ADC Therapeutics SA (ADCT) 2022 Q4 法說會逐字稿

Welcome to the ADC Therapeutics Fourth Quarter and Full Year 2022 Financial Results Conference Call. My name is Andrea, and I will be your operator for today's call.

歡迎參加 ADC Therapeutics 第四季度和 2022 年全年財務業績電話會議。我叫安德里亞，我將擔任今天電話會議的接線員。

(Operator Instructions) I will now turn the call over to Amanda Loshbaugh, Investor Relations Manager. Amanda, you may begin.

（操作員說明）我現在將電話轉給投資者關係經理 Amanda Loshbaugh。阿曼達，你可以開始了。

Thank you, operator. This morning, we issued a press release announcing our fourth quarter and full year 2022 financial results and business updates. This release is available on the ADCT website at ir.adctherapeutics.com under the Press Releases section.

謝謝你，運營商。今天上午，我們發布了一份新聞稿，宣布了我們第四季度和 2022 年全年的財務業績和業務更新。該新聞稿可在 ADCT 網站 ir.adctherapeutics.com 的新聞稿部分下獲取。

On today's call, Ameet Mallik, Chief Executive Officer; Kristen Harrington-Smith, Chief Commercial Officer; Mohamed Zaki, Chief Medical Officer; and Pepe Carmona, Chief Financial Officer, will discuss recent business highlights and review our fourth quarter and full year 2022 financial results before opening the call for questions.

在今天的電話會議上，首席執行官 Ameet Mallik； Kristen Harrington-Smith，首席商務官； Mohamed Zaki，首席醫療官；和首席財務官 Pepe Carmona 將討論最近的業務亮點，並在開始提問之前回顧我們第四季度和 2022 年全年的財務業績。

Before we begin, I would like to remind listeners that some of the statements made during this conference call will contain forward-looking statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Examples of forward-looking statements include those related to our future financial and operating results; our ability to achieve our guidance for 2023 ZYNLONTA revenue; operating expenses and cash requirement projections; future revenue growth; prescription volumes; product launches and market share for our products, either alone or through our foreign partners; timing and results of ongoing and future development programs and clinical trials for our products, either alone or in combination with our partner products; FDA and foreign regulatory authorities actions and potential regulatory approval for our products, either alone or in combination with our strategic partners' products; future strategic partnerships and business development efforts; and our ability to repay our outstanding debt obligations.

在我們開始之前，我想提醒聽眾，在本次電話會議中所做的一些陳述將包含前瞻性陳述，這些陳述符合 1995 年美國私人證券訴訟改革法案安全港條款的含義。前瞻性示例報表包括與我們未來的財務和經營業績相關的報表；我們有能力實現我們對 2023 年 ZYNLONTA 收入的指導；運營費用和現金需求預測；未來的收入增長；處方量；我們產品的產品發布和市場份額，無論是單獨還是通過我們的外國合作夥伴；我們產品正在進行和未來的開發計劃和臨床試驗的時間安排和結果，無論是單獨使用還是與我們的合作夥伴產品結合使用； FDA 和外國監管機構對我們的產品採取的行動和潛在的監管批准，無論是單獨使用還是與我們的戰略合作夥伴的產品結合使用；未來的戰略夥伴關係和業務發展努力；以及我們償還未償債務的能力。

These forward-looking statements are subject to certain risks and uncertainties, and actual results could differ materially. They are identified and described in today's press release and the accompanying slide presentation on Slide 2 and in the company's filings with the SEC on Form 20-F and is updated in ADCT's recent periodic filings on Form 6-K. ADCT is providing this information as of the date of today's conference call and does not undertake any obligation to update any forward-looking statements contained in this conference call as a result of new information, future events or circumstances after the date hereof, except as required by law or otherwise. The company cautions investors not to place undue reliance on these forward-looking statements.

這些前瞻性陳述受某些風險和不確定性的影響，實際結果可能存在重大差異。它們在今天的新聞稿和幻燈片 2 上的隨附幻燈片演示以及公司向美國證券交易委員會提交的 20-F 表格文件中進行了識別和描述，並在 ADCT 最近定期提交的 6-K 表格文件中進行了更新。 ADCT 在今天的電話會議之日提供此信息，並且不承擔任何義務根據本協議日期之後的新信息、未來事件或情況更新本電話會議中包含的任何前瞻性陳述，除非另有要求通過法律或其他方式。該公司告誡投資者不要過分依賴這些前瞻性陳述。

Today's presentation also includes non-IFRS financial measures. These non-IFRS measures have limitations as financial measures and should be considered in addition to and not in isolation or as a substitute for the information prepared in accordance with IFRS. You should refer to the information contained in the company's fourth quarter and full year earnings release for definitional information and reconciliations of historical non-IFRS measures to the comparable IFRS financial measures.

今天的演示文稿還包括非 IFRS 財務措施。這些非 IFRS 措施作為財務措施有局限性，應作為根據 IFRS 編制的信息的補充而不是孤立地考慮或替代。您應參考公司第四季度和全年收益發布中包含的信息，了解歷史非 IFRS 措施與可比 IFRS 財務措施的定義信息和調節。

It is now my pleasure to pass the call over to Ameet Mallik. Ameet?

現在我很高興將電話轉給 Ameet Mallik。見面？

Thanks, Amanda, and thank you all for joining us today. 2022 was a year of evolution for ADC Therapeutics, a year in which we laid the groundwork to help optimize ZYNLONTA's potential, prioritized our pipeline, strengthened our leadership team and bolstered our capital position, all with the intention of elevating the company to the next level.

謝謝，阿曼達，感謝大家今天加入我們。 2022 年是 ADC Therapeutics 發展的一年，這一年我們奠定了基礎以幫助優化 ZYNLONTA 的潛力，優先考慮我們的管道，加強我們的領導團隊並鞏固我們的資本狀況，所有這些都是為了將公司提升到一個新的水平.

We are now positioned to execute our strategic initiatives in 2023 and unlock the tremendous untapped value of the company. We expect to see this value unfold to our 3 core pillars of growth: Maximizing the ZYNLONTA opportunity, advancing our PBD-based pipeline and expanding our ADC platform.

我們現在準備在 2023 年執行我們的戰略計劃，釋放公司巨大的未開發價值。我們希望看到這一價值體現在我們的三大增長核心支柱上：最大限度地利用 ZYNLONTA 機會，推進我們基於 PBD 的管道並擴展我們的 ADC 平台。

Beginning with the highlights of the quarter, ZYNLONTA net sales were $19.8 million in the fourth quarter, a 16.5% increase year-over-year, and $74.9 million for the full year. We are encouraged to see strong underlying trends and have a focused plan in place to help drive future growth. Kristen will take you through these initiatives momentarily.

從季度亮點開始，ZYNLONTA 第四季度淨銷售額為 1980 萬美元，同比增長 16.5%，全年為 7490 萬美元。我們很高興看到強勁的潛在趨勢，並製定了一個重點計劃來幫助推動未來的增長。克里斯汀將帶您暫時了解這些舉措。

By executing successfully, we expect to drive ZYNLONTA net sales by a double-digit percentage year-over-year, even when taking into account the gross to net headwinds and expected approval of bispecifics. We also expect ZYNLONTA to achieve commercial brand profitability this year and for its sales to begin funding pipeline development by the end of the year.

通過成功執行，我們預計 ZYNLONTA 淨銷售額同比增長兩位數，即使考慮到總淨逆風和雙特異性藥物的預期批准。我們還預計 ZYNLONTA 今年將實現商業品牌盈利，其銷售將在年底前開始為管道開發提供資金。

As a reminder, while success in the third line and third line-plus setting is hugely important, we believe this patient segment only represents around 20% of the commercial potential for ZYNLONTA. The larger opportunity lies in combinations in earlier-stage settings. Here, we firmly believe that ZYNLONTA's strong single-agent activity and manageable side effect profile make it an ideal combination partner of choice.

提醒一下，雖然在三線和三線以上環境中取得成功非常重要，但我們認為這一患者群體僅代表 ZYNLONTA 商業潛力的 20% 左右。更大的機會在於早期設置中的組合。在這裡，我們堅信 ZYNLONTA 強大的單藥活性和可控的副作用特徵使其成為理想的首選聯合合作夥伴。

We are exploring ZYNLONTA in combination with rituximab in earlier lines of therapy in the LOTIS-5 and LOTIS-9 studies. We are also excited about combining ZYNLONTA with bispecifics which we are investigating in the LOTIS-7 study. If we are able to expand our approved indication and capture earlier lines, we believe combination opportunities for ZYNLONTA have the potential to deliver peak annual sales of between $500 million and $1 billion in the U.S., with additional opportunity through partnerships ex U.S.

在 LOTIS-5 和 LOTIS-9 研究中，我們正在探索 ZYNLONTA 與利妥昔單抗聯合用於早期治療。我們也很高興將 ZYNLONTA 與我們正在 LOTIS-7 研究中研究的雙特異性結合。如果我們能夠擴大我們批准的適應症並獲得更早的產品線，我們相信 ZYNLONTA 的組合機會有可能在美國實現 5 億至 10 億美元的峰值年銷售額，並通過美國以外的合作夥伴關係獲得更多機會。

Regarding geographic expansion, we were very pleased to see ZYNLONTA receive approval in December from the European Commission and the U.K. MHRA for the treatment of relapsed or refractory DLBCL. Subsequently, on February 7, our European partner, Sobi, received conditional marketing authorization. We are encouraged that the team is making good progress and expect Sobi to launch in Europe in the second quarter of this year.

關於地域擴張，我們很高興看到 ZYNLONTA 於 12 月獲得歐盟委員會和英國 MHRA 的批准，用於治療復發或難治性 DLBCL。隨後，2 月 7 日，我們的歐洲合作夥伴 Sobi 獲得了有條件的營銷授權。我們對團隊取得的良好進展感到鼓舞，並期待 Sobi 將於今年第二季度在歐洲推出。

As I turn to the rest of our pipeline, we are looking forward to multiple value-driving catalysts across our portfolio in the next 12 to 18 months, including preliminary data for ADCT-901, targeting KAAG1; and ADCT-601, targeting AXL. In an effort to prioritize these programs and to potentially capture the full opportunity for ZYNLONTA, we made the decision not to pursue further clinical development of Cami on our own. But instead, to seek a partnership based on its positive Phase II data. We are strategically advancing the rest of our portfolio programs, and Mohamed will provide a more detailed update in a few minutes.

當我轉向我們的其他管道時，我們期待在未來 12 到 18 個月內在我們的產品組合中出現多種價值驅動催化劑，包括針對 KAAG1 的 ADCT-901 的初步數據；和 ADCT-601，針對 AXL。為了優先考慮這些項目並為 ZYNLONTA 抓住潛在的全部機會，我們決定不再自行進行 Cami 的進一步臨床開發。而是根據其積極的 II 期數據尋求合作夥伴關係。我們正在戰略性地推進我們其餘的投資組合計劃，Mohamed 將在幾分鐘內提供更詳細的更新。

Touching briefly on the financials. At year-end, we have a strong balance sheet with $326 million in cash. And with the anticipated milestone payments and lower operating expenses, we expect our cash runway to extend into mid-2025.

簡要介紹一下財務狀況。年底時，我們的資產負債表強勁，現金達 3.26 億美元。隨著預期的里程碑付款和較低的運營費用，我們預計我們的現金跑道將延長至 2025 年年中。

Moving to recent corporate events and as disclosed in regulatory filings, our largest shareholder, Auven Therapeutics, completed a secondary sale of a significant portion of its holdings to meet a debt obligation. The secondary offering of 12 million shares was placed in the hands of high-quality investors and has allowed us to broaden and strengthen our shareholder base. Following the completion of the transaction, Auven's holdings has decreased from approximately 28% of outstanding shares in December to roughly 8% after the offering, and its remaining shares are locked up for 12 months. The high level of interest shown by top-tier investors during the process was especially encouraging.

轉向最近的公司事件，正如監管文件中所披露的那樣，我們的最大股東 Auven Therapeutics 完成了對其持有的大部分股份的二次出售，以履行債務義務。二次發行的 1200 萬股股票交到了優質投資者手中，使我們能夠擴大和加強我們的股東基礎。交易完成後，奧文的持股量已從12月約28%的已發行股份減少至發行後的約8%，其剩餘股份被鎖定12個月。頂級投資者在此過程中表現出的高度興趣尤其令人鼓舞。

Last but certainly not least, I'm thrilled that we have been able to continue to strengthen our management team with the addition of truly high-caliber professionals. I would like to take this opportunity to welcome Kristen Harrington-Smith, our Chief Commercial Officer; Mohamed Zaki, our Chief Medical Officer; and Pepe Carmona, our Chief Financial Officer. We believe these new leaders bring the necessary capabilities to unlock the full value of the company and will be critical in advancing us through the next phase of growth.

最後但同樣重要的是，我很高興我們能夠通過增加真正高素質的專業人士來繼續加強我們的管理團隊。我想藉此機會歡迎我們的首席商務官 Kristen Harrington-Smith； Mohamed Zaki，我們的首席醫療官；和我們的首席財務官 Pepe Carmona。我們相信，這些新領導者俱備釋放公司全部價值所必需的能力，並將對推動我們進入下一階段的增長起到關鍵作用。

In the next 3 to 5 years, we expect to continue to grow ZYNLONTA sales, advance the pipeline, broaden our scope with new partnerships and move towards profitability.

在接下來的 3 到 5 年裡，我們預計 ZYNLONTA 的銷售額將繼續增長，推進產品線，通過新的合作夥伴擴大我們的範圍並實現盈利。

With that, I would like to turn the call over to Kristen for a commercial update. Kristen?

有了這個，我想把電話轉給克里斯汀進行商業更新。克里斯汀？

Thanks, Ameet. It is my pleasure to share an update on the ZYNLONTA launch. As Ameet mentioned, we are seeing strong underlying demand trends which have accelerated in the past 2 quarters. I'm excited by the opportunities we have to build on this momentum, and I want to spend a few minutes outlining how we refined our strategy and initiatives to deliver ZYNLONTA's full potential.

謝謝，阿米特。我很高興分享 ZYNLONTA 發布的最新消息。正如 Ameet 所提到的，我們看到過去兩個季度加速的強勁潛在需求趨勢。我很高興我們有機會在這種勢頭的基礎上再接再厲，我想花幾分鐘概述一下我們如何完善我們的戰略和舉措以發揮 ZYNLONTA 的全部潛力。

It all begins with understanding the product, the market and the various stakeholders. My focus during my first few months has been on listening and learning from the team and key thought leaders. Following the deep dive, it's clear that the key to delivering our growth aspirations for ZYNLONTA in the near term will be in the quality of our execution and in particular, in doing a few things really well.

這一切都始於了解產品、市場和各種利益相關者。在我的頭幾個月裡，我的重點是傾聽團隊和主要思想領袖的意見並向他們學習。在深入探討之後，很明顯，在短期內實現我們對 ZYNLONTA 的增長願望的關鍵在於我們的執行質量，特別是在做一些真正好的事情上。

We are focusing our cross-functional team on 3 key imperatives: One, driving awareness of ZYNLONTA's differentiated profile; two, educating physicians to optimize the patient benefit; and three, continuing to build advocacy with key thought leaders, focusing on clear patient types. Through executing on these 3 aspects of our strategy, I believe we will capture the opportunity for growth in the third line, third line-plus setting, both in the near term and over the longer term, recognizing that this is a marathon and not a sprint.

我們將跨職能團隊的重點放在 3 個關鍵任務上：一是提高 ZYNLONTA 差異化形象的知名度；二、教育醫生優化患者利益；第三，繼續與主要思想領袖建立宣傳，重點關註明確的患者類型。通過執行我們戰略的這三個方面，我相信我們將在短期和長期內抓住三線、三線以上環境的增長機會，認識到這是一場馬拉松，而不是一場短跑。

Let me now spend a moment explaining on each of these 3 elements of our strategy. Starting with driving awareness. ZYNLONTA has a uniquely differentiated product profile, which we believe positions us to become the standard of care in the third line, third line-plus setting. First, it has strong single-agent activity. It's associated with a rapid time to response with a median of just 41 days. It has a manageable safety profile with no cytokine release syndrome and a low incidence of neuropathy. Lastly, it has a relatively patient-friendly administration schedule, requiring a 30-minute infusion cycle once every 3 weeks.

現在讓我花點時間解釋一下我們戰略的這三個要素。從駕駛意識開始。 ZYNLONTA 具有獨特的差異化產品概況，我們相信這使我們能夠成為三線、三線以上環境中的護理標準。首先，它具有很強的單劑活性。它與快速響應相關聯，中值僅為 41 天。它具有可控的安全性，沒有細胞因子釋放綜合徵，神經病變的發生率很低。最後，它有一個相對患者友好的給藥時間表，每 3 週需要一次 30 分鐘的輸注週期。

The second strategic initiative is to educate physicians and nurses on the proper dosing to achieve the best clinical outcome for patients and the manageable safety profile of ZYNLONTA, what to expect and how to mitigate potential adverse events. We believe ZYNLONTA's safety profile is favorable in the third line, third line-plus setting, and we need to keep reinforcing this important message.

第二個戰略舉措是教育醫生和護士正確給藥以實現患者的最佳臨床結果和 ZYNLONTA 可管理的安全性、預期結果以及如何減輕潛在的不良事件。我們認為 ZYNLONTA 的安全性在三線、三線以上環境中是有利的，我們需要繼續強調這一重要信息。

Lastly, we need to work closely with our thought leaders and for them to educate and share their ZYNLONTA experience with their peers in the community. The third line, third line-plus setting landscape is increasingly complex with the availability of new, innovative options. Now more than ever, the community is looking to the thought leaders to help identify the best options for post CAR-T patients and for those who don't get to CAR-T.

最後，我們需要與我們的思想領袖密切合作，讓他們與社區中的同行一起教育和分享他們的 ZYNLONTA 經驗。隨著新的創新選項的出現，第三線、第三線以上的環境變得越來越複雜。現在，社區比以往任何時候都更期待思想領袖幫助確定 CAR-T 後患者和未接受 CAR-T 患者的最佳選擇。

As a reminder, community centers account for roughly 60% of diffuse large B-cell lymphoma patient volume as compared to 40% in the academic centers, where ZYNLONTA is mainly prescribed today.

提醒一下，社區中心約佔瀰漫性大 B 細胞淋巴瘤患者數量的 60%，而學術中心的這一比例為 40%，ZYNLONTA 目前在這些中心主要開處方。

Taking a closer look at the academic versus community setting, we have already established a strong foundation in the academic setting. Here, around 80% of accounts have experience with ZYNLONTA. Our focus will be on driving utilization in the post CAR-T patients since approximately 60% of these patients will unfortunately relapse.

仔細看看學術環境與社區環境，我們已經在學術環境中建立了堅實的基礎。在這裡，大約 80% 的客戶有使用 ZYNLONTA 的經驗。我們的重點將是推動 CAR-T 後患者的利用率，因為這些患者中約有 60% 會不幸復發。

The bigger opportunity for us is in the community, where we have the potential to drive much greater breadth of experience. At the start of 2022, roughly 25% of community accounts had tried ZYNLONTA, and we grew that to almost 35% by the end of the year. Based on the differentiated profile I discussed earlier, we believe ZYNLONTA is ideal for the community, specifically for the large proportion of patients, more than 3/4, who are unable to get to CAR-T due to the complexity, toxicity or lack of assets.

對我們來說，更大的機會在社區中，我們有可能在社區中推動更廣泛的經驗。 2022 年初，大約 25% 的社區帳戶嘗試過 ZYNLONTA，到年底我們將這一比例增加到近 35%。基於我之前討論的差異化概況，我們認為 ZYNLONTA 是社區的理想選擇，特別是對於大部分患者（超過 3/4）由於復雜性、毒性或缺乏 CAR-T 而無法獲得 CAR-T資產。

Again, we want to reinforce that the community setting is our greatest opportunity to drive growth. We recognize adoption is lower as the market is highly fragmented, but we are making steady progress and are encouraged that once physicians are familiar with ZYNLONTA, they tend to continue to prescribe it. We have an opportunity to increase awareness of ZYNLONTA's differentiated profile, and the advantages it can bring to patients and physicians.

再次強調，社區環境是我們推動增長的最大機會。我們認識到，由於市場高度分散，採用率較低，但我們正在穩步取得進展，並且令人鼓舞的是，一旦醫生熟悉 ZYNLONTA，他們往往會繼續開處方。我們有機會提高人們對 ZYNLONTA 差異化形象及其可為患者和醫生帶來的優勢的認識。

We know from brand impact data that roughly 1 in 3 treaters has unaided awareness of ZYNLONTA, which lagged that of other key competitors in the market. We have seen a consistent improvement over the past year, but we can clearly do a lot more. By sharpening our execution, particularly our promotional efforts focusing on ZYNLONTA's unique profile, we are confident we can drive much higher levels of awareness so that ZYNLONTA becomes top of mind with community physicians.

我們從品牌影響力數據中得知，大約三分之一的治療者在沒有幫助的情況下就知道 ZYNLONTA，這落後於市場上其他主要競爭對手。在過去的一年裡，我們看到了持續的進步，但顯然我們可以做得更多。通過加強我們的執行力，特別是我們專注於 ZYNLONTA 獨特形象的促銷工作，我們相信我們可以提高認知度，使 ZYNLONTA 成為社區醫生的首選。

All our focused initiatives are critical to expanding adoption and utilization. And what is really important here is that when health care systems try ZYNLONTA, they continue to order it. In fact, at the end of 2022, we saw 84% place repeat orders.

我們所有的重點舉措對於擴大採用和利用至關重要。這裡真正重要的是，當醫療保健系統試用 ZYNLONTA 時，他們會繼續訂購它。事實上，到 2022 年底，我們看到 84% 的人重複下單。

To close, we are very encouraged by the recent trends in ZYNLONTA uptake and utilization. And we have fine-tuned our strategy to fully capture the opportunity for this important medicine in the third line, third line-plus setting.

最後，我們對 ZYNLONTA 吸收和利用的最新趨勢感到非常鼓舞。我們已經微調了我們的戰略，以充分抓住這種重要藥物在三線、三線以上環境中的機會。

Now I'll turn the call over to Mohamed to provide an update on our pipeline. Mohamed?

現在我將把電話轉給穆罕默德，以提供我們管道的最新情況。穆罕默德？

Thank you, Kristen. It is my pleasure to share an update on the pipeline.

謝謝你，克里斯汀。我很高興分享有關管道的更新。

First, I want to discuss the life cycle management program for ZYNLONTA. We see potential for the treatment to be a key player in select indications. As you see here, despite current treatment options and emerging therapies, distinct unmet need remains in all lines of therapy. Having spent my entire career in the hematology and oncology space, I appreciate what ZYNLONTA can do for patients. And at this point, I believe we have barely scratched the surface.

首先，我想討論一下 ZYNLONTA 的生命週期管理程序。我們認為該療法有可能在特定適應症中發揮關鍵作用。正如您在這裡看到的，儘管有當前的治療選擇和新興療法，但所有治療領域仍然存在明顯未滿足的需求。在血液學和腫瘤學領域度過了我的整個職業生涯，我很感激 ZYNLONTA 可以為患者做些什麼。在這一點上，我相信我們只是觸及了皮毛。

As Kristen described earlier, ZYNLONTA has already demonstrated a compelling and uniquely differentiated profile in the third line setting. And our strategy here is to maximize patient utilization. The larger opportunity, however, lies in earlier lines and in combinations. ZYNLONTA is the only approved CD19-directed treatment option outside of CAR-T to have demonstrated single agent activity in DLBCL and no known overlapping toxicities in combinations currently being studied. We believe ZYNLONTA has the potential to become the combination agent of choice and eventually a backbone therapy in all lines of DLBCL.

正如 Kristen 之前所描述的，ZYNLONTA 已經在三線環境中展示了引人注目且獨特的差異化特徵。我們的策略是最大限度地利用患者。然而，更大的機會在於更早的線路和組合。 ZYNLONTA 是 CAR-T 之外唯一獲批的 CD19 靶向治療方案，已證明在 DLBCL 中具有單藥活性，並且在目前正在研究的組合中沒有已知的重疊毒性。我們相信 ZYNLONTA 有潛力成為首選的組合藥物，並最終成為所有 DLBCL 系列的骨幹療法。

When we think about the second-line DLBCL setting, the current treatment includes stem cell transplant, CAR-T targeted therapies and chemo-based regimens. Going forward, we expect to see increasing use of CAR-Ts. But even with this, there will still be unmet medical need and opportunity for those who are not eligible or cannot access transplant or CAR-T.

當我們考慮二線 DLBCL 設置時，當前的治療包括幹細胞移植、CAR-T 靶向治療和基於化療的方案。展望未來，我們希望看到 CAR-T 的使用越來越多。但即便如此，對於那些不符合條件或無法獲得移植或 CAR-T 的人來說，仍然會有未滿足的醫療需求和機會。

Here, we are exploring the combination with rituximab in our ongoing LOTIS-5 study for second line-plus DLBCL patients not eligible for transplant. This combination could benefit patients even if they receive prior CAR-T or if they are not eligible for CAR-T. The LOTIS-5 safety run-in produced early encouraging efficacy data and the enrollment of approximately 350 patients is expected to be completed next year.

在這裡，我們正在我們正在進行的 LOTIS-5 研究中探索與利妥昔單抗的組合，該研究針對不符合移植條件的二線加 DLBCL 患者。即使他們之前接受過 CAR-T 或不符合 CAR-T 條件，這種組合也可以使患者受益。 LOTIS-5安全磨合產生了早期令人鼓舞的療效數據，預計明年將完成約350名患者的入組。

Another potential application for rituximab combination is in the frontline therapy where there is a great need among unfit or frail patients not able to tolerate full doses of R-CHOP. While approximately 85% of patients receive R-CHOP and the regimen is curative in about 60% of patients, this leaves a significant population that is unable to tolerate R-CHOP and has poor outcome. Physicians are looking for nonsystemic chemo-based regimen with better outcomes in this setting.

利妥昔單抗組合的另一個潛在應用是一線治療，在這種情況下，身體不適或身體虛弱且無法耐受全劑量 R-CHOP 的患者非常需要。雖然大約 85% 的患者接受了 R-CHOP，並且該方案對大約 60% 的患者有治愈作用，但這留下了大量無法耐受 R-CHOP 且結果不佳的人群。醫生正在尋找在這種情況下效果更好的非全身性化療方案。

Based on this unmet need and the derisked profile of ZYNLONTA, we are conducting the Phase II LOTIS-9 study. This is an open-label study in the unfit and frail patients with results expected next year. We believe the potential benefit is supported by encouraging data from LOTIS-2. The data shows ZYNLONTA had a similar overall response in patients over and under 75 years of age with no notable safety issues in the older patients. In addition, data from safety run-in portion of LOTIS-5 further supports the use of this nonsystemic chemo combination and increases the likelihood of success.

基於這一未滿足的需求和 ZYNLONTA 的風險概況，我們正在進行第二階段 LOTIS-9研究。這是一項針對不健康和虛弱患者的開放標籤研究，預計將於明年取得結果。我們相信來自 LOTIS-2 的令人鼓舞的數據支持了潛在的好處。數據顯示 ZYNLONTA 在 75 歲以上和 75 歲以下患者中的總體反應相似，老年患者沒有明顯的安全問題。此外，來自 LOTIS-5 安全磨合部分的數據進一步支持使用這種非全身化療組合併增加成功的可能性。

Beyond the combination with rituximab, we are exploring novel combinations. We are particularly excited about the possibility of combining ZYNLONTA with bispecifics with their distinct mechanism of action and toxicity profile. In the LOTIS-7, we are evaluating the combination with Roche's glofitamab and mosunetuzumab as well as polatuzumab. We expect to have early data from these studies next year. We also have a collaboration with IGM to combine with its bispecific, imvotamab.

除了與利妥昔單抗的組合，我們還在探索新的組合。我們對將 ZYNLONTA 與具有獨特作用機制和毒性特徵的雙特異性藥物相結合的可能性感到特別興奮。在 LOTIS-7 中，我們正在評估與羅氏的 glofitamab 和 mosunetuzumab 以及 polatuzumab 的組合。我們預計明年將獲得這些研究的早期數據。我們還與 IGM 合作，結合其雙特異性 imvotamab。

Beyond our own clinical studies, we are encouraged to see substantial interest from investigators to explore ZYNLONTA in different combinations, including bispecific in different treatment setting and in other indications. We are closely following those studies to further understand ZYNLONTA's potential. Investigators are keen to see whether ZYNLONTA's stronger profile in the challenging DLBCL indication could potentially translate into other areas of CD19 disease biology, such as CLL, follicular lymphoma and mantle cell lymphoma.

除了我們自己的臨床研究之外，我們很高興看到研究人員對探索 ZYNLONTA 不同組合的濃厚興趣，包括在不同治療環境和其他適應症中的雙特異性。我們正在密切關注這些研究，以進一步了解 ZYNLONTA 的潛力。研究人員熱衷於了解 ZYNLONTA 在具有挑戰性的 DLBCL 適應症中的更強表現是否有可能轉化為 CD19疾病生物學的其他領域，例如 CLL、濾泡性淋巴瘤和套細胞淋巴瘤。

On my final slide, I would like to discuss our robust pipeline beyond ZYNLONTA, starting with our company sponsored program, ADCT-901 targeting KAAG1 is a novel first-in-class that target various solid tumors. The Phase I dose escalation is proceeding and we have not yet reached the maximum titrated dose. We have decided to amend the protocol to explore different dosing schedule to optimize the potential clinical outcomes for patients and to prepare for regulatory interactions as part of Project Optimus. We now expect to share preliminary data in the first half of 2024.

在我的最後一張幻燈片上，我想討論我們在 ZYNLONTA 之外的強大管道，從我們公司贊助的項目開始，針對 KAAG1 的 ADCT-901 是一種針對各種實體瘤的新型一流藥物。 I 期劑量遞增正在進行中，我們尚未達到最大滴定劑量。我們已決定修改協議，探索不同的給藥方案，以優化患者的潛在臨床結果，並為作為 Project Optimus 一部分的監管互動做好準備。我們現在預計將在 2024 年上半年分享初步數據。

Now looking at ADCT-601 targeting AXL. AXL is a validated target over expressed in many solid tumors, including sarcoma and non-small cell lung cancer. The Phase I study to optimize the combination with gemcitabine and to explore single agent activity is progressing. In parallel, a IHC assay for possible biomarker approach is being finalized. Preliminary data from the Phase I dose escalation and expansion study are expected in the first half of 2024.

現在查看針對 AXL 的 ADCT-601。 AXL 是一種經過驗證的靶標，在許多實體瘤中過度表達，包括肉瘤和非小細胞肺癌。優化與吉西他濱聯合用藥和探索單一藥物活性的 I 期研究正在進行中。與此同時，針對可能的生物標誌物方法的 IHC 檢測正在完成。 I 期劑量遞增和擴展研究的初步數據預計將於 2024 年上半年獲得。

ADCT-212 is next-generation PBD-based ADC targeting PSMA, a validated target over-expressed in the majority of metastatic castrate-resistant prostate cancers. We expect to initiate the Phase I study in the first half of 2024.

ADCT-212是下一代基於 PBD 的 ADC，靶向 PSMA，這是一種在大多數轉移性去勢抵抗性前列腺癌中過度表達的經過驗證的靶標。我們預計在 2024 年上半年啟動 I 期研究。

Now for our programs in collaboration. ADCT-602 targets CD22. MD Anderson Cancer Center presented some encouraging signs of activity from the Phase I study at ASH in a small number of acute lymphoblastic leukemia patients. The Phase I dose expansion study is expected to complete in the first half of 2024.

現在開始我們的合作項目。 ADCT-602 靶向 CD22。 MD 安德森癌症中心在 ASH 的 I 期研究中對少數急性淋巴細胞白血病患者進行了一些令人鼓舞的活動跡象。 I 期劑量擴展研究預計將於 2024 年上半年完成。

And finally, ADCT-701, targeting DLK-1, in collaboration with NCI in neuroendocrine malignancies. We expect the Phase I study to be initiated in the second half of the year.

最後，針對 DLK-1 的 ADCT-701 與 NCI 合作治療神經內分泌惡性腫瘤。我們預計 I 期研究將在今年下半年啟動。

I am really excited about the robust pipeline we have developed with multiple catalysts over the next 12 to 18 months. This is one of the reasons I came to the company. I look forward to reporting on the evolving news flow from our pipeline over the coming months.

我對我們在未來 12 到 18 個月內使用多種催化劑開發的強大管道感到非常興奮。這也是我來公司的原因之一。我期待著在未來幾個月內報導我們管道中不斷變化的新聞流。

With that, I will turn the call over to Pepe to give a financial update. Pepe?

有了這個，我會把電話轉給佩佩來提供財務更新。佩佩？

Thank you, Mohamed. Starting with our balance sheet. As of 31st of December, we had cash and cash equivalent of $326 million, representing a $55 million reduction from our position at the end of the third quarter. Subsequent to the year-end, we received a $50 million milestone from Sobi due to European approval of ZYNLONTA. And we also expect to receive a $75 million milestone from HealthCare Royalty Partners on first commercial sales in Europe expected in the second quarter of the year.

謝謝你，穆罕默德。從我們的資產負債表開始。截至 12 月 31 日，我們的現金和現金等價物為 3.26 億美元，比我們在第三季度末的頭寸減少了 5500 萬美元。年底之後，由於歐洲批准 ZYNLONTA，我們從 Sobi 獲得了 5000 萬美元的里程碑。我們還預計將在今年第二季度獲得來自 HealthCare Royalty Partners 的 7500 萬美元里程碑式的歐洲首次商業銷售。

As Ameet noted, based on our business plan, the milestone payment I mentioned and further productivity initiatives underway, we expect that our cash runway now extends into mid-2025.

正如 Ameet 指出的那樣，根據我們的業務計劃、我提到的里程碑付款以及正在進行的進一步生產力舉措，我們預計我們的現金跑道現在會延伸到 2025 年年中。

Turning to the P&L. ZYNLONTA net sales were $19.8 million in the fourth quarter, up 16.5% versus Q4 of 2021, while full year net sales more than doubled to $74.9 million with the first full year of sales compared to $34 million in a partial year in 2021. License revenues amounted to $50 million in the fourth quarter, which reflected the milestone from Sobi. For the full year, license revenue of $135 million also included $85 million in upfront payments from our partners, Sobi and Mitsubishi Tanabe.

轉向損益表。 ZYNLONTA 第四季度淨銷售額為 1980 萬美元，比 2021 年第四季度增長 16.5%，而全年淨銷售額增長了一倍以上，達到 7490 萬美元，而 2021 年的部分年份為 3400 萬美元。第四季度達到 5000 萬美元，這反映了 Sobi 的里程碑。全年，1.35 億美元的許可收入還包括來自我們的合作夥伴 Sobi 和 Mitsubishi Tanabe 的 8500 萬美元預付款。

Cost of product sales amounted to $0.5 million in the fourth quarter and $4.6 million for the full year. In addition to a full year of commercial activity, this expense line reflected impairment charges for product intermediates and antibodies that did not meet the company's specifications. Importantly, these specifications issues did not and are not expected to impact our ability to supply commercial products.

第四季度產品銷售成本為 50 萬美元，全年為 460 萬美元。除了全年的商業活動外，這條費用線還反映了不符合公司規格的產品中間體和抗體的減值費用。重要的是，這些規格問題不會也不應影響我們提供商業產品的能力。

Our largest expense line, of course, continues to be R&D where, as you heard today, we are committed to invest behind ZYNLONTA and our promising early-stage pipeline programs. R&D expenses was $48.7 million in the fourth quarter and $187.9 million for the full year. Sales and marketing expenses were $16.2 million in the fourth quarter and $69.1 million for the full year. This reflected a full year of professional expenses relating to the commercial launch of ZYNLONTA, partially offset by lower share-based compensation in the fourth quarter.

當然，我們最大的支出線仍然是研發，正如您今天所聽到的那樣，我們致力於投資 ZYNLONTA 和我們有前途的早期管道項目。第四季度的研發費用為 4870 萬美元，全年為 1.879 億美元。第四季度的銷售和營銷費用為 1620 萬美元，全年為 6910 萬美元。這反映了全年與 ZYNLONTA 商業發布相關的專業費用，部分被第四季度較低的基於股票的薪酬所抵消。

G&A expense was $15.1 million in the fourth quarter and $72 million for the full year. This reflected higher professional fees and costs associated with the C-suite transition partially offset by a lower share-based compensation in the fourth quarter.

第四季度的 G&A 費用為 1510 萬美元，全年為 7200 萬美元。這反映了與最高管理層過渡相關的更高的專業費用和成本，部分被第四季度較低的基於股份的薪酬所抵消。

Moving to the bottom of the P&L. On an adjusted basis, we reported a net loss of $7.9 million for the fourth quarter, at $0.10 per diluted share. For the full year, our adjusted net loss was $81.7 million or $1.05 per diluted share.

移動到損益表的底部。在調整後的基礎上，我們報告第四季度淨虧損 790 萬美元，攤薄後每股虧損 0.10 美元。全年，我們調整後的淨虧損為 8170 萬美元或每股攤薄虧損 1.05 美元。

Now turning to our guidance. Based on the market dynamics and the growth initiatives which Kristen highlighted, we expected to grow ZYNLONTA net product sales by double-digit percentage points year-over-year. This takes into account significant gross-to-net headwinds compared with 2022. Specifically, we expect a negative gross to net impact of approximately 2 to 3 percentage points from our GPO contracting, together with a negative impact of mid- to high single-digit percentage point to reflect the new Medicare Part B wastage policy regarding discarded unit that was implemented at the beginning of 2023.

現在轉向我們的指導。根據 Kristen 強調的市場動態和增長計劃，我們預計 ZYNLONTA 淨產品銷售額將同比增長兩位數的百分點。這考慮了與 2022 年相比的重大毛淨逆風。具體而言，我們預計我們的 GPO 合同將產生約 2 至 3 個百分點的負面影響，以及中高個位數的負面影響個百分點，以反映 2023 年初實施的關於廢棄設備的新 Medicare B 部分浪費政策。

In terms of total operating expenses, we expect a decrease in 2023 and 2024 as compared to 2022, reflecting prioritization and productivity efforts across all expense categories.

就總運營費用而言，我們預計 2023 年和 2024 年將比 2022 年有所減少，這反映了所有費用類別的優先級排序和生產力努力。

Finally, moving to the upcoming catalysts. We have a number of different value-driving catalysts over the next 12 to 18 months and well within our cash runway.

最後，轉向即將到來的催化劑。在接下來的 12 到 18 個月內，我們有許多不同的價值驅動催化劑，並且在我們的現金跑道內。

Starting with ZYNLONTA. This year, in addition to double-digit growth, we also expect to achieve a commercial brand profitability, meaning we will more than offset the total cost of commercialization, medical affairs and all related costs so that ZYNLONTA, by the end of the year, starts to pay for the development of new indications and the pipeline.

從 ZYNLONTA 開始。今年，除了兩位數的增長，我們還期望實現商業品牌盈利，這意味著我們將超過商業化、醫療事務和所有相關成本的總成本，以便 ZYNLONTA 到今年年底，開始支付新適應症和管道的開發費用。

Following European approval of ZYNLONTA, we expect our partner Sobi to launch in the second quarter of this year. In the second half of the year, we expect to initiate the Phase I study of ADCT-701 targeting DLK-1. Next year, we will complete the enrollment of our LOTIS-5 confirmatory study in the second-line setting. We will also share some preliminary results from our LOTIS-9 and LOTIS-7 studies next year.

在歐洲批准 ZYNLONTA 之後，我們預計我們的合作夥伴 Sobi 將在今年第二季度推出。下半年，我們有望啟動針對DLK-1的ADCT-701的I期研究。明年，我們將在二線環境中完成 LOTIS-5 驗證性研究的招募。明年，我們還將分享 LOTIS-9 和 LOTIS-7 研究的一些初步結果。

In terms of the pipeline, in the first half of 2024, we expect to share preliminary data from ADCT-901 targeting KAAG1 and ADCT-601, targeting AXL. We also expect to initiate the Phase I study of ADCT-212, targeting PSMA and for our partner, MD Anderson to complete the Phase I dose expansion study for ADCT-602 targeting CD22.

在管道方面，我們預計在 2024 年上半年共享來自 ADCT-901 的初步數據，目標是 KAAG1 和 ADCT-601，目標是 AXL。我們還希望啟動針對 PSMA 的 ADCT-212 的 I 期研究，並讓我們的合作夥伴 MD Anderson 完成針對 CD22 的 ADCT-602 的 I 期劑量擴展研究。

So a number of different milestones across the company, both with ZYNLONTA and our pipeline. And of course, we're continuing to advance our technology platform.

因此，整個公司都有許多不同的里程碑，包括 ZYNLONTA 和我們的管道。當然，我們會繼續推進我們的技術平台。

With that, I will turn the call back to Ameet for closing remarks. Ameet?

有了這個，我將把電話轉回 Ameet 以作結束語。見面？

Thank you, Kristen, Mohamed and Pepe. To conclude, we have a clear road map and the capabilities to execute in 2023 and to build ADC Therapeutics for years to come. We are uniquely positioned in the growing ADC space with specialized capabilities from discovery through to commercialization and have over a decade of experience.

謝謝克里斯汀、穆罕默德和佩佩。總而言之，我們有一個清晰的路線圖和在 2023 年執行並在未來幾年構建 ADC Therapeutics 的能力。我們在不斷發展的 ADC 領域處於獨特的地位，擁有從發現到商業化的專業能力，並且擁有十多年的經驗。

We have a validated technology platform, a rich pipeline of hematological and solid tumor programs and an innovative toolbox to develop next-generation assets with novel antibody constructs and payloads. And last but not least, we have a strengthened and highly talented team in place to execute on our strategies. We look forward to keep updated on our ongoing progress.

我們擁有經過驗證的技術平台、豐富的血液學和實體瘤項目管道以及用於開發具有新型抗體結構和有效載荷的下一代資產的創新工具箱。最後但同樣重要的是，我們擁有一支實力強大且才華橫溢的團隊來執行我們的戰略。我們期待隨時了解我們正在進行的進展。

Now the team will be available for questions. Operator?

現在團隊可以回答問題。操作員？

(Operator Instructions) Kelly Shi with Jefferies is online with a question.

（操作員說明）Jefferies 的 Kelly Shi 在線提問。

The first is regarding the OpEx. Can you share more details on the OpEx reduction in 2023? And where do you plan to cut the cost from? And how should we think about the magnitude of the planned cost reduction? And I have a follow-up.

首先是關於運營支出。您能否分享有關 2023 年運營支出減少的更多詳細信息？您打算從哪裡削減成本？我們應該如何考慮計劃成本削減的幅度？我有一個後續行動。

Kelly, thanks for the question. So we expect to reduce costs compared to 2022 for both years 2023 and 2024.

凱利，謝謝你的提問。因此，我們預計與 2022 年相比，2023 年和 2024 年的成本都會降低。

On the R&D line, you should expect a reduction because we are focusing our resources in the most impactful and higher return on investment projects that we have in the pipeline. As you know, we have discontinued several projects that we consider less attractive. Some of them might end up being potentially partner like coming.

在研發方面，您應該預計會有所減少，因為我們正在將資源集中在我們正在進行的最具影響力和更高投資回報的項目上。如您所知，我們已經停止了幾個我們認為不太有吸引力的項目。他們中的一些人可能最終會像未來一樣成為潛在的合作夥伴。

And on the SG&A side, we are driving productivity. We have an entire new team that have looked at the company cost structure with fresh eyes. So we believe there's significant opportunity to reduce costs year-over-year.

在 SG&A 方面，我們正在提高生產力。我們有一個全新的團隊，他們以全新的眼光審視了公司的成本結構。因此，我們相信有很大的機會可以逐年降低成本。

The second question, I couldn't hear you. [You have tagged on] something else.

第二個問題，我聽不見。 [你已經標記了]其他東西。

Yes. I also have a question regarding the ADCT-601 program targeting AXL. Do you plan to screen patients with positive AXL expression level for the dose escalation phase for also a sarcoma and non-small cell lung cancer cohorts or this is only applied to other tumor indications?

是的。我還有一個關於針對 AXL 的 ADCT-601 程序的問題。您是否計劃在肉瘤和非小細胞肺癌隊列的劑量遞增階段篩選具有陽性 AXL 表達水平的患者，或者這僅適用於其他腫瘤適應症？

And also, what is the rationale for the combo arm with gemcitabine in sarcoma? And also, what information do we have regarding 601 safety profile at the moment?

而且，在肉瘤中使用吉西他濱組合臂的基本原理是什麼？而且，目前我們有哪些關於 601 安全概況的信息？

Thanks for the question. And we do or are planning to collect biopsies for all patients currently enrolled in the study in order for us to possibly test retrospectively for AXL expression. The current protocol right now does not select patients, and the assay is being developed in parallel. As I mentioned, when it is ready, we'll be able to test patients for expression.

謝謝你的問題。我們正在或正在計劃為目前參與研究的所有患者收集活組織檢查，以便我們可能回顧性地測試 AXL 表達。當前的協議目前不選擇患者，並且正在並行開發該檢測方法。正如我提到的，當它準備就緒時，我們將能夠測試患者的表達。

In terms of the combination with gemcitabine. Gemcitabine is very active and considered one of the standard of care used in sarcoma. So it's naturally to combine as an add-on strategy in the combination and see that we have improved standard of care for hopeful future studies, from a regulatory perspective to be able to isolate the effect of the drug.

在與吉西他濱的組合方面。吉西他濱非常活躍，被認為是用於肉瘤的標準治療之一。因此，很自然地將其作為一種附加策略結合起來，從監管的角度來看，我們已經提高了有希望的未來研究的護理標準，從而能夠隔離藥物的作用。

So what was the third question, sorry?

那麼第三個問題是什麼，抱歉？

The safety profile of 601.

601的安全概況。

The safety profile? We are currently going into the escalation phase of the protocol. And so far, we have not reached the maximum titrated dose.

安全概況？我們目前正進入協議的升級階段。到目前為止，我們還沒有達到最大滴定劑量。

Our next question comes from Gregory Renza with RBC Capital Markets.

我們的下一個問題來自 RBC Capital Markets 的 Gregory Renza。

This is Sudan Loganathan on for Gregory Renza. Congrats on the great quarter with ZYNLONTA and great year going forward.

這是 Gregory Renza 的 Sudan Loganathan。祝賀 ZYNLONTA 的偉大季度和偉大的一年。

Specifically, I wanted to ask on how the competitive landscape may potentially change as you go forward with LOTIS-5, LOTIS-7, LOTIS-9 programs, and look for label expansion in the earlier lines of DLBCL therapy? Are there kind of developments occurring kind of tandem at this point that may change how a comparator arm is looked at or what standard of care may be that should be a comparator arm for the ZYNLONTA trials?

具體來說，我想問一下，隨著 LOTIS-5、LOTIS-7、LOTIS-9 項目的推進，以及在 DLBCL 治療的早期系列中尋找標籤擴展，競爭格局可能會發生怎樣的潛在變化？在這一點上是否有某種串聯的發展可能會改變對比較臂的看待方式，或者 ZYNLONTA 試驗的比較臂應該採用什麼樣的護理標準？

And then are these things developments that could occur in the 1- to 5-year time frame? And just wanted to get your take on how that's going to play out in the years to come.

那麼這些事情的發展是否會在 1 到 5 年的時間範圍內發生？只是想了解您對未來幾年將如何發揮作用的看法。

Yes. So I think I'll start and then Mohamed and Kristen can feel free to add on to it.

是的。所以我想我會開始，然後 Mohamed 和 Kristen 可以隨意添加。

As you said, the DLBCL market is quite dynamic, and there has been a lot of change. I mean, for example, CAR-Ts are moving pretty clearly, particularly the academic institutions from third to second line setting. That's, I would say, in the academic setting, shrinking some of the population that's not either going to get a CAR-T or a transplant.

正如您所說，DLBCL 市場充滿活力，發生了很多變化。我的意思是，例如，CAR-T 正在非常明顯地發展，尤其是學術機構從三線設置到二線設置。也就是說，我會說，在學術環境中，減少一些既不會接受 CAR-T 也不會接受移植的人口。

Now of course, in the community, CAR-T use is much more limited. And so there still remains quite a sizable nontransplant non-CAR-T population in the second line population.

當然，現在在社區中，CAR-T 的使用更加有限。因此，二線人群中仍然存在相當大的非移植非 CAR-T 人群。

In terms of the comparator arm, which is R-GemOx, we don't anticipate any change. I mean, that's been discussed obviously with the FDA from a regulatory standpoint. And we feel like we still have the right comparator arm, the right study design to move towards approval on a broader label in that second-line setting.

就比較臂 R-GemOx 而言，我們預計不會有任何變化。我的意思是，從監管的角度來看，這顯然已經與 FDA 進行了討論。我們覺得我們仍然擁有正確的比較臂，正確的研究設計，可以在二線環境中獲得更廣泛標籤的批准。

With the front line setting, there is also a lot of competitive dynamics going on. As you know, 85% of patients can tolerate full dose of R-CHOP. And R-CHOP has very good outcomes. I mean, 60% of patients are going to get cured. So it really is the standard of care.

隨著前線設置，也有很多競爭動態。如您所知，85% 的患者可以耐受全劑量的 R-CHOP。而且R-CHOP的效果非常好。我的意思是，60% 的患者會得到治愈。所以這確實是護理標準。

And when you look at a lot of trials, whether it be with Polivy or the bispecifics, many of them are trying to augment R-CHOP, and to try to deliver even better outcomes for those 85% of patients who can target R-CHOP. But for the 15% of patients who are frail and unfit, these are patients 80 years and above with or without comorbidities. These patients oftentimes can't tolerate full doses of R-CHOP and are getting mini R-CHOP or other chemotherapy regimens, and their options are much poor.

當您查看大量試驗時，無論是使用 Polivy 還是雙特異性抗體，其中許多試驗都在嘗試增強 R-CHOP，並試圖為那些可以靶向 R-CHOP 的 85% 的患者提供更好的結果.但對於 15% 的虛弱和不健康的患者，這些患者是 80 歲及以上的患者，有或沒有合併症。這些患者通常不能耐受全劑量的 R-CHOP，而正在接受迷你 R-CHOP 或其他化療方案，他們的選擇非常少。

This is where we're playing right now with ZYNLONTA plus rituximab with our LOTIS-9 study. And in this population, it's a single-arm study. So it's not really a comparator at this point. If we were to move forward, obviously, the comparator for this is really mini R-CHOP, and that hasn't changed.

這就是我們現在在 LOTIS-9 研究中使用 ZYNLONTA 加利妥昔單抗的地方。在這個人群中，這是一項單臂研究。所以在這一點上它並不是真正的比較器。如果我們繼續前進，顯然，這個比較器實際上是迷你 R-CHOP，而且沒有改變。

So we don't think the competitive landscape is going to alter what our current development plans are. I think the big thing could be the introduction of bispecific where they have the chance to start to, over time, potentially change the treatment landscape across all lines of therapy.

所以我們認為競爭格局不會改變我們目前的發展計劃。我認為最重要的可能是雙特異性的引入，隨著時間的推移，他們有機會開始潛在地改變所有治療線的治療前景。

And we think we're actually well positioned to partner with bispecifics. As the only targeted CD19 therapy with single-agent efficacy and manageable side effect profile, and we believe has the potential even to be not overlapping, of course, has to be tested, we are uniquely positioned to combine across different bispecifics, and we're doing that in our LOTIS-7 study as well as in partnership with IGM with their imvotamab compound.

我們認為我們實際上已經做好了與雙特異性藥物合作的準備。作為唯一具有單藥療效和可控副作用的靶向 CD19 療法，我們相信甚至有可能不重疊，當然，必須進行測試，我們具有獨特的優勢，可以結合不同的雙特異性抗體，而且我們'在我們的 LOTIS-7 研究中以及與 IGM 合作使用他們的 imvotamab 化合物時，我們正在這樣做。

So we think we actually have a chance to combine and actually ride with one of the biggest competitive changes that I think will affect DLBCL over the coming years.

因此，我們認為我們實際上有機會結合併實際應對我認為將在未來幾年影響 DLBCL 的最大競爭變化之一。

Our next question comes from Matthew Harrison with Morgan Stanley.

我們的下一個問題來自摩根士丹利的馬修哈里森。

Our next question comes from Naureen Quibria with Capital One Securities.

我們的下一個問題來自第一資本證券公司的 Naureen Quibria。

Congrats on the progress. So first one, I guess it's very basic. Are you able to comment on ZYNLONTA's market share now in the third line, third line-plus DLBCL? And what fraction have you penetrated to date? And how do you see that penetration with respect to, obviously, Polivy moving to the front line?

祝賀進步。所以第一個，我想這是非常基本的。您能否評論 ZYNLONTA 現在在三線、三線加 DLBCL 中的市場份額？到目前為止，您已經滲透了多少？您如何看待 Polivy 移動到前線的這種滲透？

Yes. I can just say we still believe that there's a lot of potential, but I'm going to let Kristen comment further on some of the details.

是的。我只能說我們仍然相信有很大的潛力，但我會讓 Kristen 進一步評論一些細節。

Sure. So I've worked in the DLBCL space for years now, and there really is no good source of data for market share, especially in the later lines. It's just a very dynamic and fragmented space.

當然。所以我在 DLBCL 領域工作了很多年，確實沒有很好的市場份額數據來源，尤其是在後期。這只是一個非常動態和碎片化的空間。

However, when we look at our research and we use Brand Impact data. What we're seeing is that we're leading a new patient share in the third-line setting, and we are really encouraged by this and confident in our potential to continue to further to penetrate the third line space and become the standard of care here.

然而，當我們查看我們的研究時，我們會使用品牌影響力數據。我們所看到的是，我們在三線環境中引領了新的患者份額，我們對此感到非常鼓舞，並對我們繼續深入滲透三線空間並成為護理標準的潛力充滿信心這裡。

When you also talk about market penetration, one of the things that I shared upfront was that where we see our greatest opportunity is in the community setting, where only 35% of community sites have tried ZYNLONTA. The good news is we know that when they try it, they continue to repeat orders. So that is our greatest opportunity to continue to grow that share in the third-line setting.

當你還談到市場滲透時，我預先分享的一件事是，我們認為我們最大的機會是在社區環境中，只有 35% 的社區網站嘗試過 ZYNLONTA。好消息是我們知道，當他們嘗試時，他們會繼續重複訂單。因此，這是我們在三線環境中繼續擴大份額的最大機會。

Okay. Great. That's helpful. So 2 more. I guess the next 1 is probably for Pepe. Are you able to provide a bit more color on the Sobi launch, like which countries might be targeted first? And if you might be able to give any guidance for that trajectory?

好的。偉大的。這很有幫助。所以還有2個。我想下一個可能是給佩佩的。您能否在 Sobi 發佈時提供更多顏色，例如哪些國家可能首先成為目標？如果您能為該軌跡提供任何指導？

We haven't provided much of a guidance there, but what we can tell you is that because it's approved with a single agent and with a single arm, it's -- the market access process is going to take longer to have approvals throughout Europe. So it's going to be a gradual growth.

我們在那裡沒有提供太多指導，但我們可以告訴你的是，因為它是通過單一代理和單一手臂獲得批准的，所以市場准入過程將需要更長的時間才能在整個歐洲獲得批准。所以這將是一個漸進的增長。

I'm going to see if Ameet want to add something.

我要看看 Ameet 是否要添加一些內容。

Yes. No, as you know, Naureen, I mean, market access is country by country in Europe, and it could take up to 12 months. And as Pepe said, given that it's approved with a single-arm study, it's going to result in very favorable reimbursement in some countries and more challenging reimbursement in other countries.

是的。不，正如你所知，Naureen，我的意思是，市場准入在歐洲因國家/地區而異，可能需要長達 12 個月的時間。正如 Pepe 所說，鑑於它通過單臂研究獲得批准，它將在一些國家產生非常有利的報銷，而在其他國家產生更具挑戰性的報銷。

So I see the launch in Europe as kind of Phase I with this current study. LOTIS-5, when we have a comparative study will open up the full opportunity in Europe. But if you think more longer term about the European opportunity, I think the volume potential in Europe may be even greater than it is in the U.S. because CAR-T penetration is much less.

因此，我認為在歐洲的推出是目前這項研究的第一階段。 LOTIS-5，當我們進行比較研究時，將在歐洲打開充分的機會。但如果你從更長遠的角度考慮歐洲的機會，我認為歐洲的銷量潛力可能比美國更大，因為 CAR-T 的滲透率要低得多。

Okay. That's very helpful. And if I could just squeeze one more in for Mohamed. With respect to the KAAG1, 901, can you talk a bit more about the amendment to the protocol and the different dosing schedules? What's the rationale behind that decision? And given that sort of shift, how many patients should we expect with -- in the upcoming update that will come up -- dose levels?

好的。這很有幫助。如果我能為穆罕默德再擠一個。關於 KAAG1、901，您能多談談方案的修訂和不同的給藥方案嗎？該決定背後的理由是什麼？考慮到這種轉變，我們應該預期有多少患者——在即將到來的更新中——劑量水平？

Yes. Thank you for the question. Actually, as you know, I came to the company almost 8 weeks ago with a fresh perspective. And looking at the KAAG1 as a novel agent, actually. So we also have quite an experience with discussion with the agency about Project Optimus, which technically agencies are exploring multiple doses and schedules.

是的。感謝你的提問。實際上，如你所知，我大約 8 週前帶著全新的視角來到公司。實際上，將 KAAG1 視為一種新型代理。因此，我們也有與該機構討論 Project Optimus 的豐富經驗，從技術上講，該機構正在探索多種劑量和時間表。

So we took a decision to pause installations and amend the protocol to explore different dosing schedules to maximize the experience for patients and patient utilization to prepare for possible future meeting with the regulators and also to prepare for the most convenient dose ready for the pivotal study.

因此，我們決定暫停安裝並修改協議，以探索不同的給藥方案，以最大限度地提高患者的體驗和患者的利用率，為未來可能與監管機構的會議做準備，並為關鍵研究準備最方便的劑量。

So as you know also, Project Optimus guideline just got published in January 2023, so many companies around the world right now are preparing and adjusting the protocol to accommodate for the requirements -- the new requirements, as I say, for regulators to come to them with multiple doses with a number of patients in each dose in each indication. So I hope that explains your question.

所以你們也知道，Project Optimus 指南剛剛於 2023 年 1 月發布，世界各地的許多公司現在都在準備和調整協議以適應要求——正如我所說的，監管機構即將提出的新要求他們在每個適應症的每個劑量中使用多個劑量進行多次給藥。所以我希望這能解釋你的問題。

Yes, it does.

是的，它確實。

Yes, I think, Naureen, we expect that dose escalation is going to be probably in general, I like their process because you're going to have to -- dose-escalation expansion, you're going to have to expand at multiple doses.

是的，我認為，Naureen，我們預計劑量遞增可能是普遍的，我喜歡他們的過程，因為你將不得不——劑量遞增擴展，你將不得不擴展多劑量.

Our next question comes from Matthew Harrison with Morgan Stanley.

我們的下一個問題來自摩根士丹利的馬修哈里森。

This is [Chris] on for Matthew. I know someone earlier asked about the potential impact of kind of new treatment paradigms entering the market, specifically for bispecifics. Can you help us think about kind of the near-term impact of that entering the market as they penetrate the 3L plus DLBCL market?

這是 [Chris] 為 Matthew 做的。我知道有人早些時候問過進入市場的新治療範式的潛在影響，特別是雙特異性抗體。您能否幫助我們考慮一下進入 3L 加 DLBCL 市場時進入市場的近期影響？

Sure. So we expect bispecifics to play a role in the third-line setting upon approval. We do think that uptake in the community will take longer. In general, the community is slower to adopt new therapies. And given the risk of CRS and ICANS with bispecifics, we think initial uptake will be limited to the academic centers.

當然。因此，我們希望雙特異性藥物在獲得批准後能夠在三線環境中發揮作用。我們確實認為社區的採用需要更長的時間。一般來說，社區採用新療法的速度較慢。考慮到具有雙特異性的 CRS 和 ICANS 的風險，我們認為最初的採用將僅限於學術中心。

When it comes to competing in that space in the academic centers, we've been competing with bispecifics for years now in that setting, given the multiple bispecifics that are being studied in clinical trials.

當談到在學術中心的那個領域競爭時，考慮到臨床試驗中正在研究的多種雙特異性藥物，我們多年來一直在那種環境下與雙特異性藥物競爭。

I would just add that the penetration of any agent in the third-line setting is still relatively low. So there's clearly room for bispecifics to penetrate, particularly in academic setting, and for us to continue to grow in both the academic and the community setting.

我補充一點，任何代理在三線設置的滲透率還是比較低的。因此，雙特異性藥物顯然有滲透的空間，特別是在學術環境中，並且我們可以在學術和社區環境中繼續發展。

Our next question comes from Boris Peaker with Cowen.

我們的下一個問題來自 Boris Peaker 和 Cowen。

Great. This is [Nick] on for Boris. I just have a couple for ZYNLONTA and the LOTIS trials. For the LOTIS-5 trial, I know this is a confirmatory trial from the single arm, but can this be used for an sNDA or regulatory submission for 2L, DLBCL in both the U.S. and EU?

偉大的。這是鮑里斯的[尼克]。我只有幾個用於 ZYNLONTA 和 LOTIS 試驗。對於 LOTIS-5 試驗，我知道這是單臂的驗證性試驗，但這是否可用於美國和歐盟 2L、DLBCL 的 sNDA 或監管提交？

And then also second, for LOTIS-7, which lines of therapy are you guys looking at? And is that different based on which combination approaches or whatnot?

其次，對於 LOTIS-7，你們在看哪些治療方法？基於哪種組合方法或諸如此類的東西，這是否有所不同？

So regarding LOTIS-5, you're absolutely correct. It is a regulatory study for both U.S. and ex U.S. It is a confirmatory study with a potential also to get an sNDA for the second line-plus setting. Remember, ZYNLONTA right now in the third line-plus setting as a single agent. We are maximizing that and getting into the second line-plus agent with a substantial number of patients in that setting, and the plan is to go worldwide with that approval. I'm sorry, you want...

所以關於 LOTIS-5，你是絕對正確的。這是一項針對美國和前美國的監管研究。這是一項確認性研究，也有可能獲得用於二線加設置的 sNDA。請記住，ZYNLONTA 現在作為單一代理處於第三線加上設置。我們正在最大限度地提高這一點，並在該環境中與大量患者一起進入二線加代理，我們的計劃是在獲得批准後走向世界。對不起，你要...

And then LOTIS-7. Yes, for LOTIS-7.

然後是 LOTIS-7。是的，對於 LOTIS-7。

For LOTIS-7, we actually have multiple agents in combination, including polatuzumab, glofitamab and mosunetuzumab. We are trying to be the drug of choice in combination with or bispecific, not to mention also that we have a collaboration with IGM with their bispecific. So pretty much we're combining with all bispecifics to be a backbone, whoever any of them gets approved and become in the landscape, we'd be able to combine with.

對於 LOTIS-7，我們實際上有多種藥物組合，包括 polatuzumab、glofitamab 和 mosunetuzumab。我們正在努力成為聯合或雙特異性的首選藥物，更不用說我們與 IGM 的雙特異性合作。因此，我們幾乎將所有雙特異性結合起來成為骨幹力量，無論他們中的任何一個獲得批准並成為風景，我們都可以與之結合。

I hope that's answered your question.

我希望這已經回答了你的問題。

Yes. And in terms of lines of therapy, I mean, I think it will be an earlier lines of therapy. Particularly second line, I think there's an opportunity to really change the landscape. And particularly if the combination works in a way that has manageable side effect profile and leads to even better outcomes, deeper responses and more durable responses, you can imagine this starting to change and expand the opportunity for targeted therapy combinations in that second-line setting.

是的。就治療線而言，我的意思是，我認為這將是較早的治療線。特別是二線，我認為有機會真正改變格局。特別是如果組合以一種具有可控副作用的方式起作用並導致更好的結果、更深入的反應和更持久的反應，你可以想像這開始改變並擴大二線環境中靶向治療組合的機會.

(Operator Instructions) Our next question comes from Brian Cheng with JPMorgan.

（操作員說明）我們的下一個問題來自摩根大通的 Brian Cheng。

My first question is for Kristen. What was the split of academic versus community used in the last quarter for ZYNLONTA? And as you emphasized that community markets where you see a lot of growth, near term, how long do you think that it will take you to get more traction there? And how do you think about just the changes with bispecific coming in? And I have a follow-up.

我的第一個問題是給克里斯汀的。 ZYNLONTA 上個季度使用的學術與社區劃分是什麼？正如您強調的那樣，您在短期內看到大量增長的社區市場，您認為您需要多長時間才能在那裡獲得更大的吸引力？您如何看待雙特異性的變化？我有一個後續行動。

Okay. So in terms of the split of academic versus community use, it's roughly 50-50. We just started to see -- as we said, the penetration in the community is consistently growing. And we've just started to match the use from an academic perspective in terms of volume.

好的。因此，就學術用途與社區用途的劃分而言，大約是 50-50。我們剛剛開始看到——正如我們所說，社區的滲透率一直在增長。我們剛剛開始從學術角度在數量上匹配使用。

Your second question was how long to penetrate the community. They are -- what we see is community treaters are generally slower to adopt new therapies. For most new oncology launches, it probably takes about 4 to 5 years to really start to hit a peak market share.

你的第二個問題是滲透社區需要多長時間。他們是——我們看到的是社區治療師通常採用新療法的速度較慢。對於大多數新推出的腫瘤藥物，可能需要大約 4 到 5 年的時間才能真正開始達到市場份額的頂峰。

But what we do see for communities is community treaters is that because they're slower to adopt, it could take longer in that setting. But we will continue to chip away since we're at about 35%. Our goal is to really match what we're seeing in the academic setting.

但我們確實看到社區是社區處理者，因為他們採用速度較慢，所以在這種情況下可能需要更長的時間。但我們將繼續削減，因為我們的比例約為 35%。我們的目標是真正匹配我們在學術環境中看到的內容。

And I'd also add, Brian, that there's a long tail. So there's a lot of fragmentation in the community centers. A lot of community doctors are seeing a patient every few months. But they also tend to be a lot stickier. So behavior changes works both ways. It's takes longer to adopt, but what we see is the accounts that are adopting are repeating and sticking with the product.

我還要補充一點，布賴恩，有一條長長的尾巴。所以社區中心有很多碎片。許多社區醫生每隔幾個月就會去看一次病人。但它們也往往更粘。所以行為改變是雙向的。採用它需要更長的時間，但我們看到的是正在採用的帳戶正在重複並堅持使用該產品。

And so -- and we keep growing penetration month-over-month. So I think as that happens, this is a great opportunity, and that's a place where you had asked about bispecifics, and I'll let Kristen comment further. Bispecifics are going to have a much more challenging time, we believe, in the community initially just given the safety profile. In the academic setting, where we've penetrated about 80% of accounts, there's still room for death, we think, even with bispecifics.

因此——我們的滲透率逐月增長。所以我認為當這種情況發生時，這是一個很好的機會，這是你詢問雙特異性抗體的地方，我會讓克里斯汀進一步評論。我們相信，在社區中，雙特異性藥物將面臨更具挑戰性的時期，最初只是考慮到安全性。在學術環境中，我們已經滲透了大約 80% 的賬戶，我們認為，即使有雙特異性抗體，仍然存在死亡空間。

But I'll let Kristen comment further on the bispecific point.

但我會讓 Kristen 進一步評論雙特異性點。

Sure. I don't have much else to add to that, but just we see the safety profile of bispecifics being one where the initial uptake will be in the academic setting. CRS, ICANS, those are not adverse events that the community is generally accustomed to treating right now. That's why CAR-Ts are reserved for the academic setting. So we feel it will take time. And again, that is where we have our greatest opportunity right now to grow ZYNLONTA.

當然。我沒有太多要補充的，但我們只是看到雙特異性抗體的安全性是最初在學術環境中採用的一種。 CRS、ICANS，這些都不是社區現在通常習慣處理的不良事件。這就是為什麼 CAR-T 只用於學術環境。所以我們覺得這需要時間。再一次，這也是我們現在擁有發展 ZYNLONTA 的最大機會的地方。

Great. And then looking at your LOTIS-5 in second line in combo with [rituximab], do you have a sense of when we could see the data from that study? And can you remind us whether there is an interim analysis built into this trial?

偉大的。然後在二線查看您的 LOTIS-5 與 [利妥昔單抗] 的組合，您是否知道我們何時可以看到該研究的數據？您能否提醒我們該試驗是否內置了中期分析？

Thanks for the question. We expect enrollment of 350 patients to be completed next year. There will not be an interim analysis for the study, it's not built in the protocol. And we'll update when we get closer to the end of the study.

謝謝你的問題。我們預計明年將完成 350 名患者的入組。不會對研究進行中期分析，它不在協議中。當我們接近研究結束時，我們會更新。

Yes. And obviously, any time lines post the enrollment depends -- it's an event-driven study. So in some ways, the longer it closes, the better, but it also depends on events. Once we complete enrollment and the study starts reading out, we'll share information.

是的。顯然，註冊後的任何時間線都取決於——這是一項事件驅動的研究。所以在某些方面，它關閉的時間越長越好，但這也取決於事件。一旦我們完成註冊並且研究開始宣讀，我們將共享信息。

Thank you. We have no further questions at this time. I'd now like to turn it back to Ameet for closing remarks.

謝謝。目前我們沒有其他問題。我現在想把它轉回給 Ameet 作結束語。

Well, thank you all for joining so much the webcast, and thanks for all the thoughtful questions. We're really excited about our ability to unlock the value of this company by maximizing ZYNLONTA, by advancing our PBD-based pipeline and by expanding our ADC platform. We have multiple value-driving catalysts over the next 12 to 18 months, and we look forward to continuing to update you on our progress. Thank you so much for joining.

好吧，感謝大家參加如此多的網絡廣播，並感謝所有深思熟慮的問題。我們真的很高興能夠通過最大化 ZYNLONTA 、推進我們基於 PBD 的管道和擴展我們的 ADC 平台來釋放這家公司的價值。在接下來的 12 到 18 個月裡，我們有多種價值驅動催化劑，我們期待繼續向您通報我們的進展情況。非常感謝您的加入。

Thank you for your participation in today's conference. This concludes the program. You may now disconnect.

感謝您參加今天的會議。程序到此結束。您現在可以斷開連接。