 in patients with moderate to severe atopic dermatitis. In addition, to the clinical readouts, there will be a heavy emphasis on PD markers of pathways and disease in this study. Moreover, we plan to demonstrate the importance of ITK. inhibition as a differentiating feature of our molecule.

投影片16 總結了異位性皮膚炎研究的設計。 PK 和早期療效跡象。此外，除了臨床讀數外，本研究還將重點關注通路和疾病的 PD 標記。此外，我們計劃展示ITK的重要性。抑制是我們分子的一個區別特徵。

In summary, as shown on slide 17, ATI 2138 is a potential best in class dual inhibitor of ITKJC. three, nonclinical potency activity at MI and safety studies supported moving the compound into clinical development, positive data from the SAD and MAD phase one studies providing clinical support to advance ATI 2138 into a proof-of-concept Phase two study in moderate to severe atopic dermatitis. Aclaris is expanding our efforts in the ITK. pathway beyond ATI 2138 with discovery efforts focused on next-generation ITK. inhibitors. Well, ITK. has been of interest to pharmaceutical companies for over 20 years has proven to be a difficult drug kinase, as evidenced by the efforts outlined on Slide 19. The research described on this slide are focused on ATP competitive inhibitors and due to poor biochemical efficiency and pharmaceutical properties they have not advanced in clinical development. More recently, covalent inhibitors of ITK. have been described with the cobas CPI. eight one eight and early clinical development on next generation efforts are focusing on selective inhibition of ITK. and eliminating core crossover on Jack kinases. As shown on slide 20, selective targeting of ITK. should provide effective modulation of both Th two and Th 17 cell functions with the potential of treating a topic in Th 17 driven diseases as summarized on slide 21 unit and mouse genetic data flows. Pharmacological inhibition strongly supports a role for ITK. and T cell biology and pathophysiology. This, coupled with the fact that dysregulated T cells are involved in a number of immune inflammatory diseases validate selective inhibitors of ITK. as an approach to treat a broad range of indications.

總之，如投影片 17 所示，ATI 2138 是一種潛在的同類最佳 ITKJC 雙重抑制劑。三、MI 的非臨床效力活性和安全性研究支持將該化合物轉入臨床開發，SAD 和MAD 一期研究的積極數據為將ATI 2138 推進中度至重度特應性反應的概念驗證二期研究提供了臨床支持皮膚炎。 Aclaris 正在擴大我們在 ITK 方面的努力。超越 ATI 2138 的途徑，發現工作重點在於下一代 ITK。抑制劑。好吧，ITK。 20 多年來，它一直受到製藥公司的關注，已被證明是一種困難的藥物激酶，幻燈片19 中概述的工作就證明了這一點。劑，並且由於生化效率差和藥物激酶他們在臨床開發中尚未取得進展的特性。最近，ITK 的共價抑制劑。已用 cobas CPI 進行了描述。八一八和下一代的早期臨床開發工作的重點是選擇性抑制 ITK。並消除 Jack 激酶上的核心交叉。如投影片 20 所示，選擇性標靶 ITK。應提供對 Th 2 和 Th 17 細胞功能的有效調節，並具有治療 Th 17 驅動疾病的潛力，如幻燈片 21 單元和小鼠遺傳數據流中總結的那樣。藥理抑制有力地支持了 ITK 的角色。 T 細胞生物學和病理生理學。再加上失調的 T 細胞參與許多免疫發炎性疾病的事實，驗證了 ITK 的選擇性抑制劑。作為治療廣泛適應症的方法。

Thank you, Joe. I'll now turn it over to Kevin to discuss our financial highlights for the quarter.

謝謝你，喬。現在我將把它交給凱文討論我們本季的財務亮點。

You know, we continue to maintain a strong balance sheet with a robust cash balance and zero outstanding debt. We ended the first quarter with cash, cash equivalents and marketable securities of $161 million, which was compared to $182 million at year end. Our cost containment initiatives are on track and progressing nicely of our total cash expenditures. In the first quarter, approximately $14 million was related to nonrecurring payments, including discontinued research and development programs. Severance benefits for individuals impacted by the reduction in force announced in December, and payments owed to third parties related to the upfront amount received under the sun licensing agreement activities associated with discontinued programs and the reduction in force are expected to be substantially completed by the second quarter of 2024. As a result, we expect our cash expenditures on a quarterly basis for the remainder of the year to be significantly reduced when compared with the first quarter without giving effect to any potential business development transactions. We continue to evaluate business development opportunities across our portfolio of assets could be a source of non-dilutive capital in the near term.

您知道，我們繼續保持強勁的資產負債表，擁有強勁的現金餘額和零未償債務。第一季結束時，我們的現金、現金等價物和有價證券為 1.61 億美元，而去年年底為 1.82 億美元。我們的成本控制計劃正在步入正軌，並且在我們的總現金支出方面進展順利。第一季度，約 1,400 萬美元與非經常性付款相關，其中包括已終止的研發項目。受 12 月宣布的裁員影響的個人的遣散費，以及根據與已終止的計劃和裁員相關的 sun 許可協議活動收到的預付款而欠第三方的款項預計將在第二個季度基本完成2024 年第四季。我們繼續評估我們資產組合中的業務發展機會，這些機會可能成為短期內非稀釋資本的來源。

With that, I will now turn the call back over to Neil for closing remarks.

現在，我將把電話轉回給尼爾，讓他發表結束語。

Thank you, Kevin. We are pleased to provide you with a pro forma portfolio update on our decision to shift to atopic dermatitis is the first proof of concept indication for ATI 2138. As a reminder, we are still in the process of reviewing various strategic options moving forward and look forward to providing additional updates in the near term.

謝謝你，凱文。我們很高興為您提供關於我們決定轉向異位性皮膚炎的預計投資組合更新，這是 ATI 2138 的第一個概念證明。內提供更多更新。

For Kyle, we would now like to poll for questions.

對於凱爾，我們現在想就問題進行民意調查。

Thank you. And as a reminder, to ask a question, please press star one one on your telephone and wait for a name to be announced. Once again, please press star one one on your telephone keypad. And to withdraw your question, please press star one one. Again, please stand by while we compile the Q&A roster.

謝謝。提醒一下，要提問，請在電話上按星號一一，然後等待宣布姓名。請再按下電話鍵盤上的星號。若要撤回您的問題，請一一按星號。再次，請大家耐心等待，我們正在整理問答名單。

Yes.

是的。

And for our first question, it comes from the line of Roger Song for Geoff.

對於我們的第一個問題，它來自羅傑·宋（Roger Song）對傑夫（Geoff）的台詞。

Great.

偉大的。

Thanks for the update and taking a little questions. Maybe now with the biology question on. So for ITK. and GX. three and the spending on that as you compare to the dependence, Jack inhibitor has been a lot of the advantage. I'm just curious, how do you think about those IQ, Kim, Jackson three in terms of having synergistic or additive effect when you're in chemicals for those preclinical models, just that curious if you're seeing in all of you compare?

感謝您的更新並提出一些問題。也許現在有生物學問題。所以對於ITK來說。和GX。三、在支出上，與你的依賴相比，傑克抑制劑已經有很多優勢了。我只是好奇，當你使用那些臨床前模型的化學物質時，你如何看待 IQ、Kim、Jackson 三人在協同或相加效應方面的作用，如果你在所有人中看到比較，那就很好奇？

Yes, that Jack three or and TK. alone kind of in a preclinical model. And I have a follow-up for their clinical question. Thank you.

是的，那個傑克三或TK。僅在臨床前模型中存在。我對他們的臨床問題進行了跟進。謝謝。

Yes, but thank you, Roger. I'll start there and all to Joe and or Wally. But yes, that's one of the attractive things about the molecule and was one of our original hypotheses about that, if we could inhibit the Jack three and then layer on maybe the hyper boost with IGK., particularly in an indication like a topic where ITK. really targets the Th two effect, we ought to see a more robust effect there. And so we certainly tested that hypothesis out in preclinical models and and actually, I know you didn't ask this, but going forward in this initial proof-of-concept study, we'll endeavor to tease out that differential effect through looking at various pharmacodynamic markers. It just definitively prove out BITK. contribution from that molecule and maybe, Joe, if you want to add anything there.

是的，但是謝謝你，羅傑。我將從這裡開始，向喬和/或沃利說起。但是，是的，這是該分子的吸引力之一，也是我們最初的假設之一，如果我們可以抑制傑克三號，然後用IGK 進行可能的超級增強，特別是在像ITK 這樣的主題的跡象中。確實針對第二個效應，我們應該在那裡看到更強大的效應。因此，我們當然在臨床前模型中測試了該假設，實際上，我知道您沒有問這個，但在這項最初的概念驗證研究中，我們將努力透過觀察來​​梳理出這種差異效應各種藥效學標誌物。它只是明確地證明了 BITK。來自那個分子的貢獻，也許，喬，如果你想在那裡添加任何東西。

And the only thing I would add is that we have profiled a January more selective inhibitor with illicit NIB versus ATI 2138 in the adoptive T T cell transfer model of colitis and at equivalent doses and exposures, we did see a boost in anti-inflammatory activity with 21, 38 compared to what was sitting there.

我唯一要補充的是，我們在結腸炎的過繼性T T 細胞轉移模型中，對非法NIB 與ATI 2138 的選擇性更強的抑製劑進行了分析，並且在相同的劑量和暴露量下，我們確實看到了抗炎活性的增強21、38 與坐在那裡的相比。

Got it.

知道了。

Yes, that makes sense. Then compared to JX three more selective compounds, may be that that's the AITK. component, but you're correct to see the PD. marketing the Phase two for sure. And then in terms of the of the Phase 2a, the plan, the Phase 2a you selecting the arm, no 10 meg Yankee, but those understanding you want to be more capital efficient to test the windows. Just curious on you know if you think about those is the best dose you can tell from the preclinical and also what the other potential dose, if that does see some seasonal. But you know, what do you have that those potential that you will well testing there, future clinical trials? And then also for the Phase IIa, any powering for dose efficacy or what is the on the ultimate kind of efficacy goal for the Phase IIa in order to move forward?

是的，這是有道理的。那麼比JX更有選擇性的三種化合物，可能就是AITK了。組件，但你看到 PD 是正確的。肯定會行銷第二階段。然後就第 2a 階段的計劃而言，第 2a 階段您選擇了手臂，沒有 10 兆揚基，但那些了解您希望以更高的資本效率來測試窗戶的人。只是好奇你是否知道這些是你可以從臨床前看出的最佳劑量，以及其他潛在劑量，如果你確實看到一些季節性的話。但你知道，你有哪些潛力可以在未來的臨床試驗中進行良好的測試？那麼對於 IIa 期，劑量功效的任何動力或 IIa 期為了向前推進的最終功效目標是什麼？

Yes.

是的。

So from so it is it is open label. So our main objective is to show the absolute treatment effect. And I think to be fair in this indication, we want to see something north of some of the standard in market Jack inhibitors. I mean, I from my perspective, they've set the bar in a die from an efficacy perspective. And historically, we kind of understand the placebo rate.

因此，它是開放標籤。所以我們的主要目標是展示絕對的治療效果。我認為公平地說，我們希望看到一些超出市場傑克抑制劑標準的東西。我的意思是，從我的角度來看，他們從功效的角度設定了模具的標準。從歷史上看，我們對安慰劑的比率有所了解。

And then the second part of the first question Joe, do you want to tackle that one?

然後是第一個問題的第二部分，喬，你想解決這個問題嗎？

Yes. So with regard to the dosing, first of all, we do have the ability to go higher than 10 milligram BID. if we choose to, we identified 10 milligrams BID. as our dose in this study based on exposures in the various preclinical disease models that we looked at, coupled with the data in red, the fitness in the clinical exposure that they had. I think with this mechanism, it doesn't seem to be driven by C-max. It doesn't seem to be driven by C. trough, it more likely is driven by a C average. And at the 10 milligrams BID., we have equivalent potency at C-max as realistic and it goes against Jack three significantly more exposure and potency at against ITK. As we described at the C average, we have higher level of inhibition of both ITK. and Jack tree at this 10 milligram BID. dose. So based on the preclinical models and based on comparison to responsiveness, that's how we chose the dose.

是的。因此，關於劑量，首先，我們確實有能力提高到高於 10 毫克 BID。如果我們選擇，我們確定 10 毫克 BID。因為我們在這項研究中的劑量是基於我們研究的各種臨床前疾病模型中的暴露，再加上紅色的數據，即他們所具有的臨床暴露的適應性。我覺得這個機制，好像不是C-max驅動的。它似乎不是由 C. 波谷驅動的，它更有可能是由 C 平均值驅動的。在 10 毫克 BID 下，我們在 C-max 下具有與現實相當的效力，並且它與傑克三相比，在對抗 ITK 時顯著更多的暴露和效力。正如我們在 C 平均值中所描述的，我們對兩種 ITK 都有更高程度的抑制。而 Jack Tree 的 BID 為 10 毫克。劑量。因此，根據臨床前模型和反應性比較，我們就是這樣選擇劑量的。

And yes, there are also other questions I have now.

是的，我現在還有其他問題。

Thank you.

謝謝。

Thank you, Ron.

謝謝你，羅恩。

Thank you. And once again, if you'd like to ask a question, please press star one one on your telephone keypad and for the next question. It comes from the line of Thomas Smith from Leerink Partners. Please go ahead.

謝謝。再次強調，如果您想提出問題，請按下電話鍵盤上的星號鍵，然後詢問下一個問題。它來自 Leerink Partners 的 Thomas Smith 家族。請繼續。

Hey, guys, good afternoon. Thanks for the updates and thanks for taking our questions. Just on the preclinical data, and I appreciate all the models and comparisons to real Sidney. And I'm just curious if you've generated any data comparing 21, 38 versus ipatasertib and selective JAK1 inhibition preclinically? And any thoughts on how 21, 38 like what would stack up in an indication like atopic dermatitis versus parasiticides?

嘿，夥計們，下午好。感謝您的更新並感謝您提出我們的問題。僅就臨床前數據而言，我很欣賞所有模型以及與真實悉尼的比較。我只是好奇您是否已產生任何臨床前比較 21、38 與 ipatasertib 和選擇性 JAK1 抑制的數據？以及任何關於 21、38 等在異位性皮膚炎與殺寄生蟲劑等適應症中如何疊加的想法？

Yes. Thanks for that question. I think it's I think the X factor here is the ITK. inhibition. And when you look at the literature on ITK. and inhibition in general, it really skews to inhibiting the Th two cytokine. So it directly acts on IL-4, IL-5, et cetera. And so we really think that that is going to give the Jack three side of Boost. And Joe, while I am not aware of direct comparisons between the it's pure covalent Jack three versus Jack one specifically in AD., I think you know, our hypothesis is when you have a dual mechanism that we demonstrated synergy, we ought to have an additive effect. So I that would be the goal is to outperform. You have the them.

是的。謝謝你提出這個問題。我認為這裡的 X 因素是 ITK。抑制。當你查看有關 ITK 的文獻時。和一般的抑製作用一樣，它確實偏向抑制 Th 2 細胞激素。因此它直接作用於IL-4、IL-5等。所以我們真的認為這將為 Jack 帶來 Boost 的三面性。喬，雖然我不知道純共價傑克三與傑克一之間的直接比較，特別是在AD 中，我想你知道，我們的假設是，當你有一個我們展示協同作用的雙重機制時，我們應該有一個附加效應。所以我的目標是跑贏大盤。你有他們。

Understood That's helpful.

明白了，很有幫助。

And just on on the Phase IIa trial design, can you talk about the rationale a little bit, I guess, specifically the choice of an open label design versus maybe a slightly larger placebo-controlled design. It sounds like here and you have some interesting biomarkers identified that that you'd like to take a look at here in terms of signal-finding, but I'm just curious in terms of maybe more definitively teasing out the clinical signal here, the switch to the open-label trial design?

就 IIa 期試驗設計而言，我想您能否稍微談談其基本原理，特別是選擇開放標籤設計與可能稍大的安慰劑對照設計。聽起來像在這裡，您發現了一些有趣的生物標誌物，您想在信號查找方面看看這裡，但我只是好奇，也許更明確地梳理出這裡的臨床信號，切換到開放標籤試驗設計？

Well, I think you know, it's a couple of things. One is that it's a lot easier these days in a relatively competitive environment to enroll studies that have just an active arm when you're when we're looking for signal finding, I think our our goal is speed and the study was our very cost-efficient way to get a lot of answers. And I think we know what the and what these molecules and different kind of surrogates can do like if we just compare look at real estate and that percentage of all these other drug categories, I think we don't have a good understanding of what the absolute responder rate needs to be across these measures. And so I think that was the balance here of trying to get data as quickly as we can. And if it works out the way we hope and expect that we would certainly be interested in progressing in a little bit larger AD. study, but also importantly, looking at some of the indications that lucitanib has as already started to blaze the ground on looking at vitiligo, looking at alopecia areata, I think there's a couple of a couple of different. We have ways to go post this initial IDE study.

嗯，我想你知道，有幾件事。一是，如今在競爭相對激烈的環境中，當我們尋找信號時，註冊只有主動臂的研究要容易得多，我認為我們的目標是速度，而研究就是我們的成本- 獲得大量答案的有效方法。我認為，如果我們只比較房地產和所有其他藥物類別的百分比，我認為我們知道這些分子和不同類型的替代物可以做什麼，我認為我們並沒有很好地理解絕對應答率需要涵蓋這些措施。所以我認為這就是盡可能快地獲取數據的平衡點。如果事情按照我們希望和期望的方式進行，我們肯定會對在更大的 AD 中取得進展感興趣。研究，但同樣重要的是，看看盧西他尼已經開始在白斑、斑禿方面取得進展的一些跡象，我認為有一些不同的。我們有辦法發表這個初步的 IDE 研究。

But I think just to go back to the original premise of your question, I think I don't think that we lose too much and not having a placebo group. We enhance the enrollment cadence, we'll get data quicker, which I think is important for us given where we're at at the moment.

但我想回到你問題的最初前提，我認為我們並沒有損失太多並且沒有安慰劑組。我們提高了註冊節奏，我們將更快地獲取數據，考慮到我們目前的處境，我認為這對我們很重要。

Got it.

知道了。

That makes sense.

這就說得通了。

And just on along those lines, Neil, with respect to study start, like I understand where putting together the protocol and the operational preparations are underway, do you have an early guess early sense of when we might be able to expect some top-line data from the Phase IIa?

沿著這些思路，尼爾，關於研究開始，就像我了解協議和操作準備工作正在進行的地方一樣，您是否對我們何時能夠期待一些頂線有一個早期的猜測？

I think we're giving guidance just yet, Tom, but it's going to be you know, it is definitely going to be within a year of this call, right? So it's a I'll give you that this hub Hexion marker, but we'll give more color on that once we get the first patient.

湯姆，我想我們現在正在提供指導，但你知道，肯定會在這次電話會議後的一年內，對吧？所以，我會給你這個中心 Hexion 標記，但一旦我們找到第一個病人，我們就會給它更多的顏色。

Got it.

知道了。

Makes sense.

說得通。

I guess thanks for taking the questions.

我想感謝您提出問題。

Thank you.

謝謝。

And your next question comes from the line of Karine Johnson from Goldman Sachs. Please go ahead.

你的下一個問題來自高盛的卡琳·約翰遜。請繼續。

Good evening.

晚安.

This is Omar on for Karin.

這是卡琳的奧馬爾。

So I had a couple of questions.

所以我有幾個問題。

One is, are you funded to complete the proof-of-concept study?

一是，您是否有資金來完成概念驗證研究？

And then to our strategy, where do you see unmet need in atopic dermatitis?

然後是我們的策略，您認為異位性皮膚炎方面未滿足的需求在哪裡？

We're certainly funded to complete this study. This is a exceedingly cost-efficient study, which was kind of by design and so we're trying to generate data very quickly. This is in contrast to what we had originally proposed at the tail end of last year, which was a study in UC, which was a lot more expensive going to take a lot more time. So we have a robust balance sheet, as Kevin alluded to in his comments.

我們當然有資金來完成這項研究。這是一項極具成本效益的研究，它是經過設計的，因此我們試圖非常快速地產生數據。這與我們去年年底最初提出的方案形成鮮明對比，那是加州大學的一項研究，成本要高得多，需要更多的時間。因此，正如凱文在評論中提到的那樣，我們擁有穩健的資產負債表。

Yes, that's that balance sheet is not going to change to appreciably through through the end of the year. And so we feel very comfortable to a very small amount of burn while we continue to review various strategic options.

是的，到今年年底，資產負債表都不會明顯變動。因此，在我們繼續審查各種戰略選擇的同時，我們對少量的燒錢感到非常滿意。

And we'll sorry, what was the first the second question.

抱歉，第一個問題和第二個問題是什麼。

where do you see the unmet need in atopic dermatitis?

您認為異位性皮膚炎的未滿足需求在哪裡？

So I don't have a strategy.

所以我沒有策略。

Yes, we're at the front end of the topic market. This is where psoriasis was years ago. We certainly I don't think anybody can claim that we've maxed out efficacy in this space. You know, obviously do Diplomat is a wildly successful drug, but 60% of the patients we aren't even getting clear or near clear by week 16 and then 50% of those patients get us some optimal response. So and that's on the biologic side on the Jack inhibitor side. And we have much better efficacy, but there's still a lot of headroom in this space and what we're trying to do here is tease out the ITK. effect. We really think this is a strong mechanistic approach to this category.

是的，我們處於主題市場的前端。這是幾年前牛皮癬的發源地。當然，我認為沒有人可以聲稱我們已經在這個領域發揮了最大功效。你知道，很明顯，Diplomat 是一種非常成功的藥物，但到第 16 週，我們甚至有 60% 的患者尚未痊癒或接近痊癒，然後其中 50% 的患者得到了一些最佳反應。這是傑克抑制劑方面的生物方面。我們的效率要好得多，但這個領域仍然有很大的空間，我們在這裡要做的是梳理 ITK。影響。我們確實認為這是針對該類別的強有力的機械方法。

And on the competitive landscape, in AD. is, as you can see by clintrials.gov, this is still in its infancy. It's continuing to evolve. A lot of people are starting to look at that space because they're, you know, we aren't where we're at with psoriasis where we're talking about positive 100.

在AD的競爭格局上。正如您在 clintrials.gov 上看到的那樣，這仍處於起步階段。它正在繼續發展。很多人開始關注這個領域，因為他們，你知道，我們的牛皮癬還沒有達到我們所說的陽性 100 的程度。

Thanks.

謝謝。

Restaurant growth.

餐廳的成長。

Yes, Kyle, is there any other questions in the queue?

是的，凱爾，隊列中還有其他問題嗎？

Our next question or comment comes from the line of Julian Harrison from Bank TRG. Your line is open.

我們的下一個問題或評論來自 TRG 銀行的 Julian Harrison。您的線路已開通。

Thank you for taking my question and for hosting this call. I got on a few minutes late. So apologies if this has already been covered, but I'm wondering if you can remind us of the scope of your IP portfolio related to the use of Jack inhibitors for alopecia and how we should be thinking about that opportunity going forward?

感謝您回答我的問題並主持本次電話會議。我遲到了幾分鐘。如果這已經被涵蓋，我深表歉意，但我想知道您是否可以提醒我們與使用 Jack 抑制劑治療脫髮相關的智慧財產權組合的範圍，以及我們應該如何考慮未來的機會？

Sure. Thanks, Julian. So we had a long time ago back in 2015, 2016 or so executed transaction with Columbia, securing the rights to the method of use IP around utilizing various Jack inhibitors for the treatment of alopecia areata and actually various other types of alopecia. And thus far to date we have we've announced two royalty deals. One is worth and Lilly for the use of baricitinib for alopecia areata. And the other is with some pharma who had acquired concert, we had a deuterated ruxolitinib, and that was also executed late last year. And so those are the two current molecules that we have granted access to the utilizing our IP. So we think it's a we think it's a very valuable estate. Clearly, we've done two deals in. We'll constantly be looking at ways to We enhanced the value of that portfolio.

當然。謝謝，朱利安。因此，我們很久以前就在 2015 年、2016 年左右與哥倫比亞公司執行了交易，確保了使用各種 Jack 抑制劑治療斑禿和實際上各種其他類型脫髮的智慧財產權使用方法的權利。到目前為止，我們已經宣布了兩項特許權使用費交易。其中之一是值得和禮來公司使用巴瑞克替尼治療斑禿。另一個是與一些收購了音樂會的製藥公司合作，我們有一種氘化的魯索替尼，這也是在去年年底執行的。這就是我們已授權使用我們的智慧財產權的兩個當前分子。所以我們認為這是一個非常有價值的遺產。顯然，我們已經完成了兩筆交易。

Thank you.

謝謝。

Thank you. Our next question or comment comes from the line of Alex THOMPSON from Stifel. Tom, your line is now open.

謝謝。我們的下一個問題或評論來自 Stifel 的 Alex THOMPSON。湯姆，您的線路現已開通。

For Alex. I guess you could just talk a little bit more about how this drug differs from the Pfizer compound?

對於亞歷克斯.我想你可以多談談這種藥物與輝瑞化合物的差異嗎？

And then is there any case for differentiation on the black box warning? Thanks.

那麼黑框警告是否有區分的理由呢？謝謝。

Do you guys still expect a black-box warning fix?

你們還期待黑盒警告修復嗎？

I'm sure that Thanks, Alex. I think until you get through an actual FDA approvals process and have those dialogues whenever we're tickling charged a Jack at this stage or is that they're thinking about?

我確信謝謝，亞歷克斯。我想，直到你通過實際的 FDA 批准程序，並在我們現階段對傑克提出指控時進行這些對話，或者他們正在考慮？

So in thinking about your black box, but I do think a lot of the black box warnings, if you look at all the government Jack inhibitors out there, they're all slightly different wind boats, bonuses, division and cohesiveness, et cetera. So beta, we'll drive some amount. And maybe Joe can handle the question about what are the different key differentiating features between our drug and motor segment.

因此，在考慮你的黑盒子時，但我確實認為很多黑盒子警告，如果你看看那裡的所有政府傑克抑制劑，它們都是略有不同的風船、獎金、分裂和凝聚力等等。因此，在測試版中，我們將推動一些工作。也許喬可以解決我們的藥物和運動細分市場之間不同的關鍵區別特徵是什麼的問題。

Yes.

是的。

The I mean, they both have called out inhibitors that target a similar cysteine residue and they both are potent inhibitors and frac three. The key differentiation for our industry is that, um, with nib has a low dose of finances, it's significantly more potent on Jack three than any excluding ITKS. And in contrast, ATH. one 38, depending on which read-out you use, it's very similar potency, refractory CAR T K kind of the clinical exposures and doses that we have, clients use it have you and what the fitness business?

我的意思是，他們都提出了類似半胱氨酸殘基的抑制劑，而且它們都是有效的抑制劑和壓裂三。我們行業的關鍵區別在於，嗯，由於 nib 的資金量較低，因此它對 Jack 3 的影響力比 ITKS 以外的任何其他產品都要強大得多。相比之下，ATH。 38，根據您使用的讀數，它的效力、難治性 CAR T K 類型與我們擁有的臨床暴露和劑量非常相似，客戶使用它有您和健身業務嗎？

I think it's pretty clear that we will garner addicts will have exposure to that criminal lead block, I should say in factories significantly, whereas with fitness is more of a jagged three biased drug with little impact on IPK. at the clinical dose and exposure.

我認為很明顯，我們會讓成癮者接觸到犯罪鉛塊，我應該說在工廠裡顯著，而健身更多的是鋸齒狀三偏向藥物，對 IPK 影響不大。臨床劑量和暴露。

Got it.

知道了。

Thank you.

謝謝。

Thank you. And one moment for your next question.

謝謝。請稍等一下，回答你的下一個問題。

Yes.

是的。

And our next question comes from the line of Kevin Clark Gardiner from Evercore ISI. Please go ahead.

我們的下一個問題來自 Evercore ISI 的 Kevin Clark Gardiner。請繼續。

Hey, thanks for taking the question.

嘿，謝謝你提出問題。

Apart from the black box side of things, I'm just wondering how you believe that providers will view the safety profile relative to the other Jack ones. And specifically, I'm wondering if there are any learnings from the alopecia or even the rheumatoid arthritis space that may give some early hints into how they may view this Yes.

除了黑盒子方面的事情之外，我只是想知道您如何相信提供者會如何看待相對於其他 Jack 的安全設定檔。具體來說，我想知道是否有從脫髮甚至類風濕性關節炎領域學到的任何經驗教訓，可以為他們如何看待這一問題提供一些早期提示：是的。

Thanks, Gavin. It's a good question because I think on the face you look at it and say, well, it's a black box. And then I mean, I could tell you having practice know, oftentimes, it's more of a chore for the physician to explain the laundry list of things that could happen. However, I would say that in talking to various colleagues over the last couple of years, I really don't think and I think it is reflected in their sales. And I really don't think it's been that big of a hindrance once you explain the issues. And then at the end of the day, patients want and their disease to be better. And we know that there really hasn't been much of a tail off at all. In fact, you know, baricitinib have been growing in alopecia areata. You've seen nice growth with Rinvoq in atopic dermatitis, and there's a reason it provides order of magnitude benefit over over biologics for sure. So I think at the end of the day, when patients want relief and they know they're going to get it very quickly rather than perhaps waiting 16 weeks for a biologic to kind of take you get the max effect.

謝謝，加文。這是一個很好的問題，因為我認為從表面上看你會說，好吧，這是一個黑盒子。然後我的意思是，我可以告訴你，透過實踐知道，通常情況下，醫生解釋可能發生的事情的清單更像是一件苦差事。然而，我想說的是，在過去幾年與各個同事的交談中，我真的不認為而且我認為這反映在他們的銷售中。我真的不認為一旦你解釋了這些問題就沒有那麼大的障礙。最終，患者希望他們的疾病能夠好起來。我們知道，其實並沒有出現太大的下滑。事實上，你知道，巴瑞克替尼一直在治療斑禿。您已經看到 Rinvoq 在異位性皮膚炎治療中取得了良好的進展，這肯定是它比生物製劑提供數量級益處的原因。因此，我認為最終，當患者想要緩解症狀並且他們知道自己很快就會得到緩解，而不是等待 16 週等待生物製劑發揮最大效果時。

Yes, that's important.

是的，這很重要。

Got it.

知道了。

Thanks.

謝謝。

Now I'm showing no further questions at this time. I would now like to turn the conference back to Neal Walker for closing remarks.

現在我不會提出任何進一步的問題。現在我想請尼爾沃克（Neal Walker）發表閉幕詞。

Well, thanks, everybody, for joining our call today, and we're excited to provide additional updates in the coming months. And appreciate your time. Thank you.

好的，謝謝大家今天加入我們的電話會議，我們很高興在未來幾個月內提供更多更新。並感謝您的時間。謝謝。

This concludes today's conference call. Thank you for participating, and you may now disconnect.

今天的電話會議到此結束。感謝您的參與，您現在可以斷開連接。