aTyr Pharma Inc (ATYR) 2022 Q4 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the aTyr Pharma Fourth Quarter and Full Year 2022 Conference Call. (Operator Instructions) As a reminder, this conference call is being recorded for replay purposes.

女士們先生們，下午好，歡迎參加 aTyr Pharma 第四季度和 2022 年全年電話會議。 （操作員說明）作為提醒，正在錄製此電話會議以供重播。

It is now my pleasure to hand the conference over to Ashlee Dunston, aTyr's Director of Investor Relations and Corporate Communications. Ms. Dunston, you may begin.

現在我很高興將會議交給 aTyr 的投資者關係和企業傳播總監 Ashlee Dunston。鄧斯頓女士，你可以開始了。

Thank you, and good afternoon, everyone. Thank you for joining us today to discuss aTyr's Fourth Quarter and Full Year 2022 operating results and corporate update. We are joined today by Dr. Sanjay Shukla, our President and CEO; and Jill Broadfoot, our CFO. On the call, Sanjay will provide an update on our corporate strategy, including our clinical program for efzofitimod and research and discovery program. Jill will review the financial results and our current financial position before handing it back to Sanjay to open the call for any questions.

謝謝，大家下午好。感謝您今天加入我們討論 aTyr 的第四季度和 2022 年全年經營業績和公司更新。今天，我們的總裁兼首席執行官 Sanjay Shukla 博士加入了我們的行列；和我們的首席財務官 Jill Broadfoot。在電話會議上，Sanjay 將提供我們公司戰略的最新情況，包括我們的 efzofitimod 臨床計劃以及研究和發現計劃。 Jill 將審查財務結果和我們當前的財務狀況，然後再將其交還給 Sanjay 以提出任何問題。

Before we begin, I would like to remind everyone that except for statements of historical facts, the statements made by management and responses to questions on this conference call are forward-looking statements under the safe harbor provision of the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements.

在我們開始之前，我想提醒大家，除了歷史事實的陳述，管理層在本次電話會議上所做的陳述和對問題的回答均為 1995 年《私人證券訴訟改革法案》安全港條款下的前瞻性陳述. 這些陳述涉及風險和不確定性，可能導致實際結果與此類前瞻性陳述中的結果存在重大差異。

Please see the forward-looking statement disclaimer in the company's press release issued this afternoon as well as the risk factors in the company's SEC filings and included in our most recent annual report on Form 10-K, subsequently filed quarterly reports on Form 10-Q and in our other SEC filings. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made, as facts and circumstances underlying these forward-looking statements may change. Except as required by law, aTyr Pharma disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances.

請參閱公司今天下午發布的新聞稿中的前瞻性聲明免責聲明以及公司提交給美國證券交易委員會的文件中的風險因素，這些風險因素包含在我們最近的 10-K 表格年度報告中，隨後在 10-Q 表格中提交了季度報告以及我們向美國證券交易委員會提交的其他文件。不應過分依賴前瞻性陳述，因為這些前瞻性陳述所依據的事實和情況可能會發生變化，前瞻性陳述僅代表發表之日的情況。除法律要求外，aTyr Pharma 不承擔任何更新這些前瞻性陳述以反映未來信息、事件或情況的義務。

I will now turn the call over to Sanjay.

我現在將把電話轉給 Sanjay。

Thank you, Ashlee. Good afternoon, everyone, and thank you for joining us for our fourth quarter and full year 2022 results conference call.

謝謝你，阿什莉。大家下午好，感謝您加入我們的第四季度和 2022 年全年業績電話會議。

At aTyr , we're working to develop a new class of medicines from our tRNA synthetase biology platform with the current focus on diseases -- disease areas related to inflammation and fibrosis with a high unmet medical need. Our lead therapeutic candidate efzofitimod is a novel immunomodulator that down regulates innate immune responses in uncontrolled inflammatory disease states. via selective modulation of neuropilin-2 or NRP-2.

在 aTyr ，我們正在努力從我們的 tRNA 合成酶生物學平台開發一類新的藥物，目前的重點是疾病——與炎症和纖維化相關的疾病領域，醫療需求未得到滿足。我們的主要治療候選藥物 efzofitimod 是一種新型免疫調節劑，可在不受控制的炎症性疾病狀態下下調先天免疫反應。通過 neuropilin-2 或 NRP-2 的選擇性調節。

We're developing efzofitimod as a potential treatment for patients with interstitial lung disease, or ILD, a group of rare immune-mediated fibrotic lung disorders, with the goal of resolving inflammation to prevent the progression of fibrosis, in order to improve outcomes for patients. 2022 was an important year for aTyr as we advanced efzofitimod to a global pivotal Phase III study in patients with pulmonary sarcoidosis, the most prevalent form of ILD that affects nearly 200,000 people in the U.S. and more than 1.2 million worldwide.

我們正在開發 efzofitimod 作為間質性肺病或 ILD 患者的潛在治療方法，ILD 是一組罕見的免疫介導的纖維化肺病，目的是解決炎症以防止纖維化進展，從而改善患者的預後. 2022 年對 aTyr 來說是重要的一年，因為我們將 efzofitimod 推進到一項針對肺結節病患者的全球關鍵 III 期研究，肺結節病是最普遍的 ILD 形式，影響美國近 200,000 人和全球超過 120 萬人。

Despite current treatments in standard of care, which is primarily steroids, approximately half of patients will develop progressive disease and nearly 1 in 5 of all patients will develop lung fibrosis. There remains a need for safer and more effective treatments, including those that reduce steroid burden for patients. This Phase III study, which is known as EFZO-FIT, is currently enrolling at multiple centers in the U.S., Europe and Japan.

儘管目前的護理標準治療主要是類固醇，但大約一半的患者會發展為進行性疾病，所有患者中將近五分之一會發展為肺纖維化。仍然需要更安全和更有效的治療，包括那些減少患者類固醇負擔的治療。這項名為 EFZO-FIT 的 III 期研究目前正在美國、歐洲和日本的多個中心招募。

We're pleased with the current pace of enrollment, and we expect to provide additional details regarding the progress of this study in the future. Our strategy for efzofitimod includes investigating the role this novel immunomodulator may play as a potential treatment for other more inflammatory forms of ILD. We announced last month that we are expanding the clinical development program for efzofitimod to include a Phase II study in patients with ILD associated with systemic sclerosis, which is known as SSC or more commonly scleroderma. This is a major type of connected tissue disease that affects nearly 100,000 people in the U.S., with up to 80% of these patients developing ILD, which is the leading cause of death in these patients.

我們對目前的註冊速度感到滿意，我們希望在未來提供有關這項研究進展的更多詳細信息。我們針對 efzofitimod 的策略包括研究這種新型免疫調節劑作為其他更具炎症性的 ILD 的潛在治療方法可能發揮的作用。我們上個月宣布，我們正在擴大 efzofitimod 的臨床開發計劃，以包括一項針對與系統性硬化症相關的 ILD 患者的 II 期研究，這種疾病被稱為 SSC 或更常見的硬皮病。這是一種主要類型的相關組織疾病，在美國影響了近 100,000 人，其中高達 80% 的患者發展為 ILD，這是這些患者死亡的主要原因。

We see SSc-ILD as a logical second indication to explore for efzofitimod, based on the clinical proof-of-concept demonstrated in pulmonary sarcoidosis patients and the translational effects seen in an animal model of SSs where efzofitimod was shown to reduce lung and skin fibrosis. Additionally, the pathology of SSc-ILD is driven by the same immune cells that are central to pulmonary sarcoidosis pathology. NRP2 is upregulated on these cells and is also implicated in scleroderma.

我們認為 SSc-ILD 是探索 efzofitimod 的第二個合乎邏輯的適應症，基於肺結節病患者的臨床概念驗證以及在 SSs 動物模型中觀察到的轉化效應，其中 efzofitimod 被證明可以減少肺和皮膚纖維化.此外，SSc-ILD 的病理學是由對肺結節病病理學至關重要的相同免疫細胞驅動的。 NRP2 在這些細胞上被上調，並且還與硬皮病有關。

Furthermore, like sarcoidosis, standard of care is limited and current treatments are not disease-modifying and do not improve quality of life. We recently received clearance of an investigational new drug application by the U.S. FDA for a Phase II study of efzofitimod in patients with SSc-ILD and we are planning to initiate this study later this year. This Phase II study is expected to be a randomized double-blind placebo-controlled proof-of-concept study to evaluate the efficacy, safety and tolerability of efzofitimod in patients with SSc-ILD. This is expected to be a 28-week study with 3 parallel cohorts randomized to either high or low dose efzofitimod or placebo, dosed intravenously monthly for a total of 6 doses.

此外，與結節病一樣，護理標準有限，目前的治療無法改善疾病，也無法改善生活質量。我們最近收到了美國 FDA 對 efzofitimod 治療 SSc-ILD 患者的 II 期研究新藥申請的批准，我們計劃在今年晚些時候啟動這項研究。這項 II 期研究預計將是一項隨機雙盲安慰劑對照的概念驗證研究，以評估 efzofitimod 在 SSc-ILD 患者中的療效、安全性和耐受性。預計這是一項為期 28 週的研究，有 3 個平行隊列隨機分配到高劑量或低劑量 efzofitimod 或安慰劑組，每月靜脈內給藥，總共 6 劑。

The study intends to enroll 25 patients with progressive disease who are currently receiving background mycophenolate therapy at multiple centers in the U.S. The primary objective of the study is to evaluate the efficacy of multiple doses of intravenous efzofitimod on pulmonary, cutaneous and systemic manifestations in patients with SSc-ILD. We expect to provide additional details about this study once it begins.

該研究擬入組 25 名進展性疾病患者，這些患者目前正在美國多個中心接受黴酚酸酯背景治療。該研究的主要目的是評估多劑量靜脈內依佐非莫德對患有以下疾病的患者的肺部、皮膚和全身表現的療效SSc-ILD。我們希望在這項研究開始後提供有關該研究的更多詳細信息。

This program expansion increases the potential market opportunity for efzofitimod in these forms of ILD. Taken collectively, we believe there is a multibillion-dollar global market opportunity for efzofitimod in pulmonary sarcoidosis and SSs-ILD and situates aTyr as the biotech leader in ILD.

該項目擴展增加了 efzofitimod 在這些形式的 ILD 中的潛在市場機會。總的來說，我們認為 efzofitimod 在肺結節病和 SSs-ILD 方面存在數十億美元的全球市場機會，並將 aTyr 定位為 ILD 的生物技術領導者。

While our primary focus is our clinical program for efzofitimod, we continue to leverage our intellectual property estate, covering fragments from all 20 human tRNA synthetases and utilize our platform as an engine to generate potential pipeline candidates and identify therapeutic targets. By leveraging the advanced technology made available to us through our research collaboration with Dualsystems Biotech, we have the opportunity to increase productivity in our discovery engine and efficiently generate new therapeutics from our tRNA synthetase domain library.

雖然我們的主要重點是我們的 efzofitimod 臨床項目，但我們繼續利用我們的知識產權，涵蓋所有 20 種人類 tRNA 合成酶的片段，並利用我們的平台作為引擎來生成潛在的管道候選者並確定治療目標。通過利用我們與 Dualsystems Biotech 的研究合作提供給我們的先進技術，我們有機會提高我們發現引擎的生產力，並從我們的 tRNA 合成酶域庫中有效地生成新的療法。

As a reminder, in addition to efzofitimod, this platform has recently generated data characterizing the extracellular targets for 2 previously uncharacterized tRNA synthetase domain, which identified specific interactions with key targets involved in fibrosis. We're excited to advance pipeline candidates through the discovery phase and unlock the unique biology underlying these novel pathways while we work to complete our 2 clinical trials for efzofitimod. We also plan to actively explore ways to accelerate these discovery programs, including through business development.

提醒一下，除了 efzofitimod，該平台最近還生成了表徵 2 個先前未表徵的 tRNA 合成酶域的細胞外靶標的數據，這些域確定了與纖維化中涉及的關鍵靶標的特定相互作用。我們很高興能夠在發現階段推進候選管道，並在我們努力完成 efzofitimod 的 2 項臨床試驗的同時，解鎖這些新途徑背後的獨特生物學。我們還計劃積極探索加速這些發現計劃的方法，包括通過業務發展。

I'll now turn it over to our Chief Financial Officer, Jill Broadfoot, to review our financial results.

我現在將其轉交給我們的首席財務官 Jill Broadfoot，以審查我們的財務業績。

Thank you, Sanjay. Our results of operations included research and development expenses of $42.8 million for the year ended 2022, which consisted of clinical development costs for the Phase III EFZO-FIT study, manufacturing costs for the efzofitimod and ATYR2810 programs and research and development costs for the efzofitimod and discovery programs.

謝謝你，桑傑。我們的經營業績包括截至 2022 年的 4280 萬美元的研發費用，其中包括 III 期 EFZO-FIT 研究的臨床開發成本、efzofitimod 和 ATYR2810 項目的製造成本以及 efzofitimod 和發現程序。

Also, our general and administrative expenses were $14 million for the year ended 2022. We ended the year 2022 with $69.3 million in cash, restricted cash, cash equivalents and investments. Subsequent to the end of the year, we received a $10 million milestone payment in connection with the Kyorin Agreement that was related to their initiation of the EFZO-FIT study in Japan, and we generated gross proceeds of approximately $52 million from the public offering of common stock.

此外，截至 2022 年，我們的一般和行政費用為 1400 萬美元。截至 2022 年，我們擁有 6930 萬美元的現金、限制性現金、現金等價物和投資。年底之後，我們收到了與 Kyorin 協議有關的 1000 萬美元里程碑付款，該協議與他們在日本啟動 EFZO-FIT 研究有關，我們從公開發售中獲得了約 5200 萬美元的總收益普通股。

Based on our current operational plans and existing cash, we believe our cash runway extends into 2026, which is expected to be sufficient to fund the company through the readout for our 2 efzofitimod clinical trials. This takes into account the allocation of resources to programs that are driving the most meaningful value for the company, namely the clinical development program for efzofitimod and maintaining an active discovery program with our tRNA synthetase pipeline candidates, where we continue to -- we intend to continue to identify targets for some of our tRNA synthetase fragments but not proceed with more costly late-stage preclinical activities. We expect this strategy to reduce our spend on late-stage preclinical activities by over 30% compared to the prior year.

根據我們目前的運營計劃和現有現金，我們認為我們的現金跑道會延伸到 2026 年，預計這將足以通過我們的 2 項 efzofitimod 臨床試驗的讀數為公司提供資金。這考慮到將資源分配給為公司帶來最有意義價值的項目，即 efzofitimod 的臨床開發項目，並與我們的 tRNA 合成酶管道候選者保持積極的發現項目，我們將繼續——我們打算繼續為我們的一些 tRNA 合成酶片段確定目標，但不繼續進行成本更高的後期臨床前活動。與上一年相比，我們預計這一戰略將使我們在後期臨床前活動上的支出減少 30% 以上。

In addition to program allocation, this forecast does not take into account any potential financial upsides, such as the opportunity for additional milestone payments from Kyorin, our partner for the development and commercialization of efzofitimod for ILD in Japan. While the forecast does consider some partial proceeds from the prudent use of our at-the-market facility, it also does not include any additional proceeds that may result from business development efforts.

除項目分配外，該預測未考慮任何潛在的財務上行空間，例如來自 Kyorin 的額外里程碑付款的機會，Kyorin 是我們在日本開發和商業化用於 ILD 的 efzofitimod 的合作夥伴。雖然該預測確實考慮了謹慎使用我們在市場上的設施所產生的部分收益，但它也不包括可能因業務發展努力而產生的任何額外收益。

Now I'd like to turn the call back over to Sanjay before we open it up to Q&A.

現在我想在我們打開問答環節之前將電話轉回給 Sanjay。

Thank you, Jill. As mentioned, 2022 was a year of significant accomplishments for aTyr as we now start 2023, we believe we have the financial resources and a strategic plan to carry us through the next inflection point of the company. Moving forward with our focus on executing our 2 clinical trials and generating discovery targets from our pipeline, we intend to only hold an annual fourth quarter and full year conference call to discuss our financial results and provide operational updates.

謝謝你，吉爾。如前所述，2022 年是 aTyr 取得重大成就的一年，因為我們現在從 2023 年開始，我們相信我們擁有財務資源和戰略計劃來帶領我們度過公司的下一個轉折點。隨著我們專注於執行我們的 2 項臨床試驗並從我們的管道中產生髮現目標，我們打算只舉行年度第四季度和全年電話會議來討論我們的財務業績並提供運營更新。

On a go-forward basis, in order to streamline our internal process, we'll release quarterly results by press release only. We plan to continue to provide a high degree of transparency regarding the progress of our programs and pipeline through press releases, presentations and events.

在前進的基礎上，為了簡化我們的內部流程，我們將僅通過新聞稿發布季度業績。我們計劃通過新聞稿、演示文稿和活動繼續提供有關我們計劃和管道進展的高度透明度。

So in closing, we appreciate your interest. At this time, Jill and I will be happy to take your questions.

最後，感謝您的關注。屆時，吉爾和我將很樂意回答您的問題。

(Operator Instructions) Our first question comes from the line of George Renza -- sorry, Gregory Renza of RBC.

（操作員說明）我們的第一個問題來自 George Renza——對不起，RBC 的 Gregory Renza。

Sanjay and team, congrats on the progress. Sanjay, to the extent possible, it would be great to hear just a little bit more about the scleroderma ILD trial. It's great to hear that getting up and running. And just as you think about setting that up, certainly, with the 28-week study, it looks like there's a possibility of having some clarity on this indication prior to the EFZO-FIT trial. So I'm just curious how you think about how that could kind of inform our understanding of efzofitimod in clinic. And then maybe just related to that, as we think about the fixed doses of 270 and 450, how we should think about that as it pertains to the dosing in the EFZO-FIT trial.

Sanjay 和團隊，祝賀取得的進展。 Sanjay，在可能的範圍內，如果能聽到更多關於硬皮病 ILD 試驗的信息，那就太好了。很高興聽到啟動和運行。就像你考慮設置它一樣，當然，通過為期 28 週的研究，看起來有可能在 EFZO-FIT 試驗之前對這個適應症有一些明確的了解。所以我很好奇你如何看待這會如何影響我們在臨床上對 efzofitimod 的理解。然後可能與此相關，當我們考慮 270 和 450 的固定劑量時，我們應該如何考慮它，因為它與 EFZO-FIT 試驗中的劑量有關。

Sure, Greg. Good question. So SSs-ILD is something that, years ago, we thought about actually moving into before sarcoidosis. We had quite a bit of debate with pulmonologists, rheumatologists around the world. They actually wanted us to move into both indications. But back then, as a sub-$10 million market cap company, we had to prioritize. And our view was we needed to establish proof of concept. Sarcoidosis was picked, but it's always been in the back of the mind of many of the rheumatology experts that efzofitimod could be useful in this indication.

當然，格雷格。好問題。所以 SSs-ILD 是多年前我們考慮在結節病之前實際進入的東西。我們與世界各地的肺病學家、風濕病學家進行了相當多的辯論。他們實際上希望我們進入這兩個適應症。但那時候，作為一家市值低於 1000 萬美元的公司，我們必須確定優先順序。我們的觀點是我們需要建立概念證明。結節病被選中，但許多風濕病學專家一直認為 efzofitimod 可能對這種適應症有用。

Back in 2017-2018 time period, we ran a very, very difficult mouse model comparing efzofitimod to nintedanib. In that model, efzofitimod did a really nice job. And in the early phase of that model, our competing nintedanib showing significant amelioration of lung and skin fibrosis. So always been in the back of our mind that this could be a natural expansion.

早在 2017-2018 年期間，我們運行了一個非常非常困難的小鼠模型來比較 efzofitimod 和 nintedanib。在那個模型中，efzofitimod 做得非常好。在該模型的早期階段，我們的競爭性尼達尼布顯示出肺和皮膚纖維化的顯著改善。所以我們一直認為這可能是一種自然的擴張。

What we've seen in the market after our proof-of-concept is an overwhelming interest by more rheumatologists and pulmonary experts on the autoimmune side to try efzofitimod with their patients. Some of the rheumatologists involved in our last trial, immediately after our results, wanted to attempt to use efzofitimod because there really isn't anything out there for these patients. Mycophenolate is used systemically but once you develop ILD and you have scleroderma, it can really be, perhaps, the most serious morbidity for these patients. And the mortality rates basically approach 75% to 80% in some of these patients.

在我們的概念驗證之後，我們在市場上看到的是，越來越多的風濕病學家和自身免疫方面的肺病專家對在他們的患者身上試用 efzofitimod 產生了極大的興趣。一些參與我們上次試驗的風濕病學家，在我們得出結果後，立即想嘗試使用 efzofitimod，因為這些患者確實沒有任何藥物。黴酚酸酯是全身性使用的，但一旦您患上 ILD 並患有硬皮病，它可能真的是這些患者最嚴重的發病率。其中一些患者的死亡率基本接近75％至80％。

So we knew we had a strong rationale. As it turns out last summer, one of the -- through some of the interactions even with the FDA, there were questions about moving into other forms of ILD, and we quickly received a fast-track designation based on our preclinical data. So over the last several months, we sat down with those experts. We wrote a protocol that we think now can establish proof-of-concept in that indication. We think this effectively doubles the market opportunity for efzofitimod. We always thought it was a solid opportunity in sarcoidosis, but now with SSC as well, we clearly are in a multibillion-dollar space. And we're the leader. We're the furthest along here.

所以我們知道我們有充分的理由。事實證明，去年夏天，其中一個——通過與 FDA 的一些互動，人們對進入其他形式的間質性肺病存在疑問，我們很快就根據我們的臨床前數據獲得了快速通道指定。因此，在過去的幾個月裡，我們與這些專家坐下來交談。我們編寫了一個我們認為現在可以在該適應症中建立概念驗證的協議。我們認為這有效地使 efzofitimod 的市場機會翻了一番。我們一直認為這是結節病的一個可靠機會，但現在有了 SSC，我們顯然處於一個數十億美元的空間。我們是領導者。我們是這裡最遠的。

With regard to the trial, it is a 6-month trial while we want to be able to establish a signal primarily looking at lung. I'll be able to provide more details probably through a KOL call as well where we can learn a little bit more about scleroderma but the existing drugs that are out there, even those that are approved, show limited, limited efficacy, mostly just less reduction of decline of FVC. We think our drug can do better. And none of those therapies that are out there for patients do anything for quality of life. They don't move the needle at all with skin inflammation or fibrosis.

關於試驗，這是一個為期 6 個月的試驗，而我們希望能夠建立一個主要針對肺部的信號。我可能還可以通過 KOL 電話提供更多詳細信息，在那裡我們可以了解更多關於硬皮病的信息，但現有的藥物，即使是那些已獲批准的藥物，也顯示出有限、有限的療效，大部分只是更少減少 FVC 的下降。我們認為我們的藥物可以做得更好。那些為患者提供的療法對生活質量沒有任何作用。他們根本不會因皮膚炎症或纖維化而移動針頭。

So efzofitimod provides a real strong opportunity for us to move into scleroderma ILD while keeping our eyes on the ball with sarcoidosis. With regards to dosing, we are -- and we have contemplated a fixed dose. This is just going to allow us to have a little bit more commercial knowledge around our drug. It's a small point, but the full 450 and 270 milligrams that you point out, they approximate 5 milligrams per kilogram and 3 milligrams per kilogram from our current trial. It's just going to give us the opportunity to look at our drug from a fixed dose versus a weight-based dose in preparation to commercialize drug.

因此，efzofitimod 為我們提供了一個真正強大的機會，讓我們在關注結節病的同時進入硬皮病間質性肺病。關於劑量，我們是 - 我們已經考慮了固定劑量。這只會讓我們對我們的藥物有更多的商業知識。這是一個小問題，但你指出的全部 450 和 270 毫克，根據我們目前的試驗，它們大約是每公斤 5 毫克和每公斤 3 毫克。它只是讓我們有機會從固定劑量和基於體重的劑量來研究我們的藥物，以準備將藥物商業化。

So it's going to give us a little bit more data looking at it in this manner in this trial. Nonetheless, I think we can get the data, and I expect to get the data in 2024. I'll probably guide to exactly when that would be. And that would be ahead of when we expect sarcoidosis readouts, which I think right now are on track, as I said, for Q1 2025.

因此，在本次試驗中，我們將以這種方式查看更多數據。儘管如此，我認為我們可以獲得數據，並且我希望在 2024 年獲得數據。我可能會指導確切的時間。這將領先於我們預期的結節病讀數，正如我所說，我認為現在正處於 2025 年第一季度的軌道上。

So there's 2 real opportunities here, I would say, in the next several years for efzofitimod to demonstrate not only clinical proof-of-concept in this indication but clinical efficacy in sarcoidosis, and this is why we think we're really poised to be the leader in a space that we're the furthest along.

所以這裡有 2 個真正的機會，我想說，在接下來的幾年裡，efzofitimod 不僅可以證明這一適應症的臨床概念驗證，還可以證明在結節病中的臨床療效，這就是為什麼我們認為我們真的準備好了我們走得最遠的領域的領導者。

That's great. Very helpful. Maybe I'll sneak in a more near-term quick one. Just with respect to ATS coming up in EMEA. I'm just curious if there's anything you wanted to highlight for those posters and presentation and just mainly around what should we and the physician community be looking at in order to really just enhance their confidence and our confidence in the efzofitimod mechanism of action? And congrats on the progress, Sanjay.

那太棒了。很有幫助。也許我會潛入一個更近期的快速。就 EMEA 即將推出的 ATS 而言。我只是想知道你是否想為這些海報和演示強調什麼，主要圍繞我們和醫生社區應該關注什麼，以便真正增強他們和我們對 efzofitimod 作用機制的信心？祝賀你取得的進步，Sanjay。

Thanks, Greg. And to mention ATS, thank you for promising that. We have 2, I think, really exciting data points coming out there. The first, you mentioned is the mechanism of action. We've made significant strides, I would say, in the last 6 to 9 months in fully understanding efzofitimod's MOA. You're going to see some more data come out at ATS, pointing to how efzofitimod modulates myeloid cells. This is something that I think is going to be really useful for us to help enrollment, but also to start to give those clinicians a better understanding of how the drug is basically changing the immune system.

謝謝，格雷格。還要提到 ATS，謝謝你的承諾。我認為，我們有 2 個非常令人興奮的數據點。首先，你提到的是作用機制。我想說，在過去的 6 到 9 個月裡，我們在充分理解 efzofitimod 的 MOA 方面取得了重大進展。您將在 ATS 上看到更多數據，指出 efzofitimod 如何調節骨髓細胞。我認為這對我們幫助註冊非常有用，但也開始讓這些臨床醫生更好地了解藥物如何從根本上改變免疫系統。

So we have a presentation that has been upgraded to symposia. And I would expect to have a full house there as most of the clinicians really want to now understand how did we see some of the outstanding effects we saw in our last trial. I'll also add that we also have a small exposure response analysis poster that's going to be coming out for those of you that understand what this means, it basically looks at our last Phase II data, gives us further confidence that as you administer basically more efzofitimod, we see better and better response.

因此，我們有一個已升級為座談會的演示文稿。我希望那裡有一個完整的房子，因為大多數臨床醫生現在真的很想了解我們是如何看到我們在上次試驗中看到的一些突出效果的。我還要補充一點，我們還有一個小型的暴露反應分析海報，將為那些理解這意味著什麼的人發布，它基本上查看了我們最後的 II 期數據，讓我們進一步相信，當你基本上管理更多 efzofitimod，我們看到越來越好的反應。

So this was a third-party analysis done by a sophisticated PK/PD group that is well known to many folks, and we'll be -- everyone will see it on the poster. This is another way that we can look at our Phase II data and say the trends we observed when we now look at it from a more sophisticated statistical PK modeling perspective, the more drug you give with efzofitimod, the better the response. And it also highlights that we're approaching E-Max, which means the 5-milligram dose is about 88%, 90% to its maximal benefit.

所以這是一個第三方分析，由許多人都熟知的複雜 PK/PD 小組完成，我們將會——每個人都會在海報上看到它。這是我們可以查看我們的 II 期數據的另一種方式，並說明我們現在從更複雜的統計 PK 建模角度查看它時觀察到的趨勢，您使用 efzofitimod 的藥物越多，反應越好。它還強調我們正在接近 E-Max，這意味著 5 毫克劑量約為 88%，達到其最大益處的 90%。

Remember, the outstanding benefits we saw in quality of life, steroid reduction and FPC have never really been seen before. Those 3 things, we check the box there that experts have been wanting for the last 50 years. This exposure response will provide even further confidence for those clinicians who really want to see some of the pharmacokinetic data. So 2 very important presentations at ATS. We'll also be spending a lot of time with our investigators, our worldwide investigators, not just from the U.S. but also from Europe and Japan. So it will be a busy week for us or 5 days for us in D.C. in May.

請記住，我們在生活質量、類固醇減少和 FPC 方面看到的顯著好處以前從未真正看到過。這 3 件事，我們勾選了過去 50 年來專家們一直想要的方框。這種暴露反應將為那些真正想要查看某些藥代動力學數據的臨床醫生提供進一步的信心。所以在 ATS 有 2 個非常重要的演講。我們還將花很多時間與我們的調查人員，我們的全球調查人員，不僅來自美國，還來自歐洲和日本。因此，這對我們來說將是忙碌的一周，或者對我們 5 月在華盛頓特區的 5 天。

Our next question comes from the line of Joseph Pantginis of H.C. Wainwright.

我們的下一個問題來自 H.C. 的 Joseph Pantginis。溫賴特。

My name is Sara on for Joe. Just following up on the earlier question regarding SSC ILD. Are there plans currently to initiate the Phase II study outside the U.S.? And then within the U.S., are there particular regions you would expect to see outperform in this study?

我的名字叫 Sara on for Joe。只是跟進之前關於 SSC ILD 的問題。目前是否有在美國以外啟動 II 期研究的計劃？然後在美國，您希望在本研究中看到哪些特定地區表現出色？

Good question. So our current plan is to focus on the U.S. We want to be able to leverage, frankly, the sites that we already have activated in sarcoidosis. Why is this important? Things such as contracts, legal start-up, it's already been negotiated on the sarcoidosis side. So I'll us, for example, and I'm using this as an example, the Cleveland Clinic, which is our lead center for the sarcoidosis trial. Colleagues down the hall in the same pulmonary group will want to launch in efzofitimod. So operationalizing and getting start-up, I think we can be a lot faster than a typical biotech by leveraging the existing sites that are interested and who have the patients in SSc-ILD. We have a lot of interest in Europe and Japan to participate. But right now, the plans are just to sort of stick to the U.S. It is a smaller trial, 25 patients. We're aiming to get proof-of-concept in this trial. And we think focusing on the U.S. here is the best way for us to get readouts as quickly as possible.

好問題。所以我們目前的計劃是專注於美國。坦率地說，我們希望能夠利用我們已經在結節病中激活的網站。為什麼這很重要？諸如合同、合法啟動之類的事情，已經在結節病方面進行了談判。所以我舉個例子，我用克利夫蘭診所作為例子，它是我們結節病試驗的牽頭中心。同一個肺組的同事將希望在 efzofitimod 中啟動。因此，運營和啟動，我認為我們可以比典型的生物技術快得多，方法是利用感興趣的現有站點以及擁有 SSc-ILD 患者的站點。我們對歐洲和日本的參與非常感興趣。但現在，這些計劃只是在某種程度上堅持美國。這是一項規模較小的試驗，有 25 名患者。我們的目標是在這次試驗中獲得概念驗證。我們認為在這里關注美國是我們盡快獲得讀數的最佳方式。

Right now, that's a plan I really feel good about given the fact that we have existing relationships with more than 30 centers in the U.S. And we're not going to need 30 centers for this trial. We'll probably focus on a core, say, 10 or 12 once we launch.

現在，考慮到我們與美國 30 多個中心建立了現有關係，而且我們不需要 30 個中心來進行這項試驗，這個計劃我真的很滿意。一旦我們發布，我們可能會專注於一個核心，比如 10 或 12。

Great, yes. That's helpful. And if I could, I'll ask one more. You reported dosing your first patient last month with your partner Kyorin in Japan. Can you give any color on the current enrollment trajectory there? Anything you can reveal about likely size or anything regarding trajectory in Japan in general?

太好了，是的。這很有幫助。如果可以的話，我會再問一個。上個月，您報告說與您在日本的合作夥伴 Kyorin 一起給您的第一位患者服用藥物。你能給那里當前的入學軌跡任何顏色嗎？你能透露任何關於日本的可能規模或任何關於日本總體軌蹟的信息嗎？

Japan, I mean we're thrilled. We're getting started there. Of course, that kicked off a $10 million -- we've received a $10 million milestone payment from our partner, Kyorin. It's a very important component of our trial. We expect to potentially enroll about -- somewhere in the neighborhood of about 10% of our patients from Japan. So you're looking at, say, 25, 26 patients. Thus far, the trajectory has been great in Japan. I've been very happy with the performance there in general.

日本，我的意思是我們很激動。我們從那裡開始。當然，這啟動了 1000 萬美元——我們已經從我們的合作夥伴 Kyorin 那裡收到了 1000 萬美元的里程碑付款。這是我們試驗的一個非常重要的組成部分。我們預計可能會招收約 10% 左右的日本患者。所以你正在看，比方說，25、26 名患者。到目前為止，日本的發展軌跡一直很好。總的來說，我對那裡的表現非常滿意。

Also, the pace of enrollment, I'm very encouraged by where we are globally. So right now, there's competition between sites and countries and we continue to generate goodwill that way. The goal here is to really focus on executing this trial in Japan is an important component. And thus far, very pleased with the fast start there.

此外，註冊的速度，我對我們在全球的位置感到非常鼓舞。所以現在，網站和國家之間存在競爭，我們繼續以這種方式產生商譽。這裡的目標是真正專注於在日本執行這項試驗，這是一個重要組成部分。到目前為止，對那裡的快速啟動非常滿意。

Our next question comes from the line of Yale Jen of Laidlaw.

我們的下一個問題來自 Laidlaw 的 Yale Jen。

Congrats on the progress. In terms of SSc-ILD trials, I recall one of the secondary endpoint in the skin analysis about 12 weeks versus the primary endpoint of 24 weeks. Just curious what's the sort of rationale behind it? And then I have another follow-up.

祝賀進步。就 SSc-ILD 試驗而言，我記得皮膚分析中的次要終點之一是大約 12 週，而主要終點是 24 週。只是好奇其背後的基本原理是什麼？然後我有另一個後續行動。

Yes, Yale. We are going to be able to look at cutaneous in SSc-ILD. As you point out, had about 12 weeks in the protocol, we're going to do some sampling to be able to look at, first of all, any kind of immune cell change that we see in those skin plaques. We may look at some of the visual changes, quality of life, things of that nature. So the advantage of SSc-ILD is easier access to skin readouts unlike sarcoidosis, where a very small percentage of patients have cutaneous nodules. These scleroderma patients are going to have skin manifestations and we believe efzofitimod could positively impact these manifestations.

是的，耶魯。我們將能夠在 SSc-ILD 中觀察皮膚。正如你指出的那樣，在協議中有大約 12 週的時間，我們將進行一些採樣，以便能夠首先查看我們在這些皮膚斑塊中看到的任何類型的免疫細胞變化。我們可能會關註一些視覺上的變化、生活質量以及那些性質的東西。因此，SSc-ILD 的優勢是更容易獲得皮膚讀數，這與結節病不同，結節病中只有極少數患者有皮膚結節。這些硬皮病患者將出現皮膚表現，我們相信 efzofitimod 可以對這些表現產生積極影響。

So we'll be looking at 12 weeks to see if we see any changes at the local histopath level, but also just clinically as well. So it is going to allow us to have a early read on the skin readouts while we really focus on lung, which has been the approved endpoint for the existing therapies for efzofitimod.

所以我們將觀察 12 週，看看我們是否在局部組織病理學水平上看到任何變化，但也只是在臨床上。因此，當我們真正關注肺部時，它將允許我們及早讀取皮膚讀數，肺部已成為 efzofitimod 現有療法的批准終點。

Okay. Great. Maybe just one more question here that given the Phase I -- given the study will be on the stable background medicines, would this, too, initially considered as a "second line therapy" or you have other thoughts in terms of how to position this drug in the SSc-ILD space in effects?

好的。偉大的。也許這裡還有一個問題，考慮到第一階段——考慮到研究將針對穩定的背景藥物，這最初是否也會被視為“二線療法”，或者您對如何定位它有其他想法藥物在 SSc-ILD 空間中的作用？

Yes. So mycophenolate is the standard of care for when you have scleroderma. Some docs can try other kinds of immunosuppressants as well but scleroderma typically is treated systemically by mycophenolate. And mycophenolate does a pretty good job in helping those patients. However, once you develop interstitial lung disease, there is a much more serious complication. And there, mycophenolate has not been able to really show the same utility as it does systemically.

是的。因此黴酚酸酯是硬皮病患者的標準治療方法。一些醫生也可以嘗試其他種類的免疫抑製劑，但硬皮病通常通過黴酚酸酯進行全身治療。黴酚酸酯在幫助這些患者方面做得很好。然而，一旦患上間質性肺病，就會出現更嚴重的並發症。在那裡，黴酚酸酯無法真正顯示出與系統性相同的效用。

We need a better therapy for these patients, and that's a more serious diagnosis. So once you progress to become fibrotic in your lungs and you have inflammation, now you have SSc-ILD. And this is where we think efzofitimod can have an advantage and play a role. So it could work on top of mycophenolate. It can help these patients in a way mycophenolate can't. So in many ways, it would be a first-line therapy for SSc-ILD, but it would be an add-on therapy for scleroderma patients.

我們需要為這些患者提供更好的治療方法，這是一個更嚴重的診斷。因此，一旦您的肺部進展為纖維化並且出現炎症，現在您就患有 SSc-ILD。而這正是我們認為 efzofitimod 可以發揮優勢並發揮作用的地方。所以它可以在黴酚酸酯之上發揮作用。它可以以黴酚酸酯無法提供的方式幫助這些患者。因此，在許多方面，它將成為 SSc-ILD 的一線療法，但它將成為硬皮病患者的附加療法。

What I don't know is if efzofitimod could also have some systemic effects. We're going to be looking at that as well because we are looking at cutaneous pulmonary and systemic. And there's also the potential for efzofitimod to do some positive things for these patients systemically working with or without mycophenolate.

我不知道 efzofitimod 是否也有一些全身性的影響。我們也將對此進行研究，因為我們正在研究皮膚肺和全身。 efzofitimod 也有可能為這些全身性使用或不使用黴酚酸酯的患者做一些積極的事情。

So this is going to be allowed in the next trial. I mean there could be -- most patients I would expect to be on mycophenolate. Could there be some that are not for various reasons, tox could be a reason, well then efzofitimod could be attractive. So we'll be able to look at with or without mycophenolate. But right now, I would anticipate most of these patients will be already on that for their systemic disease.

所以這將在下一次審判中被允許。我的意思是可能有——我預計大多數患者都會服用黴酚酸酯。是否有一些不是出於各種原因，tox 可能是一個原因，那麼 efzofitimod 可能很有吸引力。所以我們可以看看有沒有黴酚酸酯。但現在，我預計這些患者中的大多數已經因為他們的全身性疾病接受了治療。

Congrats on the progress so far.

祝賀目前取得的進展。

Thanks, Yale.

謝謝，耶魯。

I'm showing no further questions at this time. I turn the call back over to Sanjay Shukla for any closing remarks.

我現在沒有進一步的問題。我將電話轉回給 Sanjay Shukla 以聽取任何結束語。

Great. Great questions today. I appreciate everyone's interest. Tough tape today, a tough day to put out earnings. But I really think that moving forward, we are going to be focusing on execution here. Really paramount for us to keep our heads down, move these trials forward and aim for readouts here and expect good things here for -- in 2024 and 2025. So thank you all for your interest. Be well.

偉大的。今天的好問題。我感謝大家的興趣。今天的大盤艱難，發布收益的艱難日子。但我真的認為，向前邁進，我們將在這裡專注於執行。對我們來說，保持低調、推進這些試驗並以這裡的讀數為目標並期待這裡的好事是最重要的——在 2024 年和 2025 年。所以感謝大家的關注。好起來。

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.

謝謝。女士們，先生們，今天的會議到此結束。謝謝大家的參與。您現在可以斷開連接。祝你有美好的一天。