Aclaris Therapeutics Inc (ACRS) 2023 Q1 法說會逐字稿

Good day, and thank you for standing by. Welcome to Aclaris Therapeutics First Quarter 2023 Conference Call. (Operator Instructions)

美好的一天，感謝您的支持。歡迎參加 Aclaris Therapeutics 2023 年第一季度電話會議。 （操作員說明）

Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Robert Doody, Head of Investor Relations. Please go ahead.

請注意，今天的會議正在錄製中。現在，我想將會議交給今天的發言人、投資者關係主管羅伯特·杜迪 (Robert Doody)。請繼續。

Thank you. I am Robert Doody, Head of Investor Relations for Aclaris. Please note that earlier today, we issued a press release highlighting our first quarter 2023 financial results and other business matters. For those of you who have not yet seen it, you will find the press release posted under the Press Releases page of the Investors section of our website, www.aclaristx.com.

謝謝。我是 Aclaris 投資者關係主管 Robert Doody。請注意，今天早些時候，我們發布了一份新聞稿，重點介紹了 2023 年第一季度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 www.aclaristx.com 投資者部分的新聞稿頁面下找到該新聞稿。

In addition, we will be referring to a slide deck entitled Q1 2023 Investor Conference Call, which can be found on the Investor page of our corporate website and furnished as an exhibit to our Form 8-K that we filed with the SEC earlier this morning.

此外，我們將提及題為“2023 年第一季度投資者電話會議”的幻燈片，該幻燈片可以在我們公司網站的投資者頁面上找到，並作為我們今天早上向 SEC 提交的 8-K 表格的附件提供。 。

Joining me today for the call are Doug Manion, our Chief Executive Officer; Gail Cawkwell, our Chief Medical Officer; Joe Monahan, our Chief Scientific Officer; and Kevin Balthaser, our Chief Financial Officer.

今天與我一起參加電話會議的是我們的首席執行官 Doug Manion；蓋爾·考克威爾 (Gail Cawkwell)，我們的首席醫療官； Joe Monahan，我們的首席科學官；和我們的首席財務官 Kevin Balthaser。

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 Aclaris' future operations are considered forward-looking statements within the meaning of federal securities laws.

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所做的有關公司未來運營業績和財務狀況、業務戰略以及 Aclaris 未來運營計劃和目標的各種聲明均被視為前瞻性聲明。聯邦證券法的含義。

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 31, 2022, 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 Aclaris' website, www.aclaristx.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 statement we may make on this call on the account of new information, future events or otherwise.

我們的前瞻性陳述基於當前的預期，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存在重大差異。這些風險在 Aclaris 截至 2022 年 12 月 31 日的年度 10-K 表格的風險因素部分以及 Aclaris 不時向 SEC 提交的其他文件中進行了描述。這些文件可在 Aclaris 網站 www.aclaristx.com 投資者部分的 SEC 備案頁面上獲取。我們在本次電話會議上提供的所有信息均截至今天，我們沒有義務更新我們在本次電話會議上可能因新信息、未來事件或其他原因而做出的任何前瞻性聲明。

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.

請注意，今天的電話會議正在錄音並進行網絡直播。您可以在我們網站投資者部分的活動頁面下訪問網絡廣播的鏈接。

I'll now turn the call over to Doug.

我現在將把電話轉給道格。

Thanks, Bob, and good morning, everyone. I hope you had a great weekend. It is my distinct honor to be speaking with you today following not only my first quarter as CEO, but also the first quarter of operations for our new leadership team. For those who may be newer to the Aclaris Therapeutics story, we were originally founded as a specialty Pharma Company focused on dermatologic conditions. It is a great credit to my predecessors that a few years ago, the company made the decision to acquire Confluence Life Sciences based in St. Louis. The addition of this world-class discovery group focused on the human kinome allowed Aclaris to pivot its focus on research and development efforts towards addressing areas of serious unmet need in immuno-inflammatory diseases with oral or tissue-specific agents.

謝謝鮑勃，大家早上好。我希望你周末過得愉快。我非常榮幸今天能與大家交談，這不僅是我擔任首席執行官的第一個季度，也是我們新領導團隊運營的第一個季度。對於那些可能不太了解 Aclaris Therapeutics 故事的人來說，我們最初是一家專注於皮膚病的專業製藥公司。幾年前，公司決定收購總部位於聖路易斯的Confluence Life Sciences，這對我的前任來說是一個巨大的榮譽。這個專注於人類激酶組的世界級發現小組的加入，使 Aclaris 能夠將其重點放在研發工作上，以解決免疫炎症性疾病中口服或組織特異性藥物的嚴重未滿足需求領域。

As evidenced by a number of recent significant transactions in the I&I space, including Pfizer's acquisition of Arena, Takeda's acquisition of the Nimbus TYK2 program and Merck's acquisition of Prometheus, there is tremendous opportunity for significant creation of shareholder value in this space, and we find ourselves in the enviable position of having several key clinical stage assets targeting these potential diseases led by our potential first-in-class MK2 inhibitor Zunsemetinib, or ATI-450.

最近 I&I 領域的一系列重大交易（包括輝瑞收購 Arena、武田收購 Nimbus TYK2 項目以及默克收購 Prometheus）就證明了這一點，該領域存在著巨大的股東價值創造機會，我們發現我們處於令人羨慕的地位，擁有針對這些潛在疾病的幾項關鍵臨床階段資產，這些資產以我們潛在的一流 MK2 抑製劑 Zunsemetinib（ATI-450）為主導。

If you could direct your attention to Slide 3 in the slide presentation, we can discuss the agenda for our call today. We're very pleased to be speaking with you today to provide an overview of our first quarter financial results as well as an update of our timing and plans for the remainder of the year. I'll begin by providing a few opening remarks on the company's performance to date for the year and then we'll turn the call over to Gail, who will provide updates on all of our progress across the clinical development programs.

如果您可以將注意力集中到幻燈片演示中的幻燈片 3，我們可以討論今天電話會議的議程。我們很高興今天與您交談，概述我們第一季度的財務業績以及我們今年剩餘時間的時間安排和計劃的最新情況。首先，我將就公司今年迄今為止的業績做一些開場白，然後我們將把電話轉給蓋爾，他將提供我們在臨床開發項目中所有進展的最新信息。

Following that update, Gail and Joe will provide an overview of the final results from the trial in Hidradenitis Suppurativa or HS, for which we reported top line results back in March. Kevin will then provide an overview of our financial results for the period. And finally, I'll provide some closing comments prior to opening up the call to address your questions.

更新之後，蓋爾和喬將概述化膿性汗腺炎或 HS 試驗的最終結果，我們早在 3 月份就報告了該試驗的主要結果。然后凱文將概述我們這一時期的財務業績。最後，在開始通話以解決您的問題之前，我將提供一些結束語。

Overall, I'm very pleased with the performance of our company through this first quarter of 2023. Our team is making tremendous progress advancing all of our various clinical development programs, which is a testament to our team as we are a relatively small company in terms of size and overhead. I also remain impressed with our team's ability to continue to execute global clinical trials in a challenging macro environment that is continually packed by economic downturn, choke supply chains and global conflicts. Despite all these headwinds, our team is continuing to prosecute these studies and demonstrating creativity and flexibility in the face of hurdles when they arise. And for that, I could not be more proud. During the first quarter of this year, we completed and reported the top line results of our Phase IIa trial of ATI-450 NHS. Although we were disappointed that the (inaudible) results were novel we had hoped for in this challenging and so relatively misunderstood disease, our team delivered on time, a well-executed trial. Importantly, this trial further expanded our experience and understanding of ATI-450. The completion of the study has further demonstrated the foundation for the program from both a safety and pharmacodynamic perspective going into our next data readouts in rheumatoid arthritis, in Psoriatic arthritis. As a reminder, our company already had positive proof-of-concept data in array from our prior Phase IIa trial.

總體而言，我對我們公司截至 2023 年第一季度的業績感到非常滿意。我們的團隊在推進所有各種臨床開發項目方面取得了巨大進展，這證明了我們的團隊，因為我們是一家相對較小的公司規模和開銷方面。我們的團隊在充滿挑戰的宏觀環境中繼續執行全球臨床試驗的能力也給我留下了深刻的印象，這個環境不斷受到經濟衰退、供應鏈阻塞和全球衝突的影響。儘管存在這些不利因素，我們的團隊仍在繼續進行這些研究，並在遇到障礙時展現出創造力和靈活性。為此，我感到非常自豪。今年第一季度，我們完成並報告了 ATI-450 NHS IIa 期試驗的主要結果。儘管我們對（聽不清）結果感到失望，但我們在這種具有挑戰性且相對被誤解的疾病中所希望的結果是新穎的，但我們的團隊按時交付了一項執行良好的試驗。重要的是，這次試驗進一步擴展了我們對 ATI-450 的經驗和了解。該研究的完成從安全性和藥效學角度進一步證明了該計劃的基礎，進入我們下一個類風濕性關節炎和銀屑病關節炎的數據讀數。提醒一下，我們公司已經從之前的 IIa 期試驗中獲得了積極的概念驗證數據。

Shortly, Gail and Joe will be providing more details on the final results of the trial with a focus on how they inform our continued execution of the rest of the ATI-450 program. With that, I'm now going to turn the call over to Gail to begin the discussion on clinical development progress.

很快，蓋爾和喬將提供有關試驗最終結果的更多詳細信息，重點是他們如何為我們繼續執行 ATI-450 計劃的其餘部分提供信息。現在，我將把電話轉給蓋爾，開始討論臨床開發進展。

Gail?

蓋爾？

Thank you, Doug, and good morning, everybody. I also want to take a moment to commend the Aclaris team on their execution of the Hidradentitis Suppurtiva trial, but also on the tremendous work they've done in recent weeks to fully analyze all of the results from the study, thus enabling us to provide you with today's overview.

謝謝你，道格，大家早上好。我還想花點時間讚揚 Aclaris 團隊執行化膿性汗牙炎試驗，以及他們最近幾週為全面分析該研究的所有結果所做的大量工作，從而使我們能夠提供為您帶來今天的概述。

Directing you to Slide 4, and the summary of our development pipeline. Let's start with our Phase I stage clinical asset, ATI-2138 and ITK/JAK3 inhibitor. Building on the successes of the ATI-2138 single ascending dose study, the multiple ascending dose study in healthy volunteers continues to progress well. We are very much on track to have pharmacokinetic, pharmacodynamic and safety results in the second half of this year. As we previously announced, our first clinical trial of ATI-2138 in a patient population is planned to be a Phase IIa proof-of-concept study in ulcerative colitis. The planning is well underway so that we can be in a position to initiate quickly upon completion of the ongoing multiple ascending dose study. Later this year, we will provide you with more details on the ulcerative colitis study after we have the Phase I results and a fully finalized the design of this proof-of-concept study. Moving on to ATI-2231, our next-generation MK2 inhibitor, we're moving closer with our prospective academic partners to get into the ultimate objective of setting ATI-2231 in. Metastatic breast cancer and in pancreatic cancer.

引導您觀看幻燈片 4，以及我們的開發流程摘要。讓我們從我們的 I 期臨床資產 ATI-2138 和 ITK/JAK3 抑製劑開始。在 ATI-2138 單次劑量遞增研究取得成功的基礎上，針對健康志願者的多次劑量遞增研究繼續取得良好進展。我們有望在今年下半年獲得藥代動力學、藥效學和安全性結果。正如我們之前宣布的，我們計劃在患者群體中進行 ATI-2138 的首次臨床試驗，作為潰瘍性結腸炎的 IIa 期概念驗證研究。該計劃正在順利進行中，以便我們能夠在完成正在進行的多次劑量遞增研究後迅速啟動。今年晚些時候，在獲得第一階段結果並完全確定該概念驗證研究的設計後，我們將向您提供有關潰瘍性結腸炎研究的更多詳細信息。接下來是我們的下一代 MK2 抑製劑 ATI-2231，我們正在與未來的學術合作夥伴更加密切地合作，以實現將 ATI-2231 用於轉移性乳腺癌和胰腺癌的最終目標。

Now shifting to Slide 6. For ATI-1777, our topical JAK 1/3 inhibitor, which was designed for skin efficacy and minimize systemic exposure, we are conducting a Phase IIb study in atopic dermatitis as a follow-up to our successful Phase IIa study. The objectives of the trial are to further evaluate the efficacy and safety of ATI-1777 and validate the limited systemic exposure seen in the Phase IIa study. We are also studying several dose strains, including the 2% twice-daily dose studied in the Phase IIa trial and several lower dose strains as well as assessing once and twice daily applications so that we know which formulation regimen will be best for progressing into Phase III development. We also expanded our study population in the study to include children down to age 12, given the importance of this disease in children. The primary endpoint of the trial is percentage change from baseline in the Eczema Area and Severity Index score or EASI at week 4. The target enrollment is 240 patients. We've been very encouraged by the success seen recently with other topical therapies in a broader array of patients and the meaningful medical need in some milder patients.

現在轉到幻燈片 6。對於 ATI-1777，我們的局部 JAK 1/3 抑製劑，旨在提高皮膚功效並最大限度地減少全身暴露，我們正在開展特應性皮炎的 IIb 期研究，作為我們成功的 IIa 期研究的後續行動學習。該試驗的目的是進一步評估 ATI-1777 的有效性和安全性，並驗證 IIa 期研究中觀察到的有限全身暴露。我們還在研究幾種劑量菌株，包括 IIa 期試驗中研究的 2% 每日兩次劑量和幾種較低劑量菌株，並評估每天一次和兩次的應用，以便我們知道哪種配方方案最適合進入階段三、發展。鑑於這種疾病對兒童的重要性，我們還擴大了研究對象，將 12 歲以下的兒童納入其中。該試驗的主要終點是第 4 週時濕疹面積和嚴重程度指數評分或 EASI 相對於基線的百分比變化。目標入組人數為 240 名患者。最近其他局部療法在更廣泛的患者中取得的成功以及一些較輕患者的有意義的醫療需求使我們深受鼓舞。

As such, we recently extended the protocol to include not just moderate and severe atopic dermatitis but some mild patients as well. And we want to assure we can enroll adequate mild patients to meaningfully evaluate them. This protocol modification is also important because as some of you may have seen reported from other companies conducting trials in atopic dermatitis, enrollment this past winter season have encountered some challenges, particularly driven by the mild winter in many locations, particularly in the southern and eastern portions of the U.S. Since the dryness associated with cold winter weather and heating can exacerbate atopic dermatitis. In the first few weeks of this protocol amendment, which just went into effect we have already seen a meaningful increase in screening. We are updating our guidance in terms of timing of top line results to move from our prior guidance of midyear to second half of this year, and we will tighten up that guidance as we continue to learn more about the impact of the amended protocol.

因此，我們最近擴展了該方案，不僅包括中度和重度特應性皮炎，還包括一些輕度患者。我們希望確保我們能夠招募足夠的輕症患者來對他們進行有意義的評估。這一方案修改也很重要，因為正如你們中的一些人可能已經看到其他公司進行特應性皮炎試驗的報告一樣，去年冬季的入組遇到了一些挑戰，特別是受到許多地方溫和冬季的推動，特別是在南部和東部在美國部分地區，由於冬季寒冷天氣和暖氣帶來的干燥會加劇特應性皮炎。在該方案修正案剛剛生效的最初幾週內，我們已經看到篩查量顯著增加。我們正在更新我們關於頂線結果時間的指導，從之前的年中指導轉向今年下半年，並且隨著我們繼續更多地了解修訂後的協議的影響，我們將加強該指導。

Moving to Slide 7. As a reminder, in our Phase IIa trial, ATI-1777 achieved statistically significant results in the primary efficacy endpoint at week 4, and positive trends were observed in secondary endpoints, including improvements of itch, percent of modified EC50 responders, IGA responder analysis, and reduction of body surface area impacted by the disease.

轉到幻燈片 7。提醒一下，在我們的 IIa 期試驗中，ATI-1777 在第 4 週的主要療效終點中取得了統計學上顯著的結果，並且在次要終點中觀察到了積極的趨勢，包括瘙癢的改善、修改後的 EC50 應答者的百分比、IGA 反應者分析，以及減少受疾病影響的體表面積。

Shifting to Slide 8. Importantly, ATI-1777 was observed to have a favorable safety and tolerability profile and because of the soft topical approach, very low plasma levels of ATI-1777 were seen following the topical application with the average concentrations in patients never greater than 5% of the IC50 of JAK1/3, and only 3 patients had concentrations greater than 1/10 of the IC50.

轉到幻燈片 8。重要的是，ATI-1777 被觀察到具有良好的安全性和耐受性，並且由於軟局部方法，局部應用後 ATI-1777 的血漿水平非常低，患者中的平均濃度從未更高低於 JAK1/3 IC50 的 5%，只有 3 名患者的濃度高於 IC50 的 1/10。

Now moving on to ATI-450. We'll begin with a more comprehensive overview of the HS trial now that we have the full data set. As you all know from the top line results that we reported in March, ATI-450 did not fit either our primary or secondary efficacy endpoints in HS. As shown on Slide 10, we randomized 95 patients into the study with 47 on placebo and 48 on ATI-450. Overall, with 32 patients on the placebo arm complete the study and 26 on active treatment.

現在轉向 ATI-450。既然我們已經有了完整的數據集，我們將開始對 HS 試驗進行更全面的概述。正如你們從我們 3 月份報告的頂線結果中知道的那樣，ATI-450 不符合我們在 HS 中的主要或次要療效終點。如幻燈片 10 所示，我們將 95 名患者隨機納入研究，其中 47 名患者服用安慰劑，48 名患者服用 ATI-450。總體而言，安慰劑組有 32 名患者完成了研究，另外 26 名患者接受了積極治療。

As previously noted, the study did not demonstrate efficacy for ATI-450 in the treatment of HS. We saw a modest effect, which was overshadowed by an unusually large placebo effect. I do want to spend the majority of our time today on the elements from this trial that can be applied to our understanding of ATI-450 overall. These elements primarily fall into 2 buckets, safety and pharmacodynamics. I will discuss the safety elements in detail, and then Joe will discuss the pharmacodynamics.

如前所述，該研究並未證明 ATI-450 治療熱射病的功效。我們看到了適度的效果，但被異常大的安慰劑效果所掩蓋。我確實想把今天的大部分時間花在這次試驗的元素上，這些元素可以應用於我們對 ATI-450 的整體理解。這些要素主要分為兩類：安全性和藥效學。我將詳細討論安全因素，然後喬將討論藥效學。

Slide 11 shows the steady demographics and baseline characteristics. We are quite proud that we enrolled a trial that was very representative of real-world HS patient populations with more inclusion of historically underrepresented people. From a safety perspective, on Slide 12, we had no serious adverse events on ATI-450, no serious end organ toxicities and no serious or opportunistic infections.

幻燈片 11 顯示了穩定的人口統計數據和基線特徵。我們感到非常自豪的是，我們參加了一項非常具有代表性的現實世界熱射病患者群體的試驗，其中更多地納入了歷史上代表性不足的人群。從安全角度來看，在幻燈片 12 上，我們在 ATI-450 上沒有發生嚴重的不良事件，沒有嚴重的終末器官毒性，也沒有嚴重或機會性感染。

What we did see, unsurprisingly, given the lack of efficacy is a meaningful number of early discontinuations from treatment shown on Slide 13. Overall, we have 15 patients in the placebo arm and 20 active arm discontinued from study treatment. And we saw high discontinuation starting in the early days of the trial, and this observation was the primary reason we made the decision to increase the enrollment last fall. Withdrawals due to loss to follow-up, withdrawal of consent, and investigative stated lack of efficacy were relatively balanced between the ATI-450 and the placebo-treated arms. The divergence and discontinuations was noted for withdrawals due to an adverse event, with 4 withdrawals in the placebo arm and 11 from the ATI-450 arm.

毫不奇怪，鑑於缺乏療效，我們確實看到了幻燈片 13 中顯示的大量早期停止治療的情況。總體而言，安慰劑組中有 15 名患者和活性治療組有 20 名患者停止了研究治療。我們在試驗初期就看到了很高的停藥率，這一觀察結果是我們去年秋天決定增加入組人數的主要原因。 ATI-450 組和安慰劑治療組之間因失訪、撤回同意和研究表明缺乏療效而退出的情況相對平衡。因不良事件而退出的情況存在差異，其中安慰劑組有 4 例退出，ATI-450 組有 11 例退出。

When we dug a bit deeper, however, we noted that the majority of patients in the active arm who withdrew due to an adverse event, 7 of the 11 were not seeing treatment-related efficacy. Their AN count was either worse or no better than at the start of the study. While most of the adverse events leading to discontinuation of treatment were only moderate in intensity, it is not surprising that patients who are not seeing a benefit had a little incentive to continue treatment.

然而，當我們更深入地挖掘時，我們注意到活躍組中的大多數患者因不良事件而退出，其中 11 名患者中有 7 名沒有看到治療相關的療效。他們的 AN 計數要么比研究開始時更差，要么沒有好轉。雖然大多數導致停止治療的不良事件的強度僅為中等，但沒有看到獲益的患者有一點動力繼續治療也就不足為奇了。

Further, the adverse events that led to discontinuation were most commonly related to worsening HS, like new growing abscess, subcutaneous abscess or worsening acne, which is closely related to HS. We also had a few subjects withdraw due to headache or dizziness, which is a known phenomenon that occurs in some patients early in the treatment period and typically resolves even when patients continue treatment. And with further investigator education on this topic, we saw no further discontinuations for this reason. And of course, we also provided this education to investigators for the ongoing rheumatoid arthritis and Psoriatic arthritis trials.

此外，導致停藥的不良事件最常見與熱射病惡化有關，如新長出的膿腫、皮下膿腫或惡化的痤瘡，這些都與熱射病密切相關。我們還有一些受試者因頭痛或頭暈而退出，這是一些患者在治療早期發生的已知現象，通常即使患者繼續治療也會消失。隨著有關該主題的進一步研究人員教育，我們沒有看到因此原因而進一步中斷。當然，我們還為正在進行的類風濕關節炎和銀屑病關節炎試驗的研究人員提供了這種教育。

It's important to note pertaining to our current rheumatoid arthritis trial, we are well into an advanced stage of our enrollment process, and we are seeing a discontinuation rate in the trial that is quite stable and below our model projections when we initiated the trial. Now let's move on to the other topic that captured attention from the top line results, elevations in creatine phosphokinase or CK, which is shown on Slide 14.

值得注意的是，關於我們目前的類風濕關節炎試驗，我們已經進入了招募過程的高級階段，我們看到試驗的中止率非常穩定，低於我們啟動試驗時的模型預測。現在讓我們繼續討論從頂行結果中引起注意的另一個主題，即肌酸磷酸激酶或 CK 的升高，如幻燈片 14 所示。

When we issued our press release, we noted that there were 10.4% or 5 patients that had reported treatment-emergent adverse events of elevated blood CK level. Subsequent to top line, as we finalized our data, we learned that 1 of these patients had their elevated CK prior to receiving study drug, so this was not a treatment-emergent event. And as such, that patient has been removed from that category, which brings the percentage book down below the 10% threshold that we reported.

當我們發布新聞稿時，我們注意到有 10.4% 或 5 名患者報告了治療中出現的血液 CK 水平升高的不良事件。接下來，當我們最終確定數據時，我們了解到其中 1 名患者在接受研究藥物之前其 CK 升高，因此這不是治療突發事件。因此，該患者已從該類別中刪除，這使得百分比降至我們報告的 10% 閾值以下。

Overall, though, CK elevations were covered in patients both on ATI-450 and on placebo, with 19 patients with reported elevations of CK levels in laboratory drawers during some point in the study. Six of these were on placebo and 13 on ATI-450. The majority of these were modest elevations, However, as you can see on study drug, we also had 3 Grade 2, 2 Grade 3 and 1 Grade 4 CK elevation. However, moving to Slide 15, the treatment emerging CK elevations that were Grade 2 and above where most typically transient and most typically return to baseline even when patients continued on treatment. Many of them were associated with a history of exercise. More importantly is what the CK elevations were not associated with. There were no associated adverse events that would suggest something more severe was going on. For example, no reported muscle pain, weakness, kidney abnormalities or CK elevations that were not from the skeletal muscle source. We do know that benign CK elevations have been seen with other effective anti-inflammatory treatments like TNF inhibitors and JAK inhibitors.

不過，總體而言，服用 ATI-450 和安慰劑的患者均出現 CK 升高，其中 19 名患者報告在研究的某個時間點實驗室抽屜中 CK 水平升高。其中 6 人服用安慰劑，13 人服用 ATI-450。其中大多數是適度升高，但是，正如您在研究藥物上看到的那樣，我們也有 3 例 2 級、2 例 3 級和 1 例 4 級 CK 升高。然而，轉向幻燈片 15，治療出現 2 級及以上的 CK 升高，這種升高通常是短暫的，即使患者繼續治療，也通常會恢復到基線。其中許多與鍛煉史有關。更重要的是 CK 升高與之無關。沒有任何相關的不良事件表明正在發生更嚴重的情況。例如，沒有報告非骨骼肌來源的肌肉疼痛、虛弱、腎臟異常或 CK 升高。我們確實知道，其他有效的抗炎治療（如 TNF 抑製劑和 JAK 抑製劑）也可以觀察到良性 CK 升高。

Moving to Slide 16. Overall to date, we are very pleased with the safety profile we see with ATI-450 through the current stage of clinical development. The adverse event profile has continued to be as expected. We've seen transient CK elevations in some patients that generally disappear with continued treatment, and we do not have any muscle-related symptoms. We've seen no meaningful effects on kidney or liver or cytopenias and no serious or opportunistic infections. Lastly, it is important to note that in preparation for Phase III, we have completed our chronic toxicology studies, and with all of the pathology results now available, there are no issues of concern identified.

轉向幻燈片 16。總體而言，迄今為止，我們對 ATI-450 在當前臨床開發階段所看到的安全性感到非常滿意。不良事件情況繼續符合預期。我們發現一些患者出現短暫的 CK 升高，這種升高通常會隨著繼續治療而消失，而且我們沒有任何與肌肉相關的症狀。我們沒有發現對腎臟或肝臟或血細胞減少有任何有意義的影響，也沒有發現嚴重或機會性感染。最後，值得注意的是，在為第三階段做準備時，我們已經完成了慢性毒理學研究，並且所有病理學結果現已可用，沒有發現任何值得關注的問題。

With that, I'd like to turn the call over to Joe to discuss the pharmacokinetic and pharmacodynamic signings from the HS study. Joe?

說到這裡，我想將電話轉給 Joe，討論 HS 研究的藥代動力學和藥效學特徵。喬？

Thanks, Gail. Good morning, everyone. Let me start by saying that at the outset, we believe mechanistically ATI-450 had a chance of demonstrating efficacy in the HS study. However, we believe it is likely that the disease is perhaps driven more locally in the skin than through systemic pathways. I would now like to share what we have learned from the HS study pharmacokinetic and pharmacodynamic analysis. Briefly, the PK for ATI-450 behaved as expected with a modest accumulation across the first week of dosing and peak and trough drug levels similar to those observed in the Phase I MAD study and the Phase IIa RA study. For PD, we took 2 approaches to understand ATI-450 pharmacodynamics in HS patient blood, as shown on Slide 18. First, we conducted an analysis of cytokines in ex vivo stimulated patient blood on a small sample subset of 5 patients from 2 sites. We compared samples from both placebo and ATI-450 treated HS patients with healthy donor controls analyzed in parallel.

謝謝，蓋爾。大家，早安。首先我要說的是，從一開始，我們就相信 ATI-450 有機會在 HS 研究中證明其功效。然而，我們認為這種疾病可能更多地是在皮膚局部驅動的，而不是通過全身途徑驅動的。我現在想分享我們從 HS 研究藥代動力學和藥效學分析中學到的知識。簡而言之，ATI-450 的 PK 表現符合預期，在給藥第一周內有適度的積累，藥物水平的峰值和谷值與 I 期 MAD 研究和 IIa RA 研究中觀察到的結果相似。對於 PD，我們採用了 2 種方法來了解 HS 患者血液中的 ATI-450 藥效學，如幻燈片 18 所示。首先，我們對來自 2 個地點的 5 名患者的小樣本子集進行了體外刺激患者血液中的細胞因子分析。我們將安慰劑和 ATI-450 治療的 HS 患者的樣本與平行分析的健康供體對照進行了比較。

We looked at 4 pro-inflammatory cytokines, TNFa, IL-1b, IL-6 and IL-8 after the first dose and then again at the end of the study. If you direct your attention to Slide 19, you can see we provide side-by-side comparisons across 3 of the ATI-450 studies completed to date. The 7-day MAD study in volunteers, the 12-week RA Phase IIa study and the 12-week HS study. ATI-450 inhibited all 4 cytokines analyzed, while the data shown focuses on inhibition of TNFa and IL-1b.

我們在第一次給藥後觀察了 4 種促炎細胞因子：TNFa、IL-1b、IL-6 和 IL-8，然後在研究結束時再次觀察。如果您將注意力集中到幻燈片 19，您可以看到我們對迄今為止完成的 3 項 ATI-450 研究進行了並排比較。為期 7 天的志願者 MAD 研究、為期 12 週的 RA IIa 期研究和為期 12 週的 HS 研究。 ATI-450 抑制所有 4 種分析的細胞因子，而顯示的數據集中於 TNFa 和 IL-1b 的抑制。

On day 1, near complete inhibition of these 2 proinflammatory cytokines is observed across all 3 studies, suggesting that their production in healthy subjects RA patients and HS patients is similarly dependent on the MK2 pathway and sensitive to ATI-450. Also important to note here is that ATI-450 potently inhibits the cytokines at the end of each dosing period, either 7 days or 12 weeks, consistent with the lack of pathway reprogramming and tachyphylaxis across all of these studies and continued dependence of inflammatory cytokine production on MK2. Our second analysis consisted of evaluating the impact of ATI-450 on endogenous plasma cytokines in HS patients. We carried out this analysis on all 95 patients at time points where it was confirmed that subjects were dosed along with healthy donor controls, evaluating samples at day 1 pre-dose and (inaudible) with Zunsemetinib at trough.

在第 1 天，所有 3 項研究均觀察到這 2 種促炎細胞因子幾乎完全受到抑制，這表明它們在健康受試者 RA 患者和 HS 患者中的產生同樣依賴於 MK2 途徑並對 ATI-450 敏感。這裡還需要注意的是，ATI-450 在每個給藥期（7 天或 12 週）結束時有效抑制細胞因子，這與所有這些研究中缺乏途徑重編程和快速耐受以及炎症細胞因子產生的持續依賴性一致在 MK2 上。我們的第二項分析包括評估 ATI-450 對 HS 患者內源性血漿細胞因子的影響。我們對所有 95 名患者進行了這項分析，在確認受試者與健康供體對照一起給藥的時間點上，評估了給藥前第 1 天的樣本以及（聽不清）在谷值時使用 Zunsemetinib 的樣本。

If you turn your attention to Slide 20, a you can see that endogenous plasma pro-inflammatory cytokines and CRP at baseline were lower in the HS Phase IIa study compared with the RA Phase IIa study, which appears consistent with a lower level of systemic inflammation in these HS patients. The next slide provides comparisons between the RA and HS Phase II studies, analyzing the impact of ATI-450 on endogenous plasma levels of TNFa, IL-6, IL-8 and MIP-1b. While pre-dose levels of cytokines were lower in HS patients compared to RA patients in the Phase IIa studies, a similar persistent decrease in cytokine levels near to or below healthy donor levels was observed in both studies.

如果您將注意力轉向幻燈片 20，a 您可以看到，與 RA IIa 期研究相比，HS IIa 期研究的基線內源性血漿促炎細胞因子和 CRP 較低，這似乎與較低水平的全身炎症相一致在這些 HS 患者中。下一張幻燈片提供了 RA 和 HS II 期研究之間的比較，分析了 ATI-450 對 TNFa、IL-6、IL-8 和 MIP-1b 內源血漿水平的影響。雖然在 IIa 期研究中，與 RA 患者相比，HS 患者的給藥前細胞因子水平較低，但兩項研究中都觀察到細胞因子水平持續下降，接近或低於健康供體水平。

Directing your attention to Slide 22, you can see the comparison between both studies evaluating the anti-inflammatory cytokine IL-1 receptor antagonist, which is elevated in both HS and RA patients, and is not inhibited in either study by ATI-450. These data demonstrate a pro-inflammatory selective modulation of endogenous plasma cytokines in both RA and HS patients.

將您的注意力轉向幻燈片 22，您可以看到兩項評估抗炎細胞因子 IL-1 受體拮抗劑的研究之間的比較，IL-1 受體拮抗劑在 HS 和 RA 患者中均升高，並且在兩項研究中均未受到 ATI-450 的抑制。這些數據表明 RA 和 HS 患者內源性血漿細胞因子的促炎選擇性調節。

Lastly, I would like to direct your attention to Slide 23, which shows sustained inhibition of the plasma acute phase systemic inflammation marker, CRP in HS patients following ATI-450 treatment. This inhibition of CRP is similar to that observed in the ATI-450 Phase IIa RA study. CRP levels were reduced to the upper limit of normal after 7 days of dosing, and this inhibition was retained through study completion at 12 weeks in both the HS and RA IIa studies.

最後，我想請您注意幻燈片 23，該幻燈片顯示了 ATI-450 治療後 HS 患者血漿急性期全身炎症標誌物 CRP 的持續抑制。這種 CRP 抑製作用與 ATI-450 IIa 期 RA 研究中觀察到的類似。給藥 7 天后，CRP 水平降至正常上限，並且在 HS 和 RA IIa 研究中，這種抑製作用在第 12 週研究完成時得以保留。

To summarize on Slide 24, the ATI-450 dependent ex vivo stimulated cytokine inhibition in whole blood demonstrated consistent results across 3 studies with marked and sustained inhibition of pro-inflammatory cytokines and clear evidence of MK2 dependence and durability of response. In terms of the endogenous pharmacodynamic plasma biomarker analysis, we saw a subset of cytokines elevated in HS blood relative to healthy donors, but to a lesser extent than observed in the RA study, which suggests that HS is perhaps less systemically driven than other diseases such as RA.

總結幻燈片 24，全血中 ATI-450 依賴性離體刺激的細胞因子抑制在 3 項研究中顯示出一致的結果，具有顯著且持續的促炎細胞因子抑製作用，以及 MK2 依賴性和反應持久性的明確證據。就內源性藥效血漿生物標誌物分析而言，我們發現 HS 血液中的細胞因子子集相對於健康供體有所升高，但程度低於 RA 研究中觀察到的程度，這表明 HS 可能比其他疾病（如作為 RA。

ATI-450 inhibition trends with proinflammatory cytokines were similar in both HS and RA Phase IIa studies, reducing levels near 2 or below healthy donor levels. The elevated anti-inflammatory cytokine, IL-1 RA was not modulated by ATI-450 in either study suggestive of a pro-inflammatory cytokine specific effect. The acute phase systemic inflammation marker CRP demonstrated persistent inhibition patients administered ATI-450 in both the HS and RA studies in contrast to the effect previously observed with global p38 inhibitors.

在 HS 和 RA IIa 期研究中，ATI-450 與促炎細胞因子的抑制趨勢相似，將水平降低到接近 2 或低於健康供體水平。在這兩項研究中，ATI-450 均未調節升高的抗炎細胞因子 IL-1 RA，這表明促炎細胞因子具有特異性作用。在 HS 和 RA 研究中，急性期全身炎症標誌物 CRP 表現出持續抑制，與之前使用全局 p38 抑製劑觀察到的效果形成鮮明對比。

These data are consistent with ATI-450 demonstrating a similar systemic anti-inflammatory effect on both HS and RA patients, and we believe correspond to positive efficacy readouts from our completed RA trial, however, not HS. I'll turn it back over to Gail.

這些數據與 ATI-450 一致，證明 ATI-450 對 HS 和 RA 患者俱有相似的全身抗炎作用，我們相信與我們已完成的 RA 試驗中得出的積極療效讀數相對應，但與 HS 無關。我會把它轉回給蓋爾。

Thanks, Joe. Before I turn the call over to Kevin to touch on our financials, I'd like to finish up with the ATI-450 clinical program. I'm pleased to let you know that we are in the later stages in terms of enrollment for the rheumatoid arthritis Phase IIb trial, and everything is very much on track. We expect to have top line results from this 240-patient international trial in the fourth quarter of this year.

謝謝，喬。在我將電話轉給 Kevin 討論我們的財務狀況之前，我想先完成 ATI-450 臨床計劃。我很高興地告訴您，類風濕關節炎 IIb 期試驗的招募工作已進入後期階段，一切都步入正軌。我們預計將在今年第四季度獲得這項 240 名患者參與的國際試驗的主要結果。

It is also worth noting that we have an independent data safety monitoring committee that meets regularly and to date that committee has not raised any issues related to safety from this trial. Lastly, touching on the Phase IIa Psoriatic arthritis trial. Since this trial was the last of the 450 trials to get started, it was also going to be running a bit behind the rheumatoid arthritis and HS trials. This study is also heavily dependent on recruitment in our numerous Polish clinical trial sites.

還值得注意的是，我們有一個獨立的數據安全監測委員會，定期舉行會議，迄今為止，該委員會尚未提出任何與本次試驗的安全性相關的問題。最後，談談 IIa 期銀屑病關節炎試驗。由於該試驗是 450 項試驗中最後開始的一項，因此它的運行速度也將稍微落後於類風濕性關節炎和 HS 試驗。這項研究還很大程度上依賴於我們眾多波蘭臨床試驗中心的招募。

Based on some of the tensions in the region surrounding Ukraine, it took a little bit longer than anticipated for site activations. However, we've recently seen good momentum in screening and enrollment from our Polish sites. And as a result, we are adjusting our guidance for top line results of this trial from end of 2023 into the first half of 2024. This assumes, we fully complete the enrollment towards the end of this year. Overall, despite various hurdles, I am very pleased with the professionalism of our development team as well as all of our various partners and trial sites and the commitment of so many physicians and patients. I look forward to reporting the results to you. Let me now turn the call over to Kevin to discuss our first quarter results.

鑑於烏克蘭周邊地區的一些緊張局勢，站點激活時間比預期要長一些。然而，我們最近在波蘭網站的篩选和註冊方面看到了良好的勢頭。因此，我們正在將這項試驗的頂線結果指導從 2023 年底調整為 2024 年上半年。這是假設我們在今年年底完全完成註冊。總體而言，儘管存在各種障礙，但我對我們的開發團隊以及所有合作夥伴和試驗中心的專業精神以及眾多醫生和患者的承諾感到非常滿意。我期待著向您報告結果。現在讓我將電話轉給凱文，討論我們第一季度的業績。

Thank you, Gail, and good morning, everyone. Our financial highlights are projected on Slide 25. Let us begin with our cash position. We ended Q1 with cash, cash equivalents and marketable securities of $204 million, which was compared to $230 million at year-end. Additionally, near the end of Q1 we sold 3.4 million shares under our ATM facility for aggregate net proceeds of $26.7 million. This transaction closed in April after the close of the first quarter, so those funds will be recognized as part of our second quarter results. With the addition of those funds, we believe that our current cash, cash equivalents and marketable securities will continue to be sufficient to fund our operations through the end of 2025. We do like to note that our cash runway projection does not contemplate the costs associated with conducting a Phase III development program for ATI-450. Regarding our financial performance for the quarter, our net loss was $28.2 million for the first quarter of 2023 compared to $18.8 million during the first quarter of 2022. This difference is primarily driven by the advancement of our ongoing clinical programs. Total revenue for the quarter was $2.5 million compared to $1.5 million in the prior year's quarter. This increase was driven by higher licensing revenue, primarily from royalties earned on out-licensed intellectual property during the first quarter of 2023.

謝謝你，蓋爾，大家早上好。我們的財務亮點預計在幻燈片 25 上。讓我們從我們的現金狀況開始。截至第一季度末，我們的現金、現金等價物和有價證券為 2.04 億美元，而年底為 2.3 億美元。此外，在第一季度末，我們通過 ATM 設施出售了 340 萬股股票，總淨收益為 2670 萬美元。該交易於第一季度結束後的四月份結束，因此這些資金將被確認為我們第二季度業績的一部分。隨著這些資金的增加，我們相信，到 2025 年底，我們當前的現金、現金等價物和有價證券將繼續足以為我們的運營提供資金。我們確實想指出，我們的現金跑道預測並未考慮相關成本進行 ATI-450 的 III 期開發計劃。關於我們本季度的財務業績，2023 年第一季度的淨虧損為 2820 萬美元，而 2022 年第一季度的淨虧損為 1880 萬美元。這種差異主要是由我們正在進行的臨床項目的進展造成的。本季度總收入為 250 萬美元，去年同期為 150 萬美元。這一增長是由許可收入增加推動的，主要來自 2023 年第一季度對外許可知識產權所賺取的特許權使用費。

R&D expenses were $22.6 million for the first quarter of this year compared to $14.3 million in the first quarter of 2022. As previously mentioned, this increase has been driven by the advancements of ATI-450, ATI-1777 and ATI-2138. General and administrative expenses were $8.8 million during Q1 of 2023 versus $6.1 million during the same period in 2022. This increase was primarily driven due to increased compensation expenses related to increased headcount to support our growing development initiatives.

今年第一季度的研發費用為 2260 萬美元，而 2022 年第一季度的研發費用為 1430 萬美元。如前所述，這一增長是由 ATI-450、ATI-1777 和 ATI-2138 的進步推動的。 2023 年第一季度的一般和管理費用為 880 萬美元，而 2022 年同期為 610 萬美元。這一增長主要是由於為支持我們不斷發展的發展計劃而增加的員工人數導致的薪酬費用增加。

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

現在，我將把電話轉回給道格，讓他發表結束語。道格？

Thanks to you, Gail, Joe and Kevin, for those comprehensive overviews. Before we shift the call to addressing your questions, I'd like to make a few final comments. I'm very pleased with the quality and execution of our entire team here at Aclaris. We're blessed to have a world-class large pharma quality research engine that is very atypical for a biotech company of our size. The conference team continues to deliver unique and novel potential medicines against targets addressing significant unmet medical needs.

感謝蓋爾、喬和凱文的全面概述。在我們將電話轉向解決你們的問題之前，我想發表一些最後的評論。我對 Aclaris 整個團隊的質量和執行力感到非常滿意。我們很幸運擁有世界一流的大型製藥質量研究引擎，這對於我們這種規模的生物技術公司來說是非常不典型的。會議團隊繼續針對解決重大未滿足醫療需求的目標提供獨特和新穎的潛在藥物。

The fruits of that labor include ATI-450, ATI-1777 ATI-2138 along with ATI-2231 with more to come. We're very optimistic about the broad potential of ATI-450 and very eager to complete and report on the current clinical trials. We took a shot at a very difficult disease in HS knowing that we already had positive RA data in hand. We're now laser-focused on the completion and timely reporting and results of our ongoing trials in RA and Psoriatic arthritis.

這些勞動成果包括 ATI-450、ATI-1777、ATI-2138 以及 ATI-2231 以及更多即將推出的產品。我們對 ATI-450 的廣泛潛力非常樂觀，並且非常渴望完成並報告當前的臨床試驗。我們知道我們手頭已經有積極的 RA 數據，所以我們對 HS 中一種非常困難的疾病進行了嘗試。我們現在專注於完成和及時報告我們正在進行的 RA 和銀屑病關節炎試驗的結果。

The planning for Phase III studies for those indications and the continued exploration of the MK2 mechanism in other I&I indications. Importantly, we continue to execute on these programs in a fiscally prudent and conservative manner. It is also gratifying to see that several top-tier investors have either taken or increased their positions in our stock recently. These are very exciting times for Aclaris, and the next several quarters are no exception.

計劃針對這些適應症進行 III 期研究，並繼續探索其他 I&I 適應症中的 MK2 機制。重要的是，我們繼續以財政審慎和保守的方式執行這些計劃。令人欣慰的是，近期有幾位頂級投資者增持或增持了我們的股票。對於 Aclaris 來說，這是非常激動人心的時刻，接下來的幾個季度也不例外。

We have a lot of work in front of us, but we have the right team in place to execute, and we look forward to apprising you of our progress as we continue forward.

我們面前有很多工作，但我們有合適的團隊來執行，我們期待著在我們繼續前進的過程中向您通報我們的進展。

Operator, we now would like to open the line for questions.

接線員，我們現在要開通提問線路。

(Operator Instructions)

（操作員說明）

And our first question comes from the line of Louise Chen with Cantor.

我們的第一個問題來自 Louise Chen 和 Cantor 的台詞。

Congratulations on all the progress this quarter. So I wanted to ask you first on the read-through from HS to your RA study and a lot of people are anticipating results from that at the end of this year. And I'm wondering how you think about that elevated CK level, if you might see that in the RA study? And then second question I wanted to ask you was on the atopic dermatitis enrollment. And did any of that have to do with more drugs being available or really just the winter season? And if you move into milder patients, how well do you think the drug will do in milder patients or what kind of efficacy have you seen in that patient population? And the last question is just on, how did you come to choose this as your first indication? And how quickly can you get to proof of concept since this market is rapidly evolving

祝賀本季度取得的所有進展。所以我想首先問你關於從 HS 到 RA 研究的通讀，很多人都在期待今年年底的結果。我想知道您如何看待 CK 水平升高，如果您可能在 RA 研究中看到這一點？我想問你的第二個問題是關於特應性皮炎的登記。這是否與更多藥物的供應有關，或者只是與冬季有關？如果您轉向較輕的患者，您認為該藥物在較輕的患者中效果如何，或者您在該患者群體中看到了什麼樣的療效？最後一個問題是，您是如何選擇這個作為您的第一個適應症的？由於這個市場正在迅速發展，您能多快獲得概念驗證

Thanks, Louis, it's Doug here. So regarding the read-through from HS to RA, not focusing (inaudible) CPK, and we see nothing but positive. So we have significantly more confidence in the safety profile of the drug and there's really no red flags. I developed dozens of drugs, and it's a real luxury to have 1 that is looking as this 1 is. Obviously, we have to complete the program. But so far, it's tracking to be -- to have an extremely attractive and we think competitive safety profile. And the drug works systemically exactly as we thought as it would in HS and as it did in the RA Phase IIa. So we're very bullish in terms of what all that means in terms of the RA study that's going to read out in the fourth quarter of this year.

謝謝，路易斯，我是道格。因此，關於從 HS 到 RA 的通讀，不關注（聽不清）CPK，我們只看到積極的一面。因此，我們對該藥物的安全性更有信心，並且確實沒有危險信號。我開發了數十種藥物，擁有一種看起來像這個的藥物真是一種奢侈。顯然，我們必須完成該計劃。但到目前為止，它正在追踪——具有極具吸引力且我們認為具有競爭力的安全狀況。該藥物的全身作用與我們想像的完全一樣，就像它在 HS 中的作用以及在 RA IIa 期中的作用一樣。因此，我們非常看好這一切對於 RA 研究的意義，該研究將於今年第四季度公佈。

Regarding CPK, I mean, I think Gail did a great job of kind of elaborating what we did and didn't see in the study, but -- we just need to just be cognizant, elevations of CPK are clinically irrelevant. I mean most people would not even follow these in regular clinical practice, they go up and down based on exercise, and your overall level of activity. The concern would be if there was any associated symptoms with it, muscle weakness, muscle pain, none of which we saw or if, in fact, it looked like it was a cardiac origin, and we've looked at the CK fractionation on many of these patients, and there's been no elevations. So we do not think that we have a CPK issue.

關於 CPK，我的意思是，我認為蓋爾做得很好，詳細闡述了我們在研究中看到的和沒有看到的內容，但是——我們只需要認識到，CPK 的升高在臨床上是無關的。我的意思是，大多數人甚至不會在常規臨床實踐中遵循這些，它們會根據鍛煉情況和您的總體活動水平而上下波動。擔心的是是否有任何相關症狀，肌肉無力、肌肉疼痛，這些我們都沒有看到，或者事實上，它看起來像是心臟起源的，我們已經研究了許多人的 CK 分級這些患者中，沒有出現任何升高。所以我們認為我們不存在 CPK 問題。

As we mentioned, there's a data safety monitoring board that's overseeing the RA study. They've not raised any red flags at all in terms of the prosecution of the study. So I think we're in good shape. Moving on to the atopic dermatitis enrollment question. We've been following the space and lots of other companies have experienced the same things that we have. It's a little ironic for people who live in the west part of the country because we had a very, very snowy winter.

正如我們提到的，有一個數據安全監測委員會負責監督 RA 研究。他們在研究的起訴方面根本沒有提出任何危險信號。所以我認為我們的狀態很好。繼續討論特應性皮炎的註冊問題。我們一直在關注這個領域，許多其他公司也經歷了與我們相同的事情。對於生活在該國西部地區的人們來說，這有點諷刺，因為我們度過了一個非常非常多雪的冬天。

But in the areas of the U.S. that we're doing the AD Phase IIb study, which is mostly in the Northeast and the Southeast, in fact, it was a very mild winter, and we and everybody else we're seeing slowed enrollment. We do think that expanding the enrollment criteria to mild is going to certainly enhance the uptick in terms of recruitment, and we're confident in terms of the time lines that we issued today. We don't have data. The Phase IIa study was done in moderate to severe atopic dermatitis.

但在我們正在進行 AD IIb 期研究的美國地區，主要是東北部和東南部，事實上，那是一個非常溫和的冬天，我們和其他所有人都看到入學速度放緩。我們確實認為，將招生標準擴大到溫和肯定會促進招聘的增長，而且我們對今天發布的時間表充滿信心。我們沒有數據。 IIa 期研究針對中度至重度特應性皮炎進行。

We believe a drug is going to work very effectively in those mild patients, and we'll look forward to see the results in the second half of this year. And then lastly, regarding ulcerative colitis. That was a very nice deal for Merck and Prometheus and I think they have some interesting data in UC. But my experience is you don't ever kind of throw in the towel because there are other folks that are kind of hunting in the same in the same area. We think that mechanistically ATI 2138, it looks very attractive in the indications that we're seeking, UC initially and a whole bunch of other T cell diseases subsequently, and we'll see how the market evolves.

我們相信一種藥物將對這些輕症患者非常有效，我們期待在今年下半年看到結果。最後，關於潰瘍性結腸炎。對於默克和普羅米修斯來說，這是一筆非常好的交易，我認為他們在 UC 中有一些有趣的數據。但我的經驗是，你永遠不會認輸，因為還有其他人在同一地區的同一地區打獵。我們認為，從機制上講，ATI 2138 在我們正在尋求的適應症中看起來非常有吸引力，最初是 UC，隨後是一大堆其他 T 細胞疾病，我們將看到市場如何發展。

But if you look at the Prometheus deal and the Arena deal, with Pfizer. There's an awful lot of people investing in IBD, and we think that we're going to be very competitive in that space.

但如果你看看普羅米修斯和競技場與輝瑞的交易。有很多人投資 IBD，我們認為我們在這個領域將非常有競爭力。

One moment for our next question. And our next question comes from the line of Corinne Jenkins with Goldman Sachs.

請稍等一下我們的下一個問題。我們的下一個問題來自高盛的科琳·詹金斯 (Corinne Jenkins)。

You alluded to this a little bit on the prepared remarks, but could you further contextualize how the CK elevations compare relative to other oral therapies that are approved and in development for the similar indications, including like the JAKs, TYK2s and TNFa. And then have you sought or received any feedback from KOLs regarding what's tolerable there? And then I have a follow-up.

您在準備好的評論中提到了這一點，但是您能否進一步說明 CK 升高與針對類似適應症已批准和正在開發的其​​他口服療法（包括 JAK、TYK2 和 TNFa）的比較情況。那麼您是否尋求過或收到過 KOL 的反饋，了解那裡的可容忍程度？然後我有一個後續行動。

Gail was elaborate in terms of the impact of CPK of other mechanisms in the I&I space. But the CPK issue, for lack of a better word, in our clinical trials has been a bit of a nothingburger for investigators. So dermatologists and rheumatologists understand that asymptomatic CPK elevations are really nothing to worry about. Some have even asked us why it is that we're measuring them, it's kind of standard procedure to do so.

蓋爾詳細闡述了 CPK 對 I&I 領域其他機制的影響。但由於缺乏更好的詞來形容，CPK 問題在我們的臨床試驗中對研究人員來說有點小題大做。因此，皮膚科醫生和風濕病學家明白，無症狀的 CPK 升高實際上無需擔心。有些人甚至問我們為什麼要測量它們，這是這樣做的標準程序。

So we've seen 0 concerns from clinicians that this is a clinically significant finding. Gail, do you want to elaborate about CK elevations with other mechanisms?

因此，我們看到臨床醫生對這一具有臨床意義的發現的擔憂為零。 Gail，您想詳細說明一下其他機制的 CK 升高嗎？

Sure. So I think 1 of the things to just recognize is, while not necessarily covered in the label because it doesn't seem to be a safety concern at all. If you look through the literature, particularly TNF and JAK inhibitors and particularly in rheumatoid arthritis, juvenile arthritis and inflammatory bowel disease, but also in skin diseases. You see these what's sort of been termed benign CK elevations where the CK seems to be going up as a way of showing muscle regeneration and improvement in muscle bulk and muscle function as you decrease inflammation. There's been some basic science research as well with JAK inhibitors that supports that, myocyte differentiation is an important element of what may be going on here. And that's, I think, pretty typical of what we would expect to see and what we have seen to date with really no evidence of anything pathologic happening.

當然。因此，我認為需要注意的一件事是，雖然不一定包含在標籤中，因為它似乎根本不是安全問題。如果您查閱文獻，尤其是 TNF 和 JAK 抑製劑，特別是在類風濕性關節炎、幼年關節炎和炎症性腸病方面，而且在皮膚病方面。你會看到這些被稱為良性 CK 升高的現象，其中 CK 的升高似乎是在減少炎症時顯示肌肉再生以及肌肉體積和肌肉功能改善的一種方式。一些關於 JAK 抑製劑的基礎科學研究支持這一點，肌細胞分化是這裡可能發生的事情的一個重要因素。我認為，這就是我們期望看到的和我們迄今為止所看到的非常典型的情況，實際上沒有任何病理髮生的證據。

And then you noted that didn't really show an evaluation of other endogenous cytokine just among others, IL-17, IL-12 and 23. And maybe could you just speak qualitatively to what you saw there and comment on whether you're seeing an emerging profile with respect to the cytokine knockdowns that can inform future development decisions.

然後您注意到，這並沒有真正顯示對其他內源性細胞因子（IL-17、IL-12 和 23）的評估。也許您可以定性地描述您在那裡看到的內容，並評論您是否看到了關於細胞因子敲低的新興概況可以為未來的開發決策提供信息。

I'll let Joe take that.

我會讓喬拿走。

Yes. So with the 2 cytokines that you mentioned, with IL-17, there was a subset of patients where IL-17 was measurable and was elevated. And in those patients, ATI-450 resulted in a reduction in the level of IL-17. With IL-12, IL-12 was elevated in HS patients and endogenous and ATI-450 did result in a reduction in IL-12 as well. So in both those cytokines there was a reduction in the measurable levels of those by ATI-450.

是的。因此，對於您提到的 2 種細胞因子，即 IL-17，有一部分患者的 IL-17 是可測量的並且是升高的。在這些患者中，ATI-450 導致 IL-17 水平降低。對於 IL-12，HS 患者的 IL-12 升高，內源性和 ATI-450 也確實導致 IL-12 降低。因此，ATI-450 可測量到的這兩種細胞因子的水平均有所下降。

One moment for our next question, please. And the question comes from the line of Thomas Smith with SVB Securities.

請稍等一下我們的下一個問題。這個問題來自 SVB 證券公司的托馬斯·史密斯 (Thomas Smith)。

I guess, first on the HS study and the CNS adverse events, dizziness headache tremor. Do you have a sense for the etiology through these signals? And can you clarify if there were any discontinuations due to the CNS events?

我猜，首先是關於HS研究和中樞神經系統不良事件，頭暈頭痛震顫。通過這些信號你對病因有了解了嗎？您能否澄清一下是否有因中樞神經系統事件而中斷的情況？

Yes. Tom, Doug here. So in animal studies, at least, we do not believe our drug crosses the blood-brain barrier. So it is a little bit of a of an enigma to us, if there'd be any such symptoms. But I'll let Gail speak on repercussion.

是的。湯姆，道格在這裡。因此，至少在動物研究中，我們不相信我們的藥物能夠穿過血腦屏障。因此，如果存在任何此類症狀，這對我們來說有點神秘。但我會讓蓋爾談談影響。

Yes. So I'd start by saying that, that signal of some headaches, some dizziness we've seen also -- we've seen throughout our program. We've seen it in our Phase I unit studies where patients have very care pondering because they stay in the unit for several days or even a few weeks and in those cases, it tends to be really both not unusual but also transient.

是的。所以我首先要說的是，我們也看到了一些頭痛、一些頭暈的信號——我們在整個計劃中都看到了。我們在第一階段的病房研究中看到了這一點，患者需要非常小心地思考，因為他們在病房待了幾天甚至幾週，在這些情況下，這種情況往往不僅不罕見，而且也是短暫的。

So in most of the cases, when they've been looking at this, there hasn't been any real rationale for why patients may feel this way. As Doug already said, we don't have evidence that ATI-450 crosses into the CNS. Other things that might cause headache in to CNS like changes in blood pressure have really not been seen in any of our studies, including those where patients were very closely monitored in those Phase I unit settings.

因此，在大多數情況下，當他們研究這個問題時，並沒有任何真正的理由來解釋為什麼患者會有這種感覺。正如 Doug 已經說過的，我們沒有證據表明 ATI-450 會進入中樞神經系統。在我們的任何研究中，包括那些在一期病房環境中對患者進行密切監測的研究中，實際上都沒有發現其他可能導致中樞神經系統頭痛的因素，例如血壓變化。

I think the good news is when patients know that it's going to be something that may occur and is likely to resolve what we found is patients are willing to stay on the treatment.

我認為好消息是，當患者知道這可能會發生並且很可能解決我們發現的問題時，患者願意繼續治療。

Okay. Understood. That's helpful. And then on the RA study, you provided some color on the discontinuation, right? Can you just elaborate on that at all? And if you can't provide an exact number, can you maybe characterize it relative to the HS discontinuation rate? Is it roughly in line or half or 1/3? Like how should we think about that discontinuation rate?

好的。明白了。這很有幫助。然後在 RA 研究中，您提供了一些有關停藥的信息，對嗎？您能詳細說明一下嗎？如果您無法提供確切的數字，您能否相對於 HS 停產率來描述它？是大致成一直線還是一半還是1/3？比如我們應該如何考慮停藥率？

Yes. So we can't elaborate. It's a blinded study, but suffice it to say, we based our power calculations on precedent Phase IIb and Phase III studies, and we're tracking at or below the discontinuation rates that have been seen in competitive studies.

是的。所以我們無法詳細說明。這是一項雙盲研究，但足以說明的是，我們的功效計算基於先例的 IIb 期和 III 期研究，並且我們正在跟踪或低於競爭性研究中觀察到的停藥率。

And I'd only just add to that rate has been very stable over time.

我只想補充一點，隨著時間的推移，這個比率一直非常穩定。

One moment for our next question. And our next question will come from the line of Alex Thompson with Stifel.

請稍等一下我們的下一個問題。我們的下一個問題將來自亞歷克斯·湯普森和斯蒂菲爾的線路。

Just 1 more quick 1 on the CK elevation. I wonder if you could sort of comment on where the 4 treatment emergent adverse events sort of fit in that table on Slide 14 in terms of what grade of CK elevation was observed, and then maybe if Joe could comment a little bit on PK and what kind of target coverage you're seeing in this study and the prior studies as well and the consistency there.

只是在 CK 高度上多了 1 個快 1。我想知道您是否可以評論一下幻燈片 14 上的表格中 4 種治療出現的不良事件在觀察到的 CK 升高程度方面的位置，然後也許 Joe 可以評論一下 PK 以及什麼您在本研究和之前的研究中看到的目標覆蓋範圍以及那裡的一致性。

Yes. So let me start. So it's always (inaudible) clinician that run lots of clinical studies. It's always strange to me that some people -- some investigators will choose to tick off as a clinical adverse event and asymptomatic laboratory adverse event. And so we really don't have an explanation as to why those 4 events were toggled as such, there were elevations of CPK in patients on placebo, where just by luck, they happen not to have them be adverse events. I'll let Gail elaborate regarding the magnitude of the elevations.

是的。那麼讓我開始吧。因此，總是（聽不清）臨床醫生會進行大量的臨床研究。對我來說，有些人——一些研究人員會選擇將臨床不良事件和無症狀實驗室不良事件勾選起來，這總是很奇怪。因此，我們確實無法解釋為什麼這 4 個事件會如此切換，服用安慰劑的患者的 CPK 升高，而幸運的是，他們碰巧沒有將它們視為不良事件。我將讓蓋爾詳細說明海拔的大小。

Yes. And what I can say is your best looking at Slide 15 in our deck in the graph on the right. You'll notice there we have 1 CK elevation in bright blue that occurred at baseline did not occur on treatment at all. That was 1 of our originally reported ones that is no longer being considered a treatment-emergent adverse event because it was not treatment emergent. And you can see that 1 which didn't happen on treatment was almost the highest CK elevation that we saw in the study.

是的。我能說的是，右圖中我們幻燈片 15 是您最好看的。您會注意到，我們有 1 個亮藍色的 CK 升高，這是在基線時發生的，但在治療中根本沒有發生。這是我們最初報告的事件之一，不再被視為治療引起的不良事件，因為它不是治療引起的。您可以看到，治療中未發生的 1 幾乎是我們在研究中看到的最高 CK 升高。

The second highest when we saw the study, and these were both higher grade elevations is that yellow one. And again, this was a single increase in CK, patient had a history of exercise and had no symptoms whatsoever. And when it came back on lab, she came back in. It was already down. And by the next follow-up to that, it was entirely down to normal. So these CK elevations that were reported as adverse events are in that graphic to the right excluding the blue one, which turned out to, of course, not be treatment emergent.

當我們看到這項研究時，第二高的海拔是黃色的，這些都是較高等級的海拔。再說一次，這是 CK 的單次升高，患者有運動史並且沒有任何症狀。當它回到實驗室時，她回來了。它已經下來了。到了下一次後續行動時，一切都完全恢復正常了。因此，這些被報告為不良事件的 CK 升高顯示在右側的圖表中，不包括藍色的，當然，這不是治療引起的。

But I think you can see that there's a range there of moderate to higher elevations. And then, of course, interestingly enough, there's just 1 patient in purple, where the CK elevation at -- on treatment was no higher in terms of grade of toxicity than the CK elevation before treatment. So that was considered sort of a grade 0 change.

但我認為你可以看到那裡有一個中等到更高海拔的範圍。當然，有趣的是，只有 1 名紫色患者，治療時的 CK 升高就毒性等級而言並不高於治療前的 CK 升高。所以這被認為是 0 級變化。

And to address the question about the target for PK and PD with the study. So we have targeted the 50-milligram dose to generate PD inhibition of greater than 80% in trough. And the pharmacokinetics in the HS study demonstrated that. And I think, if you look at the data that we had on the ex-vivo cytokine production, you're seeing that at day 85, at trough and at peak, we're seeing greater than 90% inhibition of TNFa and greater than 80-some percent inhibition of IL-1b. So I think we achieved that.

並通過研究解決PK和PD的靶點問題。因此，我們的目標是 50 毫克劑量，以在谷期產生大於 80% 的 PD 抑制。 HS 研究中的藥代動力學證明了這一點。我認為，如果您查看我們關於離體細胞因子產生的數據，您會發現在第 85 天，在低谷和高峰時，我們看到 TNFa 的抑制率超過 90%，並且抑制率超過 90%。 IL-1b 的抑制率為 80%左右。所以我認為我們做到了這一點。

And just to close on the CPK question, so we now have chronic tox other through 26 to 39 weeks in -- we didn't see any muscle toxicity in any of the preclinical toxicology studies that have been run to date. We've had 0 symptomatic CPK elevation in any humans today. And you see the date on Slide 15 that these are transient. They go away while on drug. We don't believe that we have to seen any issue, we'll continue to monitor in the rest of the program, of course.

最後，關於 CPK 問題，我們現在有 26 至 39 週的慢性毒性——在迄今為止進行的任何臨床前毒理學研究中，我們沒有發現任何肌肉毒性。今天，人類中出現的 CPK 升高症狀為 0。您會在幻燈片 15 上看到日期，表明這些都是暫時的。他們在吸毒期間離開。我們認為我們不必看到任何問題，當然我們將繼續監控該計劃的其餘部分。

One moment for our next question, please. And our next question comes from the line of Roger Song with Jefferies.

請稍等一下我們的下一個問題。我們的下一個問題來自 Roger Song 和 Jefferies 的對話。

Great. And I appreciate all the details for the HS data. Maybe just 1 quick one. I know a lot of questions about the CPK and just adding one. Hopefully, that's not too much for you. And in terms of the -- I understand this -- the CPK elevation transient and the kind of sales results, and the -- it's very good, you don't have the symptoms associated. Just curious, how long usually takes patients to develop any symptoms while they have some on and off for the CPK elevation? And how concerned we should be if you take the longer term therapy and they may have this kind of episodic elevation event?

偉大的。我很欣賞 HS 數據的所有細節。也許只是 1 個快速的。我知道很多關於CPK的問題，只是補充一個。希望這對你來說還不算太多。就我的理解而言，CPK 短暫升高和銷售結果的類型，而且，這非常好，你沒有相關的症狀。只是好奇，當患者出現 CPK 升高時斷時續的症狀時，通常需要多長時間才能出現症狀？如果您接受長期治療並且他們可能會出現這種偶發性升高事件，我們應該多麼擔心？

Yes. And so to date, we only have safety data in humans through week 12 in our program. We now with the chronic tox studies having been completed, we'll be able to dose beyond 12 weeks. But there's nothing in the profile of CPK that we're seeing to date that would suggest that there's going to be any long-term issues with it. It'd be different if there was smoldering elevations at CPK through 12 weeks, then you might think that there's something chronic going on, but that isn't the profile that you're seeing at all here. So I think the likelihood is relatively low. But of course, let's do the studies and do the longer-term follow-up. Gail, anything you want to add on that?

是的。到目前為止，我們的項目僅擁有截至第 12 週的人類安全數據。現在，隨著慢性毒性研究的完成，我們將能夠繼續服用 12 週以上的藥物。但迄今為止，我們在 CPK 的概況中沒有看到任何跡象表明它會出現任何長期問題。如果 CPK 在 12 週內持續升高，情況就會有所不同，那麼您可能會認為存在一些長期的情況，但這根本不是您在這裡看到的情況。所以我覺得可能性比較低。當然，讓我們進行研究並進行長期隨訪。蓋爾，你還有什麼要補充的嗎？

The only thing I'd add is measuring CK is not like measuring blood pressure. And you know if your blood pressure goes up and stays up that, that can cause harm. And of course, we haven't seen any blood pressure changes in our studies that are meaningful, of course. But with CK, it's a normal biologic thing. It's something that sits in your muscle cells. And when you do things day to day that may impact your muscles, you get increased turnover of those muscle cells and your CK can go up. And that's not associated with any harm unless there's something underlying going on or something else going on in your body, and we have no evidence of that. So even transient CK elevations over a long period of time such as these are something I would expect to see in you or in me in the course of our normal daily life in any case.

我唯一要補充的是測量 CK 與測量血壓不同。你知道，如果你的血壓升高並持續升高，就會造成傷害。當然，我們的研究中還沒有看到任何有意義的血壓變化。但對於 CK 來說，這是正常的生物學現象。它是存在於你的肌肉細胞中的東西。當您每天做的事情可能會影響您的肌肉時，這些肌肉細胞的周轉就會增加，您的 CK 也會上升。這與任何傷害無關，除非您的身體發生了潛在的情況或其他情況，而我們沒有證據表明這一點。因此，無論如何，即使是在很長一段時間內短暫的 CK 升高，我也希望在我們的正常日常生活中在你或我身上看到這樣的情況。

All right. Great. Yes, that's comforting. In terms of the cytokine, maybe can you just let us know for your RA Phase IIb study. Anything you can make a comment related to the baseline cytokine consistent with your prior or the disease background? Or have you ever seen those kind of cytokine data yet?

好的。偉大的。是的，這很令人欣慰。就細胞因子而言，也許您可以讓我們知道您的 RA IIb 期研究。您可以就與您之前或疾病背景一致的基線細胞因子發表評論嗎？或者你見過這類細胞因子數據嗎？

Yes. And so this is a blinded study. So we have not looked yet, and we wouldn't look anyway, until we look at the top-line results. But Joe, anything you want to add about what we're actually going to be looking at in terms of cytokines in the Phase IIb RA study.

是的。所以這是一項盲法研究。所以我們還沒有看，而且無論如何我們也不會看，直到我們看到最重要的結果。但是 Joe，您想補充一下我們在 IIb 期 RA 研究中實際要研究的細胞因子方面的內容嗎？

Yes. So on the Phase IIb study, we will be looking at endogenous cytokine levels. we won't be doing the ex vivo analysis and that we've already demonstrated in the IIa study, the dependence of these ex vivo cytokines on MK2 and the sensitivity of ATI-450.

是的。因此，在 IIb 期研究中，我們將關注內源性細胞因子水平。我們不會進行離體分析，而且我們已經在 IIa 研究中證明了這些離體細胞因子對 MK2 的依賴性以及 ATI-450 的敏感性。

One moment for our next question, please. And our next question comes from the line of Dipesh Patel with H.C. Wainwright.

請稍等一下我們的下一個問題。我們的下一個問題來自 Dipesh Patel 和 H.C.溫賴特。

Standing in for Raghuram Selvaraju, H.C. Wainwright. Several questions. How do you see the competitive landscape shaping up in atopic dermatitis? And what do you consider to be the key differentiators for ATI-1777.

代表 Raghuram Selvaraju，H.C.溫賴特。幾個問題。您如何看待特應性皮炎領域的競爭格局？您認為 ATI-1777 的主要區別是什麼？

It's a great question. Thanks. The landscape, in fact, is getting more attractive. I think we've all been pleasantly surprised with the successful launch of of the insight topical JAK. And by the way, that topical JAK is basically just the oral JAK that's been applied on the skin. So not surprisingly with it, you do see a fairly high level of systemic exposure, which I think is why the FDA opted to give them the class labeling with the black box, so the #1 area of differentiation that we're seeking with our soft topical JAK program is to have similar, if not better, efficacy to Opzelura, but with minimal systemic exposure and thus a significant decreased likelihood of us getting the class labeling.

這是一個很好的問題。謝謝。事實上，風景正變得越來越有吸引力。我想我們都對 Insight Topical JAK 的成功推出感到驚喜。順便說一下，外用 JAK 基本上就是塗在皮膚上的口服 JAK。因此，毫不奇怪，您確實看到了相當高水平的全身暴露，我認為這就是為什麼 FDA 選擇給它們貼上黑框類別標籤的原因，因此我們正在尋求的第一大差異化領域軟局部 JAK 計劃的目的是與 Opzelura 具有相似（如果不是更好）的功效，但全身暴露最小，因此顯著降低我們獲得類別標籤的可能性。

We don't know what's going to be in the label until we have the labeling discussions with the U.S. FDA, and they'll be based on finalized Phase III data. But just if you look at what we have from our Phase IIa study, there are minimal de minimis exposure seen in patients, I think, is tracking well to the asset profile that we're trying to achieve.

在與美國 FDA 進行標籤討論之前，我們不知道標籤中會包含什麼內容，並且它們將基於最終的 III 期數據。但如果你看看我們從 IIa 期研究中得到的結果，我認為患者中的暴露程度極小，這很好地符合我們正在努力實現的資產狀況。

Great. And then just switching gears to psoriatic arthritis. What might be possible to reaccelerate enrollment in the zumsemetinib psoriatic arthritis trial?

偉大的。然後就切換到銀屑病關節炎。怎樣才能重新加速 zumsemetinib 銀屑病關節炎試驗的入組？

And just to point out, it is a difficult part of the world to be doing these types of studies. We've seen quite an uptick in enrollment just in the last few months as we've been able to get through regulatory hurdles with the Polish government. So I think we are on track to achieve what we set out to do. But Gail, anything you want to add in terms of enrollment for it?

我只想指出，在世界上進行此類研究是困難的部分。由於我們克服了波蘭政府的監管障礙，在過去的幾個月裡，我們的入學人數大幅增加。所以我認為我們正在實現我們設定的目標。但是蓋爾，您想在註冊方面添加什麼內容嗎？

I'd only say that, like all of our studies, we track them very closely in terms of enrollment and take actions as it makes sense. In this particular study, as I said earlier, we started this a bit later. There was a challenge in the part of the world with Ukraine and then with many, many companies switching over to having more studies in Poland. But at this point, the study is going well. We're tracking the enrollment we expected. We're seeing screening continue to improve. So I think we're on track at present.

我只想說，就像我們所有的研究一樣，我們在入學方面非常密切地跟踪它們，並採取有意義的行動。在這項特殊的研究中，正如我之前所說，我們開始得晚一些。在烏克蘭這個地區面臨著挑戰​​，然後許多公司轉向在波蘭進行更多研究。但目前來看，研究進展順利。我們正在跟踪預期的註冊情況。我們看到篩查工作在不斷改進。所以我認為我們目前正步入正軌。

And lastly, we have a high level of investment enthusiasm for this. So it isn't for a lack of enthusiasm, but there are some headwinds in that part of the world that we're dealing with.

最後，我們對此有很高的投資熱情。所以這並不是因為缺乏熱情，而是因為我們正在應對的世界地區存在一些阻力。

One moment for our next question. Our next question comes from the line of Julian Harrison with BTIG.

請稍等一下我們的下一個問題。我們的下一個問題來自 BTIG 的朱利安·哈里森 (Julian Harrison)。

First, on the HS data, while it wasn't the primary endpoint, I'm curious if you could comment on what the placebo rate with high score 50, 75 and 100 were? and then on the topical JAK ATI-1777, just curious if you could talk more about the specific changes to the inclusion criteria behind that protocol? And then how much would you expect this to affect baseline characteristics for the overall study population.

首先，關於 HS 數據，雖然它不是主要終點，但我很好奇您能否評論一下高分 50、75 和 100 的安慰劑比率是多少？然後關於主題 JAK ATI-1777，只是好奇您是否可以更多地談談該協議背後的納入標準的具體變化？然後您預計這會對整個研究人群的基線特徵產生多大影響。

Yes. So we're not going into a lot of more details regarding the efficacy results for HS. Suffice it to say that placebo had a very good day on basically every endpoint. In fact, placebo did better in this study than Active did in some of the more successful Phase III studies that have already been published. atopic dermatitis, do you want to comment about that?

是的。因此，我們不會詳細介紹 HS 的療效結果。可以說，安慰劑在基本上每個終點上都表現得非常好。事實上，安慰劑在這項研究中的表現比活性藥物在一些已發表的更成功的 III 期研究中的表現更好。特應性皮炎，您想對此發表評論嗎？

Sure. So the atopic dermatitis study. First, I'd start by saying we carefully look through the literature and where there was available data on response rates, in mild patients. And the feeling was that we did not need to repower the study. Certainly, having Opzelura clinical trial data helped us come to those kind of decisions.

當然。所以特應性皮炎研究。首先，我首先要說的是，我們仔細查閱了文獻以及輕症患者緩解率的可用數據。我們的感覺是我們不需要重新啟動這項研究。當然，擁有 Opzelura 臨床試驗數據可以幫助我們做出此類決定。

What we did do is we kept the upper range as it was with the moderate and severes, but we included the IGA Class II, which is mild in the study. We also dropped body surface area from greater than equal to 5 to greater than equal to 3, and for easy inclusion, we also dropped this from greater than or equal to 5 greater than or equal to 3.

我們所做的就是保持中度和重度的上限，但我們在研究中納入了 IGA II 級，這是輕度的。我們還將身體表面積從大於等於 5 降低到大於等於 3，並且為了便於包含，我們還將其從大於或等於 5 大於或等於 3 降低。

So across the board, we simply move to including a somewhat milder population as well. And as we said, screening is going great there.

因此，從整體上看，我們只是將稍微溫和的人群納入其中。正如我們所說，那裡的篩查進展順利。

One moment for our next question. Our next question comes from the line of Tim Lugo with William Blair.

請稍等一下我們的下一個問題。我們的下一個問題來自蒂姆·盧戈和威廉·布萊爾的對話。

This is Lachlan on for Tim. A quick follow-up on the enrollment for atopic dermatitis. Are you limiting the proportion of patients in the trial that could fall into that sort of new milder cohort. If you could just talk about that. And then Gail, on the CK elevations, you mentioned a lot of them seem to be associated with exercise. So I'm wondering in the RA and PSA studies, are there any sort of limitations or restrictions on things like patients exercising before a visit in the process...

這是拉克蘭替蒂姆發言。特應性皮炎入組的快速跟進。您是否限制了試驗中可能屬於此類新的較輕症隊列的患者比例？如果你能談談這個就好了。然後蓋爾，關於 CK 海拔，您提到其中很多似乎與鍛煉有關。所以我想知道在 RA 和 PSA 研究中，是否有任何限製或限制，比如患者在就診前進行鍛煉……

Gail will take both of those.

蓋爾會接受這兩個。

Sure. So in terms of the terms of the atopic dermatitis study, excuse me, what was the question, remind me?

當然。那麼就特應性皮炎研究而言，請問問題是什麼，提醒我一下？

Are you limiting the number of files.

您是否限製文件數量。

Yes, sorry. Yes, in terms of that, no, not at all. the study enrollment study was well enrolled at the point where we're at. We certainly still have room to enroll, but we want to make sure we get adequate number of mild patients. We're not doing any kind of stratification for mild, moderate or severe. And at this point. My hope would be that we see plenty of mild patients enrolling.

是的，抱歉。是的，就這一點而言，不，一點也不。就我們目前的情況而言，研究登記研究的登記情況良好。我們當然還有招募空間，但我們希望確保獲得足夠數量的輕症患者。我們不會對輕度、中度或重度進行任何分層。而此時。我希望我們能看到大量輕症患者入組。

In terms of the CK question. The reality is that if you look at the HS study, it is in much younger population. Our mean age is in the mid-30s, most RA studies, including our IIa study is anywhere from mid-50s to mid-60s as a mean age. Also, RA as a disease where people are entering with moderate to severe muscular skeletal disease with significant arthritis. It's unusual for it to have quite the same type of problem with people just deciding to go out and do a really intensive exercise regime.

就CK問題而言。現實情況是，如果你看一下 HS 研究，就會發現它是在更年輕的人群中進行的。我們的平均年齡是 30 多歲，大多數 RA 研究，包括我們的 IIa 研究，平均年齡是 50 多歲到 60 多歲。此外，RA 是一種人們患有中度至重度肌肉骨骼疾病並伴有嚴重關節炎的疾病。對於那些剛剛決定出去進行真正高強度鍛煉的人來說，遇到同樣類型的問題是不尋常的。

That said, you always want to keep things as real world as possible in these studies. And CK elevations like we saw in the HS study with the intermittent increases that resolved on treatment are really not indicative of a concern or a reason to restrict anything in the study.

也就是說，在這些研究中你總是希望盡可能保持真實世界。像我們在 HS 研究中看到的 CK 升高（通過治療解決的間歇性升高）實際上並不表示存在擔憂或限制研究中任何內容的理由。

Operator, any more questions?

接線員，還有什麼問題嗎？

I will turn the call back over to Mr. Manion for closing remarks.

我會將電話轉回給馬尼恩先生，讓其致閉幕詞。

All right. There's no further questions. I just want to thank everyone again for their time and interest and continued support as our company continues to make strides of growth for the future. Have a great day.

好的。沒有其他問題了。我想再次感謝大家的時間、關注以及對我們公司在未來繼續取得長足發展的持續支持。祝你有美好的一天。

This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.

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。祝大家度過美好的一天。