Celldex Therapeutics Inc (CLDX) 2021 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Celldex Therapeutics Year-End 2021 Conference Call.

女士們、先生們，感謝你們的耐心等待，並歡迎參加 Celldex Therapeutics 2021 年終電話會議。

(Operator Instructions)

（操作員說明）

Please be advised that today's conference is being recorded.

請注意，今天的會議正在錄製中。

(Operator Instructions)

（操作員說明）

I would now like to hand the conference over to your speaker today, Sarah Cavanaugh. Thank you. Please go ahead.

我現在想把會議交給今天的發言人莎拉·卡瓦諾 (Sarah Cavanaugh)。謝謝。請繼續。

Good afternoon, and welcome to the Celldex Therapeutics Fourth Quarter and Full Year 2021 Financial Results and Corporate Update Conference Call.

下午好，歡迎參加 Celldex Therapeutics 2021 年第四季度和全年財務業績和公司最新動態電話會議。

Just to remind everyone, certain matters discussed in today's conference call and/or answers that may be given to questions asked are forward-looking statements that are subject to risks and uncertainties relating to future events and/or the financial future performance of the company. Actual results could differ materially from those anticipated in these forward-looking statements. The risk factors that may affect results are detailed in Celldex's most recent filings with the U.S. Securities and Exchange Commission, including our annual report on Form 10-K for the year ended December 31, 2021, which can be found on our website, celldex.com, or on sec.gov.

只是提醒大家，今天的電話會議中討論的某些事項和/或可能對提出的問題作出的回答屬於前瞻性陳述，這些陳述受到與未來事件和/或公司未來財務業績相關的風險和不確定性的影響。實際結果可能與這些前瞻性陳述中的預期存在重大差異。 Celldex 最近向美國證券交易委員會提交的文件中詳細介紹了可能影響結果的風險因素，包括我們截至 2021 年 12 月 31 日的 10-K 表格年度報告，該報告可以在我們的網站 celldex 上找到。 com 或 sec.gov。

A question-and-answer session will follow the formal presentation. As a reminder, the call is being recorded. Our press release and the slides that accompany today's call are posted on our website.

正式演講之後將舉行問答環節。提醒一下，通話正在錄音。我們的新聞稿和今天電話會議附帶的幻燈片已發佈在我們的網站上。

I will now turn the call over to Anthony Marucci, CEO of Celldex Therapeutics. Please go ahead, Anthony.

我現在將把電話轉給 Celldex Therapeutics 首席執行官 Anthony Marucci。請繼續，安東尼。

Thank you, Sarah. Good afternoon, everyone, and thank you for joining us. On today's conference call, we are excited to provide a recap of our recent progress and discuss our ongoing development plans in more detail.

謝謝你，莎拉。大家下午好，感謝您加入我們。在今天的電話會議上，我們很高興能夠回顧我們最近的進展，並更詳細地討論我們正在進行的開發計劃。

Joining me on the call today are Dr. Tibor Keler, Co-Founder and Chief Scientific Officer; Dr. Diane Young, Senior Vice President and Chief Medical Officer; Dr. Margo Heath-Chiozzi, Senior Vice President of Regulatory Affairs; and Dr. Diego Alvarado, our Executive Director of Research are also joining us remotely from our New Haven office for Q&A.

今天和我一起參加電話會議的還有聯合創始人兼首席科學官 Tibor Keler 博士； Diane Young 博士，高級副總裁兼首席醫療官； Margo Heath-Chiozzi 博士，監管事務高級副總裁；我們的研究執行總監迭戈·阿爾瓦拉多 (Diego Alvarado) 博士也將從我們的紐黑文辦公室遠程加入我們進行問答。

We had a very strong year in 2021 with promising clinical data across our programs and follow-on offering that further secured our balance sheet, providing us with an expected cash runway through the end of 2025. In July 2021, we reported positive data from our lead candidate, CDX-0159, a unique mast cell depleting antibody. The Phase I in chronic inducible urticaria results were presented during the late breaking poster discussion session at the EAACI Annual Congress, and demonstrated that patients experienced a 95% complete response rate and an overall response rate of 100% after only a single dose of 0159.

我們在 2021 年度過了非常強勁的一年，我們的項目和後續產品都取得了有希望的臨床數據，進一步確保了我們的資產負債表，為我們提供了到 2025 年底的預期現金跑道。2021 年 7 月，我們報告了我們的積極數據主要候選藥物 CDX-0159，一種獨特的肥大細胞消耗抗體。慢性誘導性蕁麻疹的 I 期結果在 EAACI 年度大會的最新海報討論會上公佈，並表明患者僅在單劑量 0159 後就獲得了 95% 的完全緩解率和 100% 的總體緩解率。

These responses were rapid and durable with a favorable safety profile. Importantly, we validated our serum biomarker, tryptase, by demonstrating correlation with depletion of skin mast cells and with the clinical endpoints. In September of 2021, at the EADV Congress, we further bolstered these results when we reported additional data, demonstrating notable improvements and symptom control and quality of life for the patients on study. In total, these data are unprecedented in this patient population and clearly demonstrate that 0159 has the potential to become an important new treatment option for patients suffering from chronic inducible urticaria.

這些反應快速、持久，且安全性良好。重要的是，我們通過證明與皮膚肥大細胞消耗和臨床終點的相關性來驗證我們的血清生物標誌物類胰蛋白酶。 2021 年 9 月，在 EADV 大會上，我們報告了更多數據，進一步證實了這些結果，證明了研究患者的症狀控制和生活質量顯著改善。總的來說，這些數據在該患者群體中是前所未有的，清楚地表明0159有潛力成為慢性誘導性蕁麻疹患者的重要新治療選擇。

In the latter part of 2021, we initiated two additional studies for CDX-0159: the first, a Phase I healthy volunteer study with our subcutaneous formulation; and the second was the initiation of CDX-0159 and prurigo nodularis in a Phase Ib placebo-controlled study. Today, we are pleased to report positive results from our Phase I subcutaneous formulation of CDX-0159 in healthy volunteers. Subcutaneous administration of CDX-0159 eliminated the mild infusion reactions observed in some individuals dosed with the IV formulation, and we were very pleased that none of the volunteers had injection site reactions as sometimes is observed with some subcutaneous formulations.

2021 年下半年，我們針對 CDX-0159 啟動了兩項額外研究：第一項是使用我們的皮下製劑進行的 I 期健康志願者研究；第二個是在 Ib 期安慰劑對照研究中啟動 CDX-0159 和結節性癢疹。今天，我們很高興地報告 CDX-0159 的 I 期皮下製劑在健康志願者中的積極結果。 CDX-0159 的皮下給藥消除了在一些接受 IV 製劑給藥的個體中觀察到的輕微輸注反應，我們非常高興的是，沒有志願者出現注射部位反應，而有時在某些皮下製劑中觀察到這種反應。

The study also demonstrated favorable pharmacokinetic and pharmacodynamic properties, supporting the use of the subcutaneous formulation in our upcoming Phase II studies in CSU and CIndU as well as other indications moving forward. The successful development of the CDX-0159 subcutaneous formulation is a key step forward in the development of these programs as it offers a convenient administration route to patients and physicians. Tibor will discuss these data in more detail later during this call.

該研究還證明了良好的藥代動力學和藥效學特性，支持我們即將在科羅拉多州立大學和 CIIndU 進行的 II 期研究以及未來的其他適應症中使用皮下製劑。 CDX-0159皮下製劑的成功開發是這些項目開發的關鍵一步，因為它為患者和醫生提供了便捷的給藥途徑。 Tibor 將在稍後的電話會議中更詳細地討論這些數據。

Our strong in-house development capabilities allowed us to rapidly advance this formulation and complete in-house manufacturing activities. In Q1 2022, we initiated the transfer of our current CDX-0159 manufacturing process to a contract manufacture organization to optimize and scale up current process to support late-stage trials and to prepare for future commercialization.

我們強大的內部開發能力使我們能夠快速推進該配方並完成內部製造活動。 2022 年第一季度，我們開始將當前的 CDX-0159 製造工藝轉移給合同製造組織，以優化和擴大當前工藝，以支持後期試驗並為未來的商業化做好準備。

In further support of our Phase II readiness activities for the urticaria studies, we are pleased to report positive interim data after completing the in-life dosing portion of our 6-month chronic toxicology study in nonhuman primates. Results from the study were fully in line with our expectations, and we believe these data strongly support our upcoming Phase II trial initiations in CSU and CIndU next quarter and continued expansion into future indications. Tibor will also discuss these findings in more detail. In addition to our preparation for our Phase II studies in CSU and CIndU, we are expecting more data this year from the CDX-0159, with data from the Phase I multiple ascending dose IV study in chronic spontaneous urticaria, planned to be submitted for presentation at EAACI 2022 in July.

為了進一步支持我們的蕁麻疹研究 II 期準備活動，我們很高興在完成對非人類靈長類動物進行的為期 6 個月的慢性毒理學研究的體內給藥部分後報告積極的中期數據。該研究的結果完全符合我們的預期，我們相信這些數據有力地支持了我們下季度即將在科羅拉多州立大學和工業大學啟動的 II 期試驗，並繼續擴展到未來的適應症。 Tibor 還將更詳細地討論這些發現。除了我們為 CSU 和 CIIndU 的 II 期研究做準備外，我們預計今年 CDX-0159 會提供更多數據，其中包括慢性自發性蕁麻疹 I 期多次遞增劑量 IV 研究的數據，計劃提交演示7 月在 EAACI 2022 上。

On today's call, Diane will provide updates on our pipeline programs and discuss in more detail our expansion into our fourth indication for CDX-0159, eosinophilic esophagitis, or EoE. In assessing future indications for expansion, we consider multiple factors, including the patient need, scientific rationale and what other insights these indications may give us into the potential future opportunities for CDX-0159. EoE is the most important type of eosinophilic gastrointestinal disease, and recent studies have suggested that mast cells may be an important driver in the disease. Given the lack of effective therapies for EoE and CDX-0159 potential as a mast cell depleting agent, we believe that EoE is an important indication and look forward to initiating this new study in the fourth quarter.

在今天的電話會議上，Diane 將提供我們的管道計劃的最新信息，並更詳細地討論我們對 CDX-0159 的第四個適應症（嗜酸粒細胞性食管炎或 EoE）的擴展。在評估未來的擴張適應症時，我們考慮了多種因素，包括患者需求、科學原理以及這些適應症可能為我們帶來 CDX-0159 未來潛在機會的其他見解。 EoE 是最重要的嗜酸性胃腸道疾病類型，最近的研究表明肥大細胞可能是該疾病的重要驅動因素。鑑於 EoE 缺乏有效的治療方法以及 CDX-0159 作為肥大細胞消耗劑的潛力，我們認為 EoE 是一個重要的適應症，並期待在第四季度啟動這項新研究。

At Celldex, our core focus is to mine our deep experience in antibody drug discovery to develop therapeutics for patients with devastating diseases. We seek to design and execute robust rigorous clinical trials as efficiently as possible and in order to support regulatory approvals and provide the broadest possible access to patients who might benefit from our investigational medicines. We believe the updates to our programs outlined today and the emerging data strongly position us to execute on these future goals.

在 Celldex，我們的核心重點是挖掘我們在抗體藥物發現方面的豐富經驗，為患有毀滅性疾病的患者開發治療方法。我們尋求盡可能高效地設計和執行穩健、嚴格的臨床試驗，以支持監管部門的批准，並為可能從我們的研究藥物中受益的患者提供盡可能廣泛的機會。我們相信，今天概述的計劃的更新和新出現的數據使我們能夠強有力地執行這些未來的目標。

With that, I will turn the call over to Tibor to go through the CDX-0159 subcutaneous formulation data results and discuss the completion of the Phase II readiness activities. Tibor?

接下來，我將把電話轉給 Tibor，以查看 CDX-0159 皮下製劑數據結果，並討論 II 期準備活動的完成情況。蒂博爾？

Thanks, Anthony. On Slide 6, you can see the trial design for our randomized, double-blind, placebo-controlled Phase I subcutaneous formulation of CDX-0159 in healthy volunteers. This study evaluated single ascending doses of CDX-0159 at 50, 150, 300 and 600 milligrams administered subcutaneously to healthy volunteers who are then followed for 12 weeks. We enrolled 4 cohorts with 8 volunteers per cohort: 6 active and 2 placebo.

謝謝，安東尼。在幻燈片 6 上，您可以看到我們在健康志願者中進行的隨機、雙盲、安慰劑對照 CDX-0159 I 期皮下製劑的試驗設計。該研究評估了健康志願者皮下注射 50、150、300 和 600 毫克 CDX-0159 的單次遞增劑量，然後隨訪 12 週。我們招募了 4 個隊列，每個隊列 8 名志願者：6 名活躍志願者和 2 名安慰劑志願者。

On Slide 7, you can see an overview of the positive results from the study. The key takeaway here is that CDX-0159 subcutaneous administration demonstrated a favorable safety profile and profound tryptase suppression. A single dose resulted in rapid and sustained decreases in serum tryptase relative to placebo. 0159 was well tolerated at all dose levels, and no injection site reactions were observed.

在幻燈片 7 上，您可以看到該研究的積極結果的概述。這裡的關鍵要點是 CDX-0159 皮下給藥表現出良好的安全性和深刻的類胰蛋白酶抑製作用。與安慰劑相比，單劑量導致血清類胰蛋白酶快速持續下降。 0159 在所有劑量水平下均具有良好的耐受性，並且未觀察到注射部位反應。

On Slide 8, you can see the tryptase data in detail. As I just highlighted, a single dose of 0159 decreased tryptase in a dose-dependent manner, demonstrating profound and sustained tryptase suppression, which importantly, we have shown correlates with mast cell depletions and relief of clinical symptoms of urticaria.

在幻燈片 8 上，您可以看到詳細的類胰蛋白酶數據。正如我剛才強調的，單劑量的 0159 以劑量依賴性方式降低類胰蛋白酶，證明了深刻且持續的類胰蛋白酶抑制，重要的是，我們已經證明這與肥大細胞耗竭和蕁麻疹臨床症狀的緩解相關。

Slide 9 shows the serum tryptase kinetics of the SubQ 300-milligram dose compared to previous studies with the IV 3-milligram per kilogram formulation in healthy volunteers and chronic inducible urticaria patients. I'd like to draw your attention to the fact that tryptase reduction kinetics with the SubQ administrations are rapid and comparable to the kinetics of tryptase decrease observed with the IV dosing.

幻燈片 9 顯示了 SubQ 300 毫克劑量的血清類胰蛋白酶動力學，與之前在健康志願者和慢性誘導性蕁麻疹患者中使用 IV 3 毫克/千克製劑的研究相比。我想提請您注意這樣一個事實，即 SubQ 給藥的類胰蛋白酶減少動力學是快速的，並且與靜脈給藥觀察到的類胰蛋白酶減少動力學相當。

On Slide 10, we show the circulating stem cell factor levels mirror the tryptase data with a rapid dose-dependent increase, which plateaued between three and fourfold over baseline values, suggestive of systemic stem cell factor blockade. Again, when SubQ dosing is compared with IV administration, we observed similar kinetics for this biomarker between the two routes of administration.

在幻燈片 10 上，我們顯示循環幹細胞因子水平反映了類胰蛋白酶數據，並呈劑量依賴性快速增加，穩定在基線值的三到四倍之間，表明系統性幹細胞因子阻斷。同樣，當將 SubQ 給藥與靜脈注射給藥進行比較時，我們觀察到兩種給藥途徑之間該生物標誌物的相似動力學。

Pharmacokinetic data has been completed through day 42 for the 50, 150 and 300-milligram dose cohorts, and are shown on Slide 11. The PK demonstrate dose-dependent exposure is consistent with a subcutaneous administration. For comparison, we also show the pharmacokinetics of CDX-0159 dosed in healthy volunteers by IV administration. Consistent with the similar pharmacodynamic effect on tryptase and stem cell factor, we see that exposures to IV 3-milligram per kilogram is similar to the SubQ 300-milligram flat dose. Together, the PK and PD data give us great confidence in selecting appropriate doses for our Phase II studies.

50、150 和 300 毫克劑量組的藥代動力學數據已在第 42 天完成，並顯示在幻燈片 11 中。PK 表明劑量依賴性暴露與皮下給藥一致。為了進行比較，我們還顯示了健康志願者靜脈注射 CDX-0159 的藥代動力學。與對類胰蛋白酶和乾細胞因子的類似藥效學作用一致，我們發現每公斤 IV 3 毫克的暴露量與 SubQ 300 毫克固定劑量相似。 PK 和 PD 數據共同為我們選擇適合 II 期研究的劑量提供了極大的信心。

A key highlight of this study, as outlined on Slide 12, is that the SubQ dosing was well tolerated across all dose levels. Consistent with our IV healthy volunteer study, no premedications were allowed on study. We were pleased to see that there were no injection site reactions observed with SubQ administration. As a reminder, this compares favorably to the IV administration, where we previously reported 45% to 50% of patients experiencing mild infusion reactions. The vast majority of volunteers treated with 0159 did not report any treatment-related adverse events.

正如幻燈片 12 中所述，本研究的一個關鍵亮點是 SubQ 劑量在所有劑量水平下均具有良好的耐受性。與我們的靜脈注射健康志願者研究一致，研究中不允許進行術前用藥。我們很高興地看到 SubQ 給藥沒有觀察到注射部位反應。提醒一下，這與靜脈注射相比有優勢，我們之前報導過 45% 至 50% 的患者經歷輕度輸注反應。絕大多數接受 0159 治療的志願者沒有報告任何與治療相關的不良事件。

The events we did see over the 12-week follow-up period were mild, almost all grade 1 and resolved quickly, most on the same day they were observed. There were three grade 2 events reported: one in a volunteer treated with 50 milligrams 0159 that developed allergic contact dermatitis on her lips one week after receiving blinded study treatment. The event resolved following treatment with topical creams. The other two events occurred in a second volunteer treated with 600 milligrams 0159, who reported urticaria 4 days post-dosing and the sore in her mouth 8 days after treatment. The urticaria resolved upon treatment with topical creams and antihistamines, and the sore resolved without treatment.

在 12 週的隨訪期間，我們確實看到的事件都很輕微，幾乎都是 1 級，並且很快就解決了，大多數在觀察到的同一天就解決了。報告了三起 2 級事件：一名接受 50 毫克 0159 治療的志願者在接受盲法研究治療一周後，嘴唇出現過敏性接觸性皮炎。使用外用乳膏治療後，該事件得到解決。另外兩起事件發生在接受 600 毫克 0159 治療的第二名志願者身上，她在用藥後 4 天報告出現蕁麻疹，在治療後 8 天出現口腔潰瘍。蕁麻疹在使用外用乳膏和抗組胺藥治療後消退，潰瘍無需治療也消退。

Slide 13 outlines the mild and asymptomatic decreases in hematology parameters that were observed in the study. Presented here are the mean values over time for each of the active groups overlaid on the placebo 95% confidence interval of the mean shown as the blue-shaded region. The dotted line at the bottom displays the lower limit of normal. As you can see, the mean white blood cells and absolute neutrophil count generally fall within the 95% confidence interval for the placebo and are within the normal range for the analytes. Overall, we are very satisfied with the results from this study, and are excited to provide patients with a more convenient form of drug administration that will also benefit the execution of the upcoming Phase II clinical trials.

幻燈片 13 概述了研究中觀察到的血液學參數的輕微且無症狀的下降。這裡呈現的是每個活動組隨時間的平均值，疊加在安慰劑的平均值的 95% 置信區間上，顯示為藍色陰影區域。底部的虛線顯示正常的下限。正如您所看到的，平均白細胞和絕對中性粒細胞計數通常落在安慰劑的 95% 置信區間內，並且位於分析物的正常範圍內。總的來說，我們對這項研究的結果非常滿意，並很高興為患者提供更方便的給藥方式，這也將有利於即將進行的 II 期臨床試驗的執行。

In further support of our Phase II urticaria program, we recently completed the in-life dosing portion of our 6-month chronic toxicology study. This study was a standard chronic toxicology study designed to support longer-term dosing in our Phase II study. We conducted the study in sexually mature nonhuman primates to allow us to also capture data on potential impact on reproductive organs. In the study, dosing was every 2 weeks at 10 or 75 milligrams per kilogram for 6 months, resulting in much higher exposure than we will use in humans. Tox studies, by their nature, are designed to inform about potential toxicities, by exceeding the exposure expected in them.

為了進一步支持我們的 II 期蕁麻疹項目，我們最近完成了為期 6 個月的慢性毒理學研究的體內給藥部分。這項研究是一項標準的慢性毒理學研究，旨在支持我們的 II 期研究中的長期給藥。我們在性成熟的非人類靈長類動物中進行了這項研究，以便我們能夠捕獲對生殖器官潛在影響的數據。在這項研究中，劑量為每兩週一次，劑量為每公斤 10 或 75 毫克，持續 6 個月，導致暴露量比我們在人類中使用的暴露量要高得多。毒性研究的本質是通過超出預期的暴露量來了解潛在的毒性。

Today, we are summarizing the high-level findings from the interim data report that is based on analysis at the completion of the dosing portion of the study at 26 weeks. This study will also continue to follow a subset of animals beyond clearance of the CDX-0159 antibody.

今天，我們總結了中期數據報告的高水平研究結果，該報告基於 26 週時研究給藥部分完成時的分析。這項研究還將繼續跟踪 CDX-0159 抗體清除後的一部分動物。

On Slide 15, we provide an overview of these findings. The only clinically adverse finding reported was on spermatogenesis, an expected and well-understood effect of KIT inhibition. Importantly, previous studies have demonstrated full reversibility of impaired spermatogenesis upon removal of KIT inhibition. I want to emphasize, there were no other clinically adverse findings or unexpected results reported in the study. Extended dosing and exposure did not further impact hematology, and these data were consistent with prior results from our 13-week study and within normal ranges for the species. We believe these data support our previously stated expectation that chronic dosing with CDX-0159 will prolong, but not enhance KIT suppression. CDX-0159 continues to demonstrate a well-tolerated safety profile, and we believe these data strongly support the company's Phase II programs and future indications.

在幻燈片 15 中，我們概述了這些發現。報告的唯一臨床不良發現是對精子發生的影響，這是 KIT 抑制的預期且眾所周知的影響。重要的是，先前的研究已經證明，在去除 KIT 抑制後，受損的精子發生是完全可逆的。我想強調的是，該研究中沒有報告其他臨床不良發現或意外結果。延長劑量和暴露不會進一步影響血液學，這些數據與我們之前 13 週研究的結果一致，並且處於該物種的正常範圍內。我們相信這些數據支持我們之前提出的預期，即長期服用 CDX-0159 將延長但不會增強 KIT 抑制。 CDX-0159 繼續展現出良好的耐受性安全性，我們相信這些數據有力地支持了該公司的 II 期計劃和未來的適應症。

I will now turn the call over to Diane to expand on the clinical update.

我現在將把電話轉給黛安，以詳細介紹臨床最新情況。

Thanks, Tibor. As you can see outlined on Slide 17, in the two years since we first introduced this molecule, we have made considerable progress, even with the backdrop of a global pandemic. We have advanced our Phase I development, completed the critical SubQ and chronic tox studies necessary to support the initiation of Phase II clinical trials in CSU and CIndU next quarter, and have expanded development into two additional indications: prurigo nodularis last year; and the eosinophilic esophagitis this year.

謝謝，蒂博爾。正如幻燈片 17 中概述的那樣，自我們首次引入該分子以來的兩年裡，即使在全球大流行的背景下，我們也取得了相當大的進展。我們已經推進了 I 期開發，完成了支持下季度在 CSU 和 CIIndU 啟動 II 期臨床試驗所需的關鍵 SubQ 和慢性毒物研究，並將開發擴展到另外兩個適應症：去年的結節性癢疹；還有今年的嗜酸粒細胞性食管炎。

As Anthony mentioned and supported by the data presented today, our Phase II CSU and CIndU trials are on track, and expected to initiate later in the second quarter of this year, an important next step for this program. The chronic tox study results were exactly as we expected and planned. And with the biologic activity seen in both our CIndU study and the SubQ healthy volunteer study, we are confident we have identified the appropriate therapeutic doses to advance into our Phase II clinical studies. We believe that with the compelling data we've seen to date across our clinical trials and with the success of the SubQ formulation, our future 0159 studies will be very appealing to patients and their physicians.

正如 Anthony 提到的並得到今天提供的數據的支持，我們的 CSU 和 CIIndU 的 II 期試驗正在按計劃進行，預計將於今年第二季度晚些時候啟動，這是該計劃的重要下一步。慢性毒性研究結果完全符合我們的預期和計劃。根據 CIIndU 研究和 SubQ 健康志願者研究中觀察到的生物活性，我們相信我們已經確定了適當的治療劑量，可以進入 II 期臨床研究。我們相信，憑藉我們迄今為止在臨床試驗中看到的令人信服的數據以及 SubQ 配方的成功，我們未來的 0159 研究將對患者及其醫生非常有吸引力。

We are initiating two Phase II studies in urticaria to begin next quarter: one in chronic spontaneous urticaria; and one in chronic inducible urticaria. In the inducible study, we plan to enroll patients with the two most common forms of inducible urticaria: symptomatic dermographism; and cold urticaria, which make up over 75% of all inducible urticaria. The CSU and CIndU studies will both be placebo-controlled, double-blinded, multi-dose studies in 150 to 200 patients each. We are planning to evaluate doses of 75 milligrams and 150 milligrams administered every 4 weeks and 300 milligrams administered every 8 weeks. These doses will be administered as 0.5 to 2-millimeter injection volumes, allowing for a single injection as we advance towards potential commercialization.

我們將於下個季度開始開展兩項針對蕁麻疹的 II 期研究：一項針對慢性自發性蕁麻疹；另一項針對慢性自發性蕁麻疹。一種是慢性誘導性蕁麻疹。在誘導性研究中，我們計劃招募患有兩種最常見形式的誘導性蕁麻疹的患者：症狀性皮膚划痕症；和寒冷性蕁麻疹，佔所有誘發性蕁麻疹的 75% 以上。 CSU 和 CIIndU 的研究均為安慰劑對照、雙盲、多劑量研究，各有 150 至 200 名患者參與。我們計劃評估每 4 週給藥 75 毫克和 150 毫克以及每 8 週給藥 300 毫克的劑量。這些劑量將以 0.5 至 2 毫米的注射量進行給藥，以便在我們邁向潛在商業化的過程中進行單次注射。

Our Phase I IV studies in both spontaneous and inducible urticaria and prurigo nodularis continue to enroll patients. We remain on track to submit data from the CSU multi-dose study for a late-breaking presentation at the July EAACI meeting, including the 0.5, 1.5 and 3-milligram per kilogram cohorts. Our focus and priority moving forward will be on advancing later-stage programs with the SubQ formulation and exploring 0159's potential across a growing broad development plan as we also complete the ongoing IV studies.

我們對自發性和誘導性蕁麻疹和結節性癢疹的 I IV 期研究仍在繼續招募患者。我們仍在按計劃提交 CSU 多劑量研究的數據，以便在 7 月的 EAACI 會議上進行最新報告，其中包括每公斤 0.5、1.5 和 3 毫克組。我們前進的重點和優先事項將是通過 SubQ 配方推進後期項目，並在我們完成正在進行的 IV 研究的同時，探索 0159 在不斷增長的廣泛開發計劃中的潛力。

With this in mind, we have amended our Phase I prurigo nodularis trial to make this trial simpler for patients and physicians and support our enrollment goals. We have decreased the study population from 40 to 30 patients and will assess single doses at 1.5 and 3 milligrams per kilogram compared to placebo, following patients for 24 weeks after dosing. These changes to the PN study enable us to achieve our clinical goals in a more efficient patient-friendly manner so we can move into subcutaneous study.

考慮到這一點，我們修改了 I 期結節性癢疹試驗，以使該試驗對患者和醫生來說更簡單，並支持我們的入組目標。我們將研究人群從 40 名患者減少到 30 名患者，並將評估單劑量每公斤 1.5 毫克和 3 毫克與安慰劑相比，在患者服藥後 24 週進行隨訪。 PN 研究的這些變化使我們能夠以更有效、患者友好的方式實現我們的臨床目標，以便我們可以進入皮下研究。

As we've discussed in the past, after reading out the CIndU data at EAACI last summer, we added two additional exploratory cohorts to increase our learnings: a 1.5-milligram per kilogram cohort in cold urticaria; and a 3-milligram per kilogram cohort in cholinergic urticaria. Enrollment to both these cohorts is ongoing. We are working to expand outreach for the cholinergic cohort. We were hopeful that by including this cohort, we can learn more about cholinergic urticaria as it is less well understood than other forms of inducible urticaria. That said, it has been challenging to identify appropriate patients. In multiple cases, patients who have presented to the clinic with symptoms consistent with cholinergic urticaria have not tested positive on provocation testing and exercise bike test.

正如我們過去討論過的，在去年夏天讀完 EAACI 的 CIIndU 數據後，我們添加了兩個額外的探索性隊列來增加我們的知識：冷性蕁麻疹每公斤 1.5 毫克的隊列；以及每公斤 3 毫克的膽鹼能蕁麻疹隊列。這兩個群體的註冊工作正在進行中。我們正在努力擴大膽鹼能人群的覆蓋範圍。我們希望通過納入這一隊列，我們可以更多地了解膽鹼能蕁麻疹，因為它比其他形式的誘導性蕁麻疹不太了解。也就是說，確定合適的患者一直是一項挑戰。在多個病例中，就診時出現與膽鹼能蕁麻疹症狀一致的患者在激發試驗和運動自行車測試中並未呈陽性。

We will continue to study because we would like to add to the knowledge base in the field on this indication, but we will not have data in July as we'd originally hoped. And moving forward, we will allow it to enroll at its own pace in the background. As I said earlier, this has no impact on our future plans for inducible urticaria, where we have planned to advance in the more common forms of the disease: cold urticaria; and symptomatic dermographism.

我們將繼續研究，因為我們希望增加該領域的知識庫，但我們不會像我們最初希望的那樣在 7 月份獲得數據。展望未來，我們將允許它在後台按照自己的節奏進行註冊。正如我之前所說，這對我們未來針對誘導性蕁麻疹的計劃沒有影響，我們計劃推進更常見的疾病形式：寒冷性蕁麻疹；和症狀性皮膚划痕症。

We are also excited to expand clinical development of CDX-0159 into eosinophilic esophagitis, the most common type of use in eosinophilic gastrointestinal disease. As you see on Slide 19, EoE is a chronic inflammatory disease of the esophagus, characterized by the infiltration of eosinophils. This chronic inflammation can result in troubled swallowing, chest pain, vomiting and impaction of food in the esophagus, which is a medical emergency.

我們還很高興將 CDX-0159 的臨床開發擴展到嗜酸性粒細胞性食管炎，這是嗜酸性粒細胞性胃腸道疾病最常見的應用類型。正如您在幻燈片 19 中看到的，EoE 是一種食道慢性炎症性疾病，其特徵是嗜酸性粒細胞浸潤。這種慢性炎症會導致吞嚥困難、胸痛、嘔吐和食物嵌塞食道，這是一種醫療緊急情況。

One of the more interesting things we have learned as we explored this indication is the thought leaders in the field have suggested eosinophilic esophagitis may be a misnomer, and it may more be called allergic esophagitis. This is where we believe CDX-0159 comes into play. Several studies have suggested that mast cells may be an important driver in the disease, and Slide 20 outlines some of this evidence.

當我們探索這一適應症時，我們了解到的更有趣的事情之一是該領域的思想領袖提出嗜酸粒細胞性食管炎可能是一個誤稱，它可能更應該被稱為過敏性食管炎。我們認為這就是 CDX-0159 發揮作用的地方。多項研究表明肥大細胞可能是該疾病的重要驅動因素，幻燈片 20 概述了其中的一些證據。

Mast cells are significantly increased in the biopsies of the esophagus in patients with EoE, including the esophageal epithelium. There is also strong evidence of mast cell activation and degranulation, which is correlated with inflammation, immune infiltration, fibrosis and pain associated with the disease. Furthermore, mast cells are associated with EoE-specific molecular signatures. Increased mast cells have also been found in biopsies of patients with histologic eosinophilic remission, but who still have persistent symptoms in endoscopic findings.

EoE 患者的食管活檢（包括食管上皮）中肥大細胞顯著增加。還有強有力的證據表明肥大細胞激活和脫粒，這與疾病相關的炎症、免疫浸潤、纖維化和疼痛有關。此外，肥大細胞與 EoE 特異性分子特徵相關。在組織學嗜酸性粒細胞緩解但內鏡檢查中仍然有持續症狀的患者的活檢中也發現了肥大細胞的增加。

Currently, there are limited treatment options for EoE. Individuals often participate in an elimination diet to identify potential food allergens that may contribute to EoE, avoid difficult to swallow foods and undergo esophageal dilation. While not approved for EoE, proton pump inhibitors and the swallowing of topical corticosteroids are also used to address the disease. Industry sources estimate, there are approximately 160,000 patients in the United States with EoE, who have undergone treatment within the last 12 months, and of these, approximately 48,000 would be biologic eligible.

目前，EoE 的治療選擇有限。人們經常參與消除飲食，以識別可能導致 EoE 的潛在食物過敏原，避免難以吞嚥的食物並進行食道擴張。雖然未獲批准用於 EoE，但質子泵抑製劑和吞嚥局部皮質類固醇也可用於治療該疾病。業內人士估計，美國大約有 160,000 名 EoE 患者在過去 12 個月內接受過治療，其中大約 48,000 名患者符合生物學資格。

Given the high unmet need in EoE, the compelling science that mast cells may be key drivers of esophageal inflammation and CDX-0159's potential as a mast cell depleting agent, we believe EoE is an important indication for future study. We look forward to initiating a Phase II study using our subcutaneous formulation in EoE in the fourth quarter.

鑑於 EoE 的需求尚未得到滿足，令人信服的科學表明肥大細胞可能是食管炎症的關鍵驅動因素，以及 CDX-0159 作為肥大細胞消耗劑的潛力，我們相信 EoE 是未來研究的重要指標。我們期待在第四季度在 EoE 中使用我們的皮下製劑啟動 II 期研究。

We are very pleased with the progress we have made overall, and in particular, with our successful efforts toward the advancement of CDX-0159 to the next stage of development. We believe CDX-0159 is a potential pipeline in a product and 2022 should be an exciting year. Alongside CDX-0159, our oncology program, CDX-1140 and CDX-527 continue to enroll patients, and we look forward to providing updates on these programs later in 2022.

我們對整體取得的進展感到非常高興，特別是對我們為將 CDX-0159 推進到下一開發階段所做的成功努力。我們相信 CDX-0159 是一個潛在的產品線，2022 年應該是令人興奮的一年。除了 CDX-0159 之外，我們的腫瘤學項目 CDX-1140 和 CDX-527 繼續招募患者，我們期待在 2022 年晚些時候提供這些項目的更新。

With that, I will ask Anthony to close the call.

這樣，我會要求安東尼結束通話。

Thank you, Diane. To summarize on Slide 22, we believe the data presented today further support the unique profile of CDX-0159, and suggests a potential treatment option, which could represent a significant advancement over current standard of care in the treatment of diseases with mast cell involvement. On Slide 23, you can see an overview of our expected initial 2022 milestones. We ended the year of 2021 with $408 million cash, supporting a cash runway through 2025. With multiple ongoing clinical trials and expected data readout this summer, we are very well positioned to execute and further advance our pipeline. Lastly, I'd like to thank all the patients and the physicians who are collaborating with us to advance treatment options in these diseases.

謝謝你，黛安。總結幻燈片 22，我們相信今天提供的數據進一步支持 CDX-0159 的獨特特徵，並提出了一種潛在的治療選擇，這可能代表著肥大細胞參與疾病的治療相對於當前護理標準的重大進步。在幻燈片 23 上，您可以看到我們預期的 2022 年初始里程碑的概述。截至 2021 年，我們擁有 4.08 億美元現金，支持到 2025 年的現金跑道。通過多項正在進行的臨床試驗和今年夏天的預期數據讀出，我們完全有能力執行和進一步推進我們的產品線。最後，我要感謝所有與我們合作推進這些疾病的治療方案的患者和醫生。

I'd like to now open up the call for questions. Operator, if you can begin the Q&A session, please?

我現在想開始提問。接線員，您可以開始問答環節嗎？

(Operator Instructions)

（操作員說明）

Your first question comes from the line of Yatin Suneja from Guggenheim Partners.

你的第一個問題來自古根海姆合夥人公司的 Yatin Suneja。

Just a couple for me. Maybe first on the Phase Ib data that's coming at EAACI. Number one, do you anticipate including any refractory -- any patients that are refractory to biologic? And then with regard to your disclosure, it seems like the 4.5-milligram cohort data might not be there. Do you need data from that cohort before you hone in a dose for future study or do you think the 3-milligram is enough to get you the full information as you think about the dosing?

對我來說只是一對。也許首先是 EAACI 即將發布的 Ib 期數據。第一，您預計會包括任何難治性患者——任何對生物製劑耐藥的患者嗎？然後，根據您披露的情況，4.5 毫克隊列數據似乎不存在。在為未來的研究確定劑量之前，您是否需要該隊列的數據，或者您認為 3 毫克足以讓您在考慮劑量時獲得完整信息？

Yes. Thanks, Yatin. I'll let Diane take that question.

是的。謝謝，亞汀。我會讓黛安回答這個問題。

Yatin, yes, we have included in the study. We have allowed patients to enroll that are refractory to biologic therapy. So we expect some of those patients in the study. And in terms of the 4.5-milligram cohort, no, we don't believe that we need that data to move forward. We believe that based on the compelling clinical activity we've seen at the 3-milligram per kilogram IV and then the recent data with the SubQ with the profound reductions of tryptase at 300-milligram that we will not need that dose to go forward.

Yatin，是的，我們已經納入研究範圍。我們允許生物治療難治的患者入組。因此，我們預計其中一些患者會參與研究。就 4.5 毫克隊列而言，不，我們認為我們不需要這些數據來推進。我們相信，基於我們在 3 毫克每公斤 IV 劑量下所看到的令人信服的臨床活性，以及​​ SubQ 的最新數據以及類胰蛋白酶在 300 毫克劑量下的大幅減少，我們將不需要繼續使用該劑量。

Got it. Then maybe just one more on the SubQ, and then I'll go back in the queue. Can you just talk about the heme profile that you are seeing with SubQ, how it might be relative to the IV dosing? And with regard to the two heme parameter that you disclosed, neutrophils and white blood cell counts, did you see any patient that went below the normal range?

知道了。然後也許再在 SubQ 上再講一個，然後我就會回到隊列中。您能談談您在 SubQ 中看到的血紅素分佈嗎？它與靜脈注射劑量有何關係？至於你透露的兩個血紅素參數，中性粒細胞和白細胞計數，你是否看到任何病人低於正常範圍？

Yes. So basically, we see a similar -- very similar and consistent profile to what we've seen before in terms of just mild decreases in heme parameters. Margo may want to comment further.

是的。所以基本上，我們看到了與我們之前看到的類似的、非常相似且一致的情況，只是血紅素參數略有下降。瑪戈可能想進一步發表評論。

Yatin, this is Margo. Yes, so as shown on Slide 13, that have very similar to what we saw with IV in normal volunteers. And we did include the shaded area, which is the 95% confidence interval on the placebos. In terms of any excursions out of the normal range, as we've said from previous studies, again, in this study, the subjects you start closest to the bottom of the normal range are the ones that are most likely to see a transient excursion below and then come back.

雅汀，這是瑪戈。是的，如幻燈片 13 所示，這與我們在正常志願者中通過靜脈注射看到的情況非常相似。我們確實包括了陰影區域，即安慰劑的 95% 置信區間。就任何超出正常範圍的偏移而言，正如我們在之前的研究中所說，在這項研究中，您開始最接近正常範圍底部的受試者是最有可能出現短暫偏移的受試者下面然後再回來。

So the consistent pattern of drop that then stabilizes and comes back with continued observation is what we across normal volunteers and the patients that were dosed between mg per kg in the inducible urticaria study. So it really is a very consistent pattern and doesn't look different than what we've previously seen.

因此，在誘導性蕁麻疹研究中，我們對正常志願者和服用毫克/公斤之間劑量的患者進行了一致的下降模式，然後穩定下來並通過持續觀察恢復。所以它確實是一個非常一致的模式，看起來與我們之前看到的沒有什麼不同。

Got it. If I can squeeze one more question. So with regard to the new indication, the EoE indication, I think you touched on a certain phenotype that are more associated with mast cell activity. Are there biomarkers that can help you find these patients or enroll these patients as you plan a Phase II?

知道了。如果我能再問一個問題的話。因此，關於新的適應症，EoE 適應症，我認為您觸及了與肥大細胞活性更相關的某種表型。在您計劃 II 期臨床試驗時，是否有生物標誌物可以幫助您找到這些患者或招募這些患者？

So Diego may know that. Diego, do you know the biomarkers that we're looking at?

所以迭戈可能知道這一點。迭戈，你知道我們正在研究的生物標誌物嗎？

No, I don't think there's any biomarker that I know of necessarily that would predict that. I think maybe Diane can comment further on this, but we will -- we plan to just enroll all-comers from the point of view of mast cell involvement.

不，我認為據我所知，沒有任何生物標誌物能夠預測這一點。我想也許黛安可以對此發表進一步評論，但我們會——我們計劃從肥大細胞參與的角度招募所有參與者。

Yes. So for -- yes, for our study, we're going to -- for this initial study, we're going to look at really what we consider a biologic eligible population that's clearly diagnosed with EoE because we really want to really understand what happens to the mast cells and then understand better what biomarkers might be used in the future.

是的。所以對於——是的，對於我們的研究，我們將——對於這項初步研究，我們將真正了解我們認為明確診斷為 EoE 的生物學合格人群，因為我們真的想真正了解什麼發生在肥大細胞上，然後更好地了解未來可能使用哪些生物標誌物。

Does that help, Yatin?

這有幫助嗎，雅汀？

Yes, very good.

是的，很好。

Your next question comes from the line of Chris Howerton from Jefferies.

您的下一個問題來自 Jefferies 的 Chris Howerton。

Great. I guess, the one for me was just maybe an easy clarification. With respect to the CSU data for the Phase Ib, I assume that's informing your Phase II work in that indication. Is that going to be gating before you actually start the Phase II or do you already have those data and you're just not sharing it? And I guess, I was just a little confused as to how the kind of current Phase Ib is going to inform and gate going into the Phase II, if at all.

偉大的。我想，這對我來說可能只是一個簡單的澄清。關於 Ib 期的 CSU 數據，我認為這為您在該適應症中的 II 期工作提供了信息。在你真正開始第二階段之前，這是否會被限制，或者你是否已經擁有這些數據，但你只是不分享它？我想，我只是有點困惑，不知道當前的 Ib 階段將如何通知和控制進入 II 階段（如果有的話）。

And then the second question I had was, I guess, was there any kind of other findings with respect to (inaudible) production, let's say, with female nonhuman primates? Was there any observations there? And as the -- just equate to that, I guess, for Diego, what would be the kind of kinetics in terms of the expectations for normalization for spermatogenesis to kind of resume.

然後我的第二個問題是，我想，關於（聽不清）生產，比如說，雌性非人類靈長類動物，是否有任何其他發現？那裡有什麼觀察嗎？我想，對於迭戈來說，就相當於這一點，對於精子發生正常化以恢復的預期而言，動力學是什麼樣的。

Okay. So let's go with Diego first since that was your last question, and then we'll work backwards. Diego?

好的。所以讓我們先談談迭戈，因為這是你的最後一個問題，然後我們再倒著回答。迭戈？

Yes. Thanks. So obviously, from the point of view of 0159, we don't know necessarily the kinetics. What we do know is that at least in mice, it takes about a month for -- from count to resume once it's been ablated. So we might expect a bit of a lag once the drug clears.

是的。謝謝。顯然，從 0159 的角度來看，我們不一定知道其動力學。我們所知道的是，至少在小鼠中，一旦被消融，從計數到恢復需要大約一個月的時間。因此，一旦藥物清除，我們可能會預期會有一點滯後。

So Chris, it's Margo. Just to point out that we need 0159 to clear out of the system before you'd expect primate recovery of hematogenesis. And so because 0159 was given at such high doses, we expect it to take a good long time before the antibody gets cleared, and then we'll see sperm recovery. So it's not going to be something that occurs quickly. People might have a better understanding of what we think the time profile would be, but it will take quite a long time to clear the primates first.

克里斯，是瑪戈。只是想指出，在靈長類動物恢復造血功能之前，我們需要 0159 從系統中清除。因此，由於 0159 的劑量如此之高，我們預計抗體需要很長時間才能被清除，然後我們就會看到精子恢復。所以這不會是很快發生的事情。人們可能會更好地理解我們認為的時間概況，但首先清除靈長類動物需要相當長的時間。

Yes, that's a good point, Margo. And we expect to be able to inform further about the recovery from this hematogenesis probably late this year.

是的，這是一個很好的觀點，瑪戈。我們預計可能會在今年晚些時候進一步了解造血的恢復情況。

Okay. And was there any observations in female (inaudible) at production?

好的。生產時對雌性（聽不清）有任何觀察嗎？

No. So we were very pleased to see that from this study, we did not observe any effects in terms of -- from a histology analysis of female reproductive organs. So that certainly is very, very comforting. And we do have additional work to do on potential reproductive effects, but our data so far really supports lack of any significant concern from a female reproduction point of view.

不會。所以我們很高興地看到，從這項研究中，我們沒有觀察到任何影響——從女性生殖器官的組織學分析來看。所以這確實非常非常令人欣慰。關於潛在的生殖影響，我們確實還有更多的工作要做，但到目前為止，我們的數據確實支持從女性生殖的角度來看，沒有任何重大問題。

Yes, this is Diane. So in terms of the CSU data, it's not gating. We don't need that information to plan the study -- initiate a study.

是的，這是黛安。所以就科羅拉多州立大學的數據而言，它不是門控。我們不需要這些信息來計劃研究——啟動研究。

Your next question comes from the line of Thomas Smith from SVB Leerink.

您的下一個問題來自 SVB Leerink 的 Thomas Smith。

Congrats on the progress. So sort of a follow-up on the Phase Ib CSU study and the 4.5 mg per kg dose. Understand that the data aren't going to be EAACI, and they're not going to be gating for the Phase II study. But are you still planning to enroll this cohort? And if so, when do you think we'll have visibility into that data? And then separately, when can we expect to see the initial data from the Phase Ib 1.5 mg per kg cold year to carry a cohort?

祝賀取得的進展。這是 Ib 期 CSU 研究和每公斤 4.5 毫克劑量的後續行動。請理解，這些數據不會是 EAACI，也不會成為 II 期研究的門控。但您還打算招收這個群體嗎？如果是這樣，您認為我們什麼時候可以看到這些數據？另外，我們什麼時候可以看到 Ib 期 1.5 mg/kg 冷年的初始數據？

Okay. This is Diane again. So in terms of the Phase Ib CSU, we are planning to enroll that cohort. That's really a matter of just wanting to have additional data at exposures higher than you're planning to go forward early in the drug development program. In terms of the 1.5-milligram per kilogram dose data, we're going to enroll that, and we'll present it at a subsequent meeting when we have sufficient data. We haven't really guided a specific date.

好的。這又是黛安。因此，就 Ib 期 CSU 而言，我們計劃招募該群體。這實際上只是想獲得比您計劃在藥物開發項目早期進行的暴露更高的額外數據。至於每公斤1.5毫克的劑量數據，我們將進行登記，當我們有足夠的數據時，我們將在隨後的會議上介紹它。我們還沒有真正確定具體的日期。

Okay. Great. And just a follow-up, I guess, Tibor, on maybe your comments. Can you just walk us through, I guess, the remaining reproductive tox work, both that's ongoing as well as planned?

好的。偉大的。我想，Tibor，這只是對您的評論的後續行動。我想，您能否向我們介紹一下剩餘的生殖毒素工作，無論是正在進行的還是計劃中的？

Sure. So these are standard toxicology studies that are required by and well outlined by FDA guidelines that we would look at the effect of antibody treatment in pregnant -- through pregnancy and birth, and that's -- these are called ePPND studies. And those are studies that will evaluate the effect of 0159 on fetus development and birth. Again, our expectation there is based on what's known in the literature is really not concerning, but of course, we need to go through those studies. We also believe we will need to do some juvenile toxicology studies before we go into pediatric populations, and of course, there's some evaluation in terms of development of reproductive organs there as well. The timing is not fully developed yet, but we're working with the CROs to get those done soon.

當然。因此，這些是 FDA 指南所要求和詳細概述的標準毒理學研究，我們將研究抗體治療在懷孕期間（整個懷孕和分娩）的效果，這就是 - 這些稱為 ePPND 研究。這些研究將評估 0159 對胎兒發育和出生的影響。同樣，我們的期望是基於文獻中已知的內容，這實際上並不令人擔憂，但當然，我們需要進行這些研究。我們還認為，在進入兒童群體之前，我們需要進行一些青少年毒理學研究，當然，也需要對生殖器官的發育進行一些評估。時機尚未完全確定，但我們正在與 CRO 合作，盡快完成這些工作。

Your next question comes from the line of Sam Slutsky from LifeSci Capital.

您的下一個問題來自 LifeSci Capital 的 Sam Slutsky。

Just two quick ones for me. First, for cholinergic urticaria, I guess, is there a potential to include that CIndU subtype in the registrational study or should we mainly be focused on SD and cold urticaria as we think about potential approvals?

對我來說只有兩個快速的。首先，對於膽鹼能蕁麻疹，我想是否有可能將 CIndU 亞型納入註冊研究，或者在考慮潛在批准時我們應該主要關注 SD 和寒冷性蕁麻疹？

Sam, yes, this is Diane. I mean, I think potentially for the Phase III, we might include it. I think, right now, we're focusing on the two most common forms, the ones that are best understood, which are cold and symptomatic dermographism, and we're continuing to enroll in our cohort to see if we can learn more about finding the right patient population and treating them.

薩姆，是的，這是黛安。我的意思是，我認為對於第三階段，我們可能會將其包括在內。我認為，現在我們重點關注兩種最常見的形式，也是最容易理解的形式，即感冒和症狀性皮膚病，我們將繼續加入我們的隊列，看看我們是否可以了解更多關於尋找正確的患者群體並對其進行治療。

Okay. Got it. And then lastly, too, just outside of the ongoing reproductive preclinical studies, I guess, any other key ones that are needed at this point or we treat the bulk of them?

好的。知道了。最後，我想，除了正在進行的生殖臨床前研究之外，目前還需要任何其他關鍵研究，或者我們對其中的大部分進行治療？

I'm sorry. I can't hear quite -- yes.

對不起。我聽不太清——是的。

Sam, we didn't quite hear that. Can you say that again?

薩姆，我們沒聽清楚。你能再說一遍嗎？

Yes. I was saying, outside of the ongoing reproductive preclinical studies, I guess, are you through the bulk of preclinical tox studies, or are there any others that we should expect updates on?

是的。我是說，除了正在進行的生殖臨床前研究之外，我想，您是否完成了大量的臨床前毒性研究，或者還有其他我們應該期待的更新嗎？

These are the major studies that need to be executed for support of 0159. So the current 6-month chronic study is one that performed to support the chronic dosing that we plan to do with our Phase II programs going forward. So we're in good shape.

這些是支持 0159 需要執行的主要研究。因此，當前為期 6 個月的長期研究是為了支持我們計劃在未來的 II 期項目中進行的長期給藥而進行的一項研究。所以我們的狀態很好。

And Tibor brought out the other piece that we would need to do the juvenile indications, and we're working on those as well.

蒂博爾提出了我們需要做青少年適應症的另一件事，我們也在研究這些。

Your next question is from the line of Kristen Kluska from Cantor Fitzgerald.

您的下一個問題來自康托·菲茨杰拉德 (Cantor Fitzgerald) 的克里斯汀·克魯斯卡 (Kristen Kluska)。

The first one I had is, whether you had any thoughts on how the placebo arm might perform in the CSU study across the key end points at different times based on what we've seen from other data sets, including some findings that were reported over the weekend? And then on efficacy, getting a lot of questions specifically about what you would view as success here, and how much of this might be determined based on understanding the patient profiles on an individual basis, such as their previous exposure to biologics.

我的第一個問題是，根據我們從其他數據集中看到的情況（包括報告的一些發現），您是否對安慰劑組在 CSU 研究中在不同時間的關鍵終點上的表現有何想法？週末？然後是關於功效，特別是關於您認為什麼是成功的問題，以及其中有多少可以根據了解患者的個人資料（例如他們以前接觸過生物製劑）來確定。

This is for the CSU study, Kristen?

這是科羅拉多州立大學的研究，克里斯汀？

Yes.

是的。

Yes. So yes, in terms of the placebo response, I think there -- it depends on what endpoint you're looking at and what study. There is anywhere from 20% to 40% in some of the endpoints we're looking at. I think -- does that answer your question? Did you have something more specific?

是的。所以，是的，就安慰劑反應而言，我認為這取決於你正在研究的終點和研究的內容。我們正在研究的一些端點的比例在 20% 到 40% 之間。我想——這能回答你的問題嗎？你有更具體的事情嗎？

Yes. No, that's fine.

是的。不，沒關係。

Okay. And then in terms of success criteria for the CSU study, we've always said that we're expecting to see results similar to or better than what's been seen with Xolair, which -- in one or more dose groups, given that we're looking at several doses and reasonably small numbers of patients. But yes, so about a 50% response in terms of having well control urticaria by UAS7, and then hopefully having a good percentage of those be complete response.

好的。然後，就 CSU 研究的成功標準而言，我們總是說，我們期望看到與 Xolair 相似或更好的結果，在一個或多個劑量組中，考慮到我們“正在研究幾種劑量和相當少量的患者。但是，是的，所以就通過 UAS7 很好地控制蕁麻疹而言，大約有 50% 的反應，然後希望其中有很大一部分是完全反應。

Right. And we're also anxious to see how we would do with the recurrent patient study as well, Kristen.

正確的。我們也很想知道我們如何進行定期患者研究，克里斯汀。

Yes. And we expect that the people who are recurrent after Xolair should respond as do naive with the same way that we saw that in our (inaudible) patients.

是的。我們預計 Xolair 治療後復發的患者應該像天真的患者一樣做出反應，就像我們在（聽不清）患者中看到的那樣。

Okay. And then I know part of your strategy in choosing indications for 0159 has been to understand specific disease aspects such as it for PN. So when you chose EoE as the fourth indication, maybe could you speak to what you're hoping to learn more broadly across the platform with this indication as well as some future opportunities that could go beyond EoE and understanding the role of 0159 in mast cells here?

好的。然後我知道你們選擇 0159 適應症的部分策略是了解特定的疾病方面，例如 PN。因此，當您選擇 EoE 作為第四個適應症時，也許您可以談談您希望通過該適應症在整個平台上更廣泛地了解什麼，以及一些可能超越 EoE 並了解 0159 在肥大細胞中的作用的未來機會這裡？

Yes. So we're very excited about EoE because of the recent data that suggests that mast cells can be a driver in the disease as well as the unmet medical need. Another really nice thing is that as routine care in these patients, they require biopsies. So it's a really -- we'll be able to see really, really well what actually happens to tissue mast cells in the GI track and really understand what's going on, and that could lead us to other gastrointestinal diseases where mast cells are involved.

是的。因此，我們對 EoE 感到非常興奮，因為最近的數據表明肥大細胞可能是該疾病以及未滿足的醫療需求的驅動因素。另一件非常好的事情是，作為這些患者的常規護理，他們需要進行活檢。因此，我們將能夠非常非常清楚地看到胃腸道組織肥大細胞實際上發生了什麼，並真正了解正在發生的事情，這可能會導致我們患上與肥大細​​胞有關的其他胃腸道疾病。

Your next question comes from the line of Joe Pantginis from H.C. Wainwright.

您的下一個問題來自 H.C. 的 Joe Pantginis。溫賴特。

I guess, I just want to go back in -- regarding the spermatogenesis observation in the nonhuman primates. So I guess, can you -- I'll do 3 things: clarify, expand and even repeat a little bit of what you just said that these nonhuman primates obviously are -- a couple of you said are receiving very high doses. So that's part of the observation. These doses are much higher than what would be seen in the clinic. So what level of confidence do you have that this may or may not be seen once it reaches with regard to human doses?

我想，我只是想回到關於非人類靈長類動物精子發生的觀察。所以我想，你能——我會做三件事：澄清、擴展，甚至重複一下你剛才所說的，這些非人類靈長類動物顯然是——你們說的其中一些正在接受非常高的劑量。這就是觀察的一部分。這些劑量比臨床上看到的劑量要高得多。那麼，一旦達到人體劑量，您對這種情況是否會出現的信心有多大？

This is Tibor, Joe. I'll take that question. So let me start by clarifying or expanding or repeating what we said, which was that the one single clinically adverse finding reported from our 6-month chronic tox study was an impact on spermatogenesis, which we fully expected because this has been well described and studied as an effect of KIT inhibition. We also discussed that prior studies that have published on antibodies that impact -- that block KIT signaling have reported this effect in spermatogenesis, both in mice as well as in nonhuman primates, and in both cases, have reported full reversibility of that.

這是蒂博爾，喬。我來回答這個問題。首先，讓我澄清、擴展或重複我們所說的話，即我們為期 6 個月的慢性毒性研究報告的一項臨床不良發現是對精子發生的影響，這是我們完全預料到的，因為這已經得到了充分的描述和研究。作為 KIT 抑制的作用。我們還討論了之前發表的關於阻斷 KIT 信號傳導的抗體的研究報告了在小鼠和非人類靈長類動物的精子發生中的這種效應，並且在這兩種情況下，都報告了這種效應的完全可逆性。

The dose response with regards to what our expectations are is unclear. As you mentioned, we use extremely high doses when we do toxicology studies and repeated dosing, which accumulates in these animals. So that's perhaps something that we can learn in terms of as the antibody clears, and we see reversibility. We might be able to make some predictions about dose levels that are relevant to impact spermatogenesis, but at this point, that would be speculation.

關於我們預期的劑量反應尚不清楚。正如您提到的，我們在進行毒理學研究和重複給藥時使用極高劑量，這些劑量會在這些動物體內積累。因此，這也許是我們可以從抗體清除方面了解到的東西，並且我們看到了可逆性。我們也許能夠對與影響精子發生相關的劑量水平做出一些預測，但目前這還只是猜測。

Sure. No, that's helpful color. And I guess I'd like to maybe just go to a higher level now with regard to urticaria from a macro standpoint. Obviously, even over the last month or so, the field has seen a lot of additional news from other competitive products or other assets in urticaria -- for treating urticaria. And I guess, I'm not asking for a compare and contrast, but look, you've certainly made the case already regarding the role of mast cells as the underlying core part of the disease. So I guess, I would ask my question this way. Do you feel that any of the other approaches out there may be complementary to 0159 approach?

當然。不，這是有用的顏色。我想，從宏觀的角度來看，我想也許現在就蕁麻疹而言，我想達到一個更高的水平。顯然，即使在過去一個月左右的時間裡，該領域也看到了許多來自蕁麻疹的其他競爭產品或其他資產的額外消息——用於治療蕁麻疹。我想，我並不是要求進行比較和對比，但是看，您肯定已經證明了肥大細胞作為疾病的潛在核心部分的作用。所以我想，我會這樣問我的問題。您認為其他方法是否可以補充 0159 方法？

Complementary?

補充？

Yes.

是的。

I don't like to use the word competitive because I think just our mechanism of action is different. Where they're targeting receptors on the mast cell, we are targeting the mass cell itself. So I just think that our mechanism of action is different than the others that are out there.

我不喜歡用競爭這個詞，因為我認為只是我們的行動機制不同。他們針對肥大細胞上的受體，而我們則針對質量細胞本身。所以我只是認為我們的作用機制與其他的不同。

Sure. No, very fair. And just to switch gears real quick, thanks for the patience. Regarding 1140 and 527, Diane, you mentioned about how things are going and hopefully get a little view on how enrollment is going overall? And how should we view your communication strategy around those two programs? Are you really gaining -- obviously, it's data driven, but are you gaining around certain patient numbers, or overall, what should we expect?

當然。不，非常公平。只是為了快速切換，感謝您的耐心等待。關於 1140 和 527，Diane，您提到了事情的進展情況，希望能了解一下總體註冊情況？我們應該如何看待你們圍繞這兩個項目的溝通策略？你真的有所收穫嗎？顯然，這是數據驅動的，但是你是否在某些患者數量上有所收穫，或者總體而言，我們應該期待什麼？

This is Tibor again, Joe, I think we're -- as you know in the expansion cohorts for both of those programs and our view is, we'd like to complete enrollment into those expansion cohorts and then we'd have something more meaningful to say about the next steps for each of those.

又是蒂博爾，喬，我想我們——正如你所知，在這兩個項目的擴展隊列中，我們的觀點是，我們希望完成這些擴展隊列的註冊，然後我們會有更多的東西談論其中每一個的後續步驟都是有意義的。

We have a follow-up from Chris Howerton from Jefferies.

我們有傑富瑞 (Jefferies) 克里斯·豪爾頓 (Chris Howerton) 的後續報導。

I guess, one would be, I just wanted to clarify, Anthony, I think you were saying that you had started a tech transfer for CDMO for 0159. Has -- is it started or has it been completed, or I guess, how would you characterize the status of that process? Was it just a clarification?

我想，其中一個是，我只是想澄清一下，安東尼，我想你是說你已經開始了 0159 的 CDMO 技術轉讓。已經——它開始了嗎？已經完成了，或者我猜，如何您描述了該過程的狀態嗎？這只是澄清嗎？

Yes, it's been started, and we'll complete it sometime this year. But it has been started. Work has already been done.

是的，它已經開始，我們將在今年某個時候完成。但它已經開始了。工作已經完成。

Got it. And then the other one is probably early, and I'm sure you guys -- I know what you'll say already, but I'll ask anyway, which is, if you look at the volumes of your subcutaneous formulations, probably can't be self-administered. So I guess, is that correct in my estimation that, that will probably be administered by some sort of medical staff? And if that's true, do you think that, that matters from a commercialization perspective?

知道了。然後另一個可能是早期的，我相信你們 - 我已經知道你們會說什麼，但無論如何我都會問，也就是說，如果你看看皮下製劑的體積，可能可以不要自我管理。所以我想，我的估計是否正確，這可能會由某種醫務人員來管理？如果這是真的，您認為從商業化的角度來看這重要嗎？

I think that long term, we are going to try to formulate it. So it is self-administering Chris. I mean, obviously, we'll try to work through that through clinical development, but we're going to start it out as being administered by a professional in the clinical trials and that work our way that upon commercialization that they would be self-administered.

我認為從長遠來看，我們將嘗試制定它。所以這是克里斯的自我管理。我的意思是，顯然，我們將嘗試通過臨床開發來解決這個問題，但我們將首先由專業人士在臨床試驗中進行管理，並以我們的方式進行，在商業化時，它們將是自我的管理。

Yes. Just to add to what Anthony said, the current doses that we're planning range from 0.5 to 2 milliliters, which are within the range of what patients eventually could self-administer.

是的。補充一下安東尼所說的，我們目前計劃的劑量範圍是 0.5 到 2 毫升，這在患者最終可以自行給藥的範圍內。

Congratulations on the progress.

祝賀取得的進展。

We also have a follow-up from Yatin Suneja from Guggenheim.

我們還有來自古根海姆的 Yatin Suneja 的後續作品。

This is on EoE and it's more related to the mechanism of actions. Can you just talk about what is the relationship or what do we know about the relationship between mast cells numbers and eosinophil numbers? Because it is our understanding that in EoS -- in EoE, the clinical endpoint is actually -- you have to show a reduction in EoS numbers. I'm just trying to get a sense of what is that relationship.

這是關於EoE的，它更多地與作用機制相關。您能否談談肥大細胞數量和嗜酸性粒細胞數量之間的關係是什麼？或者我們對肥大細胞數量和嗜酸性粒細胞數量之間的關係了解多少？因為我們的理解是，在 EoS 中——在 EoE 中，臨床終點實際上是——你必須顯示 EoS 數量的減少。我只是想了解一下這種關係是什麼。

Sure. I can ask Diego to take that. Diego?

當然。我可以請迭戈接受。迭戈？

Yes. Thanks, Yatin. I appreciate the question. So we -- there is a lot of evidence in the literature, both in, I think, in EoE and other disorders and just biological studies that eosinophils and mast cells regulate one another and form couples, and mast cells are known to secrete other mediators, for example, Interleukin-5, which is known to recruit eosinophils.

是的。謝謝，亞汀。我很欣賞這個問題。因此，我認為，文獻中有很多證據，無論是在 EoE 和其他疾病中，還是在生物學研究中，都表明嗜酸性粒細胞和肥大細胞相互調節並形成伴侶，並且眾所周知，肥大細胞會分泌其他介質例如，白細胞介素 5（Interleukin-5），已知它可以募集嗜酸性粒細胞。

And we know based on preclinical studies, albeit in different needs eosinophilic disorders that the precursor molecule to 0159 actually significantly reduces eosinophil infiltration into the relevant tissues. So I think there's a strong rationale for believing that mast cells will influence us infill infiltration after the secretion of Th-2 cytokines, including IL-5.

根據臨床前研究我們知道，儘管在不同需要的嗜酸性粒細胞疾病中，0159的前體分子實際上顯著減少了嗜酸性粒細胞浸潤到相關組織中。因此，我認為有充分的理由相信肥大細胞在分泌 Th-2 細胞因子（包括 IL-5）後會影響我們的填充浸潤。

I am showing no further questions at this time. I would now like to turn the conference back to Anthony Marucci.

我目前沒有提出任何進一步的問題。現在我想把會議轉回由安東尼·馬魯奇主持。

Thank you, operator, and thanks, everyone, today for joining with us. We are very excited, and look forward to providing future updates as soon throughout the year. So have a great night and look forward to catching up soon. Thank you.

謝謝運營商，也謝謝大家今天加入我們。我們非常興奮，並期待在全年盡快提供未來的更新。祝您度過一個愉快的夜晚，並期待很快能趕上。謝謝。

This concludes today's conference call. Thank you all for your participation. You may now disconnect.

今天的電話會議到此結束。感謝大家的參與。您現在可以斷開連接。